Dr. Ashish Bavdekar*
Consultant Pediatric Gastroenterologist Department of Pediatrics, KEM Hospital, Pune.*
Of over 300 known human diseases due to IEM, about 100 present in the neonatal period of early infancy. The clinical diagnosis of IEM in newborns may be difficult due to the following reasons (i) The neonate has limited responses to overwhelming illnesses and the predominant signs and symptoms are nonspecific - poor feeding, lethargy, failure to thrive, etc. Neonates with IEM are often misdiagnosed to have sepsis of other disorders, (ii) Many physicians think that since individual IEMs are rare, they should only considered after ruling out other conditions. This invariably causes a delay in diagnosis, starting therapy and hence outcome is poor, (iii) Although most IEMs are hereditary and transmitted as recessive disorders, most cases appear sporadically, (iv) Sepsis accompanies many IEMs and quite often investigations stop once sepsis found, (v) A single IEM can have variable presentations while various IEMs may have similar presentations causing confusion and diagnostic problems, (vi) Lack of adequate facilities in India to diagnose IEMs.

A high index of suspicion is necessary to make early diagnosis. The following factors should raise the suspicion of IEM - (i) family history of similar illness/ death, (ii) illness following a period of normalcy, (iii) hypotonia, coma, convulsions not explained by other illness, (iv) jaundice, organomegaly, (v) unusual odor, (vi) dysmorphic features
Clinical Presentations of IEM:
  • Neurological deterioration: Most IEMs are referred to the doctor because of neurological deterioration. Usually the newborns are normal at birth and there is a symptom-free interval of few hours to weeks. The illness starts with poor sucking and feeding after which the baby goes into a coma. Hypertonic episodes/hypotonia, convulsions, apnea, hypertrophic cardiomyopathy, rapid neurological deterioration and occasionally dysmorphism is present.
  • Seizures: In non-ketotic hyperglycinemia, pyridoxine dependency, molybdenum co-factor deficiency, seizures occur early. In most other IEMs, seizures occur late and are usually associated with coma or metabolic disturbances like hypoglycemia.
  • Liver Disease: Metabolic disorders can present in early infancy with liver failure, ascites and oedema, cholestatic jaundice. They may have associated hepatosplenomegaly, elevated transaminases developmental delay, dysmorphic features, etc. Disorders include lysosomal disorders, galactosemia, fructosemia, tyrosinemia, alpha l antitrypsin deficiency, etc.
  • Hepatosplenomegaly without liver dysfunction: With a hard liver suspect tyrosinemia, galactosemia, and alpha-antitrypsin deficiency. With normal or soft liver and splenomegaly consider mucolipidosis, Gaucher's, Niemann Pick type A.
  • Cardiomyopathy, cardiac failure: Three main groups of IEMs present with cardiac involvement. (a) Pompe's disease, (GSD ll) - cardiomyopathy occurs early in infancy and is associated with severe hypotonia, macroglossia and EGG changes with normal mentation. (b) Respiratory chain disorders - cardiomyopathy usually associated with development delay, diverse neurological signs and hyperlacticacidemia. (c) Fatty acid oxidation defects may be associated with cardiomyopathy and/or heartbeat disorders.
  • Severe diarrhea: (a) Severe watery diarrhea with dehydration occurring immediately after birth or after weaning, consider congenital chloride diarrheas, primary lactase, sucrase, isomaltase deficiencies (all very rare) (b) Chronic Diarrheas: Associated with steatorrhoea, vitamin deficiency, osteopenia, hypocholesterolemia - consider bile acid disorders, infantile Refsum disease, respiratory chain disorders. (c) Diarrhea with failure thrive, hypotonia, frequent infections and hepatosplenomegaly consider glycogen storage disease Type l, Wolman's disease and lysinuric protein intolerance.
Investigations for IEM
Metabolic investigations should be initiated as soon as the possibility of IEM is considered, not after all other illnesses have been eliminated. This is particularly important for conditions associated with hyperammonemia as the outcome is directly related to the rapidity with which management is initiated.
  1. Hemogram and complete blood count
  2. Blood gases and electrolytes,
  3. glucose, ammonia, lactate, amino acids
  4. Liver functions tests (liver disease)

  1. Ketones, reducing substances, keto acids, screening tests

Special tests
  1. Serum amino acids - quantitative, urine organic acids, GALT/Biotinidase enzyme estimations Acyl carnitine profile , other enzyme/DNA mutation studies.

Clinical Approach
Depending on the major clinical presentation and the laboratory data most children with IEM can be assigned to one of the five syndromes.

Type I : Neurological distress - with ketosis
Type l is represented by Maple Syrup Urine Disease (MSUD) which is one of the commonest aminoacidopathies in India. There is usually a symptom-free interval of 4-5 days after which poor feeding develops and coma ultimately occurs. There may be a maple syrup odor to the urine, and urine DNPH is strongly positive. There is usually no acidosis and diagnosis is confirmed by serum amino acid estimation which reveals elevation of branched chain amino acids leucine, isoleucine and valine , and presence of alloisoleucine.

Type II : Neurological distress - with ketoacidosis
Organic acidemias (OA) are a major component of this type. These children are usually acutely ill, dehydrated, acidotic with increased anion gap. There is usually associated hyperammonemia, ketosis and neutropenia, thrombocytopenia. The commonest OAs are methylmalonic acidemia, propionic acidemia and isovaleric academia. These disorders are diagnosed by identifying specific abnormal metabolites in the urine by GC/ MS.

Type III : Neurological Distress with Lactic Acidosis
These babies may have a very diverse clinical presentation. The predominant finding is the acidosis with high lactate levels. Ketosis is usually present. The common disorders in this group are pyruvate carboxylase deficiency, pyruvate dehydrogenase deficiency, respiratory chain disorders and multiple carboxylase deficiency. Definite diagnosis is often not possible but may be attempted with enzyme assays.

Type IV (a) : Neurological Distress - Hyperammonemia without ketoacidosis
Urea cycle defects occur in this group. There is a variable symptom-free interval after which profound hypotonic coma may occur along with coagulopathy, hepatosplenomegaly and raised transaminases. Blood ammonia levels rise rapidly to very high levels with frequent evidence of respiratory alkalosis, hyperlacticacidemia but no ketosis. These conditions are diagnosed by serum amino acid analysis and urine orotic acid excretion. Some fatty acid oxidation disorders may rarely mimic urea cycle disorders.

Type IV (b) : Neurological Distress - no ketoacidosis and no hyperammonemia
Non-ketotic hyperglycinemia is characterized by coma, seizures soon after birth. Diagnosis is based on demonstration on elevated CSF and serum glycine levels. Molybdenum co-factor deficiency present similarly with hypotonia, seizures, dysmorphic features and cataracts. Diagnosis is suggested by very low plasma uric acid and presence of sulphite in the urine.

Type lV (c) : Storage Disorders without Metabolic Disturbances
Few lysosomal disorders present in neonatal period. They are usually associated with hydrops fetalis, neonatal ascites and oedema. These disorders are GM 1 gangliosidosis, Gaucher's disease, Niemann - Pick disease type C, MPS Vll, sialidosis.

Type V : Hepatomegaly and Liver Dysfunction
Disorders like galactosemia, tyrosinemia type l, and fructosemia usually present with jaundice, liver cell failure and associated hypoglycemia. Disorders like glycogen storage disease type l and lll, and fructose 1, 6-biphosphatase deficiency usually present with hypoglycemia as the presenting feature and associated hepatomegaly ketosis and lactic acidosis. Disorders like Alpha 1 antitrypsin deficiency, bile acid disorders present with isolated cholestatic jaundice with hepatomegaly.
Management of IEM
Emergency management
  1. Minimize intake and endogenous production of toxic metabolites - Stop dietary of parenteral intake or all proteins and fats. Administer high calorie, high carbohydrate lV fluids (10-12% dextrose). Administer 1-15 times the maintenance fluid requirement to promote diuresis but avoid fluid overload. After a few days, when clinical improvement occurs, proteins or amino acids may be started in doses of 0.5 gm/kg/day up to 1 gm/kg/day. lV fats may be started once fat disorders like FAOD are ruled out.

  2. Treat hypoglycemia, acidosis, electrolyte imbalance, infections, coagulopathies by conventional means.

  3. Consider dialysis (hemodialysis) for severe hyperammonemia, resistant life threatening metabolic acidosis. Peritoneal dialysis is too slow and exchange transfusions cause rebound hyperammonemia.

  4. Pharmacological agents may be used to detoxify or accelerate the excretion of toxic metabolites. Sodium benzoate, arginine in urea cycle defects.

  5. Increase residual enzyme activity by co-factor therapy - Vitamins B1 (50 mg) B2 (50 mg) B6 (50 mg), B12 (1 mg) Biotin (10 mg) Folic acid (5 mg) daily.

  6. Secondary carnitine deficiency occurs in many IEMs and oral carnitine is supplemented (100 mg/kg/day).

Subsequent management
Subsequent management depends on the type of IEM and the underlying pathogenetic mechanism. Some disorders are treatable by dietary manipulations; others require external drugs to control levels of toxic metabolites. Still others require exogenous replacement of the deficient products. Some management principals for individual disorders are given below:

  • Urea cycle defect - protein restriction, arginine, citrulline supplementation, sodium benzoate therapy

  • Organic academia- diet low in valine, isoleucine, threonine, methionine, Carnitine and glycine supplementation. Antibiotics to reduce odd chain fatty acids.

  • MSUD - diet low in branched chain amino acids

  • Galactosemia - galactose free diet

  • Tyrosinemia - Diet low in phenylalanine, tyrosine supplementation

  • Phenylketonuria - Methionine restricted diet, Vit. B6 and betaine supplementation

  • Gaucher's disease - enzyme therapy

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