Inborn Errors of Metabolism — USMLE Step 1 Notes

Amino-acid disorders

• Phenylketonuria (PKU): deficient phenylalanine hydroxylase (or its BH4 cofactor) blocks conversion of phenylalanine to tyrosine (amino-acid metabolism). Phenylalanine accumulates → intellectual disability, seizures, a musty odour, fair skin/eczema (tyrosine becomes essential, so melanin falls). Detected on newborn screening; treat with a phenylalanine-restricted diet, avoid aspartame, and supplement tyrosine.
• Maple syrup urine disease: deficient branched-chain alpha-ketoacid dehydrogenase (needs thiamine) blocks breakdown of the branched-chain amino acids leucine, isoleucine and valine. Their ketoacids accumulate → sweet, maple-syrup-smelling urine, vomiting, poor feeding, encephalopathy in the newborn. Treat by restricting branched-chain amino acids (I Love Vermont maple syrup).
• Homocystinuria: most often deficient cystathionine synthase (transsulfuration of homocysteine to cystathionine); homocysteine accumulates → marfanoid habitus, downward lens dislocation, thrombosis and intellectual disability. Some forms respond to high-dose vitamin B6; also treat with methionine restriction and cysteine/folate/B12.
• Alkaptonuria: deficient homogentisate oxidase in the tyrosine degradation pathway; homogentisic acid accumulates → urine that darkens on standing, blue-black connective tissue (ochronosis) and arthritis. Largely benign; a curiosity of tyrosine catabolism.

Transport & organic-acid disorders

• Cystinuria: a defect of the renal (and intestinal) transporter for dibasic amino acids (Cystine, Ornithine, Lysine, Arginine — 'COLA'); cystine is poorly soluble and forms recurrent hexagonal cystine stones. Diagnose with urinary cyanide-nitroprusside; treat with hydration, urinary alkalinisation and chelators (penicillamine).
• Organic acidaemias (e.g. methylmalonic, propionic): defects in breaking down certain amino acids/odd-chain fats (methylmalonyl-CoA mutase needs B12; propionyl-CoA carboxylase needs biotin). Organic acids accumulate → a neonate with a high-anion-gap metabolic acidosis, hyperammonaemia, vomiting and lethargy. These link to the propionate-to-succinyl-CoA route into the TCA cycle.

Glycogen storage diseases

• Type I — von Gierke (glucose-6-phosphatase): blocks the final step of glycogenolysis AND gluconeogenesis → severe fasting hypoglycaemia, lactic acidosis, hyperuricaemia, hyperlipidaemia and a huge liver.
• Type II — Pompe (lysosomal acid alpha-glucosidase/acid maltase): a LYSOSOMAL disease that spares blood glucose but causes cardiomegaly, hypotonia and early death ('Pompe trashes the Pump').
• Type III — Cori (debranching enzyme): a milder von-Gierke-like picture with abnormal, short-branched glycogen; gluconeogenesis is intact, so less severe hypoglycaemia and no lactic acidosis.
• Type IV — Andersen (branching enzyme): abnormal, poorly branched glycogen → hepatosplenomegaly, cirrhosis and failure to thrive.
• Type V — McArdle (muscle glycogen phosphorylase): affects MUSCLE only → exercise intolerance, cramps and no rise in lactate, with a 'second wind'; blood glucose is unaffected.

Lysosomal storage diseases

• Overview: deficient lysosomal enzymes let their substrates accumulate. Sphingolipidoses (Tay-Sachs, Fabry, Gaucher, Niemann-Pick, Krabbe, metachromatic leukodystrophy) and mucopolysaccharidoses (Hurler, Hunter) are the high-yield groups.
• Tay-Sachs: hexosaminidase A deficiency → GM2 ganglioside accumulates; cherry-red macula, hyperacusis/startle, neurodegeneration, and NO hepatosplenomegaly (contrast Niemann-Pick).
• Niemann-Pick: sphingomyelinase deficiency → sphingomyelin accumulates; cherry-red macula WITH hepatosplenomegaly and neurodegeneration; foamy 'lipid-laden' macrophages.
• Gaucher (commonest): glucocerebrosidase (beta-glucosidase) deficiency → glucocerebroside accumulates; hepatosplenomegaly, pancytopenia, bone crises/avascular necrosis and 'crumpled tissue-paper' Gaucher cells. Enzyme replacement therapy is available.
• Fabry (X-linked): alpha-galactosidase A deficiency → ceramide trihexoside accumulates; neuropathic pain (acroparaesthesiae), angiokeratomas, and renal and cardiac disease.
• Krabbe: galactocerebrosidase deficiency → galactocerebroside/psychosine accumulate; a leukodystrophy with peripheral neuropathy, optic atrophy, developmental regression and globoid cells.
• Metachromatic leukodystrophy: arylsulfatase A deficiency → cerebroside sulfate accumulates; central and peripheral demyelination with ataxia and dementia.

Mucopolysaccharidoses (Hurler vs Hunter)

• Hurler (MPS I): alpha-L-iduronidase deficiency (autosomal recessive) → heparan/dermatan sulfate accumulate; coarse facial features, corneal clouding, hepatosplenomegaly, skeletal dysplasia and developmental delay.
• Hunter (MPS II): iduronate sulfatase deficiency (X-linked) → a milder picture that is aggressive-behaviour-associated and has NO corneal clouding ('Hunters aim for the X and see clearly').

Connecting the dots — pathway map

• Amino-acid catabolism: PKU (phenylalanine → tyrosine), alkaptonuria (tyrosine degradation), homocystinuria (methionine/transsulfuration), maple syrup urine disease (branched-chain catabolism).
• Cofactor links: homocystinuria may respond to B6; methylmalonic acidaemia needs B12; propionic and pyruvate/branched-chain steps need biotin and thiamine — the same cofactors from the vitamins module.
• Glycogen metabolism: von Gierke and McArdle map onto glycogenolysis/gluconeogenesis; Pompe is really a lysosomal disease that happens to store glycogen.
• Lysosomal degradation: sphingolipidoses and mucopolysaccharidoses are failures to recycle membrane lipids and glycosaminoglycans; the accumulated substrate names the disease.

High-yield revision notes; verify against a primary source before clinical use.