INBORN ERRORS OF METABOLISM

The term quot;Inborn errors of metabolismquot; refers to a broad group of genetic defects with qualitative or quantitative deficiency in one or more enzymes or their co-factors, involved in synthesis, transport, storage, metabolism or degradation of various biochemical compounds in body.

Consequently, these enzymatic defects may lead to: (a) deficiency of final metabolite product, (b) accumulation of proximal substrate in metabolic pathway, or (c) acti­vation of alternate metabolic pathways with formation of abnormal metabolites.

More than 300 of such disorders are known, with an estimated incidence of 3-4/1000 births, though many of them are asymptomatic or never diagnosed. According to the predominant metabolic defect, these disorders may be broadly classified as disorders of: (a) amino acid metabolism, (b) fat metabolism, (c) carbohydrate metabolism, (d) nucleic acid metabolism, and (e) miscellaneous errors (Table 11.15).

When to Suspect an IEM

Clinical spectrum of IEMs is extremely wide, depending on the type and severity of specific enzyme defect and

TABLE 11.15: Classification of inborn errors of metabolism (IEM)

• Amino acid metabolism

- Aminoacidurias

- Urea cycle defects

- Organic acidemias

• Carbohydrate metabolism

- Glycogen storage disorders (GSDs)

- Galactosemia and fructose intolerance

- IEMs with lactic acidosis

- Glycoproteinoses

- Mucopolysaccharoidoses (MPS)

• Fat metabolism

- Mitochondrial fatty acid oxidation defects

- Peroxisomal disorders

- Lipoprotein metabolism/transport defects

- Lipid storage disorders (lipidoses)

• Nucleic acid metabolism

- Purine metabolism, e.g. Lesch-Nyhan syndrome

- Pyrimidine metabolism, e.g. Orotic aciduria

- Gout

• Miscellaneous disorders

- Heme metabolism, e.g. porphyria

- Trace element metabolism, e.g. Wilson disease

- Others, e.g.

ranges from completely asymptomatic patients to severe and lethal disease in neonatal period. Generally, these babies are normal at birth as toxic metabolites are cleared by placenta.

IEMs, which manifest in neonatal period, are usually severe and frequently lethal. High index of suspicion is essential for early diagnosis of these defects as presentations are usually non-specific and easily confused with more common problems, e.g. infections, hypoxia, etc. Important clinical indicators of IEM are given in Table 11.11.

History of consanguinity in parents or similar illness in previous sibling with/without death is an important warning for IEMs in newborns or early infancy. However, most of the fatal IEMs are autosomal recessive and similar family history may not be obvious.

IEMs, which manifest after neonatal period, are usually milder variants of autosomal recessive defects or trans­mitted by dominant inheritance. Family history of similar or unexplained illness is often present in these cases.

Laboratory Diagnosis in IEM

Precise diagnosis is essential for appropriate genetic counseling. However, considering the costs involved, a step-wise approach is advised in laboratory workup of these cases involving certain baseline investigations before specific tests. In illnesses with intermittent presentation, all biochemical investigations should be done during the symptomatic phase, as these tests may be false-negative during normal phase. Important investigations in IEMs include:

a. Baseline investigations in all cases:

- Blood: Complete hemogram, sugar, ammonia, electrolytes, liver enzymes, bicarbonates, lactate and pyruvate levels and arterial blood gases.

- Urine: Color, odor, pH, reducing sugar, ketones, ferric chloride test.

- Others: CSF, nerve conduction studies, etc.

b. Specific investigations for suspected cause:

- Biochemical estimations of metabolic substrates, e.g. phenylalanine.

- Tissue biopsies, e.g. liver, muscle, bone marrow or skin biopsy for storage disorders.

- Specific enzyme assays in blood or other tissues.

c. Molecular diagnosis for exact genetic defect in the index case and suspected carriers, as discussed in previous chapter using amplification, e.g. PCR or sequencing tests, e.g. NGS (Ch 11.4).

d. Prenatal diagnosis by enzyme studies or molecular tests in chorionic villous biopsy or cultured amniotic cells (Ch 11.5).

In morbidly sick children with suspected IEM, it is advised to collect following samples for later studies and genetic counseling: (a) clinical photograph, (b) relevant X-rays, (c) 5-10 ml of blood in heparin and EDTA vials, (d) urine sample, (e) CSF sample, (f) skin, liver, muscle and bone marrow biopsy. All these samples should be adequately stored and transported for further studies.

Some important IEMs from the Indian perspective, are discussed here in greater details.

11.6.1