inborn error of metabolism

Inborn Error of Metabolism

Single gene mutations

Alteration of primary protein structure

Alteration of the amount of protein synthesized

Mild to lethal

Inheritance:

• Most IEM…… autosomal recessive genetic traits

• Urea cycle disorder ornithine transcarbamylase

deficiency…….. X linked

• Some are mitochondrial inheritance

Metabolic disorders can be classified using a

variety of schemes based on:

the clinical presentation

the age of onset

the tissues or organ systems involved

the defective metabolic pathways

Classifications of IEM

Amino acids • Phenylketonuria- Homocystinuria - tyrosinemia

Lipidoses • Tay sach’s disease – Gaucher’s disease –

metachromatic leukodystrophy

carbohydrates • Galactosemia – fructose intolerance –

Glycogen storage disorders

Organic acidemia • Methylmalonic aciduria- propionic aciduria-

maple syrup urine disease

Transport disorders • Cystinuria cystinosis – hypercholesterlemia

(AD)

Peroxisomal disorders

• Adrenoleukodystrophy – zellweger syndrome – chondrodysplasia punctata

Lysosomal storage disorders

• mucopolysaccaridosis

Urea cycle disorders • Ornithine transcarbamylase deficiency-

arginosucciniase deficiency- carbamyl phosphate synthetase deficiency

Metal metabolic disorders

• Wilson’s disease – Menkes disease

Group 1

Anabolism/

catabolism

Lysosomal, Peroxisomal, glycosylation, and cholesterol synthesis defects

some Lysosomal disorders can be efficiently treated by enzyme replacement or substrate reduction therapies

Group 2

intermediary

metabolism

Aminoacidopathies, organic acidurias, urea cycle disorders, sugar intolerances, metal disorders and porphyrias

Acute or chronic intoxications

Neonatal to adulthood

Most …. treatable emergency removal of the toxin by special diets, extracorporeal procedures, cleansing drugs or vitamins

Group 3

energy production/

utilization

Cytoplasmic defects encompass those affecting glycolysis, glycogenosis, gluconeogenesis, hyperinsulinisms, and creatine and pentose phosphate pathways; the latter are untreatable.

Mitochondrial defects include respiratory chain disorders, and Krebs cycle and pyruvate oxidation defects, mostly untreatable, and

disorders of fatty acid oxidation and ketone bodies that are treatable

Clinical presentations:

• Pregnancy:

acute fatty liver of pregnancy- HELLP

syndrome………… long chain 3 hydroxy coenzyme

A dehydrogenase deficiency (LCHADD)

Clinical presentations:

• Sepsis like presentation

• Mental retardation

• Neurological impairment, Seizures,

Encephalopathy, tone abnormalities

• Sudden infant death

• Metabolic acidosis

• Hypoglycemia

• Liver dysfunctions

• Dysmorphic features

• Cardiac disease

• Hydrops fetalis

• Abnormal urine odor

Inborn Errors of Metabolism with hydrops

fetalis

• Lysosomal disorders:

- Mucopolysaccaridosis types I, IVA, VII

- Gaucher disease

- Nieman pick disease type c

- Farber disease

• Hematologic disorders:

- G-6-PD deficiency

- Pyruvate kinase defieciency

• Others:

- Neonatal hemochromatosis

- Respiratory chain disorders

Evaluation

• History, Family history:

parental consanguinity, unexplained neonatal

deaths

• Physical examination:

facial dysmorphism, cataracts, retinopathy,

structural brain anomalies, hypertrophic or dilated

cardiomyopathy, hepatomegaly, multicystic

dysplastic kidneys and myopathy.

Evaluation

Initial Evaluation

CBC

Blood glucose

Plasma ammonia

Plasma lactate,

pyruvate Liver

functions tests

Urine reducing

substances

Urine ketones

Electrolytes, Ca, Mg

2nd line Evaluation

carnitine, acylcarnitine

s, vLCFA enzymes

Magnetic resonance imaging

(MRI)

Magnetic resonance spectroscopy (MRS)

Plasma aminoaci

d analysis Urine

organic acid

analysis

EEG

Mutation analysis

CSF aminoacid analysis

Phenylketonuria Disorder

1:15000 Incidence

Autosomal recessive Inheritance

Phenylalanine hydroxylase (> 98 percent)

Biopterin metabolic defects (< 2 percent)

Metabolic error

Mental retardation, acquired microcephaly Key manifestation

Plasma phenylalanine concentration Key laboratory test

Diet low in phenylalanine Therapy approach

Maple syrup urine disease Disorder

1:150,000 Incidence


Branched-chain 3-keto acid

dehydrogenase

Metabolic error

Acute encephalopathy, metabolic

acidosis, mental retardation

Key manifestation

Plasma amino acids and urine organic

acids

Dinitrophenylhydrazine for ketones

Key laboratory test

Restriction of dietary branched-chain

amino acids

Therapy approach

Carbohydrate metabolism Galactosemia Disorder

1:40000 Incidence


Galactose 1-phosphate

uridyltransferase (most common);

galactokinase; epimerase

Metabolic error

Hepatocellular dysfunction, cataracts Key manifestation

Enzyme assays, galactose and

galactose 1-phosphate assay,

molecular assay

Key laboratory test

Lactose-free diet Therapy approach

Glycogen storage disease, type Ia

(von Gierke's disease)

Disorder

1:100000 Incidence


Glucose-6-phosphatase Metabolic error

Hypoglycemia, lactic acidosis, ketosis Key manifestation

Liver biopsy enzyme assay Key laboratory test

Corn starch and continuous overnight

feeds

Therapy approach

Fatty acid oxidation

Medium-chain acyl-CoA

dehydrogenase deficiency

Disorder

1:15000 Incidence


Medium-chain acyl-CoA dehydrogenase Metabolic error

Nonketotic hypoglycemia, acute

encephalopathy, coma, sudden infant

death

Key manifestation

Urine organic acids, acylcarnitines, gene

test

Key laboratory test

Avoid hypoglycemia, avoid fasting Therapy approach

Lactic acidemia

Pyruvate dehydrogenase deficiency Disorder

1:100000 Incidence

X linked Inheritance

E1 subunit defect most common Metabolic error

Hypotonia, psychomotor retardation,

failure to thrive, seizures, lactic acidosis

Key manifestation

Plasma lactate

Skin fibroblast culture for enzyme

assay

Key laboratory test

Correct acidosis; high-fat, low-

carbohydrate diet

Therapy approach

Lysosomal storage

Gaucher disease Disorder

1:60,000; type 1–1:900 in Ashkenazi

Jews

Incidence


β-glucocerebrosidase Metabolic error

Coarse facial features,

hepatosplenomegaly

Key manifestation

Leukocyte β-glucocerebrosidase assay Key laboratory test

Enzyme therapy, bone marrow transplant Therapy approach

Fabry's disease Disorder

1:80,000 Incidence


α-galactosidase A Metabolic error

Acroparesthesias, angiokeratomas

hypohidrosis, corneal opacities, renal

insufficiency

Key manifestation

Leukocyte α-galactosidase A assay Key laboratory test

Enzyme replacement therapy Therapy approach

Hurler's syndrome Disorder

1:100000 Incidence


α-l-iduronidase Metabolic error

Coarse facial features,

hepatosplenomegaly

Key manifestation

Urine mucopolysaccharides Leukocyte α-

l-iduronidase assay

Key laboratory test

Bone marrow transplant Therapy approach

Organic aciduria

Methylmalonic aciduria Disorder

1:20000 Incidence


Methylmalonyl-CoA mutase, cobalamin

metabolism

Metabolic error

Acute encephalopathy, metabolic

acidosis, hyperammonemia

Key manifestation

Urine organic acids Skin fibroblasts for

enzyme assay

Key laboratory test

Sodium bicarbonate, carnitine, vitamin

B12, low-protein diet, liver transplant

Therapy approach

Propionic aciduria Disorder

1:50000 Incidence


Propionyl-CoA carboxylase Metabolic error

Metabolic acidosis, hyperammonemia Key manifestation

Urine organic acids Key laboratory test

Dialysis, bicarbonate, sodium benzoate,

carnitine, low-protein diet, liver transplant

Therapy approach

Peroxisomes

Zellweger syndrome Disorder

1:50000 Incidence


Peroxisome membrane protein Metabolic error

Hypotonia, seizures, liver dysfunction Key manifestation

Plasma very-long-chain fatty acids Key laboratory test

No specific treatment available Therapy approach

Urea cycle

Ornithine transcarbamylase deficiency Disorder

1:70000 Incidence


Ornithine transcarbamylase Metabolic error

Acute encephalopathy Key manifestation

Plasma ammonia, plasma amino acids

Urine orotic acid

Liver (biopsy) enzyme concentration

Key laboratory test

Sodium benzoate, arginine, low-protein

diet, essential amino acids; dialysis in

acute stage

Therapy approach

Treatment

Prevent Catabolism:

Administration of calories is used in the treatment of

acute episodes to try to slow down catabolism.

Limit the Intake of the Offending Substance:

the basis of treatment in Galactosemia, fructose

intolerance and PKU.

Increase Excretion of Toxic Metabolites:

by exchange transfusion, peritoneal dialysis (PD),

hemodialysis, forced diuresis, using alternative

pathways for the excretion of toxic metabolites. For

example, carnitine is useful in the elimination of organic

acids in the form of carnitine esters. Sodium benzoate

and phenylacetate are useful in treating

hyperammonemia.

Enzyme Replacement Therapy:

Human alpha glucosidase enzyme (pompe’s disease)-

Laronidase (Aldurazyme) enzyme(MPS I)patients-

Fabry-specific enzyme replacement therapy (ERT) with

recombinant alpha-Gal A (Fabrazyme) is safe and

effective, Imiglucerase (Gaucher disease)

Increase the Residual Enzyme Activity:

B12 decreases the urinary levels of methyl malonate by

enhancing activity of Trans Cobalmin II

Reduce Substrate Synthesis:

Inhibition of substrate synthesis has been used as a

strategy for treating glycolipid Lysosomal storage

disease.

Replacement of the End Product:

Hypoglycaemia can be prevented by frequent feeds

during the day and continuous nasogastric feeding

at night, in infancy and early childhood. Raw

cornstarch (2 g/kg every six hours) has been shown

to be effective in preventing hypoglycaemia in older

children with glycogen storage disease type I as

well as decreasing the hyperlipidaemia,

hyperuricaemia, and lactic acidaemia

Transplantation and Gene Therapy:

For the last 25 years, hematopoietic cell

transplantation (HCT) has been used as effective

therapy for selected inborn errors of metabolism

(IEMs), mainly Lysosomal storage diseases and

Peroxisomal disorders. The main rational for HCT in

IEMs is based on the provision of correcting

enzymes by donor cells within and outside the blood

compartment

Prevention

Genetic counselling and prenatal diagnosis:

The samples required are chorionic villus tissue or

amniotic fluid. Modalities available are:

• Substrate or metabolite detection: useful in

phenylketonuria, peroxisomal defects.

• Enzyme assay: useful in lysosomal storage

disorders like Niemann-Pick disease, Gaucher

disease.

• DNA based (molecular) diagnosis: Detection of

mutation in proband/ carrier parents is a

prerequisite.

Neonatal screening: tandem mass spectrometry

Selective screening for inborn errors of metabolism

by tandem mass spectrometry in Egyptian children:

A 5 year report

• A relatively high number of patients (203/3380 (6%))

were confirmed with 17 different types of IEMs.

Averages for age at diagnosis for different disorders

ranged from 2.5 months to 6.6 years with general

developmental delay and irreversible neurological

damage being the most common presenting features

(75.9% and 65.5%, respectively). Amino acid disorders

(127/203 (62.6%)), mainly phenylketonuria (100/203

(49.3%)), were the most encountered, followed by

organic acidemias (69/203 (34%)), while fatty acid

oxidation defects (7/203 (3.4%)) were relatively rare.

88% of patients were born t consanguineous parents.

References

• Talkad S. Raghuveer and et.al. Inborn Errors of

Metabolism in Infancy and Early Childhood: An

Update. American Family Physician j.2006:

17:1981-1990

• Atlas of Metabolic Diseases, 2nd edition

• Ananth N Rao, J Kavitha, Minakshi Koch and

Suresh Kumar V. Inborn Errors of Metabolism:

Review and data from a tertiary care center.

Indian Journal of Clinical Biochemistry, 2009: 24

(3) 215-222

• Anju Gupta. To Err is Genetics: Diagnosis and

Management of Inborn Errors of Metabolism

(IEM)

• Laila A. Selim and et.al. Selective screening for

inborn errors of metabolism by tandem mass

spectrometry in Egyptian children: A 5 year

report. Clinical Biochemistry 47 (2014) 823–828

inborn error of metabolism

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