Inborn Errors of Metabolism

Inborn errors of metabolism (IEM) are a large group of monogenic disorders, usually autosomal recessive, in which a single enzyme defect blocks a metabolic pathway. The result is accumulation of toxic precursors, deficiency of essential products, or both. They are a perennial favourite in NEET PG paediatrics and genetics, tested through odour clues, classic enzyme defects, urine/blood findings, and the diet/drug of choice.

Definition & classification

An IEM is a heritable disorder caused by a defect in a specific enzyme, transporter, or cofactor that disrupts normal biochemistry. Garrod coined the term "inborn errors of metabolism" (alkaptonuria, albinism, cystinuria, pentosuria — the original four). Most follow autosomal recessive inheritance; notable exceptions are X-linked (Hunter syndrome, Fabry disease, OTC deficiency, Lesch-Nyhan, G6PD) and mitochondrial (maternal) inheritance.

A practical pathophysiology-based classification used in exams:

Group	Mechanism	Examples
Disorders of intoxication	Acute/progressive toxin accumulation; symptom-free interval then crisis	PKU, MSUD, organic acidaemias, urea cycle defects, galactosaemia
Disorders of energy metabolism	Defective energy production/utilisation	Glycogen storage diseases, mitochondrial disorders, fatty acid oxidation defects
Disorders of complex molecules	Storage of large molecules; permanent, progressive	Lysosomal storage diseases (Gaucher, Niemann-Pick, MPS), peroxisomal disorders

High-yield: "Intoxication" disorders typically have a symptom-free interval after birth (toxin builds up after feeding starts), present with metabolic crisis, and may be reversible with diet/dialysis. "Storage" disorders are progressive, present with organomegaly/coarse features, and are largely irreversible.

A useful clinical screen — the metabolic crisis triad: hypoglycaemia + metabolic acidosis (high anion gap) + hyperammonaemia, often with vomiting, lethargy, seizures in a previously well neonate after a feed/intercurrent illness.

Disorders of amino acid metabolism

Phenylketonuria (PKU)

The single most tested IEM. Deficiency of phenylalanine hydroxylase (PAH), which converts phenylalanine → tyrosine. Cofactor is tetrahydrobiopterin (BH4); rarer BH4-deficient ("malignant") variants exist and need different treatment.

• Genetics: autosomal recessive, chromosome 12.
• Clinical: normal at birth; untreated infants develop progressive intellectual disability, seizures, hyperactivity. Reduced tyrosine → reduced melanin → fair skin, blue eyes, blond hair (hypopigmentation), eczema. Phenylacetic acid causes a musty / mousy odour of urine and sweat.
• Diagnosis: newborn screening using the Guthrie bacterial inhibition assay (now largely tandem mass spectrometry). Confirm with elevated serum phenylalanine (> 20 mg/dL, normal < 2). Always check BH4 status to exclude cofactor variants.
• Management — diet of choice: lifelong phenylalanine-restricted diet (special low-Phe formula); tyrosine becomes essential and must be supplemented. Sapropterin (synthetic BH4) helps responsive (especially mild) cases. Maintain Phe roughly 2–6 mg/dL.

High-yield: Maternal PKU — a mother with PKU who is not on a strict low-Phe diet during pregnancy exposes the fetus to high phenylalanine, causing microcephaly, congenital heart disease, IUGR, and intellectual disability in a child who does NOT have PKU. Strict dietary control before conception is essential.

High-yield: Aspartame is contraindicated in PKU (it is metabolised to phenylalanine).

Maple syrup urine disease (MSUD)

Deficiency of branched-chain alpha-ketoacid dehydrogenase (BCKD) complex → accumulation of branched-chain amino acids leucine, isoleucine, valine and their ketoacids.

• Clinical: neonatal encephalopathy — poor feeding, lethargy, opisthotonus, "boxing/bicycling" movements, seizures. Urine and cerumen smell of maple syrup / burnt sugar.
• Key marker: leucine is the most neurotoxic; its ketoacid causes the odour and cerebral oedema.
• Diagnosis: plasma amino acids (raised BCAA, presence of alloisoleucine is pathognomonic), DNPH test positive in urine.
• Management: BCAA-restricted diet; thiamine (B1) trial in thiamine-responsive variants; dialysis/exchange for acute crisis.

Homocystinuria

Classic form: deficiency of cystathionine beta-synthase (CBS) → accumulation of homocysteine and methionine.

• Clinical (resembles Marfan but differs): tall, thin, arachnodactyly, downward and inward (infero-nasal) lens dislocation (ectopia lentis), intellectual disability, and a strong tendency to thromboembolism (the major cause of death).
• Diagnosis: raised plasma homocysteine and methionine; urinary homocystine; positive cyanide-nitroprusside test.
• Management: about 50% are pyridoxine (vitamin B6) responsive — pyridoxine is first-line; non-responders need a methionine-restricted diet plus cysteine, betaine (remethylates homocysteine), and folate/B12.

High-yield: Marfan vs homocystinuria is a classic two-mark question.

Feature	Marfan	Homocystinuria
Inheritance	Autosomal dominant	Autosomal recessive
Lens dislocation	Up & out (supero-temporal)	Down & in (infero-nasal)
Intellect	Normal	Often impaired
Thrombosis	No	Yes (hallmark)
Joints	Hyperlax	Stiff/contractures

Tyrosinaemia & alkaptonuria (brief)

• Tyrosinaemia type I: fumarylacetoacetate hydrolase deficiency → liver failure, renal tubulopathy, cabbage-like odour. Drug of choice: nitisinone (NTBC) + low Phe/Tyr diet.
• Alkaptonuria: homogentisate oxidase deficiency → urine darkens on standing, ochronosis (blue-black cartilage), arthritis. One of Garrod's original IEMs.

Galactosaemia

Classic galactosaemia: deficiency of galactose-1-phosphate uridyltransferase (GALT).

• Trigger: ingestion of lactose (breast/cow milk → galactose). Toxic galactose-1-phosphate and galactitol accumulate.
• Clinical: neonate after milk feeds develops jaundice, hepatomegaly, vomiting, hypoglycaemia, cataracts (galactitol, "oil-droplet"), and a striking susceptibility to E. coli neonatal sepsis.
• Diagnosis: reducing substances in urine (positive Benedict's, negative glucose oxidase dipstick); confirm with low RBC GALT enzyme assay.
• Management: immediate, lifelong lactose/galactose-free diet (soy formula). Cataracts and acute features reverse; ovarian failure and learning issues may persist.

High-yield: Galactosaemia neonate + gram-negative sepsis → think E. coli. Cataracts in galactosaemia are due to galactitol via aldose reductase.

Glycogen storage diseases (GSD)

Defects in glycogen synthesis/degradation. The big three for exams:

GSD	Eponym	Enzyme	Organ	Hallmark
Type I	Von Gierke	Glucose-6-phosphatase	Liver/kidney	Severe fasting hypoglycaemia, lactic acidosis, hyperuricaemia, hyperlipidaemia, doll-like facies, hepatomegaly
Type II	Pompe	Lysosomal acid alpha-glucosidase (acid maltase)	Heart/muscle (generalised)	Cardiomegaly + hypotonia in infancy; normal blood glucose
Type V	McArdle	Muscle phosphorylase (myophosphorylase)	Skeletal muscle	Exercise intolerance, cramps, second-wind phenomenon, myoglobinuria; flat lactate on ischaemic exercise

Also worth knowing: Type III (Cori/Forbes — debranching enzyme), Type IV (Andersen — branching enzyme, cirrhosis), Type VI (Hers — liver phosphorylase).

High-yield: Pompe disease is the only GSD that is also a lysosomal storage disorder, and the only one with prominent cardiomegaly. It does NOT cause fasting hypoglycaemia (blood sugar is normal because it is a lysosomal, not cytosolic, defect).

High-yield: McArdle's — failure of blood lactate to rise during ischaemic forearm exercise; ammonia still rises. The second-wind phenomenon (improved tolerance after a brief rest) is classic.

Management of GSD I focuses on preventing hypoglycaemia: frequent feeds, cornstarch therapy, and avoiding fructose/galactose. Pompe is treated with enzyme replacement therapy (alglucosidase alfa).

Lysosomal storage disorders

Deficient lysosomal enzymes → accumulation of undigested substrate. Progressive multisystem disease.

Gaucher disease

• Deficiency of glucocerebrosidase (acid beta-glucosidase) → glucocerebroside accumulates.
• Most common lysosomal storage disorder; high carrier rate in Ashkenazi Jews; autosomal recessive.
• Clinical: hepatosplenomegaly (massive splenomegaly), pancytopenia, bone pain/Erlenmeyer flask deformity of distal femur, avascular necrosis. Type 1 (non-neuronopathic, adult, commonest) vs types 2/3 (neuronopathic).
• Pathology: Gaucher cells — lipid-laden macrophages with "crumpled tissue paper / wrinkled silk" cytoplasm.
• Treatment: enzyme replacement therapy — imiglucerase; substrate reduction (miglustat/eliglustat).

Niemann-Pick disease (types A/B)

• Deficiency of sphingomyelinase → sphingomyelin accumulates.
• Clinical: hepatosplenomegaly, neurodegeneration, and a cherry-red spot at the macula (type A).
• Pathology: foamy / "sea-blue" histiocytes in marrow.

High-yield: Cherry-red spot at the macula is shared by Tay-Sachs, Niemann-Pick, and Sandhoff. Distinguish: Tay-Sachs has NO hepatosplenomegaly (hexosaminidase A deficiency, GM2 ganglioside, with exaggerated startle/hyperacusis), whereas Niemann-Pick HAS hepatosplenomegaly.

Tay-Sachs, Fabry, Hurler/Hunter quick table

Disease	Enzyme deficient	Accumulated substrate	Distinctive clue
Tay-Sachs	Hexosaminidase A	GM2 ganglioside	Cherry-red spot, no organomegaly, hyperacusis
Fabry (X-linked)	Alpha-galactosidase A	Ceramide trihexoside	Angiokeratomas, acroparaesthesia, renal/cardiac disease
Hurler (MPS I)	Alpha-L-iduronidase	Heparan/dermatan sulfate	Coarse facies, corneal clouding, intellectual disability
Hunter (MPS II, X-linked)	Iduronate-2-sulfatase	Heparan/dermatan sulfate	Like Hurler but NO corneal clouding
Krabbe	Galactocerebrosidase	Galactocerebroside	Globoid cells, irritability, peripheral neuropathy
Metachromatic leukodystrophy	Arylsulfatase A	Sulfatides	Demyelination, ataxia

High-yield: Hurler vs Hunter — Hunter is X-linked, milder, and has no corneal clouding; Hurler is autosomal recessive with corneal clouding. Mnemonic: "Hunter sees clearly (no corneal clouding) but is aggressive (behavioural issues)."

Newborn screening & diagnostic approach

Newborn screening (NBS) is heel-prick blood spot collected ideally 48–72 hours after birth (after feeds established). Modern programmes use tandem mass spectrometry (MS/MS) to screen dozens of disorders at once. Classic targets: PKU, congenital hypothyroidism, galactosaemia, MSUD, congenital adrenal hyperplasia, biotinidase deficiency, and (where included) sickle cell disease and G6PD.

Stepwise emergency workup of a sick neonate suspected to have an IEM:

Suspect IEM → Send first-line tests: blood glucose, ABG (anion gap), serum ammonia, lactate, ketones, electrolytes → Pattern recognition (hypoglycaemia? acidosis? hyperammonaemia?) → Specific tests: plasma amino acids, urine organic acids, acylcarnitine profile → Stabilise: stop protein/offending feed, give IV dextrose (anabolism), correct acidosis, dialysis/haemofiltration for severe hyperammonaemia → Confirm: enzyme assay / molecular genetics.

A simple discriminator:

1. Hyperammonaemia + respiratory alkalosis, normal anion gap → think urea cycle defect (e.g., OTC deficiency, X-linked).
2. Hyperammonaemia + high anion gap metabolic acidosis + ketosis → think organic acidaemia (methylmalonic, propionic, isovaleric — "sweaty feet" odour).
3. Hypoketotic hypoglycaemia → think fatty acid oxidation defect (e.g., MCAD).

High-yield: OTC deficiency is the commonest urea cycle disorder and is X-linked (the only one not autosomal recessive). Look for raised orotic acid; treat hyperammonaemia with sodium benzoate/phenylacetate and arginine.

Enzyme replacement therapy (ERT) — principles

ERT delivers recombinant enzyme intravenously, which is taken up by cells via the mannose-6-phosphate receptor and delivered to lysosomes. It works best for non-neuronopathic, peripheral disease.

• Effective for: Gaucher (imiglucerase), Pompe (alglucosidase alfa), Fabry (agalsidase), MPS I/II/VI.
• Major limitation: recombinant enzyme does not cross the blood-brain barrier, so it does not correct CNS disease (e.g., neuronopathic Gaucher, Tay-Sachs).
• Alternatives/adjuncts: substrate reduction therapy (miglustat), pharmacological chaperones, haematopoietic stem cell transplant (useful early in Hurler/MPS I), and gene therapy (emerging).

Complications

• Permanent intellectual disability/neurodegeneration if intoxication disorders are treated late.
• Acute metabolic crises with cerebral oedema and death (MSUD, urea cycle defects).
• Thromboembolism (homocystinuria), cirrhosis/hepatocellular carcinoma (tyrosinaemia, GSD), renal failure (Fabry, tyrosinaemia).
• Cataracts (galactosaemia), ectopia lentis (homocystinuria).
• Skeletal disease and pathological fractures (Gaucher, MPS).

Key differentials

• Sepsis is the great mimic of neonatal metabolic crisis — always screen for IEM in a "septic" neonate who is culture-negative and deteriorating after feeds.
• Hypoxic-ischaemic encephalopathy and intracranial haemorrhage may mimic metabolic encephalopathy.
• Among the storage disorders, organomegaly + coarse facies should prompt distinction between MPS, Gaucher, Niemann-Pick.
• A child with "Marfanoid" habitus → differentiate Marfan vs homocystinuria (see table).

Recently asked / exam angle

• Odour clues are repeatedly tested: musty/mousy → PKU; maple syrup/burnt sugar → MSUD; sweaty feet → isovaleric/glutaric acidaemia; cabbage → tyrosinaemia; rotten fish → trimethylaminuria.
• Enzyme matching single-best-answer: PAH-PKU, GALT-galactosaemia, glucocerebrosidase-Gaucher, sphingomyelinase-Niemann-Pick, hexosaminidase A-Tay-Sachs, acid maltase-Pompe.
• Cherry-red spot differential (Tay-Sachs vs Niemann-Pick by organomegaly) is a classic image/clinical vignette.
• Cofactor-responsive IEMs: B6 → homocystinuria; B1 → MSUD (thiamine-responsive); B12 → some methylmalonic acidaemias; biotin → biotinidase deficiency; BH4 → some PKU.
• GSD identification: Von Gierke (hypoglycaemia + lactic acidosis), Pompe (cardiomegaly + hypotonia), McArdle (exercise cramps + second wind).
• Inheritance traps: OTC deficiency, Hunter, Fabry, Lesch-Nyhan, G6PD are X-linked; the rest of the commonly asked IEMs are autosomal recessive.

Rapid revision

1. Most IEMs are autosomal recessive; X-linked = OTC, Hunter, Fabry, Lesch-Nyhan, G6PD.
2. PKU — phenylalanine hydroxylase deficiency, musty odour, fair hair/blue eyes, low-Phe diet + tyrosine; avoid aspartame; sapropterin (BH4) for responders.
3. MSUD — branched-chain ketoacid dehydrogenase deficiency; leucine is most toxic; maple-syrup urine; alloisoleucine diagnostic.
4. Homocystinuria — CBS deficiency; lens dislocates down and in; thrombosis; ~50% B6-responsive; give betaine.
5. Galactosaemia — GALT deficiency; oil-droplet cataract (galactitol); E. coli sepsis; lactose-free diet.
6. Von Gierke (GSD I) — G6Pase deficiency; severe fasting hypoglycaemia + lactic acidosis; cornstarch therapy.
7. Pompe (GSD II) — acid maltase; only GSD that is a lysosomal disorder; cardiomegaly + hypotonia, normal sugar; ERT = alglucosidase alfa.
8. McArdle (GSD V) — myophosphorylase deficiency; exercise intolerance, second wind, flat lactate on ischaemic exercise.
9. Gaucher — glucocerebrosidase; massive splenomegaly, Erlenmeyer flask femur, "crumpled tissue paper" cells; treat with imiglucerase.
10. Niemann-Pick (A) — sphingomyelinase; cherry-red spot WITH hepatosplenomegaly; foamy histiocytes. Tay-Sachs = cherry-red spot WITHOUT organomegaly.
11. Hurler vs Hunter — both MPS; Hunter is X-linked with no corneal clouding.
12. Sick neonate: send glucose, ABG, ammonia, lactate; ERT does not cross the blood-brain barrier.