Inborn error of metabolism important in mbbs for exam
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Inborn Errors of Metabolism (IEM): MBBS exam high-yield list
Definition: Genetic disorders in which an enzyme, transporter, cofactor, or other protein defect disrupts a metabolic pathway. This can cause toxic metabolite accumulation, deficiency of an essential product, storage of complex molecules, or energy failure. Goldman-Cecil Medicine, Ch. 189.
Classification with must-know examples
| Group | Core mechanism | Important examples |
|---|---|---|
| Amino acid disorders | Amino acid or toxic metabolite accumulation | Phenylketonuria (PKU), maple syrup urine disease (MSUD), homocystinuria, tyrosinemia |
| Carbohydrate disorders | Defective metabolism of galactose, fructose, or glycogen | Galactosemia, hereditary fructose intolerance, glycogen storage diseases |
| Organic acidemias | Organic acid accumulation after protein catabolism | Methylmalonic acidemia, propionic acidemia, isovaleric acidemia |
| Urea cycle defects | Failure to convert ammonia to urea | OTC deficiency, citrullinemia, argininosuccinic aciduria |
| Fatty-acid oxidation disorders | Failure to use fatty acids during fasting | MCAD deficiency, carnitine deficiency |
| Lysosomal storage disorders | Accumulation of complex substrates in lysosomes | Gaucher disease, Tay-Sachs disease, Niemann-Pick disease, mucopolysaccharidoses |
| Mitochondrial / energy disorders | Impaired ATP production | MELAS, Leigh syndrome, pyruvate dehydrogenase deficiency |
| Purine-pyrimidine disorders | Abnormal nucleotide metabolism | Lesch-Nyhan syndrome, ADA deficiency |
The most important individual disorders
1. Phenylketonuria (PKU)
- Defect: Phenylalanine hydroxylase deficiency, or rarely tetrahydrobiopterin deficiency.
- Biochemistry: Increased phenylalanine and phenylketones; decreased tyrosine.
- Features: Intellectual disability if untreated, seizures, eczema, hypopigmentation, musty/mousy odor.
- Diagnosis: Newborn screening with raised phenylalanine.
- Treatment: Lifelong low-phenylalanine diet, tyrosine supplementation; avoid aspartame. Some cases respond to sapropterin.
Exam point: Maternal PKU can cause fetal microcephaly, congenital heart disease, growth restriction, and intellectual disability.
2. Galactosemia
- Classic defect: Galactose-1-phosphate uridyltransferase deficiency.
- Presentation after milk feeding: Vomiting, jaundice, hepatomegaly, failure to thrive, hypoglycemia, cataracts, and E. coli sepsis.
- Diagnosis: Raised galactose-1-phosphate, low enzyme activity.
- Treatment: Eliminate lactose and galactose from diet.
Exam clue: Neonate with jaundice + cataract + E. coli sepsis after breastfeeding or formula milk.
3. Hereditary fructose intolerance
- Defect: Aldolase B deficiency.
- Presentation: After introduction of fructose, sucrose, or fruit juice: vomiting, sweating, tremor, hypoglycemia, jaundice, hepatomegaly.
- Treatment: Avoid fructose, sucrose, and sorbitol.
Differentiate from essential fructosuria: Essential fructosuria is due to fructokinase deficiency and is benign.
4. Maple syrup urine disease (MSUD)
- Defect: Branched-chain alpha-ketoacid dehydrogenase deficiency.
- Biochemistry: Increased leucine, isoleucine, and valine.
- Features: Poor feeding, vomiting, encephalopathy, seizures, and urine smelling like maple syrup/burnt sugar.
- Treatment: Restrict branched-chain amino acids, especially leucine; urgent treatment during metabolic crisis.
5. Homocystinuria
- Usual defect: Cystathionine beta-synthase deficiency.
- Features: Marfanoid habitus, intellectual disability, osteoporosis, thromboembolism, and downward lens subluxation.
- Treatment: Pyridoxine trial, folate/B12 as indicated, methionine restriction, cysteine supplementation, betaine.
Very common viva comparison with Marfan syndrome:
| Homocystinuria | Marfan syndrome |
|---|---|
| Downward lens displacement | Upward lens displacement |
| Thromboembolism common | Aortic root disease common |
| Intellectual disability may occur | Usually normal intelligence |
| Raised homocysteine | Normal homocysteine |
6. Urea cycle defects
- Main problem: Severe hyperammonemia.
- Typical presentation: Normal baby initially, then poor feeding, vomiting, lethargy, seizures, encephalopathy, coma.
- Laboratory clue: High ammonia with respiratory alkalosis, often without marked metabolic acidosis.
- Most common: Ornithine transcarbamylase deficiency, an X-linked disorder.
- Treatment principle: Stop protein temporarily in crisis, give high-calorie glucose/lipids to prevent catabolism, nitrogen scavengers, arginine/citrulline where appropriate, and dialysis for severe hyperammonemia.
Exam clue: Neonate with encephalopathy + high ammonia + respiratory alkalosis = think urea cycle defect. Bradley and Daroff's Neurology in Clinical Practice, neonatal IEM section.
7. Organic acidemias
Examples: Methylmalonic acidemia and propionic acidemia.
- Features: Neonatal vomiting, dehydration, lethargy, encephalopathy, ketosis, high-anion-gap metabolic acidosis, hyperammonemia, and sometimes neutropenia/thrombocytopenia.
- Diagnosis: Plasma acylcarnitine profile and urine organic acids.
- Treatment: Stabilize metabolic crisis, stop protein briefly, provide glucose, use disorder-specific cofactors such as vitamin B12 in selected methylmalonic acidemia.
Differentiate from urea-cycle defects: Organic acidemias cause metabolic acidosis with ketosis; urea-cycle defects classically cause respiratory alkalosis.
8. Glycogen storage disease type I, von Gierke disease
- Defect: Glucose-6-phosphatase deficiency.
- Features: Severe fasting hypoglycemia, hepatomegaly, lactic acidosis, hyperuricemia, hyperlipidemia, doll-like facies.
- Treatment: Frequent feeds, uncooked cornstarch, avoidance of fructose and galactose.
9. McArdle disease, GSD type V
- Defect: Muscle glycogen phosphorylase deficiency.
- Features: Exercise intolerance, painful muscle cramps, myoglobinuria, no rise in lactate after exercise.
- Key point: No hepatomegaly or fasting hypoglycemia.
10. Lysosomal storage disorders
| Disorder | Defect | Key feature |
|---|---|---|
| Tay-Sachs | Hexosaminidase A | Cherry-red spot, neurodegeneration, no hepatosplenomegaly |
| Niemann-Pick | Sphingomyelinase | Cherry-red spot + hepatosplenomegaly |
| Gaucher | Glucocerebrosidase | Hepatosplenomegaly, bone crises, cytopenias, Gaucher cells |
| Hurler syndrome | Alpha-L-iduronidase | Coarse facies, developmental delay, corneal clouding, hepatosplenomegaly |
| Hunter syndrome | Iduronate sulfatase, X-linked | Like Hurler but no corneal clouding |
General clinical clues suggesting IEM
Think of IEM in a neonate or child with:
- Consanguinity, sibling death, recurrent unexplained illness
- Poor feeding, vomiting, lethargy, seizures, coma
- Developmental delay or regression
- Unusual body or urine odor
- Hepatomegaly, cardiomyopathy, cataract, coarse facies
- Recurrent hypoglycemia, especially after fasting
- Metabolic acidosis, ketosis, lactic acidosis, or hyperammonemia
Small-molecule disorders such as aminoacidopathies, organic acidemias, urea-cycle defects, and galactosemia may cause acute neonatal encephalopathy after an initially well period. Bradley and Daroff's Neurology in Clinical Practice, neonatal IEM section.
First-line investigations in suspected IEM
- Blood glucose
- Arterial blood gas and electrolytes
- Serum ammonia
- Lactate
- Urine ketones
- Liver-function tests
- Plasma amino-acid analysis
- Urine organic acids
- Acylcarnitine profile
- Newborn-screening result, but do not wait for it in an acutely ill infant.
One-line emergency approach
Stabilize ABCs, stop catabolism with IV dextrose, correct hypoglycemia/acidosis, send metabolic samples before treatment if possible, treat hyperammonemia urgently, and involve a metabolic specialist.
Last-minute mnemonic: “PKU-GUM”
- P: PKU
- K: Ketotic organic acidemias
- U: Urea-cycle defects
- G: Galactosemia / glycogen storage diseases
- U: Unusual odors and urine findings
- M: Mitochondrial and lysosomal metabolic disorders
A recent review of IEM management discusses expanding options such as enzyme replacement, substrate reduction, and genetic therapies, but for MBBS exams the diagnostic patterns and dietary or acute metabolic treatment principles remain the priority (2024 systematic review).
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