Biochemistry: Inborn errors of metabolism and the molecular basis of disease

🧪 Inborn errors of metabolism and the molecular basis of disease. Inherited metabolic diseases are individually rare but collectively common (about 1 in 800 births). They teach how a single enzyme defect produces disease by accumulation of a toxic substrate, deficiency of a product, or diversion into side pathways - principles that also explain porphyria, lysosomal and peroxisomal disorders, and protein misfolding diseases. Many are detected by newborn screening; others present acutely in the neonatal period or with illness-triggered crises later in life.
Your four questions: Is this an "intoxication" disorder (acute crisis with illness or feeding), an energy disorder, or a storage disorder (progressive)? What accumulates and what is deficient? Which emergency tests (glucose, ammonia, gas, lactate, ketones) are needed now? What is the inheritance?

---

How Inborn Errors Cause Disease

• Most are autosomal recessive (consanguinity increases risk); some are X-linked (OTC deficiency, Fabry disease, Hunter syndrome, G6PD deficiency, Lesch–Nyhan) or mitochondrial.
• Mechanisms:
  • Toxic accumulation of substrate (PKU - phenylalanine; urea cycle defects - ammonia; organic acidaemias; galactosaemia).
  • Product deficiency (albinism - melanin; congenital adrenal hyperplasia - cortisol).
  • Diversion to alternative pathways (CAH - androgens; homocystinuria).
  • Energy deficiency (fatty acid oxidation defects, glycogen storage diseases, mitochondrial disease).
  • Storage of undegraded macromolecules (lysosomal storage disorders).
• Triggers for decompensation - catabolism (fasting, infection, vomiting, surgery), protein load, specific sugars (fructose, galactose).

Presentations and Emergency Tests

• Neonatal: a baby well at birth who deteriorates after starting feeds (poor feeding, vomiting, lethargy, encephalopathy, seizures) - often mistaken for sepsis; unusual odour (maple syrup, sweaty feet - isovaleric acidaemia); liver failure (galactosaemia, tyrosinaemia).
• Later: recurrent encephalopathy or vomiting with intercurrent illness, hypoglycaemia, developmental regression, organomegaly, coarse facies, cardiomyopathy, myopathy, unexplained metabolic acidosis.
• First-line emergency tests ("metabolic screen" - take during the acute episode): blood glucose, ammonia (free-flowing sample on ice, analysed promptly), blood gas and lactate, ketones, U&E, LFTs, CK; urine organic acids, plasma amino acids and acylcarnitines (store samples).
• Interpreting the screen:

Finding	Suggests
High ammonia, respiratory alkalosis, no ketosis	Urea cycle defect
High ammonia, metabolic acidosis, high anion gap, ketosis	Organic acidaemia
Hypoglycaemia with low ketones	Fatty acid oxidation defect, hyperinsulinism
Hypoglycaemia with lactic acidosis, hepatomegaly	Glycogen storage disease type I
Lactic acidosis with neurological or multi-organ disease	Mitochondrial disorder

• Emergency principle: stop the offending intake (protein, galactose, fructose), give high-dose IV glucose to reverse catabolism, correct acidosis, and remove toxins (ammonia scavengers - sodium benzoate, sodium phenylbutyrate; haemofiltration). Many patients carry a BIMDG emergency regimen letter.

Amino Acid and Organic Acid Disorders

• PKU, homocystinuria, maple syrup urine disease, tyrosinaemia type 1 (liver failure, renal tubulopathy, hepatocellular carcinoma - treated with nitisinone) - see the Metabolism chapter for PKU and homocystinuria.
• Organic acidaemias (methylmalonic, propionic, isovaleric acidaemia) - neonatal encephalopathy with ketoacidosis, high ammonia, neutropenia; protein restriction and carnitine.
• Cystinuria - defective renal reabsorption of cystine, ornithine, lysine and arginine (COLA) → cystine stones (hexagonal crystals); high fluid intake and urinary alkalinisation.
• Hartnup disease - neutral amino acid transport defect → pellagra-like rash (niacin deficiency).

Lysosomal Storage Disorders

• Lysosomal enzymes degrade macromolecules; deficiency → progressive storage, organomegaly, neurological decline.

Disorder	Enzyme	Features	Inheritance
Gaucher disease	Glucocerebrosidase	Hepatosplenomegaly, bone crises and pain, pancytopenia, "crumpled tissue paper" macrophages; commonest LSD; Ashkenazi Jewish; GBA variants increase Parkinson's risk; enzyme replacement	AR
Tay–Sachs disease	Hexosaminidase A	Neurodegeneration in infancy, cherry-red spot on the macula, no hepatosplenomegaly; Ashkenazi Jewish	AR
Niemann–Pick disease (A/B)	Sphingomyelinase	Cherry-red spot with hepatosplenomegaly, foam cells	AR
Fabry disease	α-galactosidase A	Painful neuropathy (burning hands and feet), angiokeratomas, hypohidrosis, renal failure, cardiomyopathy, early stroke; enzyme replacement	X-linked
Pompe disease	Acid maltase (α-glucosidase)	Infantile cardiomyopathy and hypotonia; late-onset limb-girdle weakness	AR
Hurler syndrome (MPS I)	α-L-iduronidase	Coarse facies, corneal clouding, intellectual disability, hepatosplenomegaly, dysostosis multiplex	AR
Hunter syndrome (MPS II)	Iduronate sulfatase	As Hurler but no corneal clouding, aggressive behaviour	X-linked

• Treatments: enzyme replacement therapy, substrate reduction therapy, haematopoietic stem cell transplant (Hurler), gene therapy (emerging).

Peroxisomal and Mitochondrial Disorders

• Peroxisomes - β-oxidation of very-long-chain fatty acids (VLCFA), plasmalogen synthesis, hydrogen peroxide metabolism.
• X-linked adrenoleukodystrophy - ABCD1 mutation; raised VLCFA → adrenal insufficiency and progressive demyelination in boys (or myelopathy in adult men); screen boys with Addison's disease for VLCFA.
• Zellweger syndrome - peroxisome biogenesis disorder: severe hypotonia, seizures, liver disease, craniofacial dysmorphism.
• Refsum disease - phytanic acid accumulation: retinitis pigmentosa, neuropathy, ataxia, ichthyosis; dietary restriction.
• Mitochondrial disorders - mtDNA (maternal inheritance, heteroplasmy) or nuclear DNA mutations; tissues with high energy demand (brain, muscle, heart, retina, cochlea): MELAS (mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes), MERRF (myoclonic epilepsy, ragged red fibres), Leber's hereditary optic neuropathy, Kearns–Sayre syndrome (ophthalmoplegia, retinopathy, heart block), maternally inherited diabetes and deafness; aminoglycoside-induced deafness (m.1555A>G variant). Valproate is dangerous in POLG-related disease (liver failure).

Porphyrias and Haem Synthesis

• Haem synthesis: glycine + succinyl-CoA → δ-aminolevulinic acid (ALA) (ALA synthase - rate-limiting, needs B6) → porphobilinogen (PBG) → porphyrins → haem (iron added by ferrochelatase). Haem inhibits ALA synthase (negative feedback).
• Acute intermittent porphyria - autosomal dominant PBG deaminase deficiency; attacks triggered by drugs that induce CYP enzymes (barbiturates, carbamazepine, phenytoin, sulfonamides, some antibiotics), alcohol, fasting, oestrogen/progesterone (luteal phase, pill), infection, stress: severe abdominal pain, vomiting, constipation, tachycardia, hypertension, hyponatraemia (SIADH), neuropathy (motor, can progress to respiratory failure), seizures, psychiatric symptoms; no skin lesions. Urine darkens on standing; raised urine PBG during an attack. Treat with IV haem arginate and carbohydrate, stop triggers, analgesia (opioids are safe); check every drug against the porphyria drug database.
• Porphyria cutanea tarda - commonest porphyria; photosensitive blistering and fragile skin on the backs of the hands, hypertrichosis; associated with alcohol, hepatitis C, iron overload (HFE), oestrogens; treat with venesection or low-dose hydroxychloroquine.
• Erythropoietic protoporphyria - painful photosensitivity (burning without blisters) from childhood.
• Lead poisoning - inhibits ALA dehydratase and ferrochelatase → raised ALA and zinc protoporphyrin; microcytic anaemia with basophilic stippling, abdominal pain, neuropathy (wrist drop), encephalopathy in children, Burton's line on the gums.
• Sideroblastic anaemia - impaired haem synthesis with ring sideroblasts: congenital (X-linked ALA synthase), alcohol, lead, isoniazid (B6 deficiency), myelodysplasia.

Protein Misfolding, Amyloid and Connective Tissue Disorders

• Amyloidosis - misfolded proteins form β-pleated sheets (apple-green birefringence with Congo red under polarised light): AL (light chains - myeloma), AA (serum amyloid A - chronic inflammation, e.g. rheumatoid arthritis, familial Mediterranean fever), ATTR (transthyretin - hereditary or wild-type senile cardiac amyloid; tafamidis), Aβ (Alzheimer's), β2-microglobulin (long-term dialysis - carpal tunnel). See the Pathology chapters.
• α-1 antitrypsin deficiency - the Z variant misfolds and polymerises in hepatocytes (liver disease) and is deficient in the lung (emphysema).
• Cystic fibrosis - commonest variant F508del causes misfolding of the CFTR chloride channel; CFTR modulators (elexacaftor–tezacaftor–ivacaftor) correct folding and gating.
• Prion diseases - misfolded prion protein (PrPSc) induces misfolding of normal protein: sporadic, variant (BSE-linked) and familial CJD; rapidly progressive dementia with myoclonus.
• Collagen and connective tissue disorders: osteogenesis imperfecta (type I collagen - fractures, blue sclerae, deafness - consider in suspected non-accidental injury), Ehlers–Danlos syndromes (hypermobility, skin hyperextensibility; vascular type - arterial and bowel rupture), Marfan syndrome (fibrillin-1 - tall, lens dislocation upwards, aortic root dilatation and dissection, autosomal dominant), scurvy (acquired defect of collagen hydroxylation).

Newborn Screening for Metabolic Disease

• UK newborn blood spot (day 5): PKU, MCADD, maple syrup urine disease, isovaleric acidaemia, glutaric aciduria type 1, homocystinuria, plus congenital hypothyroidism, sickle cell disease and cystic fibrosis.
• Tandem mass spectrometry analyses acylcarnitines and amino acids from a single dried blood spot.
• Positive screen → same-day referral to the specialist metabolic team (MCADD: avoid fasting, emergency regimen during illness).
• Not screened in the UK (but clinically important): galactosaemia, urea cycle disorders, organic acidaemias (other than IVA, GA1), fatty acid disorders other than MCADD, lysosomal disorders.

Principles of Treatment

• Dietary restriction of the substrate (protein/phenylalanine, galactose, fructose, long-chain fat).
• Supplementation of the deficient product or cofactor (cofactor-responsive forms - B6 in homocystinuria, BH4/sapropterin in some PKU, B12 in some methylmalonic acidaemia, biotin in biotinidase deficiency).
• Avoidance of fasting and emergency regimens (glucose polymer drinks; IV 10% glucose in hospital).
• Toxin removal - ammonia scavengers, dialysis.
• Enzyme replacement, substrate reduction, organ transplantation (liver for urea cycle disorders, HSCT for MPS I), gene therapy.
• Genetic counselling and cascade testing - most are autosomal recessive (25% recurrence risk for each pregnancy); prenatal and pre-implantation diagnosis available.

Inborn Errors at a Glance

Clue	Think
Neonate deteriorating after feeds	Galactosaemia, urea cycle defect, organic acidaemia, MSUD
High ammonia + alkalosis	Urea cycle defect (OTC)
Hypoketotic hypoglycaemia	MCAD deficiency
Cherry-red spot	Tay–Sachs (no organomegaly), Niemann–Pick (organomegaly), CRAO
Painful neuropathy, angiokeratomas, renal failure	Fabry disease (X-linked)
Abdominal pain, hyponatraemia, neuropathy, dark urine	Acute intermittent porphyria
Blistering on backs of hands, hypertrichosis	Porphyria cutanea tarda
Basophilic stippling, wrist drop	Lead poisoning

Spot the Diagnosis

• A 3-day-old boy, breastfeeding, becomes lethargic and tachypnoeic; ammonia 600 µmol/L, pH 7.48. → Urea cycle defect (OTC deficiency - X-linked).
• A young woman on the combined pill has severe abdominal pain, confusion, Na 121 and weakness. → Acute intermittent porphyria - urine PBG; IV haem arginate.
• A 30-year-old man with burning pain in hands, proteinuria and a stroke. → Fabry disease.
• A man with hepatosplenomegaly, bone pain and thrombocytopenia; Ashkenazi Jewish ancestry. → Gaucher disease.
• A boy with Addison's disease develops gait disturbance and behavioural change. → X-linked adrenoleukodystrophy (VLCFA).

Exam-style Scenarios

• Scenario. A child with MCAD deficiency has gastroenteritis and cannot keep fluids down. What is the plan?
  Answer: Start the emergency regimen immediately - glucose polymer drinks at home; if vomiting or unwell, admit for IV 10% glucose (avoid fasting); check glucose, ketones and gas. Do not wait for hypoglycaemia.
• Scenario. A woman with known acute intermittent porphyria needs antibiotics for a UTI and analgesia for a fracture. How do you choose?
  Answer: Check every drug against a porphyria safe-drug database (e.g. the UK Porphyria Medicines Information Service); opioids and many penicillins are safe; avoid enzyme-inducing drugs and sulfonamides; maintain carbohydrate intake.
• Scenario. Why does a boy with Hunter syndrome have clear corneas while a girl with Hurler syndrome has corneal clouding?
  Answer: They are different mucopolysaccharidoses - Hunter (MPS II, X-linked, iduronate sulfatase) characteristically lacks corneal clouding; Hurler (MPS I, autosomal recessive, α-L-iduronidase) has it.

Key Points

• Suspect an inborn error in any neonate who deteriorates after feeds - check glucose, ammonia, gas, lactate and ketones.
• High ammonia with respiratory alkalosis = urea cycle defect.
• Hypoketotic hypoglycaemia = fatty acid oxidation defect (MCAD).
• AIP: abdominal pain, hyponatraemia, neuropathy; drug triggers; IV haem arginate.
• Most inborn errors are autosomal recessive; Fabry, Hunter, OTC and G6PD deficiency are X-linked.

Further Reading

• British Inherited Metabolic Disease Group (BIMDG): emergency management guidelines
• UK Newborn Screening Programme Centre: blood spot screening
• Welsh Medicines Information Centre / UK Porphyria Medicines Information Service: drug safety in porphyria
• Saudubray JM et al. Inborn Metabolic Diseases: Diagnosis and Treatment