Inborn Errors of Metabolism: Biochemical Genetics

Amino acid disorders · Organic acidemias · Urea cycle defects · Carbohydrate disorders · Lysosomal storage diseases · Peroxisomal disorders · Mitochondrial disorders · Newborn screening · Emergency management
🧬 Key concepts: PKU, MSUD, galactosemia, glycogen storage diseases, MCAD deficiency, biotinidase deficiency, urea cycle defects (hyperammonemia), newborn screening, dietary and cofactor therapy.

📖 Biochemical genetics: disorders of metabolism

🧬 Amino acid disorders
PKU (PAH deficiency): intellectual disability, fair skin, eczema. MSUD: maple syrup urine, encephalopathy. Homocystinuria: ectopia lentis, thromboembolism. Tyrosinemia: liver failure, renal tubular dysfunction.
🧪 Organic acidemias & urea cycle defects
Propionic, methylmalonic (MMA): metabolic acidosis, hyperammonemia, ketosis. UCDs (OTC, CPS1): hyperammonemia, respiratory alkalosis, vomiting, coma.
🍬 Carbohydrate & fatty acid disorders
Galactosemia: hepatomegaly, cataracts, E. coli sepsis. GSD I (von Gierke): hypoglycemia, hepatomegaly. MCAD deficiency: hypoketotic hypoglycemia, coma.
🏺 Lysosomal & peroxisomal disorders
Gaucher, Niemann-Pick, Mucopolysaccharidoses (Hurler, Hunter). Zellweger syndrome: hypotonia, seizures, dysmorphism. Adrenoleukodystrophy (X-ALD).
⚠️ Metabolic red flags: Recurrent vomiting, lethargy, coma, metabolic acidosis with high anion gap, hypoglycemia, hyperammonemia, unusual odor (maple syrup, sweaty feet), developmental regression, hepatomegaly.

🩺 Metabolic emergency: recognition & immediate investigation

1
Recognize a metabolic crisis – Clinical: vomiting, lethargy, coma, respiratory distress (acidosis), seizures, hypotonia. Labs: high anion gap metabolic acidosis, hyperammonemia, hypoglycemia, ketosis (or absent ketosis in fatty acid defects).
2
Emergency labs (metabolic screen) – Blood gas, electrolytes, glucose, ammonia, lactate, plasma amino acids, urine organic acids, acylcarnitine profile. Call metabolic team immediately.
3
Stabilization – IV glucose (10% dextrose to stop catabolism). IV fluids, bicarbonate (if severe acidosis). Treat hyperammonemia: stop protein, consider sodium benzoate/phenylbutyrate, hemodialysis if severe.
4
Differential diagnosis by pattern – Hypoglycemia + absent ketosis → fatty acid oxidation defect. Hyperammonemia + acidosis → organic acidemia or UCD. Hyperammonemia + normal anion gap → urea cycle defect.
📌 Clinical pearl: In a neonate with hyperammonemia and respiratory alkalosis (normal anion gap), think urea cycle defect until proven otherwise. Urgent hemodialysis may be life-saving.

📋 Stepwise management of specific IEMs

1
PKU (phenylalanine hydroxylase deficiency) – Dietary restriction of phenylalanine, special protein substitute (amino acid formula). Monitor blood Phe. Sapropterin (BH4) responsive in some.
2
MCAD deficiency (medium-chain acyl-CoA dehydrogenase) – Avoid fasting, carnitine supplementation, IV glucose during illness. Newborn screening prevents mortality.
3
Galactosemia (GALT deficiency) – Lifelong lactose/galactose-free diet. Calcium supplementation, monitor for speech/neurologic issues.
4
Urea cycle defects (e.g., OTC deficiency) – Low protein diet, nitrogen scavengers (sodium benzoate, phenylbutyrate), arginine supplementation. Liver transplantation for severe OTC.
5
Biotinidase deficiency – Oral biotin (10-20 mg/day). Prevents hearing loss, ataxia, skin rash, developmental delay.
6
Gaucher disease (type 1) – Enzyme replacement therapy (imiglucerase, velaglucerase). Eliglustat for non-neuronopathic.
🚨 Emergency: hyperammonemia >200 µmol/L in neonate – Urea cycle defect or organic acidemia. Hemodialysis most effective, IV nitrogen scavengers, stop protein.

🧠 Reflex prompts: inborn errors of metabolism

🧬 Neonate with progressive encephalopathy, urine smells of maple syrup. Diagnosis?
Maple syrup urine disease (MSUD) – leucine, isoleucine, valine accumulation. Dialysis, dietary restriction.
🍼 Newborn feeding difficulty, hepatomegaly, cataracts, E. coli sepsis. Likely?
Galactosemia (GALT deficiency). Galactose-free diet immediately.
🧠 Child with episodic vomiting, coma after fasting. Hypoglycemia with low ketones. Diagnosis?
MCAD deficiency (medium-chain acyl-CoA dehydrogenase deficiency). Avoid fasting, carnitine.
🩸 Neonate with hyperammonemia (600 µmol/L), respiratory alkalosis, normal anion gap. Diagnosis?
Urea cycle defect (most common: OTC deficiency). Hemodialysis, nitrogen scavengers.
🧬 Infant with hypotonia, seizures, hepatomegaly, vacuolated lymphocytes. Liver biopsy shows Gaucher cells. Diagnosis?
Gaucher disease (type 2). Enzyme replacement.
👁️ Child with lens dislocation, marfanoid habitus, intellectual disability, thromboembolism. Diagnosis?
Homocystinuria (cystathionine beta-synthase deficiency). Methionine restriction, B6 responsive.
🧬 What is the first-line treatment for PKU?
Low-phenylalanine diet + medical formula (amino acids without Phe).
🩺 What is the most common fatty acid oxidation disorder detected by newborn screening?
Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency.
🧪 Which test is used for newborn screening for MCAD deficiency?
Tandem mass spectrometry (acylcarnitine profile – elevated C8, C6, C10).
💊 What cofactor is used for biotinidase deficiency?
Oral biotin (10-20 mg/day). Prevents neurological deterioration.