inborn errors of metabolism_feb2011

“The central idea of early disease detection and treatment is

essentially simple. However the path to its successful achievement

(on the one hand, bringing to treatment those with previously

undetected disease and, on the other, avoiding harm to those

persons not in need of treatment) is far from simple though

sometimes it may appear deceptively easy.”

Wilson and Jungner, 1968, WHO

Box 1

SYMPOSIUM: INBORN ERRORS OF METABOLISM

Newborn screening forinborn errors of metabolism:principles, policies andweighing the evidenceJ V Leonard

C Dezateux

AbstractNewborn screening for metabolic disorders has become a contentious

issue. The aim of screening is to identify individuals at risk and start treat-

ment before they become ill. To this end newborn screening programmes

are well established in many countries and recent technological develop-

ments have lead to an expansion of these programmes. These require care-

ful evaluation, both of the process and the outcome. The original Wilson

and Jungner criteria for evaluation are still valid but, in this review, three

main points are particularly considered. The burden and the natural history

of the disease need to be defined. The test should predict accurately those

who would develop clinical disease but current screening programmes

detect many with ‘mild’ disease, the importance of which is often unclear.

This is particularly relevant when assessing any improvement in outcome

which should be seen in terms of the advantages and problems for both

the individual and the family.

Keywords genetic testing; healthcare evaluation mechanisms; health

policy; high-throughput screening assays; infant, newborn; mass

screening; metabolism, inborn errors; Neonatal screening; public health

practice; tandem mass spectrometry

Introduction

Newborn screening for inborn errors of metabolism is now well

established in developed countries worldwide. As noted byWilson

and Jungner in their 1968 WHO report on the Principles and

Practice of Screening for Disease (Box 1), screening seems both

intuitive and attractive: it aims to detect and manage serious

diseases in order to secure an outcome better than that which

might be achieved following clinical presentation or diagnosis.

The recognition that presymptomatic diagnosis and treatment

could profoundly alter the outcome for phenylketonuria (PKU)

drove Guthrie to develop a screening test based on dried blood

spots that was cheap and feasible for mass screening of newborn

infants. Screening for PKU was first introduced in the 1960s and

was followed, in the 1970s, by screening for congenital

J V Leonard PhD FRCP FRCPCH is Professor Emeritus at UCL Institute of Child

Health, 30 Guilford Street, London WC1 1EH, UK.

C Dezateux MD FMedSci is Professor of Paediatric Epidemiology and

Director of MRC Centre of Epidemiology for Child Health, London, UK.

PAEDIATRICS AND CHILD HEALTH 21:2 56

hypothyroidism. Newborn screening programmes for these two

disorders are now almost universal in high- and middle-income

countries throughout the world. While regarded as examples of

effective preventive medicine, almost half a century later expe-

rience with newborn screening for these conditions exemplifies

some of the difficulties in establishing that all those identified

and treated as a consequence of screening do in fact need treat-

ment, and the nature of the benefit conferred.

More recently there has been a marked expansion of newborn

screening programmes, driven by the development of technolo-

gies adaptable for high through-put analyses of biomarkers in

newborn dried blood spots, notably tandem mass spectrometry

(MS-MS). It is likely that future expansion will be driven by the

development of new treatments for rare disorders or by new

approaches to identify risk for or susceptibility to more complex

or chronic diseases, as much as by new technologies. Currently

parents of newborns in many countries are now offered testing

for more than 30 disorders, many of them very rare. However,

not all countries have implemented ‘expanded’ newborn

screening on this scale, reflecting different screening policies and

approaches to their evaluation.

In this contribution, we review the criteria by which proposed

screening programmes are assessed and discuss aspects that are

specific to the assessment of newborn screening for rare condi-

tions such as inborn errors of metabolism. We highlight some of

the challenges in obtaining and evaluating the evidence needed

to inform screening policies for these conditions. Detailed infor-

mation about screening for specific disorders is covered by other

contributors to this mini-symposium.

Definition of screening

Wald defined screening as the ‘systematic application of a test or

enquiry to identify individuals at sufficient risk of a specific

disorder to warrant further investigation or direct preventive

action, amongst persons who have not sought medical attention

on account of symptoms of that disorder.’ [Wald N. Guidance on

terminology. J Med Screening 1994; 1(1): 76].

While the rationale for screening is driven primarily by

concern to improve outcome for affected individuals, in this

definition, Wald reminds us that all those offered screening do

not usually have any concerns or symptoms related to that

condition that has so far prompted them to seek medical care. In

doing so, he highlights an implicit and ethical imperative to do

no harm to those screened. The implication is that the potential

benefits of screening should be positively balanced in relation to

potential harms. This requires a judgement based on a range of

complex and often imperfect information.

� 2010 Elsevier Ltd. All rights reserved.

http://dx.doi.org/10.1016/j.paed.2010.10.011


Approaches to evaluating screening programmes

In their original WHO publication, Wilson and Jungner distin-

guished the evaluation of screening procedures from the evaluation

of effects of screening (namely reduced morbidity and mortality).

Newborn screening as a process, not just a test: the various stages in

this process require careful assessment to ensure that the perceived

advantages are genuine and outweigh any potential harm. While

most would agree that there need to be demonstrable benefits to

screening, views vary regarding the types of benefits to be consid-

ered, the weighting given to those benefits, and the evidence of

benefit which is needed before screening policy can be made and

programmes implemented. For example, some argue that early

diagnosis per se is a legitimate goal of screening, irrespective of

evidence of improved health outcomes.

Wilson and Jungner were the first to outline a broad and

systematic approach to evaluation and in their original report

identified 10 major criteria which needed to be addressed (see

Box 2). In the United Kingdom these criteria have been extended

into a framework comprising 22 criteria which are used for the

evaluation of all screening programmes by a National Screening

Committee. In certain countries, specific policies have been pub-

lished about newborn blood spot screening, for example, by the

Human Genetics Society of Australasia or the American College of

Medical Genetics. All these frameworks have common elements

and there is broad consensus that decisions should be informed by

the evaluation of scientific evidence. In this article we have iden-

tified three main areas for evaluation, summarized as (1) the

burden of the disease for which screening is being offered; (2) the

clinical validity of the screening test and (3) the clinical utility of

the screening programme. Belowwe discuss these in the context of

newborn screening for inborn errors of metabolism and highlight

some specific challenges in programmes for rare diseases. We

conclude by considering some additional issues related to rare

The Wilson and Jungner criteria for evaluatingscreening programmes

1 The condition sought should be an important health problem.

2 There should be an accepted treatment for patients with

recognized disease.

3 Facilities for diagnosis and treatment should be available.

4 There should be a recognizable latent or early symptomatic

stage.

5 There should be a suitable test or examination.

6 The test should be acceptable to the population.

7 The natural history of the condition, including development

from latent to declared disease, should be adequately

understood.

8 There should be an agreed policy on whom to treat as patients.

9 The total cost of case finding (including diagnosis and treat-

ment of patients diagnosed) should be economically balanced

in relation to possible expenditure on medical care as a whole.

10 Case finding should be a continuous process, not a “once

and for all” project.

Wilson and Jungner, 1968, WHO

Box 2


diseases, drawing on the UK National Institute for Health and

Clinical Excellence (NICE) guidance on the principles to be used

when applying social value judgements to policy evaluations and

guidance.

Epidemiological considerations: the burden of disease

The importance of a condition for which screening is offered

relates not just to its frequency but also to its consequences.

Wilson and Jungner noted that ‘phenylketonuria is extremely

uncommon but warrants screening on account of the very serious

consequences if not discovered and treated very early in life.’

A rare disease has been defined as a condition which affects

less than five people in 10,000: by this definition almost all inborn

errors of metabolism are rare. Many are, in fact, very rare which

pose problems in acquiring reliable and unbiased information

about their frequency, natural history, clinical outcome and the

effects of treatment. In the UK all paediatricians contribute to the

surveillance of rare diseases through a monthly active reporting

scheme run by the British Paediatric Surveillance Unit. This has

proved a valuable mechanism for studying the epidemiology and

early clinical course of a wide range of candidate conditions for

newborn screening, including galactosaemia, medium chain acyl

CoA dehydrogenase deficiency (MCADD), glutaric aciduria type 1

and congenital adrenal hyperplasia. This scheme can also be used

to obtain useful information about the burden of clinically pre-

senting and diagnosed disease and importantly helps to identify

whether there is a window of opportunity for screening to make

a difference, referred to by Wilson and Jungner as a latent or early

symptomatic phase which allows time for diagnosis and initiation

of definitive treatment and management.

While the natural history of those with severe disease may be

well documented, the course of those with ‘mild’ disease may

not: such individuals may present infrequently to a clinician or

may not be ascertained at all clinically but are nevertheless

identified by screening. The problems associated with the wide

range of the clinical phenotype are discussed later.

Surveillance studies of rare diseases may also provide infor-

mation about their geographical variation, but this is not usually

helpful in determining whether screening should be offered to

geographically defined populations. It can in practice be difficult to

determine whether an apparent geographical cluster of a rare

disease ascertained by active surveillance relates to a true differ-

ence in its frequency, to differential ascertainment or reporting, or

to availability of specialist services and referral patterns. While

targeting higher risk populations that may be geographically iso-

lated or separated by custom or religion is an attractive proposi-

tion, this presupposes a robust strategy for selecting those at

higher risk. For example, although tyrosinaemia type 1 was

recognized to be more prevalent in one area of Quebec e Sague-

nay-Lac St Jean e in practice screening is offered throughout the

province. Similarly where the risk of a rare disease is higher in

certain ethnic groups it may appear attractive to consider using

ethnicity as a basis for offering screening. However the difficulties

of ascertaining ethnic origin in contemporary populations with

high rates of migration and inter-ethnic union make such selection

unreliable, as has been demonstrated by the progressive aban-

donment of ‘selective’ newborn screening strategies for sickle cell

disorders in the United States.




These epidemiological considerations remain important when

considering the scientific rationale for screening policies that

utilize one technology for multiplex testing such as tandem mass

spectrometry: the addition of any individual disorder to

a screening panel requires careful appraisal of disease burden

and the likely health gain for those affected.

Evaluating the screening procedure: clinical validity

Conventionally we think of a screening procedure as discrimi-

nating those with a condition from those without, however

technological developments in presymptomatic diagnosis are

such that a broader phenotype than that which presents clinically

is detected which challenges pre-existing definitions and

concepts of disease. Clinical validity refers to the accuracy with

which a screening test can predict the presence or absence of

latent clinical disease, principally a clinical relevant phenotype

that provides the rationale for screening.

By definition, screening tests are not diagnostic tests. So

screening implies the need for further assessment by a diagnostic

test or tests to be offered to those above a predefined threshold

on that screening test in order to separate reliably those with

a specific condition from those without. This threshold is usually

set to optimize detection of affected individuals while avoiding

falsely labelling health individuals who may be worried unnec-

essarily or be exposed to the risks of subsequent diagnostic tests.

The specific threshold is informed by the biomarker distribution

in the normal population, the analytic validity (accuracy and

reliability) of the test, the aims of screening and the drawbacks of

an inaccurate positive or negative result. Data from screening

large population samples using standardized protocols are

needed to evaluate proposed newborn screening procedures for

rare diseases.

A diagnostic test is essential in order to provide those tested, or

their parents, with confirmation of diagnosis and information

about prognosis and future management. It is also essential in

order to evaluate the screening procedure, the effects of screening

in terms of reduced morbidity and mortality of those affected by

the target condition, or the unintended identification of other

conditions and their significance. Readers will be familiar with the

conventional measures used when evaluating screening proce-

dures (detection rate, false positive rate and predictive value).

Although simple to compute, collection of such information for

rare diseases poses specific challenges.

The first challenge is the need for an agreed method to define

who is affected: this requires case definitions and diagnostic

criteria that work in the absence of clinical symptoms, as the

majority of newdiagnoseswill be identified through screening and

will, by definition, be presymptomatic. Specifying ‘gold standard’

diagnostic tests and their interpretation can be challenging where

a state of the art diagnostic technology, such as tandem mass

spectrometry, is also used for newborn screening and where

clinicians have historically interpreted biochemical findings in the

context of the presenting clinical features.

The second relates to the need to ascertain all those ever

diagnosed with the condition, irrespective of whether this has

been through screening or clinical presentation. Underascertain-

ment of those ‘missed’ by screening (false negatives) will, by

definition, overestimate the detection rate or sensitivity of a test.


The precise approach to ascertaining diagnoses will depend on the

natural history of the condition (determining the duration of

follow up of a screened birth cohort), the likelihood of clinical

diagnosis in death or life (reflecting access to specialist diagnostic

services), as well as the availability of surveillance systems to

obtain and collate reports and data. For rare diseases, data are

needed at a national level, but for very rare diseases, international

collaboration may be needed in order to derive sufficiently precise

estimates.

The third challenge lies in relating the screening phenotype to

the clinical phenotype. It is well recognized that the frequency of

a rare disease rises following the introduction of screening,

reflecting the identification of individuals who might never have

developed symptoms or adverse outcomes from their disease

(milder phenotypes). It may not be possible, on the basis of tests

carried out on newborns, to differentiate those with milder

phenotypes from those likely to present clinically and hence to

determine whom to treat. This oftenmeans that all or most of those

detected by screening are treated. As a consequence it can be

difficult to be sure these are all ‘true’ cases (in the sense of having

the clinically relevant phenotype), to calculate screening test

performance (detection and false positive rates) and to characterize

the benefits of screening (in terms of reduced morbidity and

mortality).

Evaluating the effects of screening: clinical utility

Clinical utility refers to the likelihood that screening will lead to

an improved outcome for the affected individual and their family.

Conventionally interest has focused on health outcomes, princi-

pally mortality and morbidity. While these are crucial there is

increasing recognition of the importance attached by affected

individuals and their families to other health outcomes, including

patient reported outcome measures: these may include measures

of quality of life, broad aspects of cognition, intellectual and

emotional development, adult health including future reproduc-

tive potential, and so on. All reflect a wider view and concept of

benefit. Grosse and Khoury reviewing the concept of clinical

utility in relation to genetic testing note the shift to a broader

perception of benefits in debates around expanded newborn

screening, including reduction in the ‘diagnostic odyssey’, the

right to diagnosis even in the absence of effective treatments, and

future reproductive choices (for the parents) in the case of

inherited disorders. Hence it is important to consider and agree

the outcomes which screening seeks to improve and to define the

objectives of screening in relation to these outcomes. Whatever

the outcomes selected, Grosse and Khoury emphasize the

importance of using objective measures for the assessment.

As diagnosis alone will not achieve better health outcomes,

the clinical utility of screening will also depend on the avail-

ability of effective treatments or other interventions. This in turn

depends on evidence about two distinct aspects of effectiveness:

firstly, whether treatment improves the specific outcomes of

interest and secondly whether treatment following screening, i.e.

before symptoms are evident, results in a greater improvement in

outcome than achieved when treatment is given following clin-

ical diagnosis. Unfortunately in the case of most inborn errors of

metabolism, such evidence is rarely obtained from clinical trials,

rarely pertains to the range of outcomes of interest or to the




duration of follow up needed to assess them fully. Observational

studies of screening often rely on comparison with the outcome

of children diagnosed in the past before screening started or

contemporaneously following clinical diagnosis in an area where

screening is not offered. Neither is ideal since outcome may be

confounded with differences in access to other treatments or to

overall management and healthcare. Wilcken has argued that the

lack of evidence on outcome should not delay the introduction of

screening e this argument has proved persuasive in the United

States but less so in the United Kingdom. She has at the same

time highlighted the paucity of data on longer-term outcome and

the need to collect it and the challenges in doing so for very rare

conditions. One implication of this is the need to collect outcome

data following implementation.

Finally, assessments of utility also need to incorporate the

disbenefits, real and perceived, of screening in order to ensure

that overall there is more harm than good. This can be very

challenging since the majority of those tested will not have the

condition of interest and may have concerns relating to the

potential for misdiagnosis, medicalization, stigma and anxiety,

however transient, which need to be respected. As with benefits,

evidence of disbenefits e objectively measured e is needed and

is often lacking.

Generating and weighing evidence: effectiveness, cost

effectiveness, social values

We have outlined the most common elements of the frameworks

used in many countries to assess whether a new screening pro-

gramme should be introduced. Such assessments should be

based on high quality, objective and scientifically rigorous

information on a range of benefits and disbenefits relevant to the

goals of screening, which can be objectively measured. We have

identified some of the challenges in acquiring such information,

especially for rare disorders such as many inborn errors of

metabolism. Policy makers typically need to consider not only

the benefits and disbenefits but also the value for money and

opportunity costs of deploying limited healthcare resources into

a new screening programme. Health economists help to make

these decisions more rationally based by using formal methods of

combining evidence and its uncertainty in cost effectiveness

analyses that incorporate multiparameter evidence synthesis.

This allows the costs and effects of different policy options to be

compared and may provide conclusive support for one particular

option.

Such decisions need also to take account of wider social values

and the ethical principles which underlie decisions on healthcare.

These have been clearly summarized in a very useful document

produced by the UK National Institute of Health and Clinical

Excellence which sets out some of the procedural and bioethical

principles to be considered in developing guidance and policies

formulated and developed following wide public consultation. The

processes which lead to guidance or policy should be scientifically

rigorous, including all parties with a legitimate interest in the

guidance under consideration, be transparent, independent, open

to challenge and timely. The ethical and moral principles which

underpin clinical and public health practice include respect for

autonomy, non-maleficence, beneficence and distributive justice

or fairness and these need to be considered when making


judgements about effectiveness, cost effectiveness and allocation

of resources. NICE highlights the importance of developing

evidence-based guidance recognizing that recommendations

should not be made where evidence is too weak to permit

reasonable conclusions to be drawn. Where there is a lack of

evidence of effectiveness more research is needed and it is

important that there is a mechanism for funding such research

based, if necessary, on large-scale pilot studies.

Public involvement and informed choices

Implicit in much of our discussion about outcomes and social

values is the need for scientists and clinicians to work in part-

nership with parents and the public in order to develop guidance

and policies and then to implement them. The rapid expansion in

screening programmes in the United States, driven in part by

advocacy from groups representing families affected by specific

rare conditions, now means that the parents of a new baby are

being asked to consent to testing of up to 30 conditions. This

poses challenges in obtaining informed consent. Qualitative

research suggests that relative ineffectiveness of some treatment

may moderate parental enthusiasm for some tests and more

work is needed if we are to implement programmes that respect

autonomy of child and parent in their decision making in

a meaningful way.

Summary

We have set out a broad framework which we believe should be

employed for the evaluation of proposed newborn screening

programmes, elaborating some challenges which apply when

considering rare inborn errors of metabolism. It is essential to

establish the goals and outcomes of screening for each condition

and then to appraise the evidence for disease burden, clinical

validity and clinical utility. In weighing this evidence a set of

procedural and ethical principles can be applied in order to make

difficult decisions in the best way possible.

Role of the funding source

James Leonard is retired and has no sources of funding.

Carol Dezateux is employed by University College London. Her

post is funded by the Higher Education Funding Council of

England (HEFCE) and the Department of Health. Work carried

out at the MRC Centre of Epidemiology for Child Health benefits

from funding from the Medical Research Council (G0400546).

None of these sponsors had any role in the writing of this

manuscript.

Conflict of interest

James Leonard is chairman of the Diagnostic Review Panel of the

UK Collaborative Study of Newborn Screening for MCADD. He

has chaired and received payment for a workshop funded by

Swedish Orphan on newborn screening for Tyrosinaemia type 1

(fumarylacetoacetase deficiency).

Carol Dezateux is Strategic Director of the UK Newborn

Screening Programme Centre which is funded by the UK Depart-

ment of Health but has contributed to this article in a personal

capacity. She is principal investigator of the UKCollaborative Study

of Newborn Screening for MCADD which is funded by the UK



Practice points

C Newborn screening programmes for inborn errors of meta-

bolism should be evaluated using recognized frameworks.

C It is essential to establish the goals and outcomes of

screening for each disorder.

C Screening policy requires evidence on the burden of the

disorder for which screening is being offered, the clinical

validity of the test and the outcome.

C For rare diseases, systematic strategies to evaluate longer-

term outcomes are needed in order to evaluate benefits of

screening.


Department of Health. The opinions expressed here are her own

and she has no conflicts of interest to declare. A

FURTHER READING

ACMG Newborn Screening Expert Group. Newborn screening panel and

system. Genet Med 2006; 8: 1Se252.

Grosse SD, Khoury MJ. What is the clinical utility of genetic testing? Genet

Med 2006 Jul; 8: 448e50.

Human Genetics Society of Australasia. HGSAeRACP Newborn Screening

Joint Subcommittee. Newborn blood spot screening; 2008.

National Institute For Health And Clinical Excellence. Social value judge-

ments: principles for the development of NICE guidance. 2nd Edn;

2008.

National Screening Committee. Criteria for appraising the viability, effec-

tiveness and appropriateness of a screening programme. London:

Department of Health, 2003. www.library.nhs.uk/screening (accessed

Sep 2010).


Wilcken B. Expanded newborn screening: reducing harm, assessing

benefit. J Inherit Metab Dis 2010. doi:10.1007/s10545-010-9106-6.

Wilson JMG, Jungner G. Principles and practice of screening for disease.

Geneva: World Health Organization, 1968.


http://www.library.nhs.uk/screening



PhenylketonuriaMaureen Anne Cleary

AbstractPhenylketonuria remains one of the most common inborn errors in the

United Kingdom. It is detected on the newborn heel-prick screening

sample allowing early treatment with a strict low phenylalanine diet sup-

plemented with artificial amino acids, and appropriate vitamin and

minerals. Although the long-term prognosis is good, there is an increasing

body of evidence highlighting subtle problems in neuropsychological

function with slower reaction times and poorer executive function than

peers. White matter changes clearly seen on brain magnetic resonance

imaging may have some relationship to these neuropsychological difficul-

ties but their significance is not clearly understood. The diet, although

successful, is difficult to follow lifelong and with its attendant risks of

nutritional deficiencies needs careful specialist management. In view of

these challenges new treatments such as sapropterin (a tetrahydrobiop-

terin analogue) and large neutral amino acids are currently being used

in phenylketonuria and a human trial has started using ammonia lyase

as enzyme replacement therapy. Maternal phenylketonuria syndrome

remains a risk for those who conceive whilst blood phe is elevated and

females must be counselled early in childhood to avoid this risk.

Keywords hyperphenylalaninaemia; phenylketonuria; PKU; sapropterin

therapy

Phenylketonuria (PKU) can claim at least three ‘firsts’: the first

metabolic disorder to have a successful treatment; the first to be

controlled by diet; and the first to be detected by newborn

screening. This review describes the current management and

outcome of PKU and summarizes developments of new

therapies.

Terminology

PKU was first described in 1934 by Folling as ‘imbecillitas phe-

nylpyruvica’ following the finding of phenylpyruvic acid

(a phenylketone) in the urine of two siblings with mental retar-

dation. The term phenylketonuria was later used by Penrose and

has remained the most widely used name for hyper-

phenylalaninaemia (HPA) due to phenylalanine hydroxylase

deficiency. It is now generally applied to the more severe end of

the spectrum in which phenylalanine is greater than 1200 mmol/l

whilst consuming a normal protein intake and this type is also

referred to as classical PKU. HPA is a frequently used term to

describe those with phe levels 600e1200 mmol/l on a normal

protein intake whereas levels between 120e600 mmol/l is called

mild HPA. All arise due to defects in the enzyme phenyalanine

hydroxylase (PAH); the severity relates to the nature of the

Maureen Anne Cleary MBChB MRCP MRCPCH MD is a Consultant Metabolic

Paediatrician in the Metabolic Unit, Great Ormond Street Hospital NHS

Trust, Great Ormond Street, London WC1 N 7JH, United Kingdom.

Conflict of interest: none.


underlying genetic mutation. In less than 2% of cases a raised

phenylalanine (phe) level is caused by a defect in the production

or recycling of tetrahydrobiopterin (BH4). PKU is still the most

commonly used term in the United Kingdom (UK) and is used in

the remainder of this article.

Natural history

PKU causes severe intellectual impairment. In classical PKU

developmental delay is apparent within the first year of life and

progresses to severe mental retardation (IQ < 50). Examination

shows limb spasticity, tremor and microcephaly. A seizure

disorder is frequently present and EEG abnormalities are common.

Other findingsmay include hypopigmentation of the hair, skin and

iris due to reduced melanin synthesis. Parkinsonian features and

gait abnormalities are also often observed in the untreated indi-

vidual. Abnormalities of behaviour are very common including

hyperactivity, aggression, anxiety and social withdrawal. The

natural phenotype is rarely seen now due to widespread newborn

screening for this condition. However, PKU should be considered

as a possible diagnosis particularly in an individual born in

a country where newborn screening may not be available.

Detection

In most first-world countries the diagnosis of PKU is made

through newborn screening. PKU can be readily detected by

a raised phenylalanine on the newborn heel-prick blood test.

Blood phenylalanine (phe) and tyrosine (tyr) are measured. In

PKU the ratio between these two metabolites is greater than 3.

The cut-off value for a presumed positive screen varies between

countries depending on the infant’s age at screening. The UK

practice is to sample between days 5e8, using a cut-off phe of

240 mmol/l. Other causes of elevated phe, aside from PKU,

include a disorder of biopterin production or recycling, liver

dysfunction or premature babies receiving amino acid containing

parenteral feeds.

Disorders of biopterin production or recycling can cause

raised phe since tetrahydrobiopterin (BH4) is the co-factor for the

phenylalanine hydroxylase enzyme (see Figure 1). These disor-

ders, previously called ‘malignant PKU’, are best named by their

respective enzyme deficiency. In all positive screening cases

a disorder of biopterin is excluded by measuring total biopterins

and DHPR enzyme activity on blood spots. BH4 disorders result

in neurotransmitter deficiencies and individuals need replace-

ment of dopamine and 5-hydroxytrypophan in addition to BH4;

some still need dietary treatment to reduce phe levels.

Liver dysfunction can cause an elevation of phe but in these

cases other amino acids such as tyrosine, methionine and leucine/

isoleucine are also raised thus keeping the phe: tyr normal or less

than 3. Preterm babies may have raised phe levels whilst on a high

protein intake. Again, in this situation other amino acids are also

elevated making it unlikely that PKU would be missed. Preterm

babies should be tested at the same time as other newborns and

their gestation and feed content noted on the request form.

Epidemiology

The incidence of this condition in the UK is approximately 1 in

10,000 newborns. PKU is prevalent in Europe and the US. It is



Pterin-4a-carbinolamine

Phenylalanine Tyrosine

PAH

q-BH2

BH4

PhenylpyruvatePhenylacetatePhenyllactate

PAH, phenylalanine hydroxylase; BH4, tetrahydrobiopterin;

q-BH2, q-dihydrobiopterin

Figure 1 The phenylalanine hydroxylation system.


relatively common in some parts of China but is rare in African

nations. The highest incidence is observed in Turkey where the

incidence is 1 in 2600.

Biochemistry and genetics of PKU

Phenylalanine is an essential amino acid which is metabolized in

the liver by the enzyme phenylalanine hydroxylase (PAH). The

first step of catabolism of phenylalanine is irreversible conver-

sion to tyrosine. The PAH enzyme requires tetrahydrobiopterin

as its co-factor. PKU develops due to deficiency in, or absent

activity, of the PAH enzyme and results in elevated phenyalanine

and reduced levels of tyrosine. When the pathway to tyrosine is

blocked, excess phe is transaminated to phenylpyruvic acid and

excreted in urine. The enzyme is coded by the PAH gene located

on the long arm of chromosome 12. More than 400 pathological

mutations are recognized and most affected subjects are

compound heterozygotes in that they carry two different muta-

tions. There is a good correlation between pre-treatment phe

levels, phe tolerance and genotype. However, outcome is affected

by many factors and genotype knowledge is of limited value in

predicting clinical management. But mutation analysis has some

value in predicting BH4 responsiveness (see below).

PKU is inherited as an autosomal recessive condition. Prenatal

diagnosis, although rarely requested, is possible by mutation

analysis if the mutations are already identified in the index case.

Treatment

The aim of PKU treatment is the reduction of blood phe to a level

allowing normal brain development. An individual’s blood

phe depends upon dietary intake of phe and the residual activity

of phe hydroxylase. Although in some cases it is possible to

augment phe hydroxylase activity (see new treatments), in most

cases treatment relies upon reducing phe intake by a restriction of

natural protein. In most cases meat, cheese, bread, fish and milk

must be avoided. A semi-synthetic diet is used which comprises:

� foods of low phe content in unlimited amounts such as many

fruits and vegetables;

� weighed amounts of foods containing medium amounts of

phe (e.g. broccoli, potato). The amount of phe ingested is


often calculated using an exchange system. In the UK system

1 ‘exchange’ ¼ 50 mg phe which is approximately 1 g protein;

� phe-free amino acid mixtures to provide normal or supra-

normal total protein intake;

� vitamins, minerals and trace elements.

The diet should be strictly followed with these food groups

evenly distributed throughout the day. Aspartame should be

avoided as it contains large amounts of phe. Infant formulae

feeds which are phe-free are available; many contain added

essential fatty acids. These are used in conjunction with a small

amount of standard infant formulae. It is possible to continue

breast feeding even in severe PKU by giving a measured amount

of phe-free formula prior to a breast feed. All PKU diets should be

administered with the advice of a specialist dietician.

Monitoring of treatment

It is vital to monitor phenylalanine levels, usually through

frequent blood spot analysis. Guidelines vary between countries

regarding frequency and acceptable phe levels. In the UK, infants

and young children should have weekly samples aiming at levels

120e360 mmol/l; school-age children fortnightly samples with

a range of 120e480 mmol/l; and in adolescents and adults

monthly samples with an upper limit of 700 mmol/l. These

guidelines are currently under review and changes can be viewed

through the UK newborn blood spot screening programme

website (see below). In addition to monitoring phe levels, other

nutritional indices such as vitamin B12, folate, iron, calcium,

phosphate and essential fatty acids should be measured in those

with poor dietary adherence. Growth parameters are also moni-

tored. Some clinics advocate regular neuropsychological testing

whereas others only refer for such assessment where difficulties

are suspected.

Nutritional issues in PKU

The nutritional sufficiency of the PKU diet must be regularly

monitored by a specialist dietician. Vitamin B12 deficiency is

a particular risk in adolescents and adults who have stopped

taking their supplements but are still restricting their protein

intake by habit. Other vitamin or mineral deficiencies have

occasionally been noted in PKU such as iron, selenium and

calcium. Bone mineral density may be lower than normal in this

group of patients although the reasons for this are unclear.

Polyunsaturated fatty acids levels are frequently low in the

plasma and red cells of PKU children on diet. This is probably

due to its low animal protein content. Although it seems prudent

to supplement PUFAs, there is not yet clear evidence on

requirements in this group nor on the long-term impact on

neurodevelopment.

Dietary adherence

Adherence to treatment in PKU is particularly challenging for

several reasons: the strict diet creates awkward social occasions;

the diet itself is unpalatable; frequent blood tests lead to needle

phobia in some children; and the diet is time consuming and may

be costly in some countries. It is important to provide education

programmes to help compliance; such as toddler groups and

teenage camps.




Duration of diet

Despite the knowledge that has accumulated on PKU, the risk of

stopping diet in adulthood is not yet known. The oldest early-

treated patients are now entering middle age. The vast majority of

these remain neurologically healthy but the possibility of late

neurological decline cannot be excluded. Current recommenda-

tion is diet for life. This is based upon the evidence of poorer

neuropsychological performancewhen phe levels are elevated and

the knowledge thatMRI of the brain shows abnormalities ofmyelin

of uncertain significance.Where diet for life is refused then at least

monitoring for life by regular clinic attendance is encouraged.

New treatments for PKU

As long-term dietary compliance is difficult there is a need for

alternative modes of treatments:

Enzyme replacement therapy

The non-mammalian enzyme phe ammonia lyase converts phe to

a non-toxic substance called transcinnamic acid. It has been

tested using enteral, intraperitoneal and subcutaneous routes.

More recently enzyme stability has been achieved by pegylation.

Plasma phe falls significantly in the mouse model experiments

and the first human trial is underway in the US.

Large neutral amino acids

The large neutral amino acids (LNAA) including phe compete at

the blood brain barrier for entry to the brain through the same

transporter (LAT1). Increasing the concentration of LNAA in the

blood therefore reduces phe entry to the brain. There is a similar

mechanism in the gut, and absorbed phe is lower if LNAA are

supplemented in generous amounts. It is unlikely that LNAA

given as sole treatment without phe restriction could replace diet

in childhood but may be a useful approach for adults.

Sapropterin therapy

BH4 therapy has been used for some time to treat defects in the

pterin pathway. However it has recently been shown that admin-

istration of BH4 can result in a reduction of phe levels even in

phenylalanine hydroxylase deficiency. The mechanisms are not

completely understood but include stabilization of residual protein

thus suggesting that thosewithmild PKU aremost likely to benefit,

however, some patients with classical PKU have also shown

a response. It is estimated that 80% of those with mild PKU and

40% of those with classical PKU will benefit from this treatment.

Genotype canhelp in predicting responsebut it cannot be assumed,

and a short therapeutic trial is required to judge BH4 responsive-

ness. Sapropterin dihydrochloride is a synthetic formulation of the

active 6R-isomerofBH4whichhasbeen licensed recently inEurope

andUS for the treatment of PKU. In Europe the license is granted for

children over 4 years of age with phenylalanine hydroxylase defi-

ciencywhohave showna response to the drug. In theUKguidelines

are needed to best define a ‘response’ to treatment in order for this

treatment to become available beyond commercial trials.

Gene therapy

The most promising results come from experiments using

recombinant adeno-associated virus vector in which long-term

correction without adverse effects has been reported in the mouse

model (PKUenu2). There are no human gene therapy studies yet.


Liver transplantation

This procedure effectively provided phe hydroxylase activity in

a child with PKU who required liver transplantation for an

unrelated problem. The risks and complications of transplant

render it an unrealistic option.

Outcome of PKU

The outcome for PKU is good. If dietary treatment is started early

(before 3 weeks of age) and blood phe levels remain satisfactory,

then ultimate IQ should be in the average range although slightly

reduced in comparison with peers or siblings. After the age of 10

years IQ is stable. The small number of adolescents and adults

who have developed overt neurological disease have had poor

metabolic control in childhood. However recent research does

identify some problems in the treated PKU population.

Magnetic resonance imaging (MRI) of the brain

Brain MRI in children and adults commonly shows abnormalities

in the cerebral white matter even in treated PKU. These signal

changes are likely to be intramyelinic oedema which usually

affects the periventricular whitematter.Milder changes affect only

the occipital lobe but more severe involvement progresses

rostrally to the frontal lobe. The degree of white matter change is

associated with recent metabolic control (average phe level in the

preceding year and current phe levels) but not to early phe levels.

Despite years of investigation the functional consequences of

these findings are unclear. There is some recent evidence sug-

gesting a correlation between neuropsychological performance

and more widespread white matter changes. The MRI changes are

reversible upon lowering blood phe within about 2 months. The

lesions appear static at least over a 5-year period in adulthood if

phe levels remain stable.

Neuropsychological studies

Despite many neuropsychological studies in treated PKU it

remains difficult to draw clear conclusions: the numbers studied

are often small; the types of neuropsychological test vary

between studies; the ages are different (children or adults); the

background phe control and phe level at the time of testing vary.

The tentative conclusion is that some neuropsychological

damage occurs even in treated PKU.

Reaction times are delayed in PKU and this relates to

concurrent elevated phe levels. Executive function i.e. higher

level processes requiring interactions between several areas of

the brain, has been extensively studied as it is governed by the

pre-frontal cortex. This is a dopamine sensitive area of the brain

which may be especially vulnerable in PKU. Of the various

subsets of executive function studies, inhibitory control is

impaired in early-treated PKU. Tests of working memory may

have an age-related effect as children show largely normal results

but a decline in function is observed in adolescents and adults.

There are other behavioural and psychiatric symptoms

attributed to PKU. Poor dietary control early in life results in

anxiety, hyperactivity and social withdrawal, and those with

satisfactory early treatment still appear to have a higher risk of

low self-esteem and possibly depression. Further research is

required in this field: the size of studies must increase and their

uniformity be ensured. Longitudinal projects should also be

developed.



Practice points

C PKU remains one of the most common IEM in the UK with an

incidence 1 in 10,000

C Dietary therapy remains the mainstay of treatment

C Long-term monitoring requires a specialist team in order to

avoid nutritional deficiencies

C Prognosis is good as long as phe levels are kept within

treatment guidelines

C There may be mild deficits in neuropsychological function

even in treated patients

C Treatment with sapropterin benefits some individuals with

PKU usually those with milder disease

C Enzyme replacement therapy human trials are underway.


Maternal PKU

Infants born to mothers with blood phe above 1200 mmol/l show

fetal damage including low birth weight, microcephaly, dys-

morphic facies, slow postnatal growth and development and

intellectual impairment. The facial features are similar to fetal

alcohol syndrome: small palpebral fissures, epicanthic folds, long

philtrum and thin upper lip. Although congenital heart disease is

the most common, other organ malformation can occur. The risk

to mothers with milder PKU is smaller and appears to correlate

with phe level. In view of these risks all females with PKU must

be monitored for the duration of their lives, being counselled

early in their childhood and having a longstanding trusting

relationship with their PKU team. The aim for managing

maternal PKU is for women to be on a strictly controlled diet

preconception with regular phe monitoring showing levels

between 100 and 250 mmol/l. There is also evidence that if diet is

started by 10e12 weeks of pregnancy a satisfactory outcome can

be achieved.

Summary

PKU is a success story. It can be detected early in life allowing

early instigation of dietary therapy. The treatment is effective and

children grow and develop normally. Within this framework of

success however there are still unanswered questions about

long-term neuropsychological outcome and the necessity of diet

for life. Dietary treatment remains challenging for many patients

hence the importance of the alternative approaches now on the

horizon. A

FURTHER READING

Anderson PJ, Leuzzi V. White matter pathology in phenylketonuria.

Mol Genet Metab 2010; 99(Suppl 1): S3e9.


Blau N, Erlandsen H. The metabolic and molecular bases of tetrahy-

drobiopterin-responsive phenylalanine hydroxylase deficiency.

Mol Genet Metab 2004 Jun; 82: 101e11.

DeRoche K, Welsh M. Twenty-five years of research on neurocognitive

outcomes in early-treated phenylketonuria: intelligence and executive

function. Dev Neuropsychol 2008; 33: 474e504.

Feillet F, Agostoni C. Nutritional issues in treating phenylketonuria.

J Inherit Metab Dis; 2010 Feb 12 [Epub ahead of print].

Koch R. Maternal phenylketonuria: the importance of early control during

pregnancy. Arch Dis Child 2005; 90: 114e5.

MRC. Recommendations on the dietary management of phenylketonuria.

Arch Dis Child 1993; 68: 426e7.

Van Spronsen FJ. Future treatment strategies in phenylketonuria.

Mol Genet Med 2010; 99(Suppl 1): S90e5.

www.nspku.org.

www.newbornbloodspot.screening.nhs.uk.

www.bh4.org.


http://www.nspku.org

http://www.newbornbloodspot.screening.nhs.uk

http://www.bh4.org



Galactosaemia an updateAA Broomfield

C Brain

S Grunewald

AbstractWhile galactosaemia was originally documented over 100 hundred years

ago, it still remains poorly understood and recognized. Classical galacto-

saemia is an inherited disorder of galactose metabolism, whose main die-

tary source is lactose. In the UK which does not currently screen for

Galactosaemia lack of recognition of key symptoms can lead to delays in

diagnosis. However it has become clearer that Galactosaemia is not only

an acute disease of the neonatal period but affected children potential

are prone to a number of chronic problems later in life. This review looks

at the current thinking concerning the pathogenesis and complications of

galactosaemia and summaries our current management of patients.

Keywords galactitol; galactosaemia; galactose-1-phosphate; genetic;

inherited metabolic disease; leloir pathway

Definition

The pathogenic potential of ingested galactose was originally

described over 100 years ago. It results fromadefect in the galactose

metabolic pathway, the Leloir pathway, which consists of three

enzymes, the galactose specific kinase (Galactokinase/GALK),

galactose-1-Phosphate uridyltransferase (GALT) and uridine

diphosphate galactose 40 epimerase (GALE). While a deficiency in

any of these enzymes will lead to the biochemical finding of gal-

actosaemia i.e. an elevated plasma galactose, only deficiencies in

GALT or GALE have the potential to cause the ‘classical Gal-

actosaemia’ phenotype: an acute toxicity syndrome which resolves

on removal of exogenous galactose intake with more recently

recognized long-term complications of chronic neurological, endo-

crine, and orthopaedic problems. The outcome of these chronic

problems seems to be far less tightly linked to galactose intake.

Incidence/epidemiology

The overall incidence of classical galactosaemia, secondary to

GALT deficiency, is estimated at between 1: 23,500 and 1: 44,000

Abbreviations: GALE, Galactose 40 epimerase; GALK, Galactokinase;

GALT, Galactose-1-Phophate uridyltransferase (Gal-1-Put); GALK Gal-

actokinase, GALE Galactose 40epimerase; GAL-1-P, Galactose-1-Phopshate.

AA Broomfield MSC is a Specialist Registrar in the Metabolic Medicine

Unit, Great Ormond Street Hospital for Children, London WC1N 3JH, UK.

C Brain MD is a Consultant Paediatric Endocrinologist in the Endocrine,

Department of Great Ormond Street Hospital for Children, London

WC1N 3JH, UK.

S Grunewald PhD is a Consultant in Paediatric Metabolism in the

Metabolic Medicine Unit, Great Ormond Street Hospital for Children,

London WC1N 3JH, UK.


in the UK. This is in keeping with most of Western Europe,

however the incidence in different subpopulations varies greatly.

This is especially true in Ireland, where the incidence in the

travelling population is one in 450 live births whilst the overall

incidence is nearer to 1: 20,000. Worldwide the incidence does

appear to be lower than in Western Europe, being quoted as one

in 50,000 in the USA and as little as one in 100,000 in Japan.

The mild asymptomatic phenotype of GALE is relatively

common, with a frequency of 1: 6,200 in the African American

population, but the severe “generalized” presentation of GALE,

whose presentation is similar to that of classical galactosaemia is

limited to a few case studies worldwide. The GALK deficiency is

rare <1/100,000.

Genetics

The GALT gene is located on chromosome 9p13 and consists of

11 exons. Over 230 mutations have been described. The most

frequent mutation in the Caucasian population, with an overall

frequency of 65% (96% in the Irish population), is the Q188R

mutation, which results in a complete loss of enzymic activity.

The second commonest European mutation is the K285N,

a missense mutation, which predominates in central European

counties. This also results in a complete lack of GALT activity.

In contrast, S135L, which accounts for 50% of mutate alleles in

African Americans, shows near normal activity in mouse models.

Whilst there is a relatively good correlation between genotype

and residual enzymic function, the correlation between genotype

and clinical phenotype is more enigmatic, though Q188R is

predicative of a poorer clinical outcome, whereas S135L is

associated with the milder phenotype seen in Afro-Caribbean

patients.

The N314D mutation (c. 940A>G), so called Duarte variant,

can exist in two different forms: Duarte-1 and Duarte-2 has

a good clinical outcome. The Duarte-2 mutation is interesting, as

compound heterozygotes for the Duarte-2 variant and classical

galactosaemia, typically manifest 14e25% of normal GALT

activity resulting in some protection against severe toxicity.

Pathology

The exact mechanisms underlying the pathophysiology of clas-

sical galactosaemia is still not fully understood with the lack of

a good animal model hampering research; the GALT mouse

knockouts, having few of the clinical features found in humans.

However, the potential mechanisms can be grouped into,

primary effects which include the buildup of toxic metabolites

and the reduction in end products of the Leloir pathway and

secondary effects due to disruption of other interlinked

pathways.

With any disruption of the Leloir pathway, there is the

potential for excess galactose accumulation, which if uncon-

trolled will also result in accumulation of Galactitol and Gal-

actonate. These are formed due to the actions of the alternative

pathways of galactose metabolism i.e. aldase reductase and the

pentose phosphate pathway respectively (Figure 1).

Given that the GALK deficient patients do not manifest either

the acute toxicity, or any of the chronic manifestations seen in

GALT patients, it seems likely that Galactose-1-P which is absent

in GALK but present in GALT, plays a major role in their



Lactose

Galactose

GALK

GALE

GALT

Galactose 1-P

UDP Galactose UDP-Glucose

UDP-Glucose

Glucose 1-P

Glucose 1-P

Glucose 6-P

Glucose

1

2

3

Galactonate

Aldose

Pentose phosphate pathwayreductase

Galactitol

Figure 1 The Leloir pathway and alternative pathways for galactose

metabolism (dotted lines). 1 ¼ hexokinase, 2 ¼ phosphoglucomutase,

3 ¼ UDP-glucose pyrophosphorylase.


pathogenesis. The actions of GAL-1-P need further elucidation

with a variety of effects being seen, for a more comprehensive

review see Lia 2009. Recently there has been some speculation

that GAL-1-P toxic effects may be mediated via the human

tumour suppressor gene aplysia ras homolog I (ARHI), which,

since it is absent in mice, may also explain the clinical difference

seen in the mouse model. The accumulation of galactitol is

thought to be responsible for the cataracts seen, though whether

this is due to direct osmotic effects or due to oxidative damage

secondary to NADPH depletion is unclear. It is also unclear if

galactonate, cleared by the pentose 5 phosphate pathway,

contributes to the overall toxicity.

In terms of reduction of end product, the interplay of the

enzymes involved in the Leloir pathway ultimately controls the

levels of UDP-galactose, the galactosyl donor in cellular glyco-

protein/glycolipid biosynthesis. This potentially leads to abnor-

malities in post translational protein modification and abnormal

glycosylation has been demonstrated with abnormalities seen in

FSH and transferrin changes similar to those seen in congenital

disorders of glycosylation (CDG).

The most apparent affect on a secondary pathway, is the

reduction in levels of cellular inositol, with reductions in myo-

inositol being documented in vivo. GAL-1P competitively inhibits

human inositol monophosphatase and in the yeast model,

galactose toxicity can be overcome by over-expression of inositol

monophosphatase. The reduction in inositol might partially

explain the neurological symptoms seen in galactosaemic

patients since inositol is required for the formation of the

neuronal modulator Phosphatidylinositol bisphosphate.


The clinical symptoms of acute toxicity syndrome of classical

galactosaemia

The natural history of classical galactosaemia is of an early onset,

potentially life threatening acute toxicity syndrome, occurring

after several days of exposure to dietary galactose from milk.

However liver dysfunction has been described as early as day 1

and milder phenotypes presenting at several weeks of age are

seen. Overall, in 266 out of 336 cases (79%) in one study, acute

symptoms were reported within 2 months of birth.

Initial symptoms are non specific with affected neonates

presenting with vomiting, diarrhoea, lethargy, hypotonia or poor

feeding with resultant poor weight gain. Given the limited

neonatal repertoire of response to illness, this is easily confused

with sepsis, a situation complicated further by the apparent

susceptibility of galactosaemics to Escherichia coli. sepsis.

Examination on presentation may reveal signs of liver

impairment such as jaundice, hepatomegaly and signs of

abnormal bleeding; as well as occasional fullness of the anterior

fontanelle either due to sepsis or pseudotumour cereberi. While

cataracts are a recognized feature of GALT deficiency they are

infrequent with only 14% of patients affected in one series with

only 20% of these presenting in the neonate period. Even when

present, they may require the use of a slit lamp for visualization.

Cataracts are the only complication in GALK deficiency,

though very rarely pseudotumour cereberi has also been repor-

ted. GALE presentation falls on a spectrum varying from isolated

hyperglactosaemia, to the severe classical galactosaemia type

picture. While there are reports of motor and intellectual delays

in the more severely affected, given the extremely small number

of reported patients and the parental cosanguineouity it is diffi-

cult to be sure these are truly features of the GALE deficiency.

Investigations

As discussed above the affected glactosaemic baby will classi-

cally present with differing severity of liver dysfunction. Table 1

gives a list of investigations that covers the common causes of

neonatal hepatic dysfunction, while Table 2 gives the specific

tests, both screening and confirmatory for galactosaemia.

The diagnosis of GALT deficiency can be confirmed by

measuring the GAL-1-PUT activity using either the Beutler fluo-

rescent spot test or an actual quantitative assay of red blood cell

galactose-1-phosphate uridyltransferase activity. The later,

though more labour intensive, has the advantage of being able to

distinguish variants with residual activity. Both assays are

erythrocyte based and invalidated by recent blood transfusions,

though quantitative assays of both parents can be informative in

these circumstances as they can determine potential carrier

status.

Differential diagnosis

(1) Galactosaemia e There are few causes of galactosaemia

outside Leleoir pathway defects, though any significant liver

dysfunction has the potential to decrease galactose handling;

an example of this is an infant with extrahepatic portosys-

temic shunting found to be galactosaemia post feeds.

(2) Liver dysfunction e The differential diagnosis for neonatal

liver dysfunction is far wider, ranging from infections to

structural abnormalities e.g. biliary atresia, to inborn error of



The routine biochemical investigations for suspected neonates with severe hepatic dysfunction

Sample Specific test Rational/finding

Urine Reducing substances Refection of tubulopathy seen in some metabolic conditions

Protein/creatinine ratio Raised with tubulopathy seen concurrently

Urine amino acids Generalized aminoaciduria in renal dysfunction especially galactosaemia

and Tyrosinaemia

Urine organic acids To insure no succinylacetone (Tyrosinaemia type 1) and organic acidemias

Stool Check pigmentation If reduced discuss with hepatology team re biliary atresia

Routine blood FBC Can show signs of haemolytic anaemia

UþEs LFTs, including GGT and clotting Reflecting of degree of liver dysfunction

Blood gas/calculate anion gap Potential acidosis reflecting renal bicarbonate loss Increase anion gap

indicative of accumulating cations e.g. organic acidaemia

UrineþBlood culture/CRP/Viral serology To look for infection To rule out Hep AeC, CMV, EBV and Parvovirus

Lactate Indication of the a disorder of the respiratory chain (NB also raised

in severe liver dysfunction)

Ferritin/LDH To insure no Haemochromatosis

Cortisol(fasting) Assessment of adrenal function

CK Potentially raised in a fatty acid oxidation disorders

Ammonia To rule out urea cycle defect

Specialized blood Acylcarnitine profile To rule out FA oxidation disorder OA

Plasma AA Raised phenylalanine, tyrosine and methionine expected

Transferrin isoelectrofocusing Indicative of CDG if positive

Chitotriosidase To look for NiemannePick C

Alpha 1-antitrypsin

Radiology Abdominal ultrasound post fast Liver, Spleen size/Hepatic vessel size/direction of flow. Bilary system

Table 1


metabolism (IEM). Thus any child with acute liver

dysfunction in the neonatal period should be thoroughly

investigated both biochemically and radiologically. Of the

IEMs, urea cycle, fatty acid oxidation disorders and organic

acidemias can present with impairment in liver function.

However the inborn error that most closely mirrors gal-

actosaemia’s presentation is tyrosinaemia type 1 which also

presents in the neonatal period with acute liver and renal

tubular dysfunction. The investigations listed above while

not an exhaustive list are designed to exclude most of the

more common causes (see Table 1).

Management

The initial management of classical galactosaemia is systemic

support for the acute toxicity and the withdrawal of exogenous

galactose. Withdrawal should be instituted immediately if

Specific investigations for Galactosaemia

Tests Sample

Screening tests Urine dipstick Urine

Galactose-1-P Blood lithium heparin (

Confirmatory tests Gal-1-Put Blood lithium heparin (

DNA Blood (EDTA 2 ml)

Table 2


Galactosaemia is considered with suitable milk formulations

being either soya based preparations, or in patients with a degree

of acute hepatic dysfunction and possibly limited absorption,

Pregestimil (which still contains traces of galactose). The support

of severe liver dysfunction includes the administration of vitamin

K, antacids, the maintenance of at least 6 mg/kg/min of glucose

(often requiring high concentration dextrose, as fluid restriction

is normally recommended).

Chronic manifestations of galactosaemia

Despite early dietary intervention Glactosaemic patients may still

develop a number of long-term complications:

Neurology/motor development

Neurological manifestations linked with galactosaemia include,

diffuse cerebral oedema and pseudotumour cereberi. This is

Rational

Reducing substances positive after a lactose

containing feed galactose

minimum 1 ml) Raised in Leloir pathway defects

minimum 1 ml) To look for GALT activity NB pre transfusion




thought to be secondary to the osmotic action of increasing

amount of intracerebral galacticol and has only been noted in

neonates.

Some galactosaemic patients may develop a progressive

extrapyramidal disorder, which tends to manifest as tremor and

ataxia, though infantile onset of choreiform movements is also

known. The cause is unknown but functional scanning with PET

scans has shown both a decrease in activity in the cerebellum

and an increase in activity in the basal ganglia; the latter being is

also observed in Parkinsonian patients.

Significant involvement of the cerebral white matter has also

been noted, with widespread decreases in metabolism across

most of the cerebral cortex. This mirrors what has been seen on

both autopsies and neuroimaging of GALT patients. Indeed up to

1/3 of patients show some signs of cerebral atrophy on MRI

scanning, with a corresponding amount having abnormal EEGs.

However the day-to-day correlation of these changes with the

overall clinical outcome is still unclear and the precise under-

lying pathological mechanisms which result in these white

matter changes are still unknown.

Neuropsychological/language

The structural and functional changes of the cerebral white matter

underlie the verbal dyspraxia and intellectual impairment which

has been witnessed in many galactoseamic patients. Overall the

mean IQ of patientswith classical galactosaemia has typically been

found to be in the range of 70e90 though normal intelligence

has been noted. There is no evidence from the longitudinal studies

published that there is any decline in IQ with age though this

conflicts with large cross sectional studies from the early 1990s.

There appears to be a generalized impairment in both

performance related IQ and verbal IQ. One area that long been

Follow up recommendations for classical Galactosaemia patie

Recommendation

Biochemical control Gal-1-P to be kept below 150 mmol/l red cells,

50 mg/ml packed cells,

5 mg/100 ml,

0.5 mmol/g haemoglobin

Bone Calcium & bone profile. 25 OH Vitamin D levels sh

between 70e120 nmol/L

DEXA scanning 2 yearly during adolescence

Endocrinology (1) FSH/LH/oestradiol

(2) Referral to a paediatric endocrinologist by the

10 years

Gal-1-put Regular assessment of development and cognitiv

function are indicated using standardized testsd

example, Griffiths scales, Bailey scales, British ab

scales. In particular, assessment should be direc

towards early detection of speech impairment

Ophthalmology Slit lamp examination for cataract

Table 3


recognized to cause particular problems for galactosaemics is

language with 56% of patients having language difficulties with

problems in articulation being particularly common i.e. verbal

dyspraxia. This appears to be related to, but is not only the result,

of the lower cognition found in patients. The overall impact of

speech therapy on outcome in galactosaemic patients is still to be

determined.

Endocrine/fertility: impairment in ovarian function was initially

noted by Kaufman et al in 1979, with over 80% of female patients

being observed to have hypergonadotorphic hypogonadism with

increased FSH levels, often from an early age. This presents

with pubertal delay or with primary or secondary amenorrhoea,

with subsequent progression to premature ovarian failure. The

proposed mechanisms for the ovarian failure include, the direct

effect of galactose and its metabolites leading to early oocyte

toxicity effects or effects secondary to hypoglycosylation of FSH,

resulting in an aberrant isoform, which is unable to induce cyclic

AMP activation. Recent work highlighting a reduction in anti-

mullerian hormone from early in life, coupled with normal

bioactivity of FSH from Galactosaemics would suggest that the

reduction in ovarian function, is through primary toxicity (at least

partially in utero), rather than due to secondary insensitivity. The

risk of premature ovarian failure does not seem to be reduced by

good dietary control, also suggesting early gonadal toxicity Some

Galactosaemia women can spontaneously become pregnant

however, with 55 reported cases in the medical literature.

There has been no convincing evidence of male gonadal

impairment and normal testosterone levels have been seen in

a number of studies.

Apart from the rise in FSH, relatively low levels of IGFBP-3

and IGF-1 have also been shown in patients of both sexes, there

nts

Frequency of review

<1 year, every 3 months

1e14 years, every 6 months

> 14 years, annually

ould be If less than <50 nmol/l then give high dose 3000e6000

u/day for 3 months then put on 400e1000 u/day ongoing

maintenance

age of

At 6 months and then at 10 years and 12 years

e

for

ility

ted

Regular local follow up with child developmental centre

review

Assessment should be made at the time of diagnosis,

then yearly until the age of 3. It should be then be

reviewed if concerns with compliance




has however been no incidence of defects in the thyroid function,

cortisol or prolactin profiles of 37 patients on a lactose free diet.

Bone metabolism/growth

The work of Panis et al has shown a predisposition of gal-

actosaemic patients towards generalized osteopenia in treated

children. This was despite normal levels of all trace elements,

calcium, 1,25-dihydroxy-vitamin D and PTH in 40 patients

studied. Lower IGF-1, a stimulator of osteoblast division and

matrix production, and decreased levels of carboxylated osteo-

calcin was found. Subsequently supplementation with a combi-

nation of vitamin K and vitamin D3 showed significant increases

in prepubertal Bone mineral content on Dexa scanning, leading

to their proposal of regular 2-yearly assessment with Dexa

scanning and supplementation if required. It is to be remembered

however that pubertal delay & ovarian failure will also contribute

to reduced bone mineral acquisition.

Growth in galactosaemics has been controversial with

prenatal growth/birth weight, found to be reduced or normal.

Panis et al found decreased height velocity in female patients,

with the mean corrected height when compared to mid-parental

target height Z-score was less than the target height in most

patients. The low IGF-1 and IGFBP-3 levels found were thought

to be significant, without any apparent nutritional deficiencies

being apparent in these patients. However as in the Waggoner

review, there is often apparent physiological delay with eventual

normal achievement in height. Careful monitoring of growth and

pubertal development is recommended.

Eyes/cataracts

The overall frequency of cataracts was reported initially at about

30%. Nearly half of the cataracts in this study were described as

“mild”, “transient” or “neonatal” and tended to resolve with

dietary treatment; though one neonatal onset cataract did require

surgery. However more recent reviews indicate that the rate of

cataracts is lower (14%) and none had a significant impact on

vision. There have been no recorded cases of development of

cataracts in patients who are compliant with diet.

Treatment

Long-term management is dietary, with the current recommen-

dations being to avoid lactose containing foods with no restric-

tions beyond this. The rational being that although fruit,

vegetables and offal are known to contain small amounts of

lactose, the concentration is minimal, <30 mg/day in a typical

unrestricted diet to 54 mg/day in a fruit enriched diet, when

compared to the endogenous production of galactose which has

been calculated at >1000 mg/day in a typical adult. There are

reported cases of adults homozygous for the Q188R mutation

who had discontinued their diet in early childhood without

apparent ill effects. Generally however the current recommen-

dations are to continue the use of galactose restricted diet life-

long. Those patients on this diet should insure an adequate

calcium intake.

Follow up

Ideally follow up should be based on the shared care model

between a specialized regional centre and the local paediatric

teams. The Current UK recommendations (Walter JH et al 1999


see Further reading) for monitoring are listed below are listed in

the table above (Table 3).

Prevention

Unlike much of Europe and most of the United States there is no

newborn screening program for galactosaemia in the UK. The

rational behind this is that potentially clinical symptoms start

prior to when screening is performed which is usually on days

5e7, the relative infrequency of the disease and the current lack

of demonstrable impact on long-term outcome in early screened

population. Against this only 79% present by 2 months, the

diagnosis can still be missed in the presence of typical signs and

dietary treatment is started sooner where screening is performed.

While the early commencement of dietary treatment is yet to

convincingly be shown to impact on neurological outcome, this

must be balanced with the greater need of intensive care and

longer inpatient medical care, as well as the impact on the family

of having a sick infant, when with screening this is often

preventable. A

FURTHER READING

Bandyopadhyay S, Chakrabarti J, Banerjee S, et al. Prenatal exposure to

high galactose adversely affects initial gonadal pool of germ cells in

rats. Hum Reprod 2003 Feb; 18: 276e82.

Berry GT. Galactosemia and amenorrhea in the adolescent. Ann N Y Acad

Sci 2008; 1135: 112e7.

Bosch AM. Classic galactosemia: dietary dilemmas. J Inherit Metab Dis;

2010;. doi:10.1007/s10545-010-9157-8.

Bosch AM. Classical galactosaemia revisited. J Inherit Metab Dis 2006; 29:

516e25.

Bosch M, Bakker HD, Van Gennip AH, van Kempen JV, Wanders RJ,

Wijburg FA. A clinical features of galactokinase deficiency: a review of

the literature. J Inherit Metab Dis 2002; 25: 629e34.

Chhay JS, Vargas CA, McCorvie TJ, Fridovich-Keil Jl, Timson DJ. Analysis of

UDP-galactose 40-epimerase mutations associated with the interme-

diate form of type III galactosaemia. J Inherit Metab Dis 2008; 31:

108e16.

Honeyman MM, Green A, Holton JB, Leonard JV. Galactosaemia: results of

the British Paediatric Surveillance Unit study. 1988e90 Archives of

Disease in Childhood 1993; 69: 339e41.

Holton JB, Walter JH, Tyfield LA. Galactosemia. In: Scriver CR, Beaudet AL,

Sly WS, Valle D, eds. The metabolic and molecular bases of inherited

disease. 8th Edn. New York: McGraw-Hill, 2001: 1553e88.

Kaufman FR, McBride-Chang C, Manis FR, Wolff JA, Nelson MD. Cognitive

functioning, neurologic status and brain imaging in classical galacto-

semia. Eur J Pediatr 1995; 154: S2e5.

Lai K, Tang M, Yin X, Wierenga K, Elsas L. ARHI: a new target of

galactose toxicity in classic galactosemia. Biosci Hypotheses 2008;

1: 263e71.

Lia K, Elsa LJ, Wierenga KJ. Galactose toxicity in animals. Life 2009; 61:

1063e74.

Menezo YJ, Lescaille M, Nicollet B, Servy EJ. Pregnancy and delivery after

stimulation with rFSH of a galatosemia patient suffering hyper-

gonadotropic hypogonadism: case report. J Assist Reprod Genet 2004;

21: 89e90.

Panis B, Gerver WJ, Rubio-Gozalbo ME. Growth in treated classical

galactosemia patients. Eur J Pediatr 2007 May; 166: 443e6.



Practice points

C Any neonate or infant with either progressive or severe liver

dysfunction should be considered to be galactosaemic and

started on either a soya based formulation or progestamil

until the results of the initial investigations are available.

C Initial investigation for Galactosaemia should include both

gal-1-P and GAL1PUT (taken prior to any blood transfusions).

C The current recommended treatment is a lifelong minimal

galactose diet, which is insured by having a lactose free diet.

C There are a number of increasingly well defined long-terms

problems, that affect SOME galactosaemic children, thus

children should continued to have regular reviews to identify

potential problems early and institute supportative measures.


Panis B, van Kroonenburgh MJ, Rubio-Gozalbo ME. Proposal for the

prevention of osteoporosis in paediatric patients with classical

galactosaemia. J Inherit Metab Dis 2007; 30: 982.

Potter NL, Lazarus JA, Johnson JM, Steiner RD, Shriberg LD. Correlates of

language impairment in children with galactosaemia. J Inherit Metab Dis

2008; 31: 524e32.

Prestoz LL, Couto AS, Shin YS, Petry KG. Altered follicle stimulating

hormone isoforms in female galactosaemia patients. Eur J Pediatr

1997; 156: 116e20.

Ridel KR, Leslie ND, Gilbert DL. An updated review of the long-term

neurological effects of galactosemia. Pediatr Neurol 2005; 33: 153e61.

Sanders RD, Spencer JB, Epstein MP, et al. Biomarkers of ovarian function

in girls and women with classic galactosemia. Fertil Steril 2009; 92:

344e51.

Schadewaldt P, Hoffmann B, Hammen HW, Kamp G, Schweitzer-Krantz S,

Wendel U. Longitudinal assessment of intellectual achievement in

patients with classical galactosemia. Pediatrics 2010; 125: 374e81.

Schweitzer-Krantz S. Early diagnosis of inherited metabolic disorders

towards improving outcome: the controversial issue of galactosaemia.

Eur J Pediatr 2003; 162: S50e3.

Tyfield L, Reichardt J, Fridovich-Keil J, et al. Classical galactosemia and

mutations at the galactose-1-phosphate uridyltransferase (GALT)

gene. Hum Mutat 1999; 13: 417e30.

Waggoner DD, Buist NRM, Donnell GN. Long-term prognosis in gal-

actosaemia: results of a survey of 350 cases. J Inher Metab Dis 1990;

13: 802e18.


Walter JH, Collins JE, Leonard JV. Recommendations for the management

of galactosaemia. Arch Dis Child 1999; 80: 93e6.

Webb AL, Singh RH, Kennedy MJ, Elsas LJ. Verbal dyspraxia and galac-

tosemia. Pediatr Res 2003; 53: 396e402.

Widger J, O’Toole J, Geoghegan O, O’Kefffe M, Manning R. Diet and

visually significant cataracts in galactosaemia: is regular follow up

necessary? J Inherit Metab Dis 2010; 33: 129e32.




Peroxisomal disordersCamilla Scott

Simon Olpin

AbstractPeroxisomes are complex single-membrane cell organelles found in all

cell types except erythrocytes. Peroxisomes have both catabolic and

anabolic functions & these functions include the synthesis of plasmalo-

gens, the formation of bile acids, polyunsaturated fatty acids, cholesterol

& isoprenoids, & the degradation of very long-chain fatty acids (VLCFA’s).

Peroxisomes multiply by division of existing peroxisomes & this complex

process is regulated by both PEX & non-PEX genes. Peroxisomal disor-

ders are broadly categorized into defects of peroxisomal biogenesis

with deficiencies of multiple pathways e.g. Zellweger spectrum or defects

affecting single enzymes such as D-bifunctional protein deficiency.

Peroxisomal disorders present with a wide spectrum of clinical

disease ranging from the severe neonatal Zellweger syndrome with dys-

morphic features, neurological abnormalities, hepatorenal and gastroin-

testinal dysfunction with death typically occurring within the first 6

months of life to adult onset X-linked adrenoleukodystrophy which can

be confined only to adrenal insufficiency.

Keywords bile acids; peroxisomes; PEX genes; plasmalogens; VLCFA;

X-linked ALD; Zellweger

Introduction

Peroxisomes are complex single-membrane cell organelles found

in all cell types except erythrocytes. Peroxisomes have both

catabolic and anabolic functions & these functions predomi-

nantly involve lipid metabolism. Peroxisomal functions include

the synthesis of plasmalogens which are important constituents

of cell membranes & myelin. They are also involved in the

formation of bile acids, polyunsaturated fatty acids, cholesterol &

isoprenoids. Peroxisomes b-oxidise very long-chain fatty acids

(VLCFA’s), a-oxidise phytanic acid and catabolize lysine via

pipecolic acid and glyoxylate to glycine. Importantly they also

contain catalase which converts highly reactive hydrogen

peroxide into oxygen & water.

Peroxisomes multiply by division of existing peroxisomes.

Peroxisomal membranes are assembled & peroxisomal matrix

proteins are targeted from the cytosol & then imported into the

organelle by a highly complex process dependent on specialized

Camilla Scott MSc FRCPath is a Principal Clinical Scientist in the

Department of Clinical Chemistry at Sheffield Children’s Hospital,

Western Bank, Sheffield S10 2TH, UK. Conflict of interest: none.

Simon Olpin MSc PhD FRCPath is a Consultant Clinical Biochemist in

Inherited Metabolic Disease in the Department of Clinical Chemistry at

Sheffield Children’s Hospital, Western Bank, Sheffield S10 2TH, UK.

Conflict of interest: none.


proteins termed peroxins which are encoded by PEX genes. As

a consequence peroxisomal biogenesis involves the correct

expression of multiple PEX genes of which 16 have been identi-

fied in humans. There are also a large number of single enzyme

functions within the peroxisome encoded by non-PEX genes &

defects in these results in a range of disorders with single enzyme

deficiency.

Peroxisomal disorders are broadly categorized into defects of

peroxisomal biogenesis with deficiencies of multiple pathways

e.g. Zellweger spectrum or defects affecting single enzymes such

as D-bifunctional protein deficiency. Most disorders are auto-

somal recessive, however the commonest peroxisomal disorder

X-linked adrenoleukodystrophy has an X-linked mode of

inheritance.

Peroxisomal disorders present with a wide spectrum of clin-

ical disease ranging from the severe neonatal Zellweger

syndrome with dysmorphic features, neurological abnormalities,

hepatorenal and gastrointestinal dysfunction with death typically

occurring within the first 6 months of life to adult onset X-linked

adrenoleukodystrophy which can be confined only to adrenal

insufficiency.

Peroxisomal assembly

Peroxisomal biogenesis is complex and peroxisomes multiply

by division of pre-existing peroxisomes. Peroxisomes do not

contain any DNA and subsequently all of the proteins required

for assembly and function are encoded by nuclear genes and

synthesized on free polyribosomes in the cytosol before post-

translational import into the peroxisome. Transportation is

highly selective and requires the presence of specific import

sequences known as peroxisomal targeting sequences (PTSs).

PTS1 is the C-terminal peroxisome targeting sequence and

PTS2 is the N-terminal peroxisomal targeting sequence. PTSs

are recognized by receptors (PTS1 receptor and PTS2 receptor)

which direct the peroxisomal proteins to the peroxisomal

membrane. The target protein then enters the peroxisome by

a sequential multi-step process involving recognition, dock-

ing, translocation across the peroxisomal membrane and

recycling.

All proteins (peroxins) involved in peroxisomal biogenesis

are encoded by PEX genes. To date 16 PEX genes have been

identified as essential for human peroxisomal formation. PEX5

encodes for the PTS1 receptor and PEX7 encodes for the PTS2

receptor. PEX1, PEX6 and PEX26 are required for matrix protein

import and encode proteins involved in the recycling of the

PTS1 and PTS2 receptors. PEX2, PEX10 and PEX12 encode

proteins involved in matrix protein import. PEX13 encodes

a docking factor for PTS1 and is also required for matrix

protein import. PEX3, PEX16 and PEX19 encode proteins

involved in the production of peroxisomal biogenesis proteins.

In addition to the assembly proteins, the peroxisome also

contains over 50 matrix proteins and numerous membrane

proteins.

Peroxisomal disorders

Peroxisomal disorders arise from either a defect in peroxisomal

biogenesis (the peroxisomal biogenesis defects) or a defect in




a single peroxisomal enzyme or protein (the single enzyme

defects).

Clinical presentation

The peroxisomal biogenesis defects include the Zellweger

spectrum which accounts for approximately 80% of patients,

while rhizomelic chondrodysplasia punctata (RCDP) accounts

for the remaining patients with peroxisomal biogenesis disor-

ders. RCDP is clinically and genetically distinct from the Zell-

weger spectrum.

The clinical phenotype of Zellweger spectrum, also known

as cerebrohepatorenal syndrome, consists of three over-

lapping phenotypes. The most severe phenotype being Zell-

weger syndrome (ZS) followed by an intermediate form,

neonatal adrenoleukodystrophy (NALD), which is not to be

confused with X-linked ALD, and the mildest form infantile

Refsum disease (IRD). The overall frequency of ZS is

approximately 1:50,000. ZS classically presents with charac-

teristic craniofacial features including large anterior fonta-

nelle, full forehead, shallow orbital ridges, epicanthal folds,

high arched palate, broad nasal bridge and small nose with

anteverted nares. Ocular abnormalities such as cataracts,

glaucoma and corneal clouding are common. In addition there

is encephalopathy, seizures, severe hypotonia, hepatorenal

abnormalities including renal cysts and skeletal abnormali-

ties. Patients usually succumb to the disorder within the first

few months of life and survival is extremely rare beyond

a year. Patients with the milder forms of the Zellweger spec-

trum have similar but less severe symptoms to ZS and

survival varies from four months to several decades. For

example, virtually all IRD patients have moderate dysmorphic

features and sensorineural hearing loss with pigmentary

retinopathy. Early hypotonia and deranged liver function are

common. However most IRD patients learn to walk, although

their gait is frequently ataxic and their mental function is in

the severely retarded range as compared to profound retar-

dation in NALD and ZS.

RCDP is clinically distinct from the Zellweger spectrum and

also has severe classical presentations and milder phenotypes.

Summary of the single peroxisomal protein/enzymedefects

Defective peroxisomal function Disorder

b-Oxidation of very long-chain

fatty acids

X-linked adrenoleukodystrophy

Acyl-CoA oxidase deficiency

D-bifunctional protein deficiency

Sterol carrier protein deficiency

a-methyl-acyl-CoA-racemase

deficiency

a-Oxidation of phytanic acid Refsum disease

Hydrogen peroxide metabolism Catalase deficiency

Glyoxylate metabolism Hyperoxaluria type I

Etherphospholipid biosynthesis DHAP-AT deficiency

Alkyl-DHAP synthase deficiency

Table 1


Clinically, RCDP symptoms include characteristic proximal

shortening of the limbs (rhizomelia), cataracts, facial

dysmorphism, microcephaly, small stature, and psychomotor

retardation. For all of the peroxisomal biogenesis disorders

treatment is largely symptomatic and supportive.

Single enzyme defects

The single enzyme defects result in the loss of a single protein

and subsequently the loss of a single peroxisomal function.

Although over 50 peroxisomal matrix and numerous membrane

proteins have been identified only about 10 disorders associated

with single enzyme defects have been described, indicating that

there are many more unrecognized disorders. The known single

peroxisomal enzyme/protein defects are summarized in Table 1,

the more common/frequently encountered defects are summa-

rized below.

The most common single enzyme defect is X-linked adreno-

leukodystrophy. The inheritance is X-linked with approximately

50% of female carriers eventually presenting with clinical

symptoms. The clinical phenotypes vary from the severe child-

hood cerebral presentation through to a mild adult form. There is

a form presenting solely with Addison Disease Severe childhood

disease takes the form of a progressive demyelination of the

cerebral neurones and adrenal insufficiency. This early onset

male disease usually starts between 3 and 10 years of age with

behavioural abnormalities. Initial referral is often to a psychia-

trist or psychologist. There is further progression to dementia,

speech difficulty with loss of hearing & vision and finally

relentless progression to decorticate spastic quadriparesis, with

pigmentation of the skin secondary to adrenal insufficiency. The

most effective treatment is haematopoietic stem cell trans-

plantation which is only effective if carried out in pre-symp-

tomatic or early symptomatic patients. There is also late onset

adolescent and adult cerebral forms of X-ALD which follow

a similar but delayed course. The milder adult onset X-ALD

presents with peripheral neuropathy and Addison disease

(adrenomyeloneuropathy), with or without cognitive decline,

may affect both male and female carriers. A small cohort of X-

ALD patients will present with isolated adrenal insufficiency

(Addison only X-ALD).

Refsum disease, which should not be confused with infantile

Refsum disease, is also a single enzyme defect and is due to

defective phytanoyl-CoA hydroxylase. The enzyme is required

for the a-oxidation of phytanic acid to pristanic acid. Patients

with Refusm disease accumulate large amounts of phytanic

acid in plasma and tissues. The clinical features include;

pigmentary degeneration, peripheral neuropathy and cerebella

ataxia usually presenting before the second decade of life.

However, the age of onset and clinical severity varies according

to the degree of residual enzyme activity. Effective treatment

can be achieved by strict avoidance of dietary phytanic acid

and plasmapheresis.

D-bifunctional enzyme deficiency is a single enzyme defect

due to defective bifunctional enzyme which is required for

peroxisomal b-oxidation. Bifunctional enzyme deficiency is rare

and classically presents with neonatal hypotonia, dysmorphic

features, seizures, hepatomegaly and developmental delay. The

degree of severity is however highly variable.




Diagnostic approach

As described in the clinical section, peroxisomal disorders can

be grouped into two broad subgroups; the single enzyme

defects and the peroxisomal biogenesis disorders. The initial

diagnostic approach is similar for both groups for most disor-

ders. Along with strong clinical suspicion and a panel of

metabolites in plasma and urine, a likely diagnosis can be

reached within a couple of weeks. Most specialist metabolic

laboratories investigate three or more pathways to reach

a diagnosis. The most commonly investigated pathways

include:

� b-oxidation of the very long-chain fatty acids (VLCFA’s)

� a-oxidation of phytanic acid

� biosynthesis of ether phospholipids (plasmalogens)

� bile acid synthesis.

More detailed studies involve measuring specific enzyme activi-

ties including dihydroxyacetonephosphate acyltransferase

(DHAP-AT) in blood platelets or fibroblasts and very long-chain

fatty acid oxidation and phytanic acid oxidation in cultured

fibroblasts. A suspected or likely diagnosis from clinical and

biochemical abnormalities is usually confirmed by molecular

studies wherever possible.

The most frequently investigated pathway is peroxisomal b-

oxidation of the VLCFA’s. In plasma abnormal C26:0/C22:0

ratios are seen in both the peroxisomal biogenesis disorders

and in X-ALD. These ratios are significantly raised in the

peroxisomal biogenesis disorders and are moderately raised in

males with X-ALD. In female carriers for X-ALD the ratios are

more subtly raised and it is important to be aware that

approximately 10% of female carriers will have normal plasma

VLCFA’s. In symptomatic females it may be necessary to

measure the VLCFA’s in cultured fibroblasts, although these

will still be normal in approximately 5% of patients. In this

cohort diagnosis can only be achieved by molecular studies of

the ALD gene.

Summary of biochemical investigations for peroxisomal disor

VLCFA’s

(C22:C26)

(plasma)

Phytanic acid

(plasma)

Pristanic acid

(plasma)

Zellwegers syndrome þþþ N/þ N/þNeonatal adrenoleukodystrophy þþ N/þ N/þInfantile Refsum disease þþ N/þ N/þRCDP type 1 N N/þ N/Low

X-Linked adrenoleukodystrophy þþ N N

D-bifunctional protein deficiency þþ N/þ N/þa-Methyl-acyl-CoA-racemase

deficiency

N N/þ þ

Refsum disease N þþþ Low

Hyperoxaluria type 1 N N N

Acyl-CoA oxidase deficiency þþ N N

Catalase deficiency N N N

DHAP-AT deficiency N N N

Alkyl-DHAP synthase deficiency N N N

Table 2


When a peroxisomal disorder is suspected, the second

common pathway to be investigated is the a-oxidation of phy-

tanic acid. The loss of a-oxidation results in increased phytanic

acid and if this is taken in combination with increased VLCFA’s

this strongly supports a diagnosis of a peroxisomal biogenesis

disorder. Phytanic acid is raised in isolation in the single enzyme

defect Refsum disease and clinicians should go straight to

measurements of phytanic acid when suspecting Refusm disease

on clinical grounds.

Other metabolites including red blood cell plasmalogens and

urine and plasma bile acids can also be measured to complete the

investigations for a suspected peroxisomal biogenesis disorder.

Table 2 summarizes expected results and investigations in the

single enzyme defects and in the spectrum of generalized

peroxisomal disorders.

Genetic diagnosis

Peroxisomal biogenesis disorders

Genetic diagnosis for the peroxisomal biogenesis disorders is

particularly important if future prenatal diagnosis is to be

considered. However because of the number of genes involved,

a clear strategy for investigation must be employed. Rather

than systematically working through the genes, complementa-

tion studies in cultured fibroblasts can be carried out.

Complementation involves fusing cultured fibroblasts from the

patient under investigation with fibroblasts from a cell line in

which the defect is known. The formation of peroxisomes in

the fused cell lines can be assessed by immuno-staining for the

peroxisomal enzyme catalase using fluorescent labelled anti-

bodies. If the patient has a defect in the same gene as the

known cell line, peroxisomes will not be formed, and this gene

can then be sequenced. If the patient has a defect in a different

gene then peroxisomes will be formed and further comple-

mentation studies would need to be undertaken. These elegant

studies allow identification of the defective gene in a fast and

ders

Bile acids

(urine & plasma)

Plasmalogens

(red blood cell)

DHAP-AT activity

(fibroblasts

& platelets)

Catalase

expression

(fibroblasts)

þþþ Low Low Low

þþ Low Low Low

þþ Low Low Low

N Low Low N

N N N N

N/þ N N N

þþ N N N

N N N N

N N N N

N N N N

N N N Low

N Low Low N

N Low Low N



PEX deficientcell line

Patientcell line

Complementation No complementation

Cell fusion and incubation with fluorescent labelledanti-catalase antibodies

Figure 1 Complementation studies. To identify which gene is defective

cells from the patient are fused with cells from a cell line where the

gene defect is known. If the patient and known cell line share the

same defective gene there will be no complementation & no formation

of peroxisomes. If complementation is achieved peroxisomes are

formed and can be visualized by incubation with anti-catalase

antibodies.


cost effective manor. Figure 1 demonstrates the principles of

complementation.

Over 100 mutations in PEX genes have been described in the

literature and although many mutations are private a few

common mutations have been identified. Despite many muta-

tions, the majority of patients have mutations in one of only four

of the PEX genes. PEX1 mutations account for 70% of the

peroxisomal biogenesis defects, followed by 10% in PEX6 and

5% in PEX12 and PEX26.

RCDP is genetically distinct from Zellweger syndrome spec-

trum. All mutations associated with RCDP are in the PEX7 gene

which encodes the cytosolic PTS2 receptor, Pex 7.

Single enzyme defects

Of the single enzyme defects only X-ALD will be discussed in this

review. X-ALD is caused by mutations in the ABCD1 gene. This

gene encodes for the protein ALDP which is a member of the

ATP-binding cassette (ABC) transporter protein superfamily.

ALDP is located on the peroxisomal membrane and although its

function is not fully characterized it is strongly suspected that

ALDP is involved in the transport of the VLCFA’s across the

peroxisomal membrane.

The overall incidence of X-ALD is 1:17,000 including both

hemizygotes and heterozygotes. As previously mentioned,

because not all female carriers have abnormal VLCFA’s in

plasma or fibroblasts, it is recommended that women at risk of X-

linked ALD should be screened by mutation analysis of the

ABCD1 gene.

Genetic counselling is also recommended for families when

a patient is newly diagnosed with X-ALD. De-novo mutations in

the ABCD1 gene are rare and account for less than 8% of


mutations described. Genetic investigations of the extended

family have the potential not only to identify hemizygote females

but also to identify neurologically asymptomatic males with the

potential for pre-symptomatic allogenic haematopoietic stem cell

transplantation. Early diagnosis can also help to avoid Addiso-

nian crises.

It is however important to note that there is no genotype/

phenotype correlation and siblings with the same mutation may

present with very different phenotypes.

Prenatal diagnosis

Prenatal diagnosis for all of the peroxisomal disorders is carried

out using chorionic villus CV samples or cultured amniotic fluid

cells.

The poor outcome and often early death seen in the perox-

isomal biogenesis disorders and in particular in Zellweger

syndrome make prenatal diagnosis a particularly important

service for families with previously affected children. Histori-

cally prenatal diagnosis has been carried out using biochemical

techniques; in the case of Zellweger syndrome this has

involved measuring the activity of DHAP-AT on either direct

CV or cultured CV cells. False negatives and positives have

been reported using this strategy and the biochemical basis for

prenatal diagnosis currently involves measuring both DHAP-AT

activity and VLCFA concentrations in cultured fibroblasts.

Although this has improved the sensitivity, there remains the

disadvantages of the length of time taken to grow the cells, the

potential for failure of cell growth altogether and the additional

risk of maternal cell overgrowth. Increasingly now the

preferred option is to identify the mutation in the index case

and carry out molecular analysis on direct CV with cultured CV

as a back up.

Conclusion

Much has been learned about peroxisomal diseases since the first

description of a patient with X-linked ALD in 1923 & ZS in 1964.

However it took some time before a fuller understanding of

peroxisomal function & biogenesis was achieved. In the last

25 years there has been considerable advancement in our

understanding of the biochemistry & more recently the genetics

of these disorders, but much has still to be learned. To date there

is no effective treatment for many of these disorders & this great

challenge lies ahead. A

FURTHER READING

Berger J, Pujol A, Aubourg P, et al. Current and future pharmacological

treatment strategies in X-linked adrenoleukodystrophy. Brain Pathol

2010 Jul; 20: 845e56.

Braverman NE, Moser AB, Steinberg SJ. Rhizomelic chondrodysplasia

punctata type 1. In: Pagon RA, Bird TC, Dolan CR, et al., eds. Gen-

eReviews [Internet]. Seattle (WA): University of Washington, Seattle,

1993e2001 Nov 16 [updated 2010 Mar 2].

Moser HW. Clinical and therapeutic aspects of adrenoleukodystrophy and

adrenomyeloneuropathy. J Neuropathol Exp Neurol 1995 Sep; 54:

740e5 [Review].



Practice points

C The clinical spectrum of disease in peroxisomal disorders is

very broad ranging from fetal death to presentation in the 3rd

or 4th decade of life.

C X-linked ALD males often first present with behavioural

disturbances and loss of acquired skills. Symptomatic female

hemizygotes are often only correctly diagnosed after presen-

tation of an index male within the extended family.

C A diagnosis of X-ALD in female hemizygotes should be fully excl-

uded by a combination of fibroblast VLCFA’s & molecular analysis.

C Exclude peroxisomal disorders in all infants with hypotonia &

dysmorphia by plasma VLCFA’s, phytanate & pristanate.

C Molecular confirmation of all peroxisomal disorders should be

sought in order to offer reliable prenatal diagnosis.


Moser HW. Genotype-phenotype correlations in disorders of peroxisome

biogenesis. Mol Genet Metab 1999 Oct; 68: 316e27.

Paprocka J, Jamroz E, Adamek D, et al. Clinical and

neuropathological picture of familial encephalopathy with

bifunctional protein deficiency. Folia Neuropathol 2007; 45:

213e9.

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PAEDIATRICS AND CHILD HEALTH 21:2 75 � 2010 Elsevier Ltd. All rights reserved.



Lysosomal disordersJ E Wraith

AbstractAs a group lysosomal storage disorders (LSDs) are more prevalent than

phenylketonuria. Most are recessively inherited and a combination of

good clinical history, thorough physical examination and the judicious use

of X-rays can provide a clue to the diagnosis which is usually confirmed

with a combination of urine and blood tests. Disorders that affect the

brain and bone remain difficult to treat but advances in enzyme replacement

therapy have improved the outlook for many affected patients. New

approaches to therapy are in development to try and impact the CNSdisease.

Prenatal diagnosis is available for all these conditions and affected families

need to be referred to genetic services for counselling.

Keywords enzyme replacement therapy; haematopoietic stem cell

therapy; hydrops foetalis; lysosome; prenatal diagnosis

Introduction

The lysosome is an intracellular organelle with an acidic interior

containing a range of hydrolytic enzymes such as glycosidases,

proteases, sulphatases, lipases and phosphatases. These hydrolases

together with a number of integral lysosomal membrane proteins,

transporters and targeting motifs are responsible for much of the

cells inherent recycling mechanism and defects in any of these

components can result in the pathological storage of partially

metabolized substrates within the cell. This, plus the pathological

cascades initiated as a result of the lysosomal dysfunction, gives rise

to a group of monogenic disorders known as lysosomal storage

disorders (LSDs). For a comprehensive review of the pathogenic

mechanisms involved in LSDs, the reader is guided to the review by

Walkley, 2009.

Genetics, prevalence and classification

Most LSDs are inherited as autosomal recessive traits. The excep-

tions are the X-linked enzyme deficiency disorders: Fabry disease

and mucopolysaccharidosis type II (Hunter syndrome) and the

X-linked disorder of lysosomal associated membrane protein 2

(LAMP 2) known as Danon disease.

Although individual disorders are considered rare there are

a large number of them (over 50) and thus the prevalence of the

J E Wraith MB ChB MRCP (UK) FRCPCH is Honorary Professor in Paediatric

Inherited Metabolic Medicine at The University of Manchester and

Manchester Academic Health Science Centre, Central Manchester

University Hospitals NHS Foundation Trust, Department of Genetic

Medicine, St Mary’s Hospital, Oxford Road, Manchester M13 9WL, UK.

Conflict of interest: Dr. Wraith has received travel grants and honoraria

from Genzyme PLC and Shire HGT, companies that manufacture and

market enzyme replacement therapy products for LSDs.


group as a whole is w1:5000 (compared to the UK prevalence of

w1:12,000 for phenylketonuria).

Historically the classification of LSDs has been based on the

nature of the primary stored material and this has generally

consisted of:

� Lipid storage disorders

B Sphingolipidoses e.g. Gaucher disease

B Gangliosidoses e.g. TayeSach’s disease

B Leucodystrophies e.g. Metachromatic Leucodystrophy

� Mucopolysaccharidoses

� Glycoproteinoses

� Mucolipidoses

� Others

This classification is however misleading as in many conditions

there is more than one storage material and in other disorders e.g.

mucolipidosis, the proposed primary storage products (mucolipids)

do not actually exist. For these reasons a classification based on the

nature of the defective protein has been suggested as an alternative

and Table 1 gives an attenuated version of such a classification.


The LSDs, like many other metabolic disorders, display a markedly

varied clinical phenotype. In some patients, the presentation may

be in utero or the newborn period, whereas in others, evenwith the

same enzyme deficiency (but usually a different genetic mutation),

onset may be in late adulthood. In addition, in most disorders the

rate of disease progression can vary widely between affected indi-

viduals even in those from the same sib ship. However, for most

patients the onset of symptoms will be in childhood often following

an unremarkable period of normal progress. The first signs may be

some slowing of developmental progress in those disorders with

a central nervous system component or in others there may be

enlargement of the liver and/or spleen or a dysmorphic facial

appearance. Recognition of individual physical signs or the eluci-

dation of an evocative clinical history will often guide the clinician

to the appropriate diagnostic tests.

Although the disorders are generalized, one organ or body

system may be affected more than others. What is common is that

all of the disorders are present from conception, all are progressive,

many involve the central nervous system and finally treatment in

many cases is palliative only.

Hydrops foetalis

Hydrops foetalis (HF) is the accumulation of oedemafluid in at least

two foetal body compartments and in LSDs this usually includes

ascites and pleural effusion. In affected pregnancies the placenta

may be large and should always be sent for detailed histological

examination in cases of HF. Although there are many causes of HF,

LSDs are responsible for a significant minority of non-immune HF

cases (up to 10% in some studies) particularly in familieswhere this

is a recurrent event.

Detailed algorithms for the clinical evaluation of the foetus or

newborn with non-immune HF can be helpful (Staretz-Chacham,

2009) and the disorders that have presented in this way are

indicated in Table 2.

In affected pregnancies a sample of amniotic fluid should be

obtained for metabolite analysis (glycosaminoglycans and oligo-

saccharides) and cell culture for subsequent enzyme analysis or



Classification of LSDs based on the nature of thedefective protein

1. Defects of specific lysosomal hydrolases

a. Mucopolysaccharidoses

i. Types IeIX

b. Sphingolipidoses, other lipidoses and glycogen storage

diseases

i. Fabry disease

ii. Farber disease

iii. Gaucher disease

iv. GM1 gangliosidosis

v. GM2 gangliosidosis

vi. Krabbe disease

vii. MLD

viii. NiemannePick disease types A & B

ix. NiemannePick disease type C1

x. Wolman and cholesterol ester storage disease

xi. Pompe disease (GSD II)

c. Glycoproteinoses

i. Aspartylglucosaminura

ii. Fucosidosis

iii. a and b mannosidoses

iv. Neuraminidase deficiency

v. Schindler disease

2. Defects in post-translational modification of lysosomal proteins

a. Multiple sulphatase deficiency

b. Mucolipidosis II (I cell disease)

c. Mucolipidosis III

3. Defects in activator proteins

a. GM2 gangliosidosis AB variant

b. Prosaposin deficiency

c. Saposin A deficiency

d. Saposin B deficiency

e. Saposin C deficiency

4. Defects in structural lysosomal membrane proteins, protective

proteins, transporters and trafficking

a. LAMP 2

b. LIMP 2

c. Cathepsin A deficiency

d. Mucolipidosis IV

e. Cystinosis

f. Infantile sialic acid storage disease and Salla disease

g. NiemannePick disease type C1

5. Miscellaneous

a. Cathepsin K deficiency (Pycnodysostosis)

Table 1

Disorders that have presented with hydrops foetalis

C Mucopolysaccharidosis type VII (Sly disease) e common

C Mucopolysaccharidosis type IV

C Neuraminidase deficiency (sialidosis type II)

C Galactosialidosis

C Infantile sialic acid storage disease

C Acute neuronopathic Gaucher disease (GD II)

C GM1 gangliosidosis (b-galactosidase deficiency)

C Mucolipidosis II (I cell disease)

C NiemannePick disease type A (sphingomyelinase deficiency)

C NiemannePick disease type C

C Wolman disease (acid lipase deficiency)

C Farber disease (ceramidase deficiency)

Table 2


DNA mutation studies. In infants that survive physical and

radiological examinations may provide further clues to the correct

diagnosis.

Other neonatal presentations

Dysmorphism

A number of disorders have dysmorphic features that can be

identified at or soon after birth. In fact the infant that has


a “Hurler-phenotype” at birth almost certainly does not have

mucopolysaccharidosis type IH (MPS IH). Galactosialidosis, GM1

gangliosidosis and mucolipidosis II (I cell disease) are far more

likely. The characteristic facial appearance seen in MPS IH evolves

over the first year of life and it is rare to make a diagnosis on dys-

morphic grounds before the age of 9 months except in populations

where this disorder is very common such as within the Irish trav-

elling community.

Patients with acute neuronopathic Gaucher disease (GD II) can

present with severe ichthyosis (“collodian baby”), unusual facies,

arthrogryposis, enlargement of the liver and spleen and hernias.

Another dermatological clue to the presence of underlying LSD is

the abundant Mongolian blue spots seen in children with muco-

polysaccharidoses and GM1 gangliosidosis.

Cardiac disease

In infantile Pompe disease (glycogen storage disease type II, acid

maltase deficiency), cardiac failure, cardiac arrhythmia and car-

diomegaly may all be present at birth. Indeed in a number of

affected infants cardiomegaly has been demonstrated on foetal

ultrasounds performed in the last trimester of pregnancy. Affected

infants also have macroglossia with a protruding tongue and are

generally hypotonic. In addition to the cardiomyopathy demon-

strated on echocardiography (usually hypertrophic, occasionally

dilated) there is also elevation of liver enzymes and CPK on

biochemical testing and the blood film will reveal vacuolated

lymphocytes in the vast majority of affected patients.

Hepatosplenomegaly and liver disease

Hepatosplenomegaly at birth has very many different causes and

the common ones such as bacterial and viral infections or

anatomical abnormalities need to be diagnosed quickly as

specific treatment may be available. A number of LSDs can also

be present with enlargement of the liver and spleen and in

a number of affected patients ascites will also be present. Careful

clinical and radiological examinations for other abnormalities

may be helpful and in some circumstances bone marrow or liver

biopsy may suggest underlying LSD. In contrast to this non-

specific presentation some infants with NiemannePick disease

type C (NP-C) have a very evocative clinical presentation with

liver disease in the newborn period. In these affected infants



Therapy

Modality Disorders treateda

Haematopoietic stem

cell therapy (includes

bone marrow

transplantation,

umbilical cord blood

transplantation and

peripheral blood stem

cell transplantation)

MPS IH (Hurler syndrome)

Alpha-mannosidosis

Presymptomatic Krabbe

disease

Juvenile MLD (other disorders

less commonly treated

but where there is good

theoretic chance of success:

Aspartylglucosaminuria,

Farber disease, Wolman disease,

NiemannePick disease type C2)

Enzyme replacement therapy

Aldurazyme� MPS I

Elaprase� MPS II

Naglazyme� MPS VI

Fabrazyme� Fabry disease

Replagal� Fabry disease

Cerezyme� Gaucher disease

Vpriv� Gaucher disease

Uplyso� Gaucher disease

Myozyme� Pompe disease

Substrate reduction therapy

Zavesca� Gaucher disease type I in

patients for whom ERT

is unsuitable

Zavesca� NiemannePick disease type C

a Manyconditionshavebeen treatedbut this table indicatesonly thosedisorders

where significant numbers of patients are routinely referred for transplanta-

tion. For a comprehensive list of conditions that have been treated see Vellodi,

2004. By far the largest group of patients have MPS IH (Hurler syndrome).

Table 3


(about a quarter of all patients with NP-C seen in our clinic)

severe liver dysfunction often associated with conjugated

hyperbilirubinaemia suggests a diagnosis of biliary atresia and

a number of NP-C infants have had surgical procedures to

exclude this diagnosis. A significant number of these patients will

go onto develop liver failure and die (about one third) whilst the

others will slowly improve over months (and even years in some

patients) and eventually make a full recovery from their liver

disease only to present with the neurological manifestations of

the disease often many years later.

Hepatosplenomegaly in older patients may be the presenting

manifestation of Gaucher disease (types I and III) and Nie-

mannePick disease. There are often haematological abnormalities

secondary to hypersplenism and bone marrow infiltration.

Respiratory infiltration is often under recognized in these patients

who on rare occasions will present with respiratory failure.

Skeletal disease (mesenchymal presentation)

The skeletal manifestations of LSDs known as dysostosis multi-

plex (DM) usually present for the first time in the second 6

months of life depending on the nature of the underlying

disorder. DM is best seen in the vertebral bodies, hips, pelvis and


metacarpals and when present the radiologist will often give the

first clue to diagnosis.

In mucolipidosis II (I cell disease) severe bone disease can be

present from before birth with severe osteopenia and patholog-

ical fractures. This presentation is often associated with a tran-

sient hyperparathyroidism demonstrated by an increased serum

parathyroid hormone and alkaline phosphatase activity with

a normal calcium concentration.

Presentation in infancy and childhood

Neurological presentation

Unfortunately a great majority of LSDs have a significant neuro-

logical component. In many disorders it is by far the dominating

clinical effect of the disease (e.g. most sphingolipidoses) whereas

in others it is merely one element of a more generalized disorder

(e.g. mucopolysaccharidosis type I).

In infantile TayeSach’s disease the onset of the neurological

disorder can seem very acute, with an explosive onset of seizures

starting towards the end of the first year of life in a patient initially

thought to be following a normal pattern of development. Rapid

neurodegeneration follows with visual loss, spasticity and even-

tually loss of all skills culminating in death before the age of 5

years in most affected infants. In these patients clinical examina-

tion reveals the classical macular “cherry red spot” secondary to

storage within the retinal cells.

The typical developmental pattern seen in LSDs is one of

regression. After a period of apparently uneventful progress,

development slows and peers start to acquire skills at an increas-

ingly faster rate. Eventually development plateaus and then

acquired skills are lost in a pattern. The most recently acquired

skills are lost first and eventually the child becomes dependent on

its carers for all needs.

For some disorders characteristic patterns can be seen. In

mucopolysaccharidosis type III (Sanfilippo syndrome) most of the

affected children are normaluntil the age of 12e18months and then

fail to develop normal speech. Initially this is usually ascribed to

associated middle ear disease and deafness. However, when this is

corrected speech fails to improve and developmental progress is

further impaired. Children with this disorder have only mild

somatic abnormalities and the facial features of anMPS disorder are

often not appreciated in this group. Diagnosis is usually established

when the patients develop the characteristic challenging behaviour

seen in MPS III. This is characterized by severe insomnia and often

extreme hyperactivity making management extremely difficult. As

the disease progresses skills are lost and the children become

unsteady and fall and also develop neurological dysphagia. Bymid-

teenage years most affected patients are dependent on their carers

for all needs before death occurs towards the end of the second or

early in the third decade of life.

Neuronal ceroid lipofuscinoses (NCL) is a group of disorders

said to be the commonest neurodegenerative disorder of child-

hood. The neurodegeneration occurs at a differing age of onset and

speed of progression depending on the type of NCL present. The

group as a whole is characterized by difficult to control seizures

and progressive visual loss. Enzyme assay and DNA mutation

analysis have made diagnosis of NCL more readily available.

NiemannePick disease type C (NP-C) can present with two

unusual but specific neurological abnormalities. The first involves



Learning points

C as a group more prevalent than PKU (1:5000)

C commonest cause of non-immune hydrops foetalis

C bone and brain are commonly affected and are resistant to

treatment

C there have been important advances in enzyme replacement

therapy

C refer all families for genetic counselling as prenatal diagnosis

is possible for all of these disorders


an abnormality of voluntary eye movement due to a failure to

initiate ordinary saccades. This supra-nuclear gaze palsy initially

affects vertical movements and affected patients often blink

excessively in an attempt to initiate eye movement. This is often

the first neurological abnormality detected in affected patients.

Over time the horizontal movements are also affected and the eyes

become virtually immobile. (In Gaucher disease type III horizontal

gaze palsy develops and in these patients rapid head movements

(head thrusting) are used to stimulate eye movement.)

The second neurological abnormality seen commonly in NP-C is

cataplexy, a sudden transient loss of muscular tone precipitated by

emotion, usually humour. Patients have bouts of laughter culmi-

nating in sudden hypotonia and will fall to the ground if not sup-

ported. The attacks last seconds but can recur in bouts and can be

very disabling. Cataplexy is closely related to narcolepsy another

neurological complication seen in NP-C patients. It is important to

recognize cataplexy for what it is and not diagnose the episodes as

epilepsy as cataplexy does not usually respond to standard anti-

convulsants and ismost responsive to tricyclic antidepressants such

as imipramine.

Diagnosis

Diagnosis is based on a combination of urine analysis for char-

acteristic metabolites (mucopolysaccharidoses and glycoprotei-

noses) followed by specific enzyme assay. Most laboratories do

a lysosomal enzyme screen combining a number of assays on the

same blood sample. It is important to remember that some

disorders need more specific diagnostic tests. This includes Pompe

disease where the enzyme assay is best performed on lymphocytes

in the presence of acarbose as an inhibitor of acid glucosidase

isoenzyme. NP-C has no simple diagnostic test and a histological

diagnosis (filipin staining of skin fibroblasts) plus DNA studies are

needed to confirm the diagnosis in suspected cases.

If tests come back negative but the clinician continues to have

a strong suspicion of LSD then electron microscopy of a skin

biopsy should be performed. In all LSDs characteristic lysosomal

changes will be seen and potentially guide further diagnostic tests.

Treatment

All patients can benefit from general palliative care measures

aimed at symptom control and the treatment of reversible

complications of their disease.

Advances in the specific therapy of LSDs however have been

made over the past decade. Table 3 outlines currently available

therapies and the disorders most likely to benefit from them.

Mesenchymal tissues (e.g. bone) and brain remain the most resis-

tant to therapy and as a result formost conditions therapy cannot be

regarded as curative. In most patients there is a residual disease

burden that can be severe (e.g. skeletal disease in MPS following

bone marrow transplantation).

In primary disorders of the CNS e.g. infantile TayeSach’s

disease, treatment still remains very unsatisfactory and one can

only envisage this improving with the introduction of successful

gene therapy programmes.

Other approaches to therapy are in clinical development and are

yielding promising results in some disorders. One such treatment

involves the use of small molecules as chemical “chaperones”. In

conditions where the disorder is associated with DNA mutations


leading to misfolding of the lysosomal enzymes the chaperones,

which are usually enzyme inhibitors, can bind to the enzyme

inducing stability and aid transport to the lysosome where the

chaperone dissociates. As long as themutation does not involve the

active site of the enzyme a small increase in residual enzyme

activity will result. This may, in some disorders, be sufficient to

convert a serious disorder to a more attenuated form. Chaperone

therapy for Fabry disease and Pompe disease is under development

and early clinical trials have been completed in both disorders.

Conclusions

Although rare most paediatricians will encounter one or more

LSD in their career. As treatment options are increasing, at least

for some of these disorders, it is important to make a timely

diagnosis. A combination of clinical presentation, radiology and

appropriate biochemical testing will lead to a diagnosis in most

affected patients. After diagnosis patients should be referred to

metabolic centres that have expertise in the management of these

conditions so that treatment options can be explored. A

FURTHER READING

Aldenhoven M, Sakkers RJB, Boelens J, et al. Musculoskeletal manifestations

of lysosomal storage disorders. Ann Rheum Dis 2009; 68: 1659e65.

Beck M. Therapy for lysosomal storage disorders. IUBMB Life 2010; 62:

33e40.

Parenti G. Treating lysosomal storage diseases with pharmacological

chaperones: from concept to clinics. EMBO Mol Med 2009; 1: 268e79.

Prasad VK, Kurtzberg J. Transplant outcomes in mucopolysaccharidoses.

Semin Hematol 2010; 47: 59e69.

Sanderson S, Green A, Preece MA, et al. The incidence of inheritedmetabolic

disorders in the West Midlands, UK. Arch Dis Child 2006; 91: 896e9.

Staretz-Chacham O, Lang TC, LaMarca ME, et al. Lysosomal storage

disorders in the newborn. Pediatrics 2009; 123: 1191e207.

Suvarna JC, Hajela SA. Cherry red spot. JPGM 2008; 54: 54e7.

Vellodi A. Lysosomal storage disorders. Br J Haematol 2004; 128:

413e31.

Vitner EB, Platt FM, Futerman AH. Common and uncommon pathogenic

cascades in lysosomal storage diseases. J Biol Chem 2010; 285:

20423e7.

Walkley SU. Pathogenic cascades in lysosomal disease e why so

complex? J Inherit Metab Dis 2009; 32: 181e9.

Wenger DA, Coppola S, Liu S-L. Insights into the diagnosis and treatment

of lysosomal storage diseases. Arch Neurol 2003; 60: 322e8.




Mitochondrial disease ea reviewElisabeth Jameson

Andrew AM Morris

AbstractMitochondria are the source of cellular energy. Genetically they depend on

mitochondrial genes (mtDNA) as well as nuclear genes. MtDNA inheri-

tance differs from Mendalian inheritance in many respects. As mitochon-

dria are found in all cells, mitochondrial disease has an exceptionally

wide clinical spectrum. This review summarizes the features of the clas-

sical mitochondrial disorders including the classical syndromes. The

investigation and management is also discussed.

Keywords Alpers; Barth syndrome; heteroplasmy; KearnseSayre

syndrome; Leigh syndrome; MELAS; mitochondrial disease; MERRF;

NARP; Pearson syndrome; PEO

Mitochondrial review

Introduction

Mitochondrial disorders remain challenging for the clinician due

to their unique inheritance, the myriad of clinical presentations

and diagnostic challenges. This is despite the vast progress that

has been made in our understanding of mitochondrial disease,

especially in terms of its genetics.

Mitochondria are the site for many metabolic pathways,

including the breakdown of fats and carbohydrates. Energy

released by these reactions is converted into a form that the cell

can use by the ‘respiratory chain’. This review will focus on

disorders of the mitochondrial respiratory chain.

Epidemiology

It is estimated that at least 1 in 8000 people under the age of

65 years either has or is at risk of developing a mitochondrial

disorder. Mitochondrial diseases are likely to be underestimated

as a result of the multitude of phenotypes and difficulties in

diagnosis.

Pathology

Mitochondrial biochemistry: the mitochondrial respiratory

chain consists of five ‘complexes’ floating in the mitochondrial

Elisabeth Jameson MBBCh BSc MRCPCH is a ST7 in Paediatric Inherited

Disorders of Metabolism at the Biochemical Genetics Unit, Genetic

Medicine, 6th Floor, St Mary’s Hospital, Oxford Road, Manchester M13

9WL, UK. Conflict of interest: none.

Andrew AM Morris FRCPCH PhD is a Consultant in Paediatric Inherited

Disorders of Metabolism at the Biochemical Genetics Unit, Genetic

Medicine, 6th Floor, St Mary’s Hospital, Oxford Road, Manchester M13



membrane. Each complex has multiple subunits (46 for complex

I). When fuels are burnt in the mitochondria, ‘co-factors’ are

reduced. These co-factors are re-oxidized by the respiratory

chain, which uses the energy released to synthesize ATP (aden-

osine triphosphate).

Mitochondrial genome: mitochondria are a product of two

genomes. The nuclear genome is responsible for the vast majority

of mitochondrial proteins. The mitochondrial genome (mtDNA)

consists of a small, circular, double-stranded DNA molecule. Its

genetic codediffers from that of thenucleus, so it contains genes for

ribosomal RNA and transfer RNA as well as for some subunits of

the respiratory chain. Themutation rate formtDNA ismuch higher

than that for nuclearDNA, especially for deletions. Thismeans that

some mtDNA diseases are sporadic with a low recurrence risk in

siblings (e.g. KearnseSayre syndrome). Other mtDNA defects

show matrilineal inheritance, as described below.

Heteroplasmy and homoplasmy: there can be hundreds of

copies of mtDNA in a cell, because there are many copies in each

mitochondrion and many mitochondria per cell. A mutation may

affect all (homoplasmy) or only a fraction (heteroplasmy) of

copies of the mtDNA in a cell. Clinical problems only occur when

the level of heteroplasmy exceeds a threshold, which depends on

the severity of the mutation and the susceptibility of tissues to

impaired energy metabolism. Above this threshold, the severity

of the symptoms can vary depending on the level of hetero-

plasmy. Thus, high levels of the m.3243A>G mutation cause

MELAS syndrome (Myopathy, Encephalopathy, Lactic Acidosis

and Stroke-like episodes); but patients with lower levels may

only suffer diabetes and deafness.

Mitochondrial inheritance: inheritance of nuclear gene muta-

tions obeys Mendalian principles. In contrast, mtDNA is inheri-

ted exclusively from the mother; after fertilization of an egg, the

sperm-derived mitochondria disappear in early embryogenesis. It

is also important to know that the level of heteroplasmy can vary

from mother to child.

Figure 1 shows a typical family tree for mtDNA inheritance.

Unaffected female due to low heteroplasmy

Affected female/male respectively

Unaffected female/male respectively

Figure 1 A typical family tree for mtDNA inheritance. In the scenario

shown, the initial female carries the mutation but at a low level of

‘heteroplasmy’ and thus is clinically unaffected. Her offspring then exhibit

a variety of phenotypes. There is clearly no paternal transmission.




Presentation

Mitochondrial disease can present at any age, ranging from

neonates with severe lactic acidosis to adults with oph-

thalmoplegia. The most common symptoms are neurological

symptoms such as seizures, strokes, abnormal eye movements or

developmental delay. Mitochondrial disorders are often multi-

system and these symptoms may be accompanied by diabetes,

hearing loss, cardiomyopathy, renal tubulopathy (Fanconi

syndrome) or faltering growth. Certain combinations of features

are particularly characteristic e these classic mitochondrial

syndromes are summarized in Table 1. Mitochondrial disease can

also present with isolated symptoms, e.g. neurological degenera-

tion ormyopathy,with few additional clues. A detailed history and

examination are, therefore, crucial to define the pattern of clinical

involvement and exclude alternative diagnoses.

Investigations

Once the possibility of mitochondrial disease is raised a number of

investigations are required. In patients with clinical features sugges-

tive of a classic mitochondrial syndrome it is often appropriate to

progress straight to mutation analysis. Unfortunately, many patients

do not present so clearly and additional tests are warranted. Figure 2

shows a standard investigation pathway, with the aim to define the

phenotype and to look for alternative (possibly treatable) diagnoses.

Lactate measurement: blood lactate concentrations are often

raised in mitochondrial disease and this is a valuable clue,

Classic mitochondrial syndromes

Syndrome Clinical features

Progressive external

ophthalmoplegia (PEO)

Slowly progressive loss of eye movements and

KearnseSayre Onset is before 20 years of age with PEO, pigm

retinopathy plus at least one of ataxia, heart

and CSF protein >1 g/L

Pearson Sideroblastic anaemia and exocrine pancreati

dysfunction in infancy

MELAS Mitochondrial Encephalomyopathy, Lactic Acid

and Stroke-like episodes. Other features inclu

diabetes, deafness and cardiomyopathy

MERRF Myoclonic Epilepsy and myopathy with Ragge

Fibres. Also cardiomyopathy, dementia, deafn

Typically present in adolescence

Alpers Mild developmental delay, explosive onset of

intractable seizures, regression and cerebral a

with terminal liver failure

Leigh Onset with hypotonia or developmental delay

by 2 years. Stepwise deterioration leads to d

and brainstem problems (dysphagia, ventilati

Barth X-linked cardiomyopathy, skeletal myopathy,

neutropaenia and poor growth

NARP Neurogenic muscle weakness, Ataxia and Ret

Pigmentosa

Mutations preceded with m. are located in mtDNA. Other genes, e.g. POLG1, SURF1,

Table 1


though it is a non-specific marker being raised in many other

conditions, see Box 1. Artefactually raised lactate concentrations

are to be expected if blood is obtained from a struggling child!

Raised lactate concentrations in the cerebrospinal fluid are

a more sensitive and specific marker for mitochondrial disease.

Blood and CSF lactate concentrations may, however, both be

normal, particularly in adults with mitochondrial disorders.

Radiology: magnetic resonance imaging of the brain may show

abnormalities that suggest a mitochondrial disorder. These

include symmetrical lesions of the brainstem and basal ganglia in

Leigh syndrome. In MELAS syndrome, there may be one or more

areas of infarction, predominantly affecting the cerebral cortex,

with calcification of the basal ganglia.

Muscle biopsy: this is needed in most patients and is used for

three purposes:

a) Histology. This is often normal in children with mitochondrial

disorders. Occasionally, mitochondria accumulate under the

sarcolemma, giving rise to a ‘ragged red fibre’ appearance

when stained with Gomori Trichrome.

b) Biochemical assays of the respiratory chain complexes. The

activities of complexes IeIV are measured separately, usually

in homogenized muscle. Complex V assays are less satisfac-

tory and seldom undertaken. Deficiencies may be identified in

one or more complexes. Partial deficiencies are sometimes

found and these can be hard to interpret.

Underlying defect

ptosis Variable, including single or multiple mtDNA deletions or

POLG1 mutations

entary

block

A single large scale mtDNA deletion and/or duplication

c A single large scale mtDNA deletion and/or duplication

osis

de

80% m.3243A>G, 20% other mtDNA mutations

d Red

ess.

m.8344A>G

trophy

Usually POLG1 mutations

usually

ystonia

on)

Various, including deficiencies of complex IV, e.g. due to

SURF1 mutations, complex I and pyruvate dehydrogenase

Tafazzin gene mutations

initis m.8993T>G

Tafazzin are nuclear.



Detailed history, family tree and clinical examination

Baseline investigations, e.g. liver function, echocardiography,

lactate Baseline imaging if indicated, e.g. MRI head

MRI: magnetic resonance imaging, MELAS: mitochondrial encephalopmyopathy,

lactic acidosis and stroke like episodes, MERRF: myoclonic epilpesy, ragged red

fibres, NARP: neurogenic weakness, ataxia, retinitis pigmentosa, LHON: Leber’s

hereditary optic neuropathy, CSF: cerebrospinal fluid

Is there a characteristic clinical syndrome,

e.g. MELAS, MERRF, NARP, LHON, Pearson, Barth, Alpers

MUSCLE BIOPSY

± skin biopsy, CSF lactate

Molecular Genetics

Histochemistry Biochemistry

Negative

No Yes

Test for common

mutations in blood

Figure 2 The investigation of suspected mitochondrial disease.S

kil

ls

Time (years)

Episode of decompression

Stepwise decline inage-appropriate skills

Normal development

Figure 3 Stepwise progression of Leigh syndrome.


c) Histochemistry. For complexes II and IV, this can show the

activities in individual muscle fibres. Sometimes complex IV

activity is present in some muscle fibres but absent in others,

giving a patchwork appearance; this suggests that the under-

lying defect may involve mtDNA.

When arranging muscle biopsy it is worthwhile coordinating it

with simultaneous skin biopsy and cerebrospinal fluid

sampling.

Mutation analysis: some syndromes are associated with partic-

ular genetic defects, see Table 1, and it is worth looking for these in

blood before doing a muscle biopsy. In other patients, molecular

studies are determined by the muscle biopsy results. In a patient

with Leigh syndrome due to complex IV deficiency, it may be

appropriate to sequence SURF1, a nuclear gene. In other patients,

results may point to an mtDNA defect. The mitochondrial genome

Causes of raised lactate

C Artefact due to difficult venesection

C Hypoxia

C Hypotension due to sepsis

C Cardiac disease

C Organic acidaemias

C Fat oxidation defects

C Gluconeogenesis defects

C Pyruvate dehydrogenase and pyruvate carboxylase

deficiencies

C Mitochondrial disorders

Box 1


is relatively small containing 16 569 base pairs. This allows

molecular studies to be performed relatively easily. Interpretation

can be difficult due to the high percentage of benign sequence

variants and the varying degrees of heteroplasmy.

Occasionally, a patient with a mitochondrial disorder may have

normal respiratory chain results inmuscle. This may be due to tissue

specificdisease, e.g.onlyaffecting liver,ora lowlevelofheteroplasmy

in the sample. Conversely, abnormal results may be due to artefact if

samples are not processed correctly or they may be secondary, e.g.

due to some drugs used for HIV (human immunodeficiency virus).

Management and prevention

It is essential to make the correct diagnoses as some of the

differential diagnoses respond well to treatment, e.g. fat oxidation

disorders, biotinidase deficiency. Unfortunately, mitochondrial

disease seldom responds to specific treatment. A small number of

patients have ubiquinone deficiency but even these patients may

show little clinical response to treatment with ubiquinone.

Consequently, for most patients management is a supportive care

package. This may involve anti-convulsants for seizure control,

ptosis surgery, gastrostomy feeding and home care packages. At

times of acute illness, bicarbonate replacement can be used to

correct metabolic acidosis secondary to raised lactate levels. The

lack of treatment contrasts with the great progress made in iden-

tifying the underlying genetic defects. This allows genetic coun-

selling and sometimes prenatal diagnosis (if mutations are found

in a nuclear gene but it is not usually possible for mtDNA defects).

Prognosis and explanation to family

Explanation and predictions regarding prognosis are difficult due

to the rarity of these diseases, multi-system involvement,

unpredictability and complicated genetics. Explanation is even

harder when there is uncertainty about the diagnosis or the

underlying genetic defect. The prognosis depends on the clinical

presentation but even within one syndrome it is unpredictable.

Patients, especially those with Leigh syndrome, tend to run

a relapsingeremitting course with periods of stability followed

by a decompensation from which there is a failure to recover to

their previous ability and thus a stepwise decline, see Figure 3.




Follow-up

Practice points

C Mitochondrial disease has a diverse spectrum

C Phenotype and genotype do not closely correlate

C Have a low threshold for considering mitochondrial disease in

a child with multi-system pathology

C Treatment is largely symptomatic

C Prognosis is difficult to predict.

Most patients profit from seeing a specialist (in inherited metabolic

disease or neurology) and a community paediatrician, who can liaise

with local services. The pattern of disease will guide the role of the

allied health professionals. Genetic counselling for the parents, unaf-

fected siblings and thewider family is also a key part ofmanagement.

Funding

None. A

FURTHER READING

McFarland R, Taylor RW, Turnbull DM. The neurology of mitochondrial

disease. Lancet Neurol 2002; 1: 343e51.


Taylor RW, Turnbull DM. Mitochondrial DNA mutations in human disease.

Nat Rev Genet 2005; 6: 389e402.




Glycogen storage diseaseChristian J Hendriksz

Paul Gissen

AbstractGlycogen storage disorders are a group of inborn errors of metabolism

characterized by accumulation of glycogen in various tissues. This accumu-

lation is the histological hallmark of these disorders although the pheno-

type shows variable overlap. Hepatomegaly, hypoglycaemia, elevated

lactate and urate with or without neutrophil dysfunction are the classical

presentations for the commonest disorders namely GSD types I a, 1b

and III. Elevated creatine kinase, weakness, hypertrophic cardiomyopathy

with or without rhabdomyolysis represent the commonest muscle subtypes

with the best known ones being GSD II, III and V. Control of glucose defi-

ciency by added calories, tube feeding or modified cornstarch is frequently

the main basis of treatment. Supportive therapies are needed to establish

near normality. Potential curative therapies are enzyme replacement thera-

pies by mode of liver transplantation, bone marrow transplantation or use

of recombinant enzyme.

Keywords bone marrow transplantation; cornstarch; enzyme replace-

ment therapy; GSD or glycogen storage disease; hypertrophic cardiomy-

opathy; inborn error of glycogen metabolism; liver transplantation;

rhabdomyolysis

Introduction

Glycogen storage diseases are a group of disorders characterized as

the name states by the accumulation of Glycogen in various tissues.

Glycogen is a branched chain polymer of glucose and is one of the

dynamic sources of glucose storage in muscle and liver. This is the

natural pattern but when there is excessive storage of glycogen in

these tissues due to enzyme deficiencies it will manifest with clin-

ical symptoms and signs that is associated within these two main

storage areas. For this reason the glycogen storage disorders are

frequently divided into those affecting primarily the liver and those

affecting muscle. This division is clinically useful as long as it is

remembered that there is some overlap and some other tissues and

organs are also affected.

The disorders were numbered as they were discovered and

assumed that they would be similar in their pathology and that the

most severe variants were discovered first followed by milder

Christian J Hendriksz MBChB MSc FRCPCH is a Consultant in Paediatric

Metabolic Medicine in the department of Clinical Inherited Metabolic

Disorders at the Birmingham Children’s Hospital NHS Foundation Trust,

Steelhouse lane, Birmingham B4 6NH, UK. Conflict of interest: none.

Paul Gissen MRCPCH PhD is a Consultant in Paediatric Metabolic Medicine

in the department of Clinical Inherited Metabolic Disorders at the

Birmingham Children’s Hospital NHS Foundation Trust, Steelhouse

lane, Birmingham B4 6NH, UK. Conflict of interest: none.


variants. Over time it has become clear that they don’t share the

same pathology and there are some conceptual differences and for

that reason many of these disorders were renamed on a few

occasions causing even more confusion. With this caveat in mind

it is still useful for the generalist to remember that the lower

numbered disorders do represent the more severe end of the

spectrum and generally fasting tolerance time increases as the

numbers increase. For example Glycogen storage disorder type 1 is

usually associated with severe fasting intolerance with fasting

times as short as 45 min compared to case affected by Glycogen

storage disease type IX who may have completely normal fasting

times and frequently being diagnosed by the finding of incidental

hepatomegaly.

Glycogen storage disease type I

Type I glycogen storage disease (GSD I) is the commonest most

severe childhood form and typically presents in early infancy. First

report of patients was by von Gierke in 1929, when he described

enlarged liver and kidneys containing excessive amount of

glycogen seen at autopsy. GSD I is inherited as an autosomal

recessive condition and although there are no accurate estimates

of the incidence for GSD I, for the GSDs as a group it is approxi-

mately one in 20,000 infants.

Pathophysiology

Deficiency of hepatic glucose-6-phosphatase enzyme, which

catalyses the final step of both gluconeogenesis and glycogen

breakdown operates inside the lumen of the endoplasmic retic-

ulum and must cross the endoplasmic membrane to be effective,

was found in the initial patients with GSD I (MIM232200). In

1959 a subgroup of patients without the classical glucose-6-

phosphatase defect was described and later the defect in the

transport of gucose-6-phosphate was demonstrated. Thus the

name glycogen storage disease type Ia (GSD Ia) designates

the true enzyme defect, and glycogen storage disease type Ib

(GSD Ib) designates the transport defect. GSD Ic and GSD Id

disease subtypes had also been proposed caused by an abnormal

inorganic phosphate transport, however most of the described

patients were later found to have mutations in the gene encoding

the glucose-6-phosphate translocase and therefore also belong to

the GSD Ib group (MIM232220).

In GSD I liver is unable to generate free glucose in response

to neuro-endocrine stimuli caused by hypoglycemia. The

defect results in an accumulation of glucose-6-phosphate that

enters glycolysis, which results in increased lactate

production.

Clinical and biochemical features

Childrenwith of GSD Imay be identified in the neonatal periodwith

hypoglycemia and lactic acidosis but it is more common for the

patients to first present at 3e4 months of age with hepatomegaly

and/or hypoglycaemic seizures. GSD I patients typically have doll-

like facies (due to fat deposits in the cheeks), short stature and

protuberant abdomen due to liver enlargement although final

height is frequently normal. Kidneys are also enlarged but there is

no increase in the size of other organs.

The characteristic features of GSD I are fasting lactic acidosis and

short fasting tolerance, which may be less than 2 h, however the



Practice point

C When investigating children with hypoclycaemia always check

liver size, lactate, urate and look for neutropenia.


latter improves with age. The presence of hyperuricaemia is caused

by both decreased renal clearance and increased production of

urate. Hyperlipidaemia occurs as a result of increased synthesis of

triglycerides, VLDL, and LDL and decreased peripheral lipolysis.

Patients are at an increased risk of pancreatitis due to

hypertriglyceridaemia.

Patients with GSD Ib have neutropenia and neutrophil

dysfunction leading to recurrent bacterial infections. Although

diarrhoea is frequently seen in both GSD I types, majority of GSD

Ib patients suffer from inflammatory bowel disease, similar to

Crohn’s disease. Both GSD Ia and GSD Ib patients have abnormal

platelet aggregation and have tendency for excessive bleeding.

Although patients have very significant hepatomegaly, and there

is a universal distension of hepatocytes by glycogen and fat on

histology, there is usually no marked elevation in liver

transaminases.

The long-term complications, which are observed mostly in

adult patients following poor metabolic control, include gout,

multiple liver adenomas, and a progressive renal disease.

With early diagnosis and appropriate modern clinical

management it is thought that most of the complications can

be prevented.

The diagnosis of type I glycogen storage disease can be sus-

pected on the basis of clinical presentation and abnormal lactate

and lipid values. Previously, a definitive diagnosis required

a liver biopsy to demonstrate a deficiency. Gene mutational

analysis now allows noninvasive way of diagnosing most of type

Ia and Ib patients.

Treatment and prognosis

The main stay of treatment in GSD I is maintenance of normal

blood glucose concentrations. Normoglycaemia can be achieved

using a combination of continuous nasogastric tube feeding,

uncooked cornstarch and regular oral feeds. Most of the meta-

bolic abnormalities improve with better glycaemic control.

Nasogastric tube feeds should be started at the time of diagnosis

and may consist of modified formula feeds or glucose polymer to

provide 8e10 mg/kg/min of glucose in an infant and 5e7 mg/

kg/min in an older child. Uncooked cornstarch acts as a slow-

release form of glucose and can be administered in slowly

increasing doses in infants. Dietary intake of fructose and

galactose is usually restricted because these sugars cannot be

converted to free glucose. Allopurinol is used to help reduce the

levels of uric acid. Hyperlipidaemia can be managed with lipid-

lowering drugs such as HMG-CoA reductase inhibitors and

fibrates. Microalbuminuria is an early indicator of renal

dysfunction and can be treated with low doses of angiotensin-

converting enzyme inhibitors. In type Ib glycogen storage disease

granulocyte colony-stimulating factor is used to correct the

neutropenia and neutrophil function. In the past, many young

patients with type I glycogen storage disease died, and the

prognosis was guarded for those who survived. With the

prevention of hypoglycemia, growth and metabolic parameters

improve. In patients with extremely low fasting tolerance, severe

immune compromise and compromised quality of life the option

of liver or bone marrow transplantation can be considered.

Overall much better prognosis can be given to the patients with

GSD I, although longer follow up is required to gain a more

accurate data.


Glycogen storage disease type II

Glycogen storage disease II or also called Pompe or acid maltase

deficiency is deficiency of acid alpha glycosidase (MIM 232300)

and maps to chromosome 17. It was described by Pompe in 1932

and the infantile form is distinctly different from the later onset

form of the disease. The prevalence of the infantile form is

around 1/138,000 and the later onset form around 1/57,000.

Pathophysiology

In this disease there is intra lysosomal accumulation of normal

glycogen due to abnormality of the hydrolase exporting glycogen

from the lysosomes. As the lysosomes only contribute about 3%

to energy metabolism hypoglycaemia is not a feature of this

disease but it is the destruction and accumulation inside the

lysosomes causing cell injury and loss of normal function. This

primarily affects muscle metabolism and in the infantile form

cardiac muscle is involved distinguishing it from the later onset

form where cardiac muscle is unaffected.


This is a classical proximal myopathy with or without cardiac

involvement with presentation from birth to late adulthood. The

great variability depends to some extend on the functional ability of

the enzyme to degrade and storage the excessive glycogen. The

infantile form present with cardiomegaly, recurrent respiratory

infections, weakness and delayed motor milestones. Incidental

finding of a large heart and elevated creatine kinase should always

prompt the clinician to look for this rare disorder. All cases of

hypertrophic cardiomyopathy in young infants and children should

be tested for Pompe diseases as early treatment is essential.

Enlarged tongue and wood grain consistency of the muscles can

alsobe found inmost cases but depends on experience as this canbe

subtle. In older children the inability to jump, climb stairs or dia-

phragmatic weakness will also present as motor delay, frequent

falls, clumsiness, waddling gait or obstructive sleep apnoea. In the

adolescents and adults primarily weakness and sleep disturbance

due to nocturnal hypercapnia will be the main symptoms and

should be distinguished from the other more common proximal

myopathies.

Onmuscle biopsy a vacuolatedmyopathy picture can be noticed

but with specific staining it becomes clear that the excessive

glycogen is intra lysosomal.


Early treatment with enzyme replacement therapy has the best

outcome but this is not curative. Both mortality and morbidity are

altered by early enzyme replacement therapy and improvements

in quality of life and survival has been widely reported. Enzyme

replacement therapy (alglucosidase alpha) has been available

since 2006 and is best administered in expert centres for rare

disorders. Without treatment the infantile form is associated with



Practice point

C Some patients with hypoclycaemia may developed muscle

symptoms so consider these disorders.


early death and the later onset form with significant morbidity and

mortality. Both forms are at increased risk of death during

anaesthesia and this is particularly true for the infantile form

where arrhythmias are frequently uncovered.

Supportive therapy for infections and assisted ventilation and

wheelchair use is common in older patients. Other new treatments

are in development but not commercially available at present.

Practice point

C Hypertrophic cardiomyopathy is unusual so remember to

measure creatine kinase and look for other features of

generalized muscle disorder.

Glycogen storage disease type III

GSD III is characterized by an accumulation of abnormal glycogen

with very short outer chains in patients’ liver and muscles and was

described in 1947. This condition has an autosomal recessive

inheritance (MIM232400). Most patients are deficient in

debranching-enzyme activity in both liver and muscle (GSD IIIa).

However in 15% of patients only liver is involved (GSD IIIb).

Prevalence is about 1/100,000 but much higher in North African

Jewish communities (1/5420).


In infancy and childhood, GSD III may be almost identical in

characteristics to GSD I with hepatomegaly, hypoglycaemia,

hyperlipidaemia, and delayed growth. Liver transaminases are

typically raised. Splenomegaly may be present, but the kidneys are

not enlarged. Hepatomegaly and hepatic symptoms in most GSD

III patients improve with age but progressive liver cirrhosis and

failure may occur. Hepatocellular carcinoma may occur in asso-

ciation with end-stage liver cirrhosis. In patients with GSD IIIa

muscle weakness usually becomes severe after the third or fourth

decade of life. Although ventricular hypertrophy presenting as

a cardiomyopathy is a frequent finding, cardiac failure is rare.

Diagnosis can be made by demonstrating abnormal glycogen

in liver and/or muscle and a deficient debranching-enzyme

activity in skin fibroblasts or lymphocytes. Gene mutation anal-

ysis is available and specific association of some of the mutations

with GSD IIIb disease allows sub typing of patients using DNA

analysis.


Dietary management is much simpler than in GSD I. In patients

with hypoglycaemia frequent carbohydrate-rich meals with

cornstarch supplementation and/or nasogastric tube feeding are

effective in maintaining good glycaemic control. Patients do not

need to restrict dietary intake of fructose and galactose. A high-

protein diet may also be effective in preventing hypoglycaemia

because protein can be used as substrate for gluconeogenesis.

Liver transplantation has been performed in patients with end-

stage cirrhosis and/or carcinoma. Unfortunately, there is no

specific treatment for the progressixve myopathy and patients

may become wheelchair bound.


Glycogen storage disease IV

Abnormal glycogen with fewer branch points, resulting in a struc-

ture resembling amylopectin can be found in GSD IV patients’ liver.

This autosomal recessive disorder is caused by the deficiency of

a branching-enzyme activity (MIM232500) was described in 1956.

Mutations in the same gene can cause hepatic and neuromuscular

forms of GSD IV and there is evidence for genotypeephenotype

correlation. This is very rare and no formal incidence has been

established.


This disorder is clinically variable. The typical presentation is in

infancy with failure to thrive, hepatosplenomegaly, and progres-

sive liver cirrhosis leading to death in early childhood. Patients are

unlikely to have fasting hypoglycaemia, which occurs only in

presence of significant cirrhosis.

Several neuromuscular variants of GSD IV exist and are sub-

divided into perinatal, congenital, childhood and the adult forms

depending on the age at presentation and disease severity. The

diagnosis of type IV disease requires biopsy for demonstration of

abnormal glycogen and a deficiency of branching enzyme in liver,

muscle, leukocytes, erythrocytes, or fibroblasts.Mutation analysis

can be performed in the glycogen-branching-enzyme gene.


There is no specific treatment for GSD IV althoughmaintenance of

normoglycaemia and adequate nutrition may improve liver

function and muscle strength and improve long-term outcome for

growth in some patients. Liver transplantation is an effective

treatment for patients with progressive liver disease. The majority

of patients will die in childhood either due to liver failure or severe

cardiomyopathy and associated neurological dysfunction. There

seem to be amilder subgroupwith non progressive liver disease or

adult onset neurological disease and normal survival is expected

in this subgroup.

Glycogen storage disease type V

This was described in 1951 by McArdle and also known as myo-

phosphorylase deficiency or PYGM deficiency (MIM 232600) and

most of those affected have nearly no activity of the enzyme and

complete inability to convert glycogen to glucose inmuscle. This is

a rare autosomal recessive condition with an incidence of about

one in 100,000 and the defect is located on chromosome 11. Most

cases are diagnosed in their 20’s or 30’s although with careful

history the symptoms are present from a young age but can be very

non specific.


In young children the presence of muscle aches and pains can

easily be ignored and a history of myoglobinuria is seldom

established. Parents are usually unaware of children passing dark




coloured urine and as it is painless it is hardly ever offered in the

list of concerning features in the clinical history. The condition is

also classically associated with second wind phenomena where

the patient would start an activity and then stop due to pain but

after a short period of rest is able to complete the activity. This is

also a progressive disorder so with increasing age the symptoms

and signs becomes more prominent starting from muscle aches

and pains to muscle cramps, myoglobinuria and then ultimately

rhabdomyolysis and renal failure during the acute episode.

Persistent weakness and increasing disability represents the full

blown picture in older patients. Some incidental findings may

also lead to diagnosis and creatine kinase levels are mildly

elevated in most cases. Electromyography may show non specific

myopathic changes or increased muscle irritability.

Diagnosis is by measuring the specific enzyme deficiency in

muscle biopsy samples or by molecular analysis. The histological

changes in muscle biopsy tissue may also point towards this

diagnosis and the presence of subsarcolemmal normal looking

glycogen in vacuoles will alert the astute histopathologist. Vacu-

olar myopathic changes are associated with many conditions and

only by specific staining techniques can the different chemicals be

distinguished.

Differential diagnosis can bewide especially in the young where

muscle aches and pain and elevated creatine kinase is associated

with muscular dystrophies, other glycogen storage disorders,

disorders of fatty acid metabolism and other rare disorders like

Danon’s disease. Weakness and disability in the older patients

share many similarities with other muscular disorders and rhab-

domyolysis is associated with certain drugs or viral infections.


There is no specific treatment at present and life style modifica-

tion supported by some dietary measures may be useful. Exces-

sive weight gain lowers the aerobic threshold and gentle exercise

will have beneficial effect on this as well.

This disorder has a relatively benign long-term outcome as

significant morbidity and mortality is associated with rhabdo-

myolysis and acute multi organ failure and a rare neonatal form

causing respiratory failure but both these two complications are

rarely seen. More frequently the symptoms and loss of function

over time is controlled by ability. There is increased risk with

certain anaesthetic agents and anaesthetist should be made aware

of this condition and change the drugs as needed.

Genetic counselling is possible in most cases and the condi-

tion carriers no increased risk during pregnancy.

Practice point

C When investigating fatigue always ask for history suggesting

second wing phenomena.

Glycogen storage disease VI

GSD VI also called Hers disease is due to deficiency of glycogen

phosphorylase (MIM232700) and was described in 1959. It has

an incidence of 1/60,000e85,000. GSD VI, VIII and IX are

frequently considered as a single entity.



This condition usually present with hepatomegaly and growth

retardation early in childhood. Ketotic hypoglycaemia and hyper-

lipidaemia are usually mild, if present. Lactic acid and uric acid are

typically normal. The heart and skeletal muscles are not involved

and the hepatomegaly improves with age and usually disappears

around puberty.

Although these patients have greatly diminished activity of

phosphorylase in the liver, the number of patients with primary

defect in phosphorylase is small whereas deficiency in phos-

phorylase kinase activity (GSD IX) is much more common.

Mutation analysis of liver phosphorylase gene is available for

the diagnosis.


A high-carbohydrate diet and frequent feeding are effective in

preventing hypoglycaemia, but most patients require no specific

treatment and incidental finding of asymptomatic hepatomegaly

is the commonest finding.

Glycogen storage VII

GSD VII also called Tarui’s disease caused by deficiency of

phosphofructokinase (MIM 232800) is a very rare disorder with

about 100 cases described in the literature since first reported in

1965.


The clinical features are a combination of exercise induced

muscle cramps, weakness and haemolytic anaemia. It is also

associated with myoglobinuria, rhabdomyolysis and growth

delay. Cataracts, gall stones and increased uric acids have also

been described.


There is no specific treatment and ingestion of glucose before

exercise can sometimes exacerbate symptoms or the so called

“out of wind phenomena”. Great clinical variability exits with

severe fatal neonatal form to asymptomatic late onset variants

that may not be diagnosed.

Glycogen storage disease IX

Patients with GSD IX have a deficiency in phosphorylase b kinase,

which can be demonstrated in leukocytes and erythrocytes. These

patients were initially described as GSD IV when deficient phos-

phorylase activity was found. This condition can be inherited in an

autosomal recessiveorX-linked form(initially classifiedasGSD-VIII).

The cause of the confusing numerical classification was due in

part to a lack of understanding of the genetics of phosphorylase

activating system. Phosphorylase kinase consists of four subunits

encoded by different genes on different chromosomes and

differentially expressed in different tissues.


X-linked GSD IX: X-linked liver phosphorylase kinase deficiency

occurs in approximately 75% of GSD IX (MIM306000). Besides

liver, enzyme activity also may be deficient in erythrocytes,

leukocytes, and fibroblasts. Typically patients present aged 1e5

years with protuberant abdomen due to hepatomegaly, growth

retardation, and slight delay in motor development, dyslipidaemia




and mild elevation of liver transaminases. These abnormalities

gradually disappear with age, and most adult patients are practi-

cally asymptomatic despite a persistent phosphorylase kinase

deficiency. Hypoglycemia is variable and usually is mild, if present.

Autosomal recessive GSD IX: autosomal phosphorylase kinase

deficiency can be present in (1) liver-specific, (2) liver and

muscle and (3) muscle-specific forms (MIM261750). As with the

X-linked form, in (1) hepatomegaly and growth retardation are

the predominant symptoms in childhood. In addition some of

these patients are hypotonic. Some cases of phosphorylase

kinase deficiency restricted to muscle have been reported and in

whom onset of symptoms was late (adolescence or adulthood),

however GSD IX patients with childhood presentation of myop-

athy have been described. Muscle-specific phosphorylase kinase

deficiency could be inherited in an X-linked or autosomal

recessive manner. Establishing the diagnosis of type IX glycogen

storage disease is challenging owing to underlying genetic

heterogeneity and variable expressivity. The deficiency of phos-

phorylase kinase is not consistently detectable by the erythrocyte

assay, and liver, muscle, or heart biopsy is necessary to confirm

some cases biochemically. The enzyme assay is also unable to

differentiate between patients with X-linked and an autosomal

recessive pattern of inheritance. Thus, in many instances,

mutation analysis is needed for further sub typing of the disease.

Practice point
C Remember to check urine dipsticks as a minimum in all

patients with hepatomegaly.

A high-carbohydrate diet and frequent feedings are effective in

preventing hypoglycaemia, but most patients require no specific

treatment. Prognosis is usually good; adult patients have normal

stature and minimal hepatomegaly. Out of all GSD IX patients the

autosomal recessive form typically has a more severe clinical

course with progressive liver disease.

Practice point

C Glycogen storage disorders is only one of the causes of iso-

lated asymptomatic hepatomegaly and specialist help may be

needed as some of these seemingly innocent conditions may

have significant health effects in later life.

Glycogen storage disease X

GSD X or phosphoglycerate mutase deficiency (MIM 261670) is

a rare disorder with a few isolated cases reported. It is a benign

disorder presenting with muscle cramps and weakness after stren-

uous exercise. Diagnosis is by molecular analysis of PGAM2 gene

located in chromosome 7. Patients are at risk of rhabdomyolysis but

full recovery seems to follow with appropriate treatment.

Glycogen storage disease XI

GSD XI or also called FanconieBickel Syndrome is actually

a disorder of glucose transport metabolism caused by mutations in

the gene encoding the glucose transporter 2 (GLUT2). GLUT2 is

expressed in the membranes of hepatocytes, pancreatic beta cells,

and the basolateral membranes of intestinal and renal epithelial


cells where it facilitates bilateral glucose transport. FanconieBickel

disease is characterized by proximal renal tubular dysfunction,

abnormal regulation of glucose homeostasis, and accumulation of

glycogen in liver and kidneys. Patients present in the first year of life

with failure to thrive, rickets, and a protuberant abdomen due to

hepato- and renomegaly. Moon-shaped facies and fat deposition in

the shoulders and abdomen are seen and puberty is delayed.

Hypophosphataemic rickets and osteoporosis are constant features.

These patients may exhibit intestinal malabsorption and diarrheoa.

Laboratory findings include fasting ketotic hypoglycaemia,

proximal renal tubular acidosis, hypophosphataemia, increased

serum alkaline phosphatase levels, and radiologic findings of

rickets. Liver transaminases, plasma lactate, and uric acid are

usually normal. Fasting hypoglycaemia and hepatomegalymay be

explained by an altered glucose transport out of the liver, resulting

in an increased intracellular glucose level that inhibits glycogen

degradation, leading to the glycogen storage. Hypoglycaemia is

exacerbated by renal loss of sugars across the basolateral

membranes in the proximal tubular cells.

Treatment is symptomatic paying attention to replacement of

water, electrolytes, and vitamin D, restriction of galactose intake.

Patients are managed with frequent small meals with cornstarch

supplementation and an adequate caloric intake, however,

growth retardation persists despite interventions.

Glycogen storage disease XII

GSD XII is a disorder of red blood cell aldolase A deficiency

(MIM 611881). Presenting features are haemolytic anaemia,

developmental delay and hepatomegaly due to glycogen accu-

mulation. Muscle weakness and rhabdomyolysis have also been

described and this seems to be a variable condition with unpre-

dictable prognosis.

Glycogen storage disease XIII

This very rare disorder has been described in a single case and is

due to deficiency of enolase Beta (MIM 612932). In this case

elevated creatine kinase, myalgia and exercise intolerance were

described.

Glycogen storage disease 0

Patients with GSD0 have a deficiency of liver glycogen synthase

with autosomal recessive inheritance (MIM240600). Glycogen

synthase catalyses the elongation of chains of glucose molecules

to form glycogen and is not involved in glycogen breakdown.

The patients usually present in early infancy with early-

morning drowsiness and fatigue and sometimes with convulsions

associated with ketotic hypoglycaemia. There is no hepatomegaly

or hyperlipidaemia. Postprandial hyperglycemia and a rise in

blood lactate concentration are typically seen. Occasional muscle




cramping has also been reported suggesting hepatic and muscle

variants.

Treatment is symptomatic and involves frequent high-protein

feeds and nighttime supplementation with uncooked cornstarch.

Most children do not suffer neurocognitive damage. Short stature

may occur, but no other long-term complications seen in GSDs

have been described.

Muscle glycogen synthase deficiency was reported recently in

patients with muscle glycogen synthase gene mutations

(MIM611556). Clinical features included hypertrophic cardio-

myopathy and sudden cardiac arrest at the age of 10, and skeletal

muscle fatigability.

Practice point

C Postprandial hyperglycaemia is frequently missed and can

point towards one of these disorders.

Conclusion

Although the accumulation of glycogen forms the basis of most

these disorders for the clinician there are only a few important

messages to take away. The combination of both muscular and

hepatic symptoms should make the clinicians suspect these disor-

ders. Other classical features are hypoglycaemia, increased serum

lactate and urate. Elevated creatine kinase and muscular weakness

with associated rhabdomyolysis are also important triggers.

Hypertrophic cardiomyopathy is a frequent association and post-

prandial hyperglycaemia is found in both GSCD 0 and GSD XI.

Attenuated formsmay present with asymptomatic hepatomegaly or

being diagnosed incidentally from either liver or muscle biopsy

specimens.

The main stay of treatment is control of hypoglycaemia and

other associated features. Supportive treatment is important and


enzyme replacement therapy in the form of liver transplantation,

bone marrow transplantation or recombinant enzyme gives the

greatest hope for those affected by severe phenotypes. A

FURTHER READINGELECTRONIC RESOURCES

http://emedicine.medscape.com/pediatrics_genetics#metabolic.

http://www.agsd.org.uk/.

http://www.patient.co.uk/doctor/Glycogen-Storage-Disorders.htm.

TEXTBOOKS

Chen YT. Glycogen storage diseases. In: Scriver CR, Beaudet AL, Sly WS,

eds. The metabolic and molecular bases of inherited disease. 8th Edn.

New York, NY: McGraw-Hill, 2001: 1521e51.

Smit GPA, Rake JP, Akman HO, et al. The glycogen storage diseases and

related disorders. In: Fernandes J, Saudubray JM, Berghe G, Walter JH,

eds. Inborn metabolic diseases: diagnosis and treatment. New York,

NY: Springer, 2006. Chap 6.

JOURNALS

Heller S, Worona L, Consuelo A. Nutritional therapy for glycogen storage

diseases. J Pediatr Gastroenterol Nutr 2008 Aug; 47(suppl 1): S15e21.

Ozen H. Glycogen storage diseases: new perspectives. World J Gastro-

enterol 2007 May 14; 13: 2541e53.

Rake JP, Visser G, Labrune P, et al. European Study on Glycogen Storage

Disease Type I (ESGSD I). Guidelines for management of glycogen

storage disease type I e European Study on Glycogen Storage Disease

Type I (ESGSD I). Eur J Pediatr 2002 Oct; 161(suppl 1): S112e9.

van Adel BA, Tarnopolsky MA. Metabolic myopathies: update 2009. J Clin

Neuromuscul Dis 2009 Mar; 10: 97e121.

Visser G, Rake JP, Labrune P, et al. European Study on Glycogen Storage

Disease Type I. Consensus guidelines for management of glycogen

storage disease type 1b e European Study on Glycogen Storage

Disease Type 1. Eur J Pediatr 2002 Oct; 161(suppl 1): S120e3.


http://emedicine.medscape.com/pediatrics_genetics#metabolic

http://www.agsd.org.uk/

http://www.patient.co.uk/doctor/Glycogen-Storage-Disorders.htm



Medium-chain acyl-CoAdehydrogenase deficiency ea reviewElisabeth Jameson

John H Walter

AbstractMedium-chain acyl-CoA dehydrogenase deficiency (MCADD) is an auto-

somal recessive disorder of fatty acid oxidation with an incidence in the

UK of more than 1:10,000. The majority of patients are homozygous for

a missense mutation c.985A>G. Newborn screening for this condition

was implemented nationally in England and Northern Ireland in 2009

and is planned for Scotland in 2011. Patients with MCADD are at risk

during periods of fasting stress, particularly during intercurrent infections,

of developing an encephalopathy associated with hypoketotic hypogly-

caemia. These can be prevented by giving high calorie drinks (the emer-

gency regimen) during periods of illness but hospital admission is

required for intravenous dextrose if the emergency regimen is not toler-

ated. No specific treatment is required at other times. This review high-

lights the pathogenesis, the presentation and management of MCADD.

Keywords emergency regimen; fatty acid oxidation disorder; hypo-

glycaemia; MCADD; medium-chain acyl-CoA dehydrogenase deficiency

MCADD review

Definition

Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is

an autosomal recessive disorder of mitochondrial beta oxidation

of medium chain length fatty acids. It is caused by mutations in

the ACADM gene.

Epidemiology

The disorder is panethnic but more common in Caucasians with

an incidence of one in 6000e10,000. 60e80% of symptomatic

patients are homozygous for the c.985A>G missense mutation. A

further 15e20% are compound heterozygous for c.985A>G in

combination with another mutation. The prevalence of the

common mutation likely reflects a founder effect and is thought

to have originated in northwest Europe. The genotypes in those

detected by newborn screening are more diverse suggesting that

Elisabeth Jameson MBBCh BSc MRCPCH is an ST7 in Paediatric Inherited

Disorders of Metabolism in the Biochemical Genetics Unit, Genetic

Medicine, 6th Floor, St Mary’s Hospital, Oxford Road, Manchester, M13


John H Walter MD FRCPCH is a Consultant in Paediatric Inherited

Disorders of Metabolism in the Biochemical Genetics Unit, Genetic

Medicine, 6th Floor, St Mary’s Hospital, Oxford Road, Manchester, M13



some mutations are of less clinical significance. However, at

present it is wise to assume that an individual with any mutation

associated with persistent abnormal biochemistry (see below) is

at risk from clinical illness caused by MCADD.

Pathology

In the normal post-absorptive state there is a fall in glucose

concentrationwith a parallel fall in insulin. This results in a release

of compensatory hormones and a reduction in glucose use by

muscles and peripheral tissues. Release of glucose from glycogen

(glycogenolysis) initially satisfies energy demands. However,

energy production from the oxidation of fats becomes increasingly

important both to decrease the dependency on the limited stores of

glycogen and to produce ketones that can be used as an alternative

to glucose as a fuel for the brain. This is especially important in

young children whose cerebral glucose requirements are high and

whose physiological response to periods without enteral feeds is

accelerated when compared with that in adolescents and adults.

The oxidation of fatty acids is shown in Figure 1. Fatty acids

released from triglycerides enter the mitochondria and subse-

quently undergo b-oxidation, a process bywhich the fatty acyl-CoA

molecule is sequentially shortened by two carbon units until it is

completely converted to acetyl-CoA. Electrons released from

b-oxidation enter the respiratory chain to produce ATPwhereas the

majority of the acetyl-CoA produced is converted to ketones by the

liver. Acyl-CoA dehydrogenase enzymes within this b-oxidation

cycle have activities that are chain length specific:MCAD (medium-

chain acyl-CoA dehydrogenase) hasmaximum activity for C6eC10

fatty acids. Due to a degree of overlap in chain length specificity

otherb-oxidationdehydrogenases are able tooxidisemediumchain

fatty acids and produce ketones when flux through the pathway is

low. This explains why patients with MCADD are generally able to

tolerate overnight fasting. However during periods of increased

requirements for b-oxidation there is an accumulation of medium-

chain fatty acyl-CoA derivatives and reduced acetyl-CoA and

ketone production resulting in clinical illness.

Newborn screening

Newborn screening for MCADD by tandem mass spectroscopy

underwent evaluation in England between 2004 and 2006 and

was implemented nationally in England and Northern Ireland in

2009. Screening is planned for Scotland in 2011. See ‘diagnosis’

section for further detail on newborn screening.


The classic presentation is of encephalopathy with hypoketotic

hypoglycaemia. It is important to recognize that the child may

have developed an acute encephalopathy prior to the fall in blood

glucose, which can lead to diagnostic confusion. It typically

presents between the ages of 3 and 24 months when the child

experiences their first ‘fast’ associated with an intercurrent infec-

tion (often gastroenteritis) or being placed nil by mouth prior to

a surgical procedure. The child will typically become increasingly

lethargic with nausea or vomiting which rapidly progresses to

coma. Hepatomegaly and hypotonia are often present. Tests done

at the time will show evidence of hepatocellular dysfunction,

hypoglycaemia, hypoketosis (the presence of ketones does not

exclude the diagnosis) and mild-moderate hyperammonaemia. If

the low blood sugars are not detected the child may suffer

� 2010 Published by Elsevier Ltd.


Triglyceride stores

Long chain fatty acid

Carnitine Acyl carnitine

Carnitine

Ketone bodies

Dicarboxylic acidsAcetyl-CoA

Medium chain fatty acid

-oxidation -oxidation

Cytoplasm

Mitochonrion

Mitochonrial membrane

Figure 1 Fatty acid oxidation. Triglycerides are mainly composed of long chain fatty acids which require transfer across the mitochondrial membrane as an

acylcarnitine. Medium chain fatty acids can cross the mitochondrial membrane directly. Within the mitochondrion fatty acids then undergo b-oxidation in

which the fatty acid molecule is sequentially shortened by two carbon units releasing acetyl-CoA. Certain enzymes involved in b-oxidation, including

MCAD, are chain length specific. Deficiency of this enzyme prevents the normal catabolism of both long and medium chain fatty acids and results in an

increase in medium chain acylcarnitines in blood, increased u-oxidation to form dicarboxylic acids, and a reduction in ketone body production.


a seizure, permanent neurological damage secondary to cerebral

oedema and in the worst-case scenario death. In unscreened

populations up to 25% of patients with MCADD have died in their

first episode. Sudden unexpected death in infancy (SUDI) may be

caused by undiagnosed MCADD but it is not a cause of true

Sudden Infant Death Syndrome (SIDS); generally there is always

a preceding illness associated with poor feeding.

Diagnosis

Case example of early neonatal death resulting fromMCADD

Baby 1 was born at term following an uneventful pregnancy. He

was observed on the post-natal for 24 h in view of prolonged

rupture of membranes. He was discharged home the next day on

breast feeds. On day 2 of life he appeared pale, though was

feeding well. Later that day he became apnoeic and required

resuscitation and transfer to a paediatric intensive care unit. A CT

Newborn screening: newborn screening relies on tandem mass

spectrometry to detect raised C8 (octanoylcarnitine). C8 has been

found to be both a specific (low number of false positives) and

sensitive (low number of false negatives) marker for MCADD,

particularly if combined with measurement of the C8/C10 acyl-

carnitine ratio. In addition to raised C8 there is also an increased

urine hexanoyl glycine. Table 1 highlights the key biochemical

findings in MCADD.

In the UK the newborn screening programme specifies that

blood should be collected on filter paper between days 5e8 of life.

Biochemical findings in MCADD

Investigation Result

Blood sugar Normal or low

Urinary or plasma ketones Low or absent

Urine organic acids Raised C6eC10 dicarboxylic acids

(adipic, suberic and sebacic),

hexonylglycine, suberylglycine and

phenylpropionylglycine

Blood acylcarnitines Raised octanoylcarnitine (C8) and

decanoylcarnitine (C10)

Table 1


Where MCADD screening is undertaken the large majority of

affected infants are now detected within 2 weeks of birth.

However, there are three groups of children who may still present

symptomatically and in whom the diagnosis must be considered:

1. Newborns prior to the result of the newborn screening (due

to inadequate breast-feeding or neonatal infection), see case

example below in Box 1.

head scan was consistent with hypoxic-ischaemic encephalopathy

and he remained encephalopathic. The decision to withdraw life

support was made. The cause of death was thought to be sepsis,

however the results of a blood spot acylcarnitine analysis showed

a markedly increased C8 of 10.7 mmol/l. Urine organic acids

showed heavy dicarboxylic aciduria with traces of abnormal

glycine conjugates but with no ketones. Mutation analysis went on

to confirm the baby was homozygous for the common MCADD

mutation c.985A>G.

The family’s older children will undergo mutation analysis,

even though their newborn screen was negative. Any future chil-

dren will be treated as potential MCADD sufferers until tests

results are back.

Box 1




2. Children born prior to the newborn screening program.

3. Children born in other countries where screening does not

take place.

Symptomatic: a child, who presents with a blood sugar less than

2.6mmol/l, should undergo a number of investigations at the time

of the hypoglycaemia (Table 2). However this may not always be

achieved. Characteristic abnormalities in the urine organic acids

may be transient so that samples collected when patients have

recovered from an episode may not be diagnostic. Blood octa-

noylcarnitine, however, is always increased in MCADD.

Differential diagnosis

The differential diagnosis includes those disorders that cause

encephalopathy and hypoglycaemia. Hypoketosis is associated

with other inherited disorders of fatty acid oxidation and with

hyperinsulinism. A significant ketosis is a feature of the majority

of other causes. A careful clinical history and the investigations

listed in Table 2 will usually confirm the correct diagnosis.

Management

Acute illness: it is important to emphasize that a child with

MCADD may become seriously unwell before the blood sugar

falls and it is imperative to treat early. All children with MCADD

should have an emergency regimen for use at times of illness.

The aim of the emergency regimen is to provide a source of

energy and thus prevent hypoglycaemia. The emergency regimen

consists of drinks usually of soluble glucose polymer (e.g. Max-

ijul or Polycal) though some families use alternatives in discus-

sion with a specialist dietician.

The principles of management of an unwell child with

MCADD are given below, further detail can be found on the

‘British Inherited Metabolic Disease Group’ (BIMDG) website

including emergency regimes; see http://www.bimdg.org.uk/.

Stage 1. If the child is not their usual self or may be at risk of

illness (for example post-immunization) give regular oral drinks

and reassess in 2e4 h. If the child is better when re-assessed then

they go back to their normal diet, if unwell then go to stage 2.

Stage 2. Regular drinks of the emergency regime to be given day

and night as per the child’s individual regime. This treatment

should continue until the child improves. If the child does not

improve go to stage 3.

Investigations to be taken at the time of hypoglycaemia

Blood Urine

Glucose Ketones

Acylcarnitines Organic acids

Free fatty acids and 3(OH) butyrate Reducing substances

Amino acids

Ammonia

Lactate

Growth hormone, cortisol, thyroid function,

insulin, C-peptide

Table 2


Stage 3. If the child is obviously not well, not tolerating or not

taking drinks or the family areworried contact or go to the hospital.

Stage 4. If the child is not tolerating or taking the emergency

drinks then the child will need intravenous 10% dextrose/0.45%

saline. Try to re-establish normal diet within 48 h.

Intravenous fluids with 10% dextrose/0.45% saline must also

be used if the child is nil by mouth prior to a surgical procedure.

Long term management: throughout life the emphasis is to

prevent fasting.UK recommendations for themaximumage related

fasting time are given in Table 3. MCADD is not a contraindication

to breast-feeding but bottle top-ups may be needed particularly in

the first few days after birth. Formulas made with medium chain

triglycerides are contraindicated. Weaning can be commenced at

the usual time of 6 months under the guidance of a dietician. Once

toddler age is reached the child needs to have threemeals a day and

a bedtime snack. Missed meals should be replaced with a starchy

snack or sugary drink. A normal diet should be encouraged as the

child grows but with inclusion of regular starchy foods. It is

important that the child’s school is aware of his/her disorder and is

able to recognize symptoms thatmight be related toMCADD.Once

the child reaches adolescence the issue of excess alcohol should be

addressed in view of the risk of hypoglycaemia secondary to inhi-

bition of gluconeogenesis. Individuals with MCADD are at poten-

tial risk from their disorder throughout life and should remain

under review when they reach adulthood.

Siblings of MCADD patients: since MCADD is an autosomal

recessive condition, new siblings have a one in four risk of being

affected. A summary of the guidelines for their initial manage-

ment after birth, provided by BIMDG, is as follows:

� Investigations should be undertaken between 24 and 48 h of

age with blood spot acylcarnitines, urine organic acids and

DNA mutation analysis. Cord blood is not suitable because of

the risk of maternal contamination.

� A term baby should be fed every 4 h and a preterm every 3 h.

Potential problems associated with breast-fed babies are diffi-

culties in quantifying the amount of breast milk taken and the

low supply of breast milk in the first 72 h. These babies may

need formula top-ups. If there are any concerns at all the baby

should be transferred to the neonatal unit for blood sugar

monitoring with appropriate management, i.e. formula feeds

or intravenous 10%dextrose. Thesemeasures should continue

until acylcarnitine and urine organic acid results are known.

Older siblings of patients detected by newborn screening, who

were born before screening was started or born in countries

Recommended fasting times for children with MCADDwhen well

Age of child Maximum safe fasting time (h)

0e4 months 6

From 4 months 8

From 8 months 10

From 12 months onwards 12

Table 3


http://www.bimdg.org.uk/


Case example of child detected by newborn screening

Baby 2 was born at term following an uneventful pregnancy. She

was a breast-fed infant. She had standard blood spot testing

performed on day 5 of life. This revealed a raised C8 and C10. The

result was available on day 8 and immediately passed to the

metabolic service. The GP was contacted that day and asked to

visit the family to ensure the infant was well and to inform them

that an appointment had been arranged for the baby to be seen

the following day. The next day she was seen by the Consultant in

inborn errors of metabolism who explained the test results and

the diagnosis. Blood spots were taken for repeat acylcarnitines

and also for mutation analysis. A urine specimen was collected for

urinary organic acids. The result of the repeat acylcarnitine,

available the same day, confirmed the diagnosis. She was then

reviewed by the specialist dietician who provided guidance

regarding fasting times and an emergency regime. A follow-up

appointment was made for a month’s time and the baby’s local

hospital was contacted and provided with a copy of the emer-

gency regime should she present to them.

Box 2


without screening for MCADD should also be investigated. Occa-

sionally parents have also been found to be affected demonstrating

that survival into adulthood without severe illness is possible.

Prognosis and explanation e Box 2 highlights the process

followingdiagnosis bynewborn screening andBox3 thekeypoints to

Key points to convey to parents

C The outcome for a child with MCADD deficiency is excellent

once the diagnosis is made. Growth, development and general

health are unaffected.

C When well no special treatment is required; a normal healthy

diet should be given & no specific medication is necessary.

C The recommended age related fasting times for children with

MCADD when well, err on the side of caution and do not need

to be shortened.

C The emergency regimen must be followed during periods of

illness or poor feeding to prevent complications.

C Cot death, without any preceding illness, is not caused by

MCADD.

C Parents should contact the specialist team if they have any

concerns regarding their child.

C MCADD is a genetic disorder with a recurrence risk for further

children.

Box 3


convey to the parents. Not surprisingly parental anxiety relating to

their child’s management is common and families will need consid-

erablesupport includingdirect telephoneaccess to thespecialist team.

Follow-up e children with MCADD should remain under

follow-up with a specialist metabolic Paediatrician and Dieti-

cian with regular reviews in early childhood. Once middle

childhood is reached, yearly reviews are usually sufficient.

Parents should be allowed direct access to the local hospital’s

paediatric service so that lengthy waits in emergency depart-

ments (where there may be little awareness of the necessity of

rapid treatment) are avoided. Copies of the emergency regimen

should be provided to all relevant health professionals including

the GP and local Paediatrician. Once the child reaches adoles-

cence and is more independent as a person ‘Medic-alert’

bracelets are indicated.

Funding

None. A

FURTHER READING

British Inherited Metabolic Disease Group. Available at: http://www.

bimdg.org.uk.

Clarke JTR. A clinical guide to inherited metabolic disease. Cambridge:

Cambridge University Press, 2007.

UK newborn screening programme centre. Available at: http://www.

newbornbloodspot.screening.nhs.uk.

Practice points

C Children with MCADD are at significant risk of encephalopathy

during periods of fasting stress, particularly associated with

intercurrent infection.

C A high calorie emergency dietary regimen is given when

patients are unwell to prevent clinical deterioration.

C Oral rehydration solutions do not contain sufficient glucose to

prevent illness in MCADD.

C Intravenous treatment should be started immediately if the

emergency regime is not tolerated.

C When children are well no treatment is required although

periods without food should be limited, this depending on age

(Table 3).

C Hypoglycaemia should not be relied upon as a marker of early

decompensation or impending encephalopathy.


http://www.bimdg.org.uk






HyperlipidaemiaBorunendra N Datta

Duncan S Cole

Graham J Shortland

AbstractAssessment of hyperlipidaemia in children is important to prevent cardio-

vascular disease later in life. Secondary causes of hyperlipidaemia should

always be considered during clinical assessment. There are several

primary causes of primary hyperlipidaemia, of which familial hypercholes-

terolaemia (FH) is the most important. Diagnosis of FH is by use of the

Simon Broome criteria and genetic diagnosis can be helpful, particularly

in children. DNA diagnostics also facilitate cascade testing, which is

now recognized as an important means of identifying individuals with

FH. Several classes of drugs are used to treat hyperlipidaemia in children,

but the statins are most commonly used. They are effective and safe to

use in older children.

Keywords child; genetic testing; hydroxymethylglutaryl-CoA reductase

inhibitors; hyperlipidaemias; hyperlipoproteinaemia type II

Introduction

Cardiovascular disease remains the commonest cause of

mortality and morbidity in the United Kingdom (UK). Treatment

of lipid disorders in adults has had a significant impact in

reducing the overall burden of cardiovascular disease, particu-

larly in individuals who have sustained a cardiovascular event

such as myocardial infarction or stroke (secondary prevention).

There is increasing focus on primary prevention of cardiovas-

cular disease, including consideration of the cardiovascular

health of children. It is lifetime exposure to vascular risk factors,

such as low-density lipoprotein cholesterol (LDL-C), that appears

to be of importance. This is particularly so for monogenic causes

of hyperlipidaemia, the archetype of which is familial hyper-

cholesterolaemia (FH) where an affected individual is exposed to

high levels of LDL-C from birth. Secondary causes of hyper-

lipidaemia are of increasing relevance in childhood due to the

burgeoning obesity epidemic and its association with type 2

Borunendra N Datta MB BCh MD MRCP FRCPath is an SpR in Chemical

Pathology and Metabolic Medicine at the University Hospital of Wales,

Heath Park, Cardiff CF14 4XW, UK. Conflicts of interest: none.

Duncan S Cole BSc MB BCh PhD MRCP FRCPath is an SpR in Chemical

Pathology and Metabolic Medicine at the University Hospital of Wales,

Heath Park, Cardiff CF14 4XW, UK. Conflicts of interest: none.

Graham J Shortland BM DCH FRCPCH FRCP is a Consultant Paediatrician

with Special Interest in Inherited Metabolic Disease at the University

Hospital of Wales, Heath Park, Cardiff CF14 4XW, UK. Conflicts of

interest: none.


diabetes mellitus. In this review we provide an overview of lipid

metabolism and discuss both secondary and primary causes of

dyslipidaemia in childhood, with a particular focus upon FH.

Current treatment options will also be appraised.

Overview of lipid metabolism

Two pathways of lipid metabolism are recognized: the exoge-

nous and endogenous pathways (see Figure 1). The exogenous

pathway functions to distribute triglycerides and cholesterol

absorbed from the diet to peripheral tissues for use or storage. It

is characterized by the formation of chylomicrons, large lipo-

proteins that are particularly triglyceride-rich. Once deplete of

triglycerides the particle is known as the chylomicron remnant,

which is cleared by the liver.

The endogenous pathway functions in the fasted state to

deliver lipids to peripheral tissues. This is achieved by the

formation of very low-density lipoprotein (VLDL) in the liver,

a triglyceride-rich lipoprotein which also contains cholesterol.

Triglycerides are delivered peripherally and the particle reduces

in size and increases in density; these are sequentially known as

intermediate density lipoprotein (IDL) and finally LDL. These

contain proportionally more cholesterol, and LDL in particular

delivers cholesterol to tissues. Any that remains is cleared by the

liver via the LDL-receptor (LDL-R); this is the defective step in

familial hypercholesterolaemia. The sequence of events in LDL-R

synthesis and in binding and processing of LDL is shown in

Figure 2.

A further pathway also exists, known as reverse cholesterol

transport. High-density lipoprotein (HDL) is the major lipopro-

tein involved. It is produced by the liver in a cholesterol deplete

state, and acquires cholesterol from tissues. A complex interplay

then occurs between HDL and other lipoproteins, such that

excess cholesterol is returned to the liver via HDL, and apoli-

poproteins are re-distributed.

Figure 1 Exogenous and endogenous cholesterol pathways. Triglyceride

(TG)-rich particles from the gut (chylomicrons, CM) and liver (very low-

density lipoproteins, VLDL) release fatty acids (FA) via the action of

lipoprotein lipase on TGs. Cholesterol is released to peripheral tissues

from LDL particles.



Figure 2 LDL-receptor synthesis and recycling. The LDL-receptor is

synthesized and trafficked to the cell surface ready to bind ApoB on LDL.

Once bound, the LDL/LDL-receptor complex is internalized and fusion with

a lysosome occurs. This releases the LDL and digests it, resulting in free

cholesterol efflux and recycling of the receptor back to the surface.

Mutations resulting in FH can occur at numerous points along this

pathway, all resulting in inadequate clearance of LDL from the circulation.

Laboratory investigations for the assessment ofhyperlipidaemia

Investigation

Total cholesterol, LDL-C, HDL-C, triglycerides

Renal function and urine dipstick

Bilirubin, albumin, ALP, ALT or AST

Fasting plasma glucose

Thyroid function test

LDL-C ¼ low-density lipoprotein cholesterol; HDL-C ¼ high-density lipopro-

tein cholesterol; ALP ¼ alkaline phosphatase; ALT ¼ alanine aminotrans-

ferase; AST ¼ aspartate aminotransferase.

Table 1


It is important to note that when cholesterol is measured by

a clinical laboratory, it is derived from all the lipoproteins

mentioned above. HDL cholesterol measurements isolate the

cholesterol specifically from this fraction, but LDL cholesterol

concentration is often a calculated estimate based on an

assumption of the ratio of triglyceride to cholesterol in VLDL.

This may not always be applicable, for example when chylomi-

crons are present in the non-fasted state, or where IDL is the

predominant non-HDL/non-LDL fraction.

Cholesterol concentrations also vary with age. In children

they show a slight rise until age 10e11, and then dip during

puberty before rising to adult levels. A steady rise then occurs

throughout adulthood.

Cardiovascular risk in children

The assessment of global cardiovascular risk is well established

in adults. Calculation of cardiovascular risk is commonly used to

target therapies for primary prevention. Several tools may be

used, many of which use data from the Framingham study,

a long term ongoing study of cardiovascular risk. These take into

account variables such as total cholesterol, HDL-C, age and

systolic blood pressure. The output from such risk factor calcu-

lators is usually expressed as percentage risk of developing

cardiovascular disease over a 10-year period. There is limited

data to support the use of these tools in paediatric practice and

the cardiovascular risk of a child over the next 10 years will

always be low due to the influence of young age. Post-mortem

studies, such as the PDAY (Pathobiological Determinants of

Atherosclerosis in Youth) study demonstrate that atherosclerosis,

with the formation of fatty streaks, begins in childhood, and

calculation of lifetime cardiovascular risk may therefore be more

applicable in the paediatric population. However, such calcula-

tors for children are not yet in widespread use. The American

Academy of Paediatrics therefore recommends assessment of

lipid status in overweight and obese children, and in those with


diabetes mellitus or hypertension as well as smokers and those

with a family history of dyslipidaemia or premature cardiovas-

cular disease. For individuals with FH the use of cardiovascular

risk assessment tools based upon Framingham data are inap-

propriate as they tend to underestimate cardiovascular risk in

untreated FH.

Secondary causes of hyperlipidaemia

When interpreting a lipid profile it is important to recall that

a number of conditions can be associated with dyslipidaemia.

Treatment of the underlying disease will often completely correct

this. Several biochemical tests should therefore be requested as

part of the assessment of a lipid disorder (Table 1).

Diabetes mellitus

Type 1 and type 2 diabetes mellitus are both associated with an

increased lifetime risk of cardiovascular disease. However, well-

controlled type 1 diabetes mellitus is not typically associated

with significant dyslipidaemia. The obesity epidemic has driven

the rate of development of type 2 diabetes mellitus, with

increasing numbers of cases diagnosed in childhood. Type 2

diabetes mellitus is often associated with characteristic lipid

abnormalities, typically an increase in total cholesterol and

triglycerides and a reduction in HDL-C. There is currently no

evidence to support lipid-lowering therapy for the vast majority

of children with diabetes mellitus. However, given the increased

lifetime cardiovascular risk attributable to the disease, treatment

should be considered particularly when there are multiple risk

factors present, such as obesity, smoking and hypertension.

Thyroid disease

Untreated hypothyroidism may be associated with increased total

and LDL cholesterol. This is probably due to decreased receptor-

mediated LDL catabolism. Treatment of the hypothyroidism

almost invariably results in resolution of hypercholesterolaemia.

Use of statins in untreated hypothyroidism is associated with an

increased risk of myopathy.

Renal disease

Nephrotic syndrome is associated with increased total and LDL-C

and to a lesser extent reduction in HDL-C. The degree of dysli-

pidaemia appears to be inversely related to the serum albumin



Effect of drug therapy commonly associated with lipidabnormalities

Drug Triglycerides LDL HDL


concentration. An increase in hepatic VLDL production subse-

quently results in an increase in circulating LDL-C. Evaluation of

urinary protein is easily overlooked in a patient who is referred

for evaluation of FH and should be a mandatory part of the

evaluation.

cholesterol cholesterol

Thiazides [ [ e
Liver disease
b blockers [ e Y

Oestrogens [ e [

Retinoic acid derivatives [ e e

Protease inhibitors [ [ Y

Ciclosporin e [ e

Obstructive jaundice is associated with an increase in total

cholesterol due to an increase in lipoprotein particles similar to

LDL. Hepatocellular disease is more often associated with

hypertriglyceridaemia. The latter is a predominant feature of

non-alcoholic fatty liver disease which has a strong association

with obesity and insulin resistance.

Table 3
Alcohol
Excess alcohol ingestion may be associated with hyper-

triglyceridaemia, because of increased hepatic triglyceride produc-

tion, which subsequently leads to an increase in hepatic VLDL

secretion. Enquiry regarding alcohol consumption is therefore

important in the assessment of dyslipidaemia in older children.

Anorexia nervosa

Hypercholesterolaemia is a recognized feature of eating disor-

ders. It appears to be particularly associated with the bulimic

subtype of anorexia nervosa. Multiple mechanisms are respon-

sible, including endocrine changes secondary to loss of adipose

tissue, and increased absorption of dietary cholesterol during

high-fat binging episodes. The relevance of this to cardiovascular

risk is not clear, and tackling dyslipidaemia as an isolated issue is

usually not productive unless there are other concerns with

regards cardiovascular risk or there is a family history of FH.

Drugs causing hyperlipidaemia

Several classes of drugs used in paediatric practice may be

associated with dyslipidaemia (Table 3). In some cases it may be

possible to switch to an alternative drug, for example agents used

for the treatment of hypertension. If a drug which causes

Simon Broome register criteria for diagnosis of familial hype

Lipid criteria

Definite FH

Age <16 years: total cholesterol >6.7 mmol/l or LDL-C >4.0 mmol/l

Age >16 years: total cholesterol >7.5 mmol/l or LDL-C >4.9 mmol/l

Possible FH

Age <16 years: total cholesterol >6.7 mmol/l or LDL-C >4.0 mmol/l

Age >16 years: total cholesterol >7.5 mmol/l or LDL-C >4.9 mmol/l

FH ¼ familial hypercholesterolaemia; LDL-C ¼ low-density lipoprotein cholesterol; LD

tase subtilisin kexin type 9.

Table 2


dyslipidaemia is not likely to be used for long term therapy, such

as a course of an oral retinoic acid derivative, a transient dysli-

pidaemia is likely to be clinically acceptable. Otherwise an

assessment of overall cardiovascular risk should be made, to

help decide if treatment of the dyslipidaemia is required.

Primary causes of hyperlipidaemia

Familial hypercholesterolaemia

Autosomal co-dominant FH is the most common monogenic

cause of coronary heart disease (CHD). Most cases are caused by

mutations in the LDL-R which results in high circulating LDL-C.

The estimated prevalence of heterozygous FH is 1 in 500 in

Europe and North America. Untreated it carries a risk of

premature coronary disease of >50% in men and >30% in

women by the age of 60 years.

Homozygous FH has an estimated prevalence of 1 in 1,000,000

and is associated with circulating LDL-C levels in excess of 10

mmol/l. CHD in homozygous FH presents from the second decade

of life. The risk of cardiovascular mortality andmorbidity is linked

to extensive atherogenesis affecting the proximal aorta, aortic

rcholesterolaemia

Other criteria required for diagnosis

Tendon xanthomata in patient or in first degree relative

(parent, sibling or child) or in second degree relative

(grandparent, uncle or aunt)

OR

DNA evidence of a mutation in LDL-R, apolipoprotein

B-100 or PCSK9 genes

At least one of the following:

Family history of myocardial infarction in first degree relative aged

<60 years or second degree relative aged <50 years

OR

Family history of raised total cholesterol: >7.5 mmol/l in adult first

or second degree relative or >6.7 mmol/l in child or sibling aged

<16 years

L-R ¼ low-density lipoprotein cholesterol receptor; PCSK9 ¼ proprotein conver-




valve and coronary arteries. Florid physical signs are often

present, such as tendon and subcutaneous xanthomata.

Diagnosis of familial hypercholesterolaemia: the diagnosis of

FH involves a personal and family history, physical examination,

measuring total and low-density lipoprotein cholesterol (LDL-C)

in serum and the use of DNA diagnostics. In the UK the Simon

Broome criteria (Table 2) are used as they were developed using

a UK population and are straightforward to employ in the clinic.

However all clinical diagnostic criteria lack specificity and

sensitivity, particularly in less severe presentations when

cholesterol concentrations may not reach the diagnostic thresh-

olds. This is a particular issue in children and younger people

due to the variation of cholesterol concentrations with age, and

diagnostic physical stigmata, particularly tendon xanthomata,

are often absent in children. For these reasons there is an

increasing role for a DNA diagnosis in suspected FH in paediatric

practice.

Genetics of familial hypercholesterolaemia: FH is most

commonly caused by mutations in the LDL-receptor gene, with

a smaller number of cases due to mutations in the Apo B-100 and

PCSK9 genes. There is a higher risk of CHD in individuals with an

LDL-R mutation, compared to those who are mutation negative.

Mutations may be indentified in up to 90% of individuals with

‘definite’ FH (with tendon xanthomata) and genetic testing in

patients with ‘possible’ FH can help clarify the diagnosis. Current

National Institute for Health and Clinical Excellence Clinical

Guidelines support early identification of FH in children from age

10 years and a DNA diagnosis can provide conclusive evidence of

a diagnosis to parents and their doctors. However, the absence of

a detectable DNA mutation does not exclude the diagnosis of FH

and an individual with a clinical diagnosis of FH who does not

have a demonstrable DNA mutation should still be considered at

high risk and treated accordingly.

Cascade testing for familial hypercholesterolaemia: in the UK

it is estimated that 85% of the estimated 120,000 people who are

affected by FH have not been diagnosed. Cascade testing is the

preferred strategy for identifying these individuals. The most

efficient and cost effective approach is to use DNA testing for

those families with a known mutation or cholesterol testing in

those families in whom a mutation cannot be found. Cascade

testing commenced across Wales in 2010 with extension to the

rest of UK anticipated in the next few years. One consequence of

this approach is that there will be an increase in the number of

children and young people identified with FH who will need

advice and treatment.

Polygenic hypercholesterolaemia

Polygenic hypercholesterolaemia is muchmore common than FH.

An increase in total cholesterol and LDL-C is seen, but clinically the

differentiation from FH may not be clear. DNA testing can be

particularly helpful in this situation. The genetics of this condition

are not as well understood as for FH. Several genes are likely to be

important as well as lifestyle factors, such as obesity and poor diet.

Polygenic hypercholesterolaemia is more commonly identified in

adults and the risk of premature CHD is much lower than for FH

with a documented DNA mutation.


Familial combined hyperlipidaemia

Familial Combined Hyperlipidaemia (FCHL) is an important

disorder, but is much less clearly defined than FH. It is likely that

several genes are responsible and lifestyle factors may also be

important. Typically the total and LDL-C are elevated as well as

serum triglycerides, although there does seem to be significant

heterogeneity in the lipid profiles of families with FCHL. The

abnormal lipid profile probably occurs due to overproduction of

VLDL.

Hypertriglyceridaemia

Hypertriglyceridaemia may be seen in childhood, usually due to

a precipitating factor in a susceptible individual (see Secondary

causes of hyperlipidaemia). Genetic forms also exist, such as

the rare familial lipoprotein lipase deficiency, which may result

in severe hypertriglyceridaemia. Presentation with this disorder

may be with eruptive xanthomata or acute abdominal pain,

which may be recurrent. Acute pancreatitis may occur when the

triglycerides exceed 10e15 mmol/l, and may occasionally exceed

100 mmol/l. In childhood this results from the failure to clear

chylomicrons, although in the teenage and adult years VLDL may

also accumulate. Treatment for a primary hypertriglyceridaemia

thus focuses on restriction of fat intake.

Treatment

Lifestyle interventions

Lifestyle therapies are an important component in the treatment

of hyperlipidaemia and involve avoidance of smoking and die-

tary and exercise interventions. Such interventions are important

for general long-term cardiovascular health and the prevention

and treatment of obesity. Lifestyle intervention alone is usually

not effective for the prevention of cardiovascular disease in

inherited dyslipidaemias. The role of nutritional supplements,

containing plant stanols and sterols is not clear in children, but

beneficial effects appear to be similar to those seen in adults.

Drug therapy

Statins: theyare themost commonlyusedclassofdrugsused to treat

hyperlipidaemia in both children and adults. They work through

inhibiting the rate determining step of the cholesterol biosynthesis,

HMG-CoA reductase, and effectively reduce total and LDL choles-

terol. They have limited effects upon triglyceride and HDL-C

metabolism. There are few randomized placebo controlled trials of

statins in paediatric FH, but a wealth of data has confirmed the

beneficial effects of statins in the reduction of cardiovascular

mortality and morbidity in non-FH adults. There are no outcome

studies in children and most have used surrogate markers, such as

measures of endothelial function and carotid intima media thick-

ness. These have indicated an improvement in surrogate markers

with statins in theFHpopulation. Previous concerns that statinsmay

not be safe in children appear to be unfounded, as data now confirm

that statins do not have detrimental effects upon growth and

development and are generally well tolerated. Therapy should be

considered in an individual child based upon LDL-C concentrations

and the age of onset of cardiovascular disease in family members.

Treatment with a statin should be considered in FH from the age of

10. In the UK currently Atorvastatin is licensed in children over the

age of 10 years up to a dose of 20 mg per day and Pravastatin is




licensed at a dose of 10e20 mg per day in children aged 8e14 years

and up to 40 mg in older children.

Other drug therapy: Ezetemibe decreases intestinal absorption

of cholesterol and may be used in children. Its main use is in

combination therapy with statins, in particular for children with

homozygous FH. It can also be used in monotherapy, for instance

if statin therapy is not tolerated.

Fibrates reduce hepatic triglyceride production and peripheral

lipolysis and have been used in children. Their main use is in the

treatment of hypertriglyceridaemia and they have a limited effect

in reducing LDL-C.

Bile acid sequestrants and nicotinic acid are also licensed for

use in hyperlipidaemia, but are not widely used in children.

LDL apheresis

LDL apheresis is a treatment similar to renal dialysis. Patients

usually attend fortnightly. LDL cholesterol is removed from the

patient and absorbed onto a specific LDL absorption column and

blood then returned to the patient. This invasive procedure

effectively reduces LDL cholesterol in conjunction with drug

therapy and its use should be considered in all children with

homozygous FH.

Practice points
General issues
C Assessment of serum lipids should be carried out in children

with a family history of premature cardiovascular disease or

dyslipidaemia

C Assessment of serum lipids may also be useful in children with

other cardiovascular risk factors

C Screening investigations should be used to exclude secondary

causes of dyslipidaemia

C Familial Hypercholesterolaemia is the commonest inherited

monogenic cause of premature cardiovascular disease

C Statins are effective and safe in children aged 10 years or

older

The majority of children and young people are currently

managed in specialist centres for inherited metabolic disease

where advice can be obtained. With cascade testing and an

increase in the number of children and young people identified

with FH new strategies for secondary care will need to be

considered to advise and treat these patients. A

FURTHER READING

Arambepola C, Farmer AJ, Perera R, Neil HAW. Statin treatment for children

and adolescents with heterozygous familial hypercholesterolaemia:

a systematic review and meta-analysis. Atherosclerosis 2007; 195:

339e47.


Daniels SR. Greer FR and the Committee on Nutrition. Lipid screening and

cardiovascular health in childhood. Pediatrics 2008; 122: 198e208.

Datta BN, McDowell IFW, Rees JAE. Integrating provision of specialist lipid

services with cascade testing for familial hypercholesterolaemia. Curr

Opin Lipidol 2010; 21: 366e71.

Durrington PN. Hyperlipidaemia diagnosis and management. 3rd Edn.

London: Hodder Arnold, 2007.

National Institute for Health and Clinical Excellence. Clinical guidelines

and evidence review for familial hypercholesterolaemia: the identifi-

cation and management of adults with familial hypercholesterolaemia.

Clinical Guidelines 71; 2008.

Pathobiological Determinants of Atherosclerosis in Youth Research Group.

Relationship of atherosclerosis in young men to serum lipoprotein

cholesterol concentrations and smoking. JAMA 1990; 264: 3018e24.

Umans-Eckenhausen MAW, Defesche JC, Sijbrands EJG, Scheerder RLJM,

Kastelein JJP. Review of first 5 years of screening for familial hyper-

cholesterolaemia in the Netherlands. Lancet 2001; 357: 165e8.

Wierzbicki AS, Viljoen A. Hyperlipidaemia in paediatric patients. The role

of lipid-lowering therapy in clinical practice. Drug Saf 2010; 33:

115e25.



SELF-ASSESSMENT

Self-assessment

Questions

Case 1

A 10-day-old baby girl was admitted with poor feeding, leth-

ALT 49 U/litre (1e50)

GGT 38 U/litre (0e78)

Protein 50 g/litre (60e80)

Albumin 35 g/litre (35e50)

PT 30.1 s (11.4e14.3)

APTT 82.3 s (25.2e33.5)

Fibrinogen 1.4 g/litre (1.9e4.3)

CSF microscopy Negative for infection

CSF glucose 2.2 mmol/litre

CSF protein 1.2 g/litre

Venous gas pH 7.38, pO2 4.3 kPa, pCO2 6.0 kPa,

argy and weight loss (Wt 3.01 kg; Birth wt 3.42 kg). She was

born at term, breast fed initially but formula fed from day 3.

Shewas apyrexial, warm andwell perfused but jaundiced.

Respiratory rate was 36/min and respiratory system exami-

nation was normal. Abdominal examination revealed soft

abdomen with a 3 cm liver edge palpable and cardiovascular

examination revealed the presence of a systolic murmur, but

no other abnormal findings. The peripheral pulses as well as

oxygen saturations were normal in all 4 limbs.

Blood results

Hb 16.4 g/dL (12.1e16.3)

WCC 10�109/litre (5e19.5)

Neutrophils 0.7�109/litre (2e9)

Lymphocytes 7.7�109/litre (3.5e8.5)

Platelet count 153�109/litre (150e400)

Na 133 mmol/litre (133e146)

K 5.2 mmol/litre (3.5e5.3)

Urea 2.4 mmol/litre (2.5e7.8)

Creatinine 38 mmol/litre (0e39)

CRP <5 mg/litre (<5)

Total bilirubin 379 mmol/litre (1e17)

Direct bilirubin 38 mmol/litre (0e8)

ALP 1028 U/litre (60e350)

BE e5.1 mmol/litre

Glucose 3.4 mmol/litre

Lactate 1.0 mmol/litre

Ammonia 61 umol/litre (11.2e35.4)

Ranjana Kanekal MB ChB is a Foundation year 2 Trainee in the

Department of Paediatrics at James Cook University Hospital,

Middlesbrough, UK.

Susan M George MB BS MSc PhD is a Specialist Trainee in the


Middlesbrough, UK.

Ramesh B Kumar MB BS MD MRCPCH is a Consultant Paediatrician in the


Middlesbrough, UK.

Maeve O’Sullivan MB ChB MRCPCH PhD is a Consultant Paediatrician in

the Department of Paediatrics at James Cook University Hospital,

Middlesbrough, UK.

Mark Burns MB ChB MRCPCH is a Consultant Paediatrician in the


Middlesbrough, UK.


1. Which among the following is the most important

diagnosis to consider in this baby? Choose ONE answer

a) Neonatal sepsis

b) Metabolic illness

c) Congenital cardiac disease

d) Insufficient milk intake

She was commenced on IV broad spectrum antibiotics

(Benzylpenicillin and Gentamicin, later changed to Cefo-

taxime) and acyclovir (added to cover potential viral

infection). She was kept on 60 ml/kg/day of IV fluids (and

small amounts of bottle feeds).

At 48 h, the blood culture grew E. coli but CSF culture was

reported negative. Coagulopathy improved with adminis-

tration of fresh frozen plasma and vitamin K.

She completed 14 days of IV antibiotics, and tolerated

feeds well once the formula was changed. She improved

with the above management and underwent further inves-

tigations which identified the diagnosis.

2. Which of the following metabolic illnesses is most likely

in this child? Choose ONE answer

a) Mitochondrial disease

b) Galactosaemia

c) Neonatal haemochromatosis

d) Lysosomal storage disease

e) Fructose intolerance

3. Which specific investigation would confirm this diag-

nosis? Choose ONE answer

a) Galactose 1 phosphate uridyl transferase (Gal 1 PUT)

level

b) Muscle biopsy

c) Liver biopsy

d) MRI brain

e) Urinary organic acids



SELF-ASSESSMENT

4. What are the most important management strategies

with this condition? Choose THREE answers

a) Regular paediatric follow-up

b) Pubertal development and fertility assessment

c) Prophylactic antibiotics

d) Annual ophthalmology review

e) Lactose free diet

f) Anti-epileptic medication

g) Fructose free diet

h) Cardiology assessment

i) Desferrioxamine

Case 2

A 6-month-old boy of African origin presented to A&E

following third episode of afebrile seizures within 1 week.

He was born at term by emergency caesarean section for

foetal distress. There were no antenatal or postnatal

concerns. The baby was exclusively breast fed for first 4

months. At the time of presentation, his diet consisted of

breast milk, mashed potatoes and carrots as well as

confectionaries.

Seizures lasted 2e3 min each, with increased tone

involving the whole body, during which he remained

unresponsive. There was associated up-rolling of eyes and

frothing at the mouth. No clonic movements were reported.

There was spontaneous recovery in each case after which

he became drowsy and slept for 1e2 h.

Examination revealed a thriving child who was also

neuro-developmentally normal.

Figure 1


Blood investigations

FBC Normal

Urea & electrolytes
Normal
Magnesium
0.98 mmol/litre (0.74e1.11)
Ferritin
38 mg/litre (41e400)
ALP
908 units (75e255)
Serum calcium
1.65 mmol/litre (2.1e2.6)
Phosphate
1.15 mmol/litre (1.22e2.47)
PTH
294.2 ng/litre (12e72)
1. What does this X-ray show (Figure 1)? Choose ONE

answer

a) Normal X-ray

b) Osteoporosis

c) Cupping and fraying of the ends of long bones

d) Skeletal dysplasia

2. What is the most likely underlying clinical diagnosis in

this child? Choose ONE answer

a) Nutritional rickets

b) Epilepsy

c) Osteogenesis imperfecta

d) Pseudo-hypoparathyroidism

3. What are the key components in the management of this

child? Choose THREE answers

a) Oral vitamin D administration

b) IM vitamin D administration

c) Anti-epileptic medication

d) Health education regarding diet

e) IV calcium gluconate

f) Oral calcium supplements

g) Phosphate supplements

h) Magnesium supplements

i) All of the above

Case 3

A healthy term baby girl was born with a large birth mark

involving the right side of her face. This was deep red in

colour, macular and involving the eyelid, cheek & forehead.

Newborn examination was normal.

She remained well until 5 months of age when she first

presented with seizures. Her seizures involved the left side

of the face & limbs, initially starting with facial twitching

movements, progressing to have tonic clonic movements

which started with left upper limb and subsequently

involved all four limbs. The duration and frequency

of seizures were variable with as many as five seizures in

a 24-h period.

1. What is the most likely clinical diagnosis based on the

above history? Choose ONE answer

a) Epilepsy

b) SturgeeWeber syndrome

c) Cerebral palsy

d) Congenital vascular malformation

e) Tuberous sclerosis



Figure 2

SELF-ASSESSMENT

2. What does the above MRI scan show (Figure 2)? Choose

ONE answer

a) Normal scan

b) Vascular malformation on the right side

c) Decreased in size & calcifications in the right

hemisphere

d) Right MCA territory infarction

3. What are the associated complications commonly seen

with this condition? Choose ONE answer

a) Learning difficulties

b) Glaucoma

c) Cutaneous vascular malformations

d) Intracranial & ophthalmic tubers

e) Renal involvement

4. What are the most important management strategies in

this condition? Choose THREE answers

a) Anti-epileptic medication

b) Hemispherectomy

c) Regular ophthalmology review & intraocular pressure

monitoring

d) Physiotherapy

e) Laser treatment of the facial lesion

f) Occupational therapy

g) Long term antibiotics

h) Oral anticoagulants

i) Regular monitoring of renal function

j) All of the above

Answers

Case 1

1. a) Sepsis

In a neonate presenting in this manner, three main

diagnoses must be considered e sepsis, congenital cardiac

diseases and metabolic illnesses. Deranged coagulation and


raised liver enzymes with mild jaundice in a neonate must

make one suspect neonatal sepsis. A metabolic illness is

very likely in this child suggested by the mode of presen-

tation, but needs further investigations to confirm this.

Normal cardiovascular examination makes congenital

cardiac diseases less likely. Poor milk intake is often

secondary to the underlying problem, leading to hypo-

volaemia. Poor feeding due to poor lactation or feeding

techniques can cause weight loss and hypovolaemia. Such

neonates often present with significant hypernatraemia and

raised serum & urinary osmolality.

2. b) Galactosaemia

Classical galactosaemia is an autosomal recessive

disorder of galactose metabolism caused by the deficiency

of Gal 1 PUT enzyme, with an incidence of 1/23e44,000.

Majority presents in neonatal period after ingestion of

galactose (derived from lactose in milk), with poor feeding

& feed intolerance, jaundice, hepatosplenomegaly, hepato-

cellular insufficiency, hypoglycaemia, muscle hypotonia,

cataracts and sepsis. E coli sepsis is seen more frequently in

these babies.

Mitochondrial diseases have variable presentations with

some conditions presenting early with significant metabolic

acidosis, collapse and sudden infant death.Many present later

with hypotonia, developmental delay and neurological prob-

lems. Neonatal haemochromatosis is a fatal, progressive

illness which often presents within the first few days of life,

characterized by hepatomegaly, hypoglycemia, coagulopathy

(refractory to Vitamin K therapy) hypoalbuminaemia, hyper-

ferritinaemia and hyperbilirubinaemia. Lysosomal storage

disorders (e.g.Gaucher’s) present later in infancywithhepato-

splenomegaly, psychomotor retardation and evidence of bone

marrow infiltration. Fructose intolerance can present with

very similar clinical features following introduction of fruits

and fruit juices. Age at presentation, absence of metabolic

acidosis and coagulopathy which responded to treatment

makes the above diagnoses less likely.

3. a) Galactose 1 phosphate uridyl transferase (Gal-1-PUT)

Gal-1-PUT is the enzyme that is deficient in

galactosaemia.

In view of the neonatal liver disease, coagulopathy and

E. coli sepsis, this baby was investigated for Gal-1-PUT

deficiency by measuring the enzyme activity in erythrocytes

(Patient <0.5; Normal: 18e28) and a diagnosis of classical

galactosemia was made. This was later confirmed with

DNA mutation analysis.

Classical galactosaemia is part of newborn screening

programmes of many countries.

4. a,d,e) Regular paediatric follow-up, annual ophthal-

mology review, lactose free diet

Successful management of galactosaemia requires

appropriate dietary input. A galactose-restricted diet is

advised. Lactose free milk (e.g. Wysoy) is advised in

neonatal period. After this, lactose-free diet without

restriction of galactose containing fruits and vegetables is



SELF-ASSESSMENT

recommended in most countries. Paediatric follow up with

a team that is familiar with management of galactosaemia is

required. They also require written plan for management of

acute illnesses. Patients are advised to access hospital

services early, commence IV fluids and supplementary

feeding regime in order to prevent crises.

Long-term complications include mental retardation,

verbal dyspraxia, motor abnormalities and hypogonadic

hypogonadism. This is often seen in patients despite strict

diet and is thought to be due to endogenous galactose

production.

Couples with an affected child have a 25% chance of

having an affected child in each subsequent pregnancy.

FURTHER READING

Bosch AM. Classical galactosaemia revisited. J Inherit Metab Dis

2006; 29: 516e525.

Livingston VH, Willis CE, Abdel-Wareth LO, Thiessenn P, Lockitch G.

Neonatal hypernatremic dehydration associated with breast-

feeding malnutrition: a retrospective survey. Can Med Assoc J

2000; 162: 647e652.

Weblink: British InteritedMetabolic Disease Group. www.bimdg.org.uk.

Case 2

1. c) Cupping and fraying of the end of long bones

Widening of the metaphyseal ends of radius and ulna, as

well as cupping and fraying of these bones (see arrows in

Figure 3) noted. This is a pathognomonic feature of rickets.

Figure 3


2. a) Nutritional rickets

Main sources of Vitamin D in children are foods such as

oily fish, butter & eggs, and ultraviolet irradiation of 7-

dehydrocholesterol in the skin. Dietary cholecalciferol

(Vitamin D3) is hydroxylated by liver to 25-hydroxy

cholecalciferol and then the kidneys to 1,25-dihydroxy

cholecalciferol (active form of vitamin D).

Biochemical features of nutritional rickets e low plasma

calcium, raised alkaline phosphatase & parathyroid

hormone, and decreased serum vitamin D levels e were

noted. The serum 25 OH Cholecalciferol level was 15 nmol/

litre (Normal: 40.4e168).

Radiological features of rickets include poor mineraliza-

tion of both flat & long bones, delayed development of the

epiphysis and metaphyseal changes at the growing ends of

long bones (concave, irregular margins are found together

with increased diameter e cupping, fraying & splaying).

Prominence of costochondral junctions causes ‘rachitic

rosary’. More significant abnormalities are seen in long

standing rickets. Seizures and tetany suggest hypocalcaemia.

In pseudo-hypoparathyroidism, serumphosphate is raised.

3. a,e,f) Oral Vitamin-D administration, IV calcium gluco-

nate, oral calcium supplementation

Oral Vitamin-D3 at a dose of 2000e6000 IU/day is

commenced as soon as the diagnosis is confirmed and

continued for at least 3 months. This should be followed by

daily Vitamin-D intake of 400 IU/day. IV calcium gluconate

is administered due to the presentation of hypocalcaemic

seizures. This child needs short-term oral calcium supple-

ments. With appropriate therapy, and introduction of a well

balanced diet containing adequate calcium & phosphorus,

nutritional rickets is a condition that is easily managed.

FURTHER READING

Balasubramanian S, Ganesh R. Vitamin D deficiency in exclusively

breast-fed infants. Ind J Med Res 2008; 127: 250e255.

Singh J, Moghal N, Pearce SHS, Cheetham TD. The investigation of

hypocalcaemia and rickets. Arch Dis Child Health 2003; 88:

403e407.

Case 3

1. a) SturgeeWeber syndrome

The presence of facial capillary haemangioma involving

the ophthalmic & maxillary branch distribution of trigem-

inal nerve, and focal onset of seizures with secondary

generalization points towards this diagnosis.

SturgeeWeber syndrome is the association of angiomas of

the leptomeninges and facial skin. Many children develop

seizures, developmental delay and glaucoma. Seizures often

develop in the 1st year of life, due to associated angiomas

involving the ipsilateral cerebral hemisphere. They are typi-

cally focal tonic-clonic, contralateral to the side of facial nae-

vus. There is associated shrinkage andneuronal cell loss of the

affected hemisphere. Hemiparesis and hemiplegia can occur,

which, along with recurrent seizures can lead to develop-

mental delay and disability.




SELF-ASSESSMENT

2. c) Decreased size & calcifications in the right hemisphere

The ipsilateral hemisphere shows marked decrease in

size and evidence of calcification. Isolated MCA territory

infarction is unlikely to cause this degree of shrinking &

calcification of the hemisphere. Intracranial vascular mal-

formations leads to the presence of dilated blood vessels

(may have evidence of haemorrhage), which is not the most

prominent feature in this image.

3. b) Glaucoma

Glaucoma of the ipsilateral eye is a common association

in SturgeeWeber syndrome. Other associations include

learning difficulties, hemiplegia and protracted seizures

leading to disability.


4. a,c,e) Anti-epileptic medication, regular ophthalmology

review & intra-ocular pressure monitoring, laser treat-

ment for the facial lesion

Management depends on the severity of symptoms.

Physiotherapy and occupational therapy may be required if

indicated. It is important to explain the diagnosis and

prognosis to the parents and review the child regularly.

Seizures can be difficult to manage and may require inser-

tion of vagal nerve stimulator or even surgical management

(hemispherectomy).

FURTHER READING

Nowak CB. The phacomatoses: dermatologic clues to neurologic

anomalies. Semin Paediatr Neurol 2007; 14: 140e149.




The investigation and theinitial management ofchildren with suspectedmetabolic diseasepresenting acutely*

J V Leonard

A A M Morris

AbstractInborn errors ofmetabolismare individually rare but somany have now been

described that the general paediatrician will encounter one from time to

time. For many, early treatment is important. Unfortunately most present

with non-specific symptoms and signs. It is therefore necessary to identify

and investigate those at high risk. Themost commonproblems are neurolog-

ical (including coma, seizures and stroke-like episodes), hypoglycaemia,

disorders of acidebase regulation, cardiomyopathy and acute liver disease.

Treatment should be started as soon as an inborn error is suspected.

Keywords acute liver failure; ataxia; cardiomyopathy; catabolism;

encephalopathy; hyperammonaemia; hypoglycaemia; metabolic acidosis;

respiratory alkalosis; seizures; stroke-like illness

Introduction

Inborn errors of metabolism are generally rare, although some

disorders are more common in genetically isolated populations.

Many inherited metabolic conditions are nowwell recognized and

they may present at almost any age from the newborn period into

adult life. Many disorders are now treatable and it is important to

recognize the underlying disorder at the earliest possible stage to

prevent permanent damage. Unfortunately however for most

disorders the early symptoms and signs are not specific so it is

necessary to try to identify those at high risk of having ametabolic

disorder.

* This chapter is a short introduction and cannot cover all situa-

tions. If in doubt, consult your local specialist metabolic centre.

Detailed and free instructions on the management of acute illness of

individual inborn errors of metabolism can be found on the British

Inherited Metabolic Disease Group (BIMDG) website http://www.

bimdg.org.uk/.

J V Leonard PhD FRCP FRCPCH is a Former Professor of Paediatric Metabolic

Disease at the UCL Institute of Child Health, and Consultant Paedia-

trician at Great Ormond Street Children’s Hospital, London, UK.

Conflicts of interest: none.

A A M Morris PhD FRCPCH is a Consultant in Paediatric Metabolic Medi-

cine at the Department of Genetic Medicine, St Mary’s Hospital, Oxford

Road, Manchester M13 9WL, UK. Conflicts of interest: none.


History

The key to identifying those at high risk is the history, past,

family and that of the present illness.

Past history

After resuscitation it is important to inquire about any problems

before the present one such as previous episodes, episodic vom-

iting, developmental delay and episodes of drowsiness particularly

in the morning. Patients presenting with a severe acute encepha-

lopathy particularly may have had previous episodes, commonly

much milder precipitated by intercurrent infections or fasting.

Family history

Where there is a clear history of an affected sibling (more distant

relative in the case of X-linked disorders) or highly consanguin-

eous families, these leads must be followed up carefully. There

may be a history of undiagnosed death or unexplained illness

that may provide useful clues. Consanguinity, although relevant,

only increases the risk of an autosomal recessive disorder by

a modest percentage.

Modes of presentation

Although inborn errors may present in many different ways and at

almost any age, the common presentations can be simplified into

five categories: (1) neurological presentation including acute

encephalopathy, seizures, stroke-like illness and acute ataxia, (2)

hypoglycaemia, (3) disorders of acidebase regulation, (4)

cardiomyopathy and cardiac arrhythmias and (5) acute liver

disease. Metabolic disorders may also present at or soon after birth

with a number of different problems that include ascites/hydrops,

dysmorphic syndromes, seizures and severe hypotonia. Lists of

the causes of these problems can be found in Leonard and Morris

(2006).

Neurological presentation

Acute encephalopathy: a common presentation of inborn errors is

an acute encephalopathy but there are verymany causes of such an

illness. An acute metabolic encephalopathy may be very variable

ranging frommild to severe. Typically the symptoms are of gradual

onset, unless the patient has a convulsion. The early symptoms are

often drowsiness, lethargy, altered behaviour and unsteady gait.

These symptoms may fluctuate and then often somewhat unex-

pectedly the patients may deteriorate, becoming comatose. Treat-

ment is urgent and basic metabolic investigations should always be

done in any patient with an undiagnosed encephalopathy. An

episode may be precipitated by infection and fever but evidence of

these does not exclude the metabolic disorder.

The causes of metabolic encephalopathy and the investiga-

tions that are necessary to identify the majority of metabolic

disorders are summarized in Table 1.

Seizures: those disorders that may present with seizures with the

investigations are listed in Table 2.

Stroke-like episodes: the most common metabolic causes of

stroke-like episodes with the appropriate investigations are listed

in Table 3.





Causes of acute metabolic encephalopathy

Causes Investigations

Hypoglycaemia

Hyperammonaemia including

urea cycle disordersa

Disorders of fatty acid

oxidation and ketogenesis

Amino acids disorders including

maple syrup urine disease

Organic acidaemias

Congenital lactic acidoses

Blood gases

Blood glucose

Blood lactate

Plasma electrolytes

& anion gap

Plasma ammonia

Plasma amino acids

Blood spot acyl carnitinesb,d

Liver-function tests

Plasma biotinidasec

Urine organic acids

a For a full list of inborn errors that cause hyperammonaemia see Table 20.2 in

Fernandes et al. (2006).b It can be difficult to identify carnitine transporter deficiency with blood spot

acyl carnitines as the values for free carnitine may be low but not very low.c Plasma biotinidase is included as this is a simple test and biotinidase deficiency

responds very well to treatment but this must be started at an early stage.d The results of any extended newborn screening investigations should be checked.

Table 1

Metabolic disorders that may present with seizures


Non ketotic

hyperglycinaemia

Plasma and CSF amino acids

Disorders or creatine

metabolism

Cranial MRS or urine creatine &

guanidinoacetate

GLUT1 deficiency Blood and CSF glucose

Biotinidase deficiency Plasma biotinidase

Peroxisomal disorders Plasma VLCFA, red cell plasmalogens

Molybdenum cofactor

deficiency

Plasma urate and sulphur amino acids

Menkes disease Plasma copper

Hypoglycaemia [any cause]

Maple syrup urine disease Plasma or urine amino acids

Disorders of pyridoxine

and pyridoxal phosphate

metabolism

Trial of treatment,

urine a-aminoadipic semialdehyde,

CSF neurotransmitters

Hyperammonaemia Plasma ammonia

L-2-hydroxyglutaric aciduria Urine organic acids

Mitochondrial disorders,

esp. Alpers’ syndrome

Blood and CSF lactate

NCL [Battens]: infantile,

late infantile and (juvenile)

Electron microscopy of

lymphocytes or skin,

white cell PTT1 or TPP1

enzyme assays

Krabbe (TayeSachs) &

(Sandhoff ) disease

Leukocyte lysosomal enzyme screen


Acute ataxia: occasionally patients will present with an episodic

ataxia. These patients should be screened for maple syrup urine

disease, hyperammonaemia, GLUT1 deficiency and organic

acidaemias.

(Congenital disorders of

glycosylation)

Transferrin isoelectric focussing

Hypoglycaemia

And others

Notes:

1. Seizures are a late feature of many metabolic disorders.

2. Rare causes are shown in brackets.

3. This list is long and it is advisable to discuss investigations with specialist

first. Investigation of CSF is often useful in patients presenting with fits.

If this is done, ensure that samples are collected correctly for all likely possi-

bilities to avoid need for a repeat lumbar puncture.

Any comatose patient or one who has had a fit for which there is

no explanation even if ‘febrile’, should have their blood glucose

measured. The metabolic causes and investigations of hypo-

glycaemia are listed in Table 4. The investigations should be

taken during hypoglycaemia. As a minimum, some plasma

taken during hypoglycaemia should be kept and stored deep

frozen.

Table 2
Hyperammonaemia
Metabolic disorders that may present with a stroke-likeillness


Homocystinuria Plasma amino acids and

total homocysteine

Organic acidaemias Urine organic acids

Ornithine transcarbamylase

deficiency

Plasma ammonia

Mitochondrial disorders

(e.g. MELAS)

Blood mitochondrial

DNA mutations

Plasma ammonia should be measured in every undiagnosed

encephalopathic patient since early intervention is essential.

However the interpretation of results can be problematic. Reference

values are less than 50 mmol/l but any difficulty with the ven-

epuncture, including a child struggling or a haemolyzed sample,

may increase the plasma ammonia concentration. Encephalopathic

patients usually have values>100 mmol/l although in the newborn

in the threshold usually taken to be 200 mmol/l. However it must be

emphasized that the interpretation of plasma ammonia concentra-

tions requires careful assessment of the conditions under which the

blood was collected as well as the effect of any treatment of such as

intravenous glucose.

The metabolic causes of hyperammonaemia and investiga-

tions are listed in Table 5.

Congenital disorders of

glycosylation

Serum transferrin

isoelectric focussing
Disorders of acidebase regulation
Fabry disease Enzyme tests

Table 3

Metabolic acidosis: metabolic acidosis is a common complication

of almost any illness and is usually secondary to tissue hypoxia.

However, if the history suggests previous episodes, there is marked

PAEDIATRICS AND CHILD HEALTH 21:2 52 � 2010 Elsevier Ltd. All rights reserved.


Causes of hypoglycaemia and investigations(taken during hypoglycaemia)

Causes Metabolic investigations

Glycogen storage disease Plasma urea & electrolytes

Disorders of gluconeogenesis Plasma insulin & cortisol

Disorders of fatty acid oxidation Blood glucose, lactate &

3-hydroxybutyrate

Respiratory chain disorders

involving the liver

Plasma free fatty acids

Organic acidaemias Blood spot acyl carnitines

Tyrosinaemia type 1 Liver-function tests &

clotting studies

Ketotic hypoglycaemia Urine organic acids

Endocrine disorders e

hyperinsulinaemia,

adrenal disease,

hypopituitarism, etc.

Liver disease e acute

liver failure, cirrhosis

Others e any severe illness,

poisoning malaria, etc.

Table 4

The major causes of and investigations for metabolicacidosis


Organic acidaemias particularly

methylmalonic and

propionic acidaemia

Congenital lactic acidoses

Fructose 1,6-bisphosphatase

deficiency

Defects of ketolysis

Pyroglutamic aciduria

Other causes e including

diabetes and adrenal insufficiency

Blood gases, anion gap

Blood glucose

Blood lactate

Blood 3-hydroxybutyrate

Plasma amino acids

Blood spot acyl carnitines

Urine ketones

Urine organic acids

Table 6


ketosis or the acidosis persists after tissue perfusion is corrected, the

patient should be investigated for a metabolic problem. The major

causes and the investigations are listed in Table 6.

Respiratory alkalosis: respiratory alkalosis is less common but an

unexplained respiratory alkalosis should be investigated for

hyperammonaemia (see above). This is often a subtle but partic-

ularly characteristic finding in neonates.

Acute liver disease

There are many causes of acute liver disease and the most

common metabolic ones are listed with investigations in Table 7.

Metabolic causes of hyperammonaemia


Urea cycle disorders

Organic acidaemias


oxidation

Transport defects e

lysinuric protein intolerance,

HHH syndrome,

Citrin deficiency

Others: ornithine

aminotransferase deficiency,

pyruvate carboxylase

deficiency, etc.a

Plasma ammonia

Plasma amino acids

Urine organic acids and

amino acids


Blood lactate

a For a full list of inborn errors that cause hyperammonaemia see Table

20.2 in Fernandes et al. (2006).

Table 5


Most of these have parenchymal disease with synthetic dysfunc-

tion including hypoalbuminaemia and clotting abnormalities but

some will present with a more obstructive pictures with conju-

gated hyperbilirubinaemia and secondary abnormalities caused

by the failure of absorption of fat soluble vitamins.

Cardiomyopathy and arrhythmias

Patients with inborn errors may present with a severe cardio-

myopathy and life-threatening arrhythmias. Pompe disease and

disorders of fatty acid oxidation mainly present with hyper-

trophy. In mitochondrial and Hurler disease, the findings are

very variable. Many patients with inborn errors are treated with

restricted diets and vitamin supplements are an essential

component. Omitting these supplements even for surprisingly

short periods may result in thiamine deficiency with a marked

cardiomyopathy. Supplements of thiamine may be lifesaving.

The most important causes and the appropriate investigations

are listed in Table 8.

Metabolic causes of acute liver disease


Tyrosinaemia type 1

Fructosaemia

Galactosaemia (newborn period)

Respiratory chain

disorders including

Mitochondrial DNA depletion

syndrome

Disorders of fatty acid oxidation

Wilson’s disease

Urea cycle disorders (severe)

Disorders of bile acid synthesis

a-1-Antitrypsin deficiency

Niemann Pick type C and

many others

Liver-function tests,

clotting studies

Blood glucose, lactate &

3-hydroxybutyrate,


Plasma amino acids

Serum a-fetoprotein

Serum a-1-antitrypsin

Plasma copper and

caeruloplasmin

Urine organic acids including

succinylacetone

Plasma and urine bile acids

Further investigations

including liver scans and

biopsy may be necessary

Table 7



Metabolic causes of cardiomyopathy



oxidation

Organic acidaemias

Respiratory chain disorders

including Barth syndrome

Storage disorders including

lysosomal storage disorders

such as Pompe disease,

Hurler disease

Glycogen storage disease

(type IIIb) and type IV

(Fabry diseasea)


Urine organic acids

Blood lactate & mtDNA mutations

Blood spot monolysocardiolipin

Urine GAGs [MPS screen]

Blood film for vacuolated

leucocytes

Enzyme studies

GAGs¼ glycosaminoglycans, MPS¼mucopolysaccharidosesa Rare in childhood.b Rarely a presenting feature.

Table 8

Early management of a suspected inborn of metabolism

1. Stop toxic nutrient (protein, galactose, fructose, etc.)

2. General care as with any patient in intensive care

- Secure airway

- Ensure good tissue perfusion

- Treat hypoglycaemia, infection, fits, acidosis,

hyperammonaemia

3. Give high energy intake oral or intravenous. Note: usually

glucose is used but fat emulsions may be given to increase

energy intake except in disorders of fatty acid oxidation

4. Dialysis haemofiltration/haemodialysis (peritoneal dialysis is

used if more efficient methods are not available)

5. Insulin infusion. Note: this is used to reduce catabolism starting

with 0.05 u/kg/h

6. Vitamins and specific therapy e see below

Table 9


Sudden collapse

Disorders that may respond to pharmacological dosesof vitamins or cofactors

Patients with inborn errors may collapse suddenly. Patients with

neurological problems including coma, those with hypoglycaemia

and liver disease may all have a seizure. They may also develop

cerebral oedema with consequent herniation. Patients with clot-

ting abnormalities may have a cerebral haemorrhage.

Patients with the metabolic acidosis may be able to compensate

with increased respiratory effort for a time but when they can no

longermaintain this, theymay collapse. It is important to anticipate

this and, if necessary, start assisted ventilation at an early stage.

Patients with cardiac disease may develop arrhythmias.

Management

The management of these patients is divided into two sections;

firstly the management of acute illness and secondly the preven-

tion of such illness in the first place. All patients who are at risk of

decompensation should have a plan that starts at home to try to

prevent episodes of decompensation.

Disorder Vitamin
Acute illness
Methylmalonic acidaemia Hydroxocobalamin

Biotinidase deficiency Biotin

Holocarboxylase synthetase

deficiency

Biotin

Homocystinuria Pyridoxine

Pyridoxine dependency,

PNPO deficiency

Pyridoxine, pyridoxal phosphate

Vitamin deficiency, MSUD,

Pyruvate dehydrogenase

deficiency and others

(all rare)

Thiamine

Carnitine Carnitine transporter deficiency

Riboflavin

and occasionally others

Multiple acyl-CoA dehydrogenase def

Table 10

After resuscitation and stabilization it is important to document

the clinical state. For patients with neurological illness, the Glas-

gow coma score should be noted. Efforts should be made to

identify the factor that has precipitated the illness such as infection

or fasting. This is not always possible as sometimes patients

become ill for reasons that are not clear.

The steps that should be taken in the treatment of acute illness

are listed in Table 9, together with notes about each stage of the

process.

Some inborn errors will improve markedly if given pharma-

cological doses of cofactor of the defective enzyme. The most

important disorders that may respond are listed in Table 10.

Special problems: hypoglycaemia: it is important to document

hypoglycaemia correctly. Bedside strip tests only give approxi-

mate value despite the apparent accuracy of the metres so that


blood glucose should always be measured in the laboratory. It

should then be corrected, either orally or intravenously, depend-

ing on the patient’s condition. If corrected with intravenous

glucose, give 2 ml glucose 10%/kg followed by the infusion of

10% glucose approximately equal to the normal glucose utiliza-

tion rate (children 4e7 mg/kg/min; adults 2 mg/kg/min). Blood

glucose concentrations should be reviewed after approximately

15e30 min.

Metabolic acidosis: the blood pH must be monitored carefully.

Peripheral perfusion, dehydration and infection shouldbe corrected

first and appropriate steps taken if the blood pH is critical despite

assisted ventilation. A convenient cut off is pH of <7.1 (or greater

than this if the patient is clearly deteriorating). This situation is not

the same as diabetic ketoacidosis, as the acidosiswill not respond to

insulin quickly. Hence sodiumbicarbonate should be given as a half

correction ((base deficit � weight (kg) � 0.3)/2). The sodium



Key learning points

C A high index of suspicion is needed to identify patients with

inborn errors.

C Early diagnosis and treatment are important to achieve a good

outcome.


bicarbonate should be administered slowly and reviewed

frequently. The plasma electrolytes must also be monitored. Hae-

modialysis should be considered if the plasma sodium starts to rise

or if the acidosis is not controlled.

Hyperammonaemia: the treatment of hyperammonaemic

encephalopathy is urgent. The same steps are followed as those for

the general patient. In addition arginine, sodium benzoate and

sodium phenylbutyrate should be given early if these are available

and the patient transferred to a specialist centre as quickly as

possible.

Cerebral oedema: it cannot be stressed too strongly that early

intervention is essential to prevent cerebral oedema as, once

established, it is difficult to reverse. It is commonly the cause of

death in these patients. The management once oedema is estab-

lished is standard.

Catabolism: acute decompensation in patients with inborn errors

is often precipitated by infection or fasting and triggering catabo-

lism. Every effort should be made to reverse this. A high energy

intake is given either orally or intravenously. More calories can be

given more quickly orally which is the preferred route if at all

possible. However if the patient cannot tolerate oral feeding,

glucose should be given intravenously, if necessary by central line.

Protein should always be introduced fairly early since failure to do

so will prolong the catabolic state.

Specific treatment: in a few disorders specific management is

vital. In the urea cycle disorders, the use of sodium benzoate,

sodium phenylbutyrate and arginine is essential. In tyrosinaemia

type 1, nitisinone (NTBC) is needed urgently to prevent severe

liver damage. In maple syrup urine disease, encephalopathy

results from the accumulation of branched-chain amino acids

(BCAA). This can be reduced by giving a BCAA-free amino acid

mixture. It is usually given enterally but intravenous preparations

are now available at a few specialist centres. Fructose, sorbitol and

sucrose must be omitted from patients with fructosaemia and

fructose 1,6-bisphosphatase deficiency during acute illness.

Full details of the emergency management of inborn errors that

may present acutely are on the British Inherited Metabolic Disease

Group (BIMDG) website. These are readily accessible and free.

Haemofiltration: the prognosis is poor for patients with severe

hyperammonaemia, especially for babies with values >1000

mmol/l, and this needs to be discussed with the parents before

proceeding with invasive management. If these patients are to be

managed actively, haemofiltration should be started as soon as

possible. Haemofiltration is also needed for severe acidosis

(particularly organic acidaemias) or encephalopathy (particularly

maple syrup urine disease). This intervention can be lifesaving

and will reduce subsequent handicap.

Prevention of acute decompensation

Many inborn errors are stable for much of the time but still have

episodes of acute illness. Prevention is an important part of the

management for these patients. The families must understand

the disorder, be taught to recognise both precipitating factors and


early symptoms. The factors that commonly precipitate decom-

pensation include fasting and infection. The earliest symptoms

are usually just not feeling well, anorexia, vomiting, ataxia or, in

some conditions, hyperventilation. Each patient is different and it

is important to identify the earliest symptoms and discuss these

with the family.

The family should have clear instructions of exactly what to do

and when to make decisions. Almost invariably the mainstay of the

treatment at home is a high carbohydrate drink given frequently

including during the night. The family should always carry details

of their condition and the acute management. A laminated A5 sheet

has been found tobe very acceptable.More details of the emergency

regimens can be found in Dixon and Leonard (1992).

Anaesthesia and surgery may also cause problems. If the patient

is due to have an elective procedure with an anaesthetic then this

requires careful planning (for more information please refer to the

protocols on theBIMDGwebsite). It is essential to ensure that a high

calorie intake is given throughout and after the procedure to avoid

the triggering decompensation.

Conclusions

Inborn errors that present acutely are often treatable and delay

will worsen the outcome. It is important to have a simple strategy

for identifying patients at high risk. Treatment does not need to

wait for a diagnosis but can start at once. Every effort should be

made to prevent or reduce episodes of decompensation. A

FURTHER READING

Clarke JTR. A clinical guide to inherited metabolic diseases. 3rd Edn.

Cambridge: Cambridge University Press, 2006.

Detailedand free instructions on the acute andprospectivemanagement of

inborn errors of metabolism and can be found on the British Inherited

Metabolic Disease Group (BIMDG) http://www.bimdg.org.uk/.

For more information about individual disorders readers should consult:

Fernandes J, Saudubray JM, van den Berghe G, et al. Inborn metabolic

diseases: diagnosis and treatment. 4th Edn. Heidelberg: Springer,

2006.

For details about the diagnosis and management of inborn errors in the

perinatal period refer to: Leonard JV, Morris AA. Diagnosis and early

management of inborn errors of metabolism presenting around the

time of birth. Acta Paediatr 2006; 95: 6e14.

For background to emergency regimens: Dixon MA, Leonard JV. Intercur-

rent illness in inborn errors of intermediary metabolism. Arch Dis Child

1992; 62: 1387e91.




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