Inborn errors of metabolism

At a glance

• An inborn error of metabolism (IEM) is a genetic defect in an enzyme, transporter or cofactor. Most are autosomal recessive; OTC deficiency and Fabry disease are X-linked; most acute porphyrias (AIP, variegate porphyria, hereditary coproporphyria) are dominant with low penetrance, though ALAD-deficiency porphyria is recessive.
• Three mechanisms explain the clinical patterns:
  • intoxication: substrate upstream of the block accumulates (urea cycle disorders, organic acidaemias, PKU). Episodic, triggered by catabolism or protein.
  • energy deficiency: the product is missing (fatty acid oxidation, glycogen storage, mitochondrial disease). Fasting or exercise brings it out.
  • complex molecule storage: lysosomal or peroxisomal substrate builds up slowly (Gaucher, Fabry, Pompe). Progressive and not triggered.
• Adults present with unexplained encephalopathy and hyperammonaemia, hypoketotic hypoglycaemia, exercise-induced rhabdomyolysis, multisystem storage disease, or neurovisceral attacks.
• Treatment targets the biochemistry: limit the substrate, supply the product, provide an alternative pathway, replace the enzyme, or reduce substrate synthesis.

Mechanism by category

Category	Examples	Adult clue
Urea cycle disorders	OTC deficiency, citrullinaemia (ASS1), CPS1 deficiency	Hyperammonaemic encephalopathy after surgery, steroids, GI bleed, fasting, postpartum or valproate
Organic acidaemias	Methylmalonic, propionic, isovaleric acidaemia	High anion gap acidosis, ketosis, hyperammonaemia, cytopenias
Aminoacidopathies	PKU, maple syrup urine disease, classical homocystinuria	Maternal PKU; thrombosis and lens dislocation (homocystinuria)
Fatty acid oxidation defects	MCAD, VLCAD, CPT2 deficiency	Hypoketotic hypoglycaemia; rhabdomyolysis after prolonged exercise or fasting
Glycogen storage diseases	GSD Ia (glucose-6-phosphatase), GSD V (McArdle)	Fasting hypoglycaemia with lactic acidosis; cramps and myoglobinuria with brief intense exercise
Lysosomal storage	Gaucher, Fabry, Pompe (GSD II), mucopolysaccharidoses	Splenomegaly and bone crises; cardiomyopathy, CKD and stroke; limb-girdle and diaphragm weakness
Haem synthesis	Acute intermittent porphyria	Abdominal pain, hyponatraemia, neuropathy, psychiatric change
Mitochondrial	MELAS, MERRF	Lactic acidosis, stroke-like episodes; see mitochondrial inheritance

Intoxication: hyperammonaemia

The urea cycle turns ammonia from protein catabolism into urea in hepatocytes. When it is blocked, ammonia rises and enters the brain. Astrocytes convert it with glutamate to glutamine, which is osmotically active, so astrocytes swell and cerebral oedema follows.

• Adult normal plasma ammonia is under about 50 µmol/L. Above 100 µmol/L with encephalopathy and no liver disease needs a metabolic explanation. Above about 200 µmol/L risks cerebral oedema.
• Ammonia stimulates the respiratory centre, so urea cycle disorders give respiratory alkalosis. Organic acidaemias give high anion gap metabolic acidosis from the accumulating acids. Their ammonia rises secondarily, because propionyl-CoA inhibits NAGS and so slows the cycle.
• Valproate inhibits NAGS (through valproyl-CoA) and depletes carnitine. It can unmask a heterozygous OTC carrier.
• Urine orotic acid is high in OTC deficiency (carbamoyl phosphate spills into pyrimidine synthesis) and normal in CPS1 or NAGS deficiency.

Worked example: anion gap in a metabolic crisis

A 22-year-old man is admitted drowsy after three days of vomiting. Ammonia is 180 µmol/L, Na 138, Cl 100, HCO3 10 mmol/L, glucose 4.2 mmol/L, ketones 4.5 mmol/L, ALT normal.

• Anion gap = Na − (Cl + HCO3) = 138 − (100 + 10) = 28 mmol/L (raised)
• Hyperammonaemia + high anion gap acidosis + ketosis + normal liver tests points to an organic acidaemia (propionic or methylmalonic) rather than a urea cycle disorder
• Send plasma amino acids, urine organic acids, plasma acylcarnitines and urine orotic acid together, before treatment changes the profile

Emergency principles, whatever the cause: stop protein, give IV 10% glucose (with insulin if glucose rises) to reverse catabolism, and contact the metabolic service. Nitrogen scavengers (sodium benzoate, sodium phenylbutyrate) give an alternative nitrogen exit; arginine replaces the cycle product except in arginase deficiency; carglumic acid activates CPS1 when NAGS is deficient or inhibited. Haemodialysis is used if ammonia is very high or rising. See metabolic acidosis and reduced level of consciousness.

Energy failure: fasting and exercise

During fasting, the liver oxidises fatty acids to make ketones and to fuel gluconeogenesis. A fatty acid oxidation defect produces hypoketotic hypoglycaemia: glucose falls without the expected ketone rise (insulin is appropriately suppressed). Acylcarnitines identify the block: C8 in MCAD deficiency, C14:1 in VLCAD deficiency. Treatment is avoiding fasting and giving IV glucose during illness. See hypoglycaemia.

Muscle depends on fat during prolonged exercise and on glycogen during short intense effort:

Disorder	Trigger	Non-ischaemic forearm exercise test	Other clue
CPT2 deficiency (commonest adult FAO defect)	Prolonged exercise, fasting, fever, cold	Normal	CK normal between attacks
McArdle disease (myophosphorylase)	Brief intense exercise	Flat lactate, exaggerated ammonia rise	Second wind after 8 to 10 minutes as fatty acids take over

The non-ischaemic version of the forearm test is now preferred: it separates McArdle from normal just as well without the risk of rhabdomyolysis and compartment syndrome from ischaemic exercise.

GSD Ia (glucose-6-phosphatase) blocks the final step of both glycogenolysis and gluconeogenesis. Fasting glucose falls within 3 to 4 hours and glucose-6-phosphate is diverted to lactate, urate and triglyceride: hypoglycaemia, lactic acidosis, hyperuricaemia and hypertriglyceridaemia. Uncooked cornstarch at night supplies slow-release glucose.

Storage: lysosomal diseases

A lysosomal hydrolase is missing, so its substrate accumulates within lysosomes of the cells that turn it over.

• Gaucher (glucocerebrosidase, GBA1): substrate builds up in macrophages, giving splenomegaly, thrombocytopenia, bone crises and Erlenmeyer flask femora. Raised chitotriosidase and ferritin. Heterozygous GBA1 variants are the commonest genetic risk factor for Parkinson disease.
• Fabry (α-galactosidase A, GLA, X-linked): globotriaosylceramide in endothelium, podocytes, myocytes and neurons. Acroparaesthesia, angiokeratomas, hypohidrosis, cornea verticillata, proteinuric CKD, LVH and early stroke. Women are affected because of X-inactivation. Lyso-Gb3 is a useful marker. See X-linked inheritance.
• Pompe (acid α-glucosidase): adult form causes limb-girdle weakness with early diaphragm involvement and orthopnoea, often with a raised CK. Dried blood spot enzyme assay screens for it.

Treatment options built on this biology:

• Enzyme replacement: mannose-6-phosphate on the infused enzyme targets it to lysosomes; it doesn't cross the blood-brain barrier
• Substrate reduction: eliglustat inhibits glucosylceramide synthase in Gaucher type 1 (dose depends on CYP2D6 genotype)
• Pharmacological chaperone: migalastat stabilises misfolded α-galactosidase A, and only works for "amenable" GLA variants

In Australia, enzyme replacement for Gaucher, Fabry, Pompe and several mucopolysaccharidoses is funded through the Life Saving Drugs Program, with eligibility criteria, rather than the general PBS. Fabry is the exception: migalastat (oral chaperone, since September 2024) and pegunigalsidase alfa (Section 100 HSD) are PBS Authority Required, while agalsidase alfa and beta stay on the LSDP (PBAC recommended moving them to the PBS in July 2026).

Aminoacidopathies and porphyria

• PKU (phenylalanine hydroxylase): phenylalanine accumulates and tyrosine falls. Detected by newborn bloodspot screening, which in Australia uses tandem mass spectrometry for a panel of amino acid, organic acid and fatty acid oxidation disorders. Adults need lifelong dietary control. Maternal PKU is the key adult issue: keep phenylalanine at 120 to 360 µmol/L before conception and through pregnancy. Sapropterin (synthetic BH4 cofactor) helps responsive patients.
• Classical homocystinuria (cystathionine β-synthase): marfanoid habitus, downward lens dislocation, osteoporosis and thrombosis. About half respond to pyridoxine (B6). See Marfan syndrome.
• Acute intermittent porphyria (hydroxymethylbilane synthase): drugs that induce hepatic ALA synthase 1 (enzyme inducers, progestogens), fasting and alcohol precipitate attacks of abdominal pain, hyponatraemia (SIADH), motor neuropathy and dark urine. Diagnose with raised urine PBG during the attack. Glucose and IV haem (haem arginate) both suppress ALAS1. Givosiran, an siRNA against ALAS1, prevents recurrent attacks.

How it's tested

• Acid-base reasoning in encephalopathy: alkalosis and hyperammonaemia (urea cycle) versus high anion gap acidosis (organic acidaemia).
• Drug trigger questions: valproate in an OTC carrier; enzyme inducers in AIP.
• Matching the fuel to the defect: hypoketotic hypoglycaemia with fasting; flat lactate in McArdle.
• Inheritance traps: women with Fabry or OTC deficiency; recessive disease in siblings with unaffected parents (see autosomal inheritance).
• Therapy mechanisms: scavengers, enzyme replacement, substrate reduction and chaperones.

Pitfalls

• An ammonia sample must be free-flowing, on ice and analysed within 30 minutes, or it reads falsely high.
• Hyperammonaemia with normal liver tests is a metabolic emergency until proven otherwise. Don't wait for results before stopping protein and starting glucose.
• Normal glucose with low ketones during fasting is not reassuring in suspected FAO disease.
• Taking blood for the diagnostic profile after glucose and scavengers start can hide the abnormality. Collect samples at presentation.
• Heterozygous women with X-linked IEMs are not "just carriers".
• Enzyme replacement doesn't treat central nervous system disease.