iem india perspective n b kumta maharashtra

8/12/2019 Iem India Perspective n b Kumta Maharashtra

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Indian Journal of Pediatrics, Volume 72April, 2005 325

Symposium on Fest - Schrift for Late Dr. P.M. Udani

Correspondence and Reprint requests :Dr. N.B. Kumta, Departmentof Pediatrics, KEM Hospital, Mumbai, Maharashtra, India.

Inborn Errors of Metabolism (IEM) An IndianPerspective

N.B. Kumta

Department of Pediat rics, KEM Hospital , Mumbai, M aharashtra, Indi a.

There is an accelerating demographic switch fromcommunicable diseases to genetic disorders. Theexpression of a genetic disease is the combined effect ofgenes and the environment. There are 24 million births inIndia annually; 780,000 are born with congenitalmalformation, 340,000 with G6PD, 20,800 with metabolicdisorder, 21,000 with Down syndrome, 10,400 withcongenital hypothyroidism, 9000 with thalassemia and5200 with sickle cell anemia. In a hospital based study inIndia biochemical screening of 4400 cases of mentalretardation revealed that 5.75 % (256 cases ) were due toa metabolic disorder.1,2

Mechanism of Metabolic Disorders

commenced early and long term outcome maybeimproved3and correct early diagnosis helps in geneticcounseling. Use of blood gases, electrolytes, ammonia,lactate, pyruvate, urine metabolic spot tests, gaschromatography mass spectroscopy (GCMS) or tandemmass spectrometry (TMS) for organic acids, amino acidchromatography, enzyme estimations in white cells, skinfibroblasts and other tissues have made diagnosispossible.

In neonatal IEM pregnancy, delivery is uneventful. Thenewborn baby with IEM is normal for the first three orfour days after which the disorder presents due to intakeof dietary protein etc. Neonates with IEM are

misdiagnosed to have sepsis or other disorders. Sepsisoften accompanies IEM and may confound diagnosisfurther. Pediatricians often think that neonatal IEM israre. Though individual disorders may be uncommonthese disorders are fairly common when consideredtogether. Though IEM are usually recessive disorders theyare very often occur in only one sib. The neonate has alimited response to illness and predominant symptoms &signs are poor feeding, lethargy, coma, failure to thrive,seizures, acidosis or ketosis. Emergency adequatelaboratory facilities to diagnose neonatal IEM are scarceand lacking in India leading to delays in diagnosis,treatment and hence a poor prognosis in most cases.A high index of suspicion is necessary when thefollowing are present :Parental consanguinityPositive family history of a similar illness/deathSymptoms onset a few days after feeding (refusal to feed,lethargy, vomiting, hypotonia, coma, seizures)Ketosis, acidosis, hypoglycemiaUnusual odour to the urineJaundice, visceromegalyDysmorphic features or coarse facies

Abstract.The inborn errors of metabolism (IEM) constitute a diverse heterogeneous group of disorders with protean clinicalmanifestations presenting mainly in the pediatric population. Though individually rare, together they constitute a significant

percentage of children seen in genetic and neurology clinics. This review focuses on selected IEMs and highlights those seenin the neonatal period. Data from Indian centers are presented. It also emphasizes principles of management in these difficult

disorders in the context of a developing country. [Indian J Pediatr 2005; 72 (4) : 325-332] E-mail : [email protected]

Key words : Inborn errors of metabolism; Neurometabolic; Childhood; India

Toxic metabolite D

Precursor A EA Substrate B EBC Product C

EAB is an enzyme converting A into B. EBC, the enzymeconverting B into C, is absent and is the cause of the IEM.This leads to accumulation of substrate B to abnormallevels which then gets diverted to an abnormal metabolicpathway to yield a toxic metabolite D. B or D could betoxic. B & D could be detected and EAB can be estimated

biochemically.NEONATAL IEM

Organic aciduria or urea cycle disorders are notuncommon and often present fulminantly. Earlydiagnosis is crucial for three reasons,1the condition israpidly progressive and causes irreversible damage earlyin the course,2the treatment can often be effective if


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N.B. Kumta

326 Indian Journal of Pediatrics, Volume 72April, 2005

Specific Features in Certain Neonatal IEM.(1) Abnormal urine or body odouris characteristic of some

IEM MSUD maple syrup or burnt sugar smell,Isovaleric acidemia, Glutaric aciduria type II sweaty feet smell, Phenylketonuria -mousy ormushy, methyl crotonyl aciduria tom cat urine,Methionine malabsorption cabbage, Trimethylaminuria rotting fish, Tyrosinemia rancid orfishy odour.

(2) Diarrhoea:(a) Severe watery diarrhoea congenitalchloride diarrhoea, galactosemia, primary lactase,sucrase, isomaltase deficiency. (b) Chronicdiarrhoea- bile acid disorder,infantile Refsumdisease, respiratory chain disorders associated withsteatorrhoea , vitamin deficiency osteopenia,hypocholesterolemia (c) Diarrhoea, failure to thrive,hypotonia hepatomegaly - GSD I, Wolmans disease

(3) Card i omyopa thy , Ca rd i a c Fa i l u r e- Pompesdisease GSD II,respiratory chain disorder, fatty acidoxidation (FAO) defects

(4) Hepa tomega ly - Tyrosinemia, galactosemia,fructosemia and alpha 1 antitrypsin deficiency,GSD. Hepatomegaly with splenomegaly considermucolipidosis, Gauchers disease Niemann-Picktype A

(5) Sei zur es -Nonketotic hyperglycinemia, pyridoxinedependency, and molybdenum co-factordeficiency. In most others seizures are associatedwith coma and hyperglycinemia

IEM has a Characteristic

1 Age of onset2 Temporal profile i.e. evolution of the disease with

characteristic symptom & sign as the diseaseadvances; affected sibs usually show a similartemporal profile

3 IEM has a characteristic inheritance pattern eg.ornithine transcarbamylase deficiency (OTC), Fabrysdisease, Menkes disease and Hunters disease are X-linked recessive and most others are autosomalrecessive.

4 Often there are characteristic triggers environ-mental factors which precipitate the presentation ofthe IEM e.g. diet, infection, fasting, drugs (see below)

5 Age of neurological manifestations and death

Triggering Factors Precipitating IEM1 Diet:Introduction of cane sugar - hereditary fructose

intolerance, milk - galactosemia, proteins = urea cycledisorders (UCD), MSUD and other aminoaciddisorders. carbohydrate - pyruvate dehydrogenase& respiratory chain disorders.

2 I nfect i on, Fasti ng and Fever:FAO defects, certainaminoacid disorder and organic aciduria.

3 Anaesthesia -Homocystinuria4 Dr ugs -Porphyria and G6 PD deficiency

Group 1- Aminoacidopathies: Neurologic DistressIntoxication Type With Ketosis

MSUD Maple syrup urine disease only amino aciddisorder that presents acutely in the neonatal period.

TABLE1. Diagnostic Approach to IEM - Small Molecular Diseases

Metabolic Ketosis Lactic Hyper- LiverAcidosis Acidosis ammonemia Dysfunction

Group 1 Aminoacidopathies _ + + +/- _ _ _Group 2 Organic acidopathies + + + + + + + +/- _Group 3 Primary lactic acidosis + + + + + + + +/- +/-Group 4a Urea cycle disorders _ _ _ + + + +/-Group 4b Perxisomopathies, NKH,

SO deficiency _ _ _ _ _Group 5 Galactosemia, Fructosemia,

Fat oxidation defects, GSD,tyrosinemia +/- +/- +/- _ + + +

TABLE3. Organic Acidurias (Total: 58 KEM Hospital 1978 2004 )

Glutaric academia type 1 12 B ketothiolase deficiency 6Methylmalonic academia 10 Biotinidase deficiency 2Propionic academia 7 3 methylglutaconic aciduria 2Fatty acid oxidation defects 7 Carnitine transport defect 1

Undiagnosed 11

TABLE4. Mitochondrial & Ox-phos Disorders (Total: 44 KEMHospital, Mumbai 1978 2004 )

Respiratory chain disorders 11Leigh disease 6Alper poliodystrophy 5MELAS 2Undifferential lactic acidosis/Mitochondrial disorders 16Citric acid cycle defects 3Pyruvate dehydrogenase deficiency 1

TABLE2. Analysis of Cases of IEM Investigated at KEM Bombay(from 1978 - 2004 ) Total IEM : 1016 aminoacid disorder =

204 (20.1 % )

Albinism 100 MSUD 7Alkaptonuria 27 Tyrosinemia 4Urea cycle defects 19 Hartnup disease 1Homocystinuria 16 Histidinemia 1Phenylketonuria 16 Cystinosis 1Cystinuria 12


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Inborn Errors of Metabolism (IEM) An Indian Perspective


It is a branch chain amino acid (BCAA) disorder i.e.leucine, isoleucine and valine. Deficiency of ketoaciddehydrogenase results in formation of ketoacids, whichgive a strongly positive urinary dipstick test for ketones.There is a strong smell of maple syrup to the urine. Initial3 - 4 days after birth are normal; feeding difficulties startand gradually the neonate becomes comatose withepisodic generalized hypertonia, dystonia, ophisthotonosand boxing / pedaling movements. Urine DNPH test isstrongly positive and test for acetone is negative. Plasmaamino acid chromatography displays elevation ofbranched chain amin oacids . Dialys is removes thebranched chain aminoacids and should be institutedpromptly. Treatment of cerebral oedema is mandatoryand special f ormula feeding with low BCAA is the mostimportant part of management. Liver transplant offerspromising results. Prognosis is guarded. Intercurrentinfections leads to severe ketoacidosis, cerebral oedemaand death.

Group 2 - ORGANIC ACIDOPATHIES: Methylmalonicacademia (MMA), Propionic academia (PA), Isovalericacademia (IVA) : Neurologic distress intoxication typewith ketoacidosis and hyperammonemia

Infants present with recurrent vomiting, deep acidoticbreathing and failure to thr ive. They are acutely ill,dehydrated and hypothermic. There is truncal andperipheral hypotonia and coarse limb tremors. The bloodbica rbon ate is low wi th an increased anion gapNeutropenia and thrombocytopenia are also common,along with ketonuria. GCMS or tandem massspectroscopy gives confirms the correct diagnosis andMMA, PA and IVA account for 90% of neonatal

presenting organic acidopathies. Propionic acid is a potentinhibitor of mitochondrial function resulting inaccumulation of lactic acid and ketones leading tometabolic acidosis. MMA sometimes responds to highdoses of vitamin B12while PA might respond to biotin.

Treatment:Dialysis is used to to remove the offendingorganic acid and elevated ammonia. Dietary proteinrestriction, avoidance of fasting and metronidazoletherapy ( to reduce organic acid production by gut flora)are other measures.

Differential diagnosis includes the adrenogenitalsyndrome with high potassium and low sodium, sepsiswith neutropenia and thrombocytopenia and the UCD.

Group 3 Primary Lactic Acidosis (PDH PC ETC def.)With Neurologic Distress; Energy Deficiency type

Enzyme defects in Krebs cycle leads to respiratory chaindeficiencies. The most common of these disorders arepyruvate dehydrogenase (PDH), pyruvate carboxylase(PC) and electron transport chain (ETC) deficiencies. PDHis an X-linked disorder. Boys present with severemetabolic and lactic acidosis in the neonatal period.Clinically the neonate is neurologically depressed andserum lactate is markedly elevated. There is an elevated

anion gap because of the elevated lactate and ketosis. Theketogenic diet & dichloracetate 25 to 100 mg/kg orally orparentally may produce a response in 24 hours.Thiaminesupplements may be tried. PC deficiency is an ARdisorder with lactic acidosis and neurological dysfunctionin the newborn period and intermittent ataxia in later life.PC deficiency in early life characteristically has anelevated lactate to pyruvate ratio, moderate citrullinemia,hyperammonemia and hyperlysinemia (type B) while inthe later onset variant moderate lactic acidosis &developmental delay occur (type A). The other featuresare spasticity, severe psychomotor retardation andseizures. Holocarboxylase, synthase and biotinidasedeficiencies present with rash, alopecia, lactic acidosis andwill remain asymptomatic if biotin supplementation (5 to20 mg/day) is started before brain damage occurs. This ispossible after newborn screening. A trial of biotin iswarranted in all patients with lactic acidosis

Though ETC deficiencies may respond to specificvitamins like riboflavin, L-carnitine and co-enzyme Q the

response is usually less than satisfactory.

Group 4a Urea Cycle Disorders (UCD): NeurologicDistress Due to Intoxication; HyperammonemiaWithout Ketoacidosis

Transamination reactions in most amino acid catabolicpathways result in transfer of amino group to glutamineand glycine either of which might release ammonia intothe urea cycle converting it to urea.

Proximal defects in this pathway result in severeaccumulation of ammonia vis--vis distal defects.

Ammonia is toxic and causes cerebral oedema leadingto drowsiness, lethargy, coma, seizures and early death.

Ornithine transcarbamylase (OTC) deficiency is X-linked.All others are inherited as autosomal recessive.Measurement of plasma ammonia, plasma aminoacidsand urinary amino and orotic acids are crucial to identifythe specific defects in the UCD. Citrullinemia,argininosuccinic acidemia and argininemia are diagnosedby aminoacid chromatography, whereas OTC deficiencyand carbamoylphosphate synthetase (CPS) deficiencybeing more proximal defects give deficiencies of citrullineor arginine. These latter two are differentiated on thebasis of an elevated orotic acid excretion in the urine. Thediagnosis is also confirmed by enzyme estimation in skinfibroblast or in the liver cells. Treatment of UCD involvesdietary protein restriction, sodium benzoate and phenyl

butyrate therapy. The more distal defects are moreamenable to treatments with drugs. Prognosis dependsheavily on the degree of the cerebral damage sustainedprior to the diagnosis and treatment.

Group 4b Nonketotic hyperglycinemia (NKH) :Neurologic distress due to energy deficiency; typewithout ketoacidosis and without hyperammonemia

This is characterized by poor feeding, failure to suck,lethargy hypotonia, coma, and myoclonic jerks appearing


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N.B. Kumta


TABLE5. Urea Cycle Disorders

Inheritance Deficient enzyme Orotic acid in urine Plasma citrulline Plasma argininosuccinicacid

AR CPS Low LowX-linked OTC High LowAR ASS High Very high

(> 1000 uM)AR ASL High High(100 300 uM) High

AR Arginase High Normal

CPS Carbamoylphosphate synthetase, OTC ornithine transcarbamylase, ASS argininosuccinate synthetaseASL arginiosuccinate lyase.

TABLE9. Disorders of Carbohydrate Metabolism (n=63) during1978-2004 at KEM Hospital, Mumbai

GSD 35 Galactosemia 20GIPUT DEF 11

Type 1 6 GK DEF 6Type 2 2 Duarte Variant 1Type 3 16Type 4 1 Disorders of Fructose Metabolism 2Type 6 2Type 8 1 Fructosuria 1Type 9 3 FDP Deficiency 1Untyped 5 Pentosuria 3

TABLE10. Miscellaneous Diseases at KEM Hospital, Mumbai(19782004)

Lesch Nyhan syndrome 3 Adrenoleukodystrophy 2Porphyria 7 Refsum Disease 2Criggler Najjar syndrome 3 Peroxisomal Untyped 1Cerebrotendinous Xanthomatosis 2 Uric Acid Urolithiasis 1Hypobetalipoproteinemia 3 B6 Dependancy 1Chanarin Dorfman 2 Pelizaeus Merzbacher 6

TABLE6. Small-molecule Disease VsComplex Molecular Disease -Organelle Diseases

Clinical Feature Organelle Disease Small-molecule Disease

Onset Gradual Often sudden, especially with stressCourse Slowly progressive Characterized by relapses and remissionsPhysical findings Often typical and helpful NonspecificHistopathology Often reveals typical changes Generally nonspecific

Response to supportive therapy Poor, incomplete Often briskSome examples Most lysosomal storage diseases; most Many of the aminoacidopathies; most organic

peroxisomal disorders; many mitochondrial acidopathies, UCDsETC defects

TABLE7. Distribution of Mucopolysaccharidoses (n=189) &Mucolipidosis (n=7) in KEM Hospital, Mumbai (1978 2004)

Mucopolysaccharidoses 189 Mucolipidoses 7

Type I H*/S**/HS*** 14/2/1 Type II 3Type II 33 Type III 4Type III 44Type IV 44Type VI 33

Type VII 1Untyped 17

*Hurler, **Schei's, ***Hurler - Schei's

TABLE8. Distribution of Lysosomal Storage Disorders (n=249) atKEM Hospital, Mumbai (1978 2004)

GM2 Gangliosidosis 70 Fucosidosis 4Metachromatic LD 53 Mannosidosis 3Niemann Pick disease 33 Canavan disease 2Krabbe disease 27 Farber disease 1Gaucher disease 24 Fabrys disease 1GM1 Gangliosidosis 24 Wolman disease 1Mucosulfatidosis 4 Neuronal ceroid lipofuscinosis 2

within few hours of birth in an infant with no history ofperinatal insults. A burst suppression EEG pattern,elevated plasma glycine, elevated CSF to plasma glycineratio constitutes the diagnosis of neonatal NKH.

Molybdenum co-factor deficiency / sulfite oxidasedeficiency present similarly with hypotonia, seizures,dysmorphic features and cataracts. Diagnosis is suggestedby a very low plasma uric acid and presence of sulfites infresh urine while aminoacid chromatography shows highsulfite concentration in the form of sulfocystenine.

Group 4c - Lysosomal Storage Disorders WithoutMetabolic Disturbances

Few lysosomal disorders present in the neonatal period.These disorders are GM 1 ganglioidosis, Gauchersdisease, Niemann-Pick disease type C, MPS VII andsialiodosis.

Other disorders are glycogenosis (GSD) andgluconeogesis defects, fatty acid oxidation defects etc.


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SELECTED IEMS PRESENTING AFTER THENEONATAL PERIOD

Neurometabolic/Neurodegenerative DisordersThese are genetically inherited disorders with progressiveneurologic deterioration, having a demonstrablebiochemical abnormality associated with enzyme defects.

Heterozygote detection and prenatal diagnosis ispossible. Most of them belong to the lysosomal storagedisorders leading to neural, neurovisceral and musculo-skeletal manifestations. Simple molecular disease likeamino acid, sugar, organic acids and UCD have acatastrophic presentation whereas complex moleculardiseases have an insidious onset and a chronic cour

Fig. 1. Approach to A Neonate With Hyperammonemia

NeonatalHyperammonemia

Symptoms in first24 hr of life

Symptoms in first24 hr of life

PrematureFull-term

THAN*PC Deficiency

AcidosisNo acidosis

ORGANICACIDEMIA

UREACYCLEDEFECTS

Plasma AminoacidsCitrulline

Citrullinemoderatelyelevated; ASApresent

Citrullinemarkedlyelevated;no ASA

Absentcitrulline

ARGININOSUCCINIC

ACIDURIA

CITRULLINEMIA

Urine oroticacid

ElevatedLow

OTCDEFICIENCY

CPSDEFICIENCY


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N.B. Kumta


DISORDERS OF COPPER METABOLISM

A total of 146 children were seen at the KEM with 142being Wilsons disease and 4 being Menkes disease.

Wilsons disease is an inborn error of coppermetabolism. It is an autosomal recessive disorder with anincidence 1 in 35,000 1,00,000; the gene is located at 13q

14 21. It is characterized by increased copper depositionin the liver, brain, kidneys and corneas. Classically, thereare specific progressive neurological findings, chronicliver disease or cirrhosis, renal tubular dysfunction,sunflower cataract and pigmented corneal rings (Kayser Fleischer rings). However, the variability of the diseaseis such that it should be suspected in any patient withunexplained neurologic or psychiatric dysfunction,hepatitis, hemolytic anemia, renal Fanconi syndrome orhematuria. The onset ranges from 4 to 50 years. An earlierage of onset is in general associated with liver diseaseoften without neurological manifestation and notinvariable K-F rings. Liver involvement may present withasymptomatic hepatomegaly, jaundice with edema and

ascitis, hepatosplenomegaly with vague gastrointestinalsymptoms or subacute viral hepatitis, fulminant hepatitis,chronic active hepatitis, juvenile cirrhosis, post-hepaticcirrhosis and cryptogenic cirrhosis. Neurologicalmanifestations range from dystonia-parkinsonism,dysarrthria, drooling, scholastic deterioration/dementiaand behavioural changes.

Clinical and laboratory investigations include

peripheral blood for hemolytic anemia, liver functionabnormalities, urinary abnormality suggestive of Fanconisyndrome, slit-lamp examination for K-F ring, low serumceuroplasmin ( < 20 mg/dl), increased urinary copperexcretion ( > 100 mcg/day) especially after D-penicillamine challenge ( > 1000 mcg/day), increasedliver copper ( > 250 mcg/gm dry weight liver) andpositive radioactive copper studies.

Untreated Wilsons disease is invariably fatal. Theobjective of treatment is to prevent copper fromaccumulating in the tissues. Intake should be decreasedby restricting foods high in copper content (liver, cocoa,chocolate, mushroom, shellfish, nuts, dried fruits andvegetables) to less than 0.6 mg/day of copper. Themainstay of medical therapy is the use of copper bindingagents like D-penicillamine. The usual starting dose is 10mg/kg/day increased gradually over two weeks to 20mg/kg/day for children under 10 years and 1 gm/dayfor those above 10 years. Children receiving this therapyrequire B6 supplementation, and monitoring for

proteinuria and blood count abnormalities. If treatment isbegun early the neurological and hepatic functions can benormalized and K-F rings can disappear. On the otherhand, advanced disease may not be reversible. Further,there is a subgroup of patients who seem to worsen afterinitial treatment with D-penicillamine. Though thesepatients recover, they do not usually recover topretreatment baseline. Side effects of D-penicillamine

Fig. 2. Approach to A Child with A Chronic Neurometabolic Disorder

Chronic Encephalopathy Developmental Regression Seizures Hard Neurologic Signs

Abnormalities Outside the CNS

No Yes( Only Neural) (Neuro Visceral & Muscular Skeletal)

Signs of graymatter disease seizures visual impairment dementia

Signs of white matterdisease motor difficulties disorders of tone

Muscle

Mitochondrial

myopathies

HSM + bone skincon tissue

Gaucher diseaseNDPMPS I, II, III, VII GM!Sialidosis IIZellweger

HomocystinuriaMenkesFucosidosesMSDGalactosialidosisProlidasedeficiency

B-6 dependencyBiotinidase def.NCLGM2 (early)CRSMSyndromeLeigh diseaseAlpers diseaseMELAS

Central onlyCanavanAlexanderGM2 (late)GM1 (late)XLALDAAuriasQAurias

Central +peripheral

MLDKrabbe GLDPeroxisomaldisorders


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include early and late reactions including rash,leucopenia, immune-complex nephritis, Goodpasturesyndrome, etc.

Other options for treatment are Trientene, Ammoniumtetrathiomolybdate, and oral zinc sulfate or acetate at 75 150 mg of elemental zinc per day. Zinc is becoming themainstay of maintenance treatment after the other agentsachieve initial decoppering. Liver transplant is the onlymeasure for patients with fulminant hepatic failure orwith end stage hepatic disease.

Screening of all siblings is advised. Absence ofsymptoms or abnormalities on clinical examination doesnot exclude the possibility of Wilsons, which needsinvestigation. Haplotype analysis helps to diagnosecarriers and asymptomatic patients where serumceruloplasmin levels are inconclusive. Availability ofmolecular diagnosis aids prenatal diagnosis. At themoment these sophisticated tests pose a limitation inIndian conditions.

DISORDERS OF CARBOHYDRATE METABOLISM

The commonest types are GSD3 and GSD1. GSD3 isdebrancher enzyme deficiency. The symptoms of GSD3are similar to GSD 1 but milder. Both of them havehepatomegaly and hypoglycemia .In GSD 1 there ishyperlipidemia ketoacidosis, hyperlactic acidemia andhyperuricemia. There is platelet dysfunction andprolonged bleeding time. Failure to thrive, doll-like facies,huge abdomen and early morning fasting hypoglycemiawith or without seizures and xanthomas are clinical cluesto the diagnosis. Liver biopsy reveals PAS positive anddiastase sensitive material and liver enzyme analysis

reveals glucose 6 phosphates deficiency. In GSD 3profound hypoglycemia and extreme hyperlipidemia israre. Prognosis is fair to good.

Galactosemia presents with milk-triggered symptomsof vomiting, diarrhoea, hypoglycemia, jaundice and thelater development of cirrhosis, mental retardation andcataract. Reducing substances are present in the urine onBenedicts test while glucostix are negative suggesting thatthe sugar is other than glucose. Sugar chromatographyconfirms the diagnosis. Treatment is avoiding milkcontaining lactose and giving soy milk.

MANAGEMENT OF INBORN ERRORS OFMETABOLISM (IEM)

Basic Principles of Therapy(a) Prevention of the accumulation of toxic levels of the

precursor substance. Restrict offending substrate inthe diet.

(b) Stimulation of elimination of a toxic substrate /precursor by an alternative pathway

(c) Supply the deficient product.(d) Enhance the activity of the deficient enzyme by

providing co-factors e.g. vitamins (see below).

(e) Supply essential nutrients / disease specific diet afterthe diagnosis is established, sometimes specificsynthetic medical formulae are ideal

In majority of aminoacid disorders human breast milkprovides least protein load e.g.1gm%. Breast milk isrelatively safe to give except in galactosemia Animal milkis unsafe because of high lactose concentration.

Emergency Management General Principles

1. Minimize intake of substrates that produce toxicmetabolite viz. protein in aminoacidopathies lactosein galactosemia, sugar in hereditary fructoseintolerance, fats in fatty acid oxidation disorders.Administer high carbohydrate IV fluids (10%dextrose), maintainence fluid requirement 1.5 timesto promote diuresis and to avoid overload. As thechild improves, increase protein intake graduallyfrom 0.5 gm/kg/day to 1gm/kg/day. Avoid triggerfactors mentioned above.

2. Treat hypoglycemia, metabolic acidosis, electrolyte

imbalance, infections and coagulopathies usingconventional treatments.

3. Dialysis for sever hyperammonemia and resistantlife-threatening metabolic acidosis; peritonialdialysis is slower but less technologically/hemodynamically demanding than haemodialysis

4. Pharmacological agents to detoxify and acceleratethe excretion of toxic metabolites.

5. Vitamin co-factor therapy to increase residualenzyme activity (see below).

6. Secondary carnitine deficiency occurs in many IEMsand oral carnitine should be supplemented (100 mg/kg/day). In critical cases collect enough blood -

separate plasma and RBCS collect 50-100 ml urineand freeze it at -20 C. This could come useful fordiagnosis and genetic counseling. The importance ofdiagnosis is underestimated. Once the samples arecollected one can start the treatment.

VITAMINS & COFACTORS

Vitamins which act as cofactors give strikingimprovement in many simple molecular diseases.

TABLEL11. Vitamin Responsive IEM Disorders

Disorder Vitamin used in the treatment

Maple syrup urine disease Thiamine

Homocystinuria Pyridoxine, folic acid & vitaminB12

Propionic academia BiotinMethylmalonic academia HydroxycobalaminGlutaric academia RiboflavinBiotinidase deficiency BiotinHartnup disease Nicotinic acidPyruvate dehydrogenase Thiaminedeficiency/Leigh's diseaseRespiratory chain disorders Riboflavin


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N.B. Kumta


REFERENCES

1. Verma IC. Burden of genetic disease in India. Indian J Pediatr2000; 67 (12) : 893-898.

2. ICMR Collaborating centres & central coordinating unit.Multicentric study on genetic causes of mental retardation inIndia.Indian J Med Res(B) 1991; 94 : 161-169.

3. Muranjan M. Personal communication analysis of data onInborn Errors of Metabolism seen over a period from 1979 to2004 at the Genetic clinic PRL, KEM Hospital Mumbai.

Recommended readings

1. The Metabolic and Molecular Basis of Inherited Disease. CR

Scriver, AL Beaudet, WS Sly, D Valle, eds. 7thedn (1995)McGraw Hill, Newyork.

2. Clinical Biochemistry and The Sick Child.BE Clayton, JM. Round.2ndedn (1994), Blackwell Scientific Publications, Oxford.

3. A Clinical Guide to Inherited Metabolic Diseases.JTR Clarke 1996Cambridge University Press, Cambridge

4. Burton BK. Inborn errors of metabolism in infancy : a guide to

diagnosis. Pediatrics1998; 102: 6.

5. Neurology of Hereditary Metabolic Diseases of Children;Gilles Lyon;Raymond D Adams Edwin H Kolodny. McGraw-Hill; 2ndedn.

Guiding Principle for Feeding Infantsand

Young ChildrenDuring Emergencies

World Health Organization (WHO), Geneva. http://bookorders.who.int

This book reveals the guiding principles intended to serve as a starting point for organizingsustained pragmatic interventions that will be ensure appropriate feeding and care for infants andyoung children at all stages of an organized emergency response.

Book Published

iem india perspective n b kumta maharashtra

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