Inborn errors of metabolism

The logic of inborn errors

• An inherited enzyme defect causes harm in two ways: the substrate before the block accumulates (often toxic), and the product after the block is missing. Most are autosomal recessive because one working copy usually gives enough enzyme.
• Treatment follows the same logic: restrict the substrate, supply the missing product, give a cofactor, or replace the enzyme.

Lysosomes and storage disease

• Lysosomes hold about 50 acid hydrolases working at pH about 5 (kept acid by proton pumps). They digest material arriving by endocytosis, phagocytosis and autophagy; autophagy explains regression of the uterus and breast after pregnancy.
• Enzymes are tagged with mannose-6-phosphate in the Golgi. In I-cell disease (mucolipidosis II) the phosphotransferase fails, so enzymes are secreted into blood instead of reaching lysosomes: coarse facies, gingival hyperplasia, restricted joints, early death.
• Storage material swells cells (foam cells, Gaucher cells) and enlarges organs. Inheritance is autosomal recessive except Fabry and Hunter (X-linked recessive).

Sphingolipidoses

• Sandhoff disease lacks hexosaminidase A and B: Tay–Sachs plus organomegaly.
• A cherry-red macula appears because lipid-laden ganglion cells whiten the retina around the fovea, which has no ganglion cells, so the red choroid shows through. It is also seen in central retinal artery occlusion.

Exam trap Tay–Sachs: cherry-red spot without hepatosplenomegaly. Niemann–Pick: cherry-red spot with it.

Mucopolysaccharidoses

• Hurler (α-L-iduronidase): corneal clouding, gargoyle facies, hepatosplenomegaly, airway obstruction, valve disease, intellectual disability.
• Hunter (iduronate-2-sulphatase, X-linked): milder, no corneal clouding, aggressive behaviour.
• Urinary dermatan and heparan sulphate are raised in both.

Glycogen storage diseases

• Glycogen in the liver maintains blood glucose; glycogen in muscle fuels the muscle itself. So liver defects cause fasting hypoglycaemia and hepatomegaly, while muscle defects cause exercise intolerance.

• In von Gierke disease glucose-6-phosphate cannot leave the liver as glucose, so it is pushed into glycolysis (lactate), the pentose pathway (purines, then urate) and fat synthesis. Glucagon gives no glucose rise.
• In McArdle disease muscle cannot break down its glycogen. On an ischaemic forearm exercise test, lactate fails to rise (no glycogen enters glycolysis) while ammonia rises normally. The second wind after a brief rest comes as blood glucose and fatty acids reach the muscle. Blood glucose is normal because liver phosphorylase is a different isoenzyme.

Exam trap McArdle disease spares the liver: no hypoglycaemia, no hepatomegaly.

Amino acid disorders

• PKU is the commonest inborn error of amino acid metabolism and is picked up on heel-prick screening. A minority have tetrahydrobiopterin (BH4) deficiency, which also blocks dopamine and serotonin synthesis and does not respond to diet alone. Maternal PKU (high maternal phenylalanine) causes microcephaly and heart defects in the fetus.

Sugar disorders: galactose and fructose

• Cataracts in both galactose disorders come from galactitol, made by aldose reductase and trapped in the lens.
• In HFI, fructose-1-phosphate builds up and traps phosphate, so ATP falls and glycogenolysis and gluconeogenesis stop. Treatment is strict avoidance of fructose, sucrose (glucose plus fructose) and sorbitol.

Remember The earlier the enzyme in the pathway, the milder the disease: galactokinase and fructokinase defects are mild; GALT and aldolase B defects trap toxic phosphorylated sugars.

Peroxisomal disorders

• Peroxisomes carry out β-oxidation of very long-chain fatty acids, α-oxidation of phytanic acid, plasmalogen (myelin) synthesis and H₂O₂ breakdown by catalase.
• Zellweger syndrome: peroxisomes fail to form (PEX genes): hypotonia, seizures, hepatomegaly, facial dysmorphism, early death.
• X-linked adrenoleukodystrophy (ABCD1): VLCFA build-up in adrenal cortex and white matter: adrenal insufficiency with demyelination in boys.
• Refsum disease: phytanic acid accumulates: retinitis pigmentosa, neuropathy, ichthyosis.

Purine disorders and gout

• Gout: monosodium urate crystals, needle-shaped and negatively birefringent; first MTP joint; tophi.
• Hyperuricaemia mostly from underexcretion (renal impairment, thiazide and loop diuretics, low-dose aspirin, alcohol, ciclosporin, pyrazinamide) and less often overproduction (myeloproliferative disease, tumour lysis, psoriasis, Lesch–Nyhan HGPRT deficiency, von Gierke).
• Pseudogout: calcium pyrophosphate, rhomboid, weakly positively birefringent; knee; chondrocalcinosis; linked to haemochromatosis, hyperparathyroidism, low magnesium.
• Acute attack: NSAIDs, colchicine, steroids. Prevention: allopurinol or febuxostat (xanthine oxidase inhibitors), probenecid; rasburicase in tumour lysis.

Copper and iron overload

• Wilson disease (ATP7B, autosomal recessive): copper cannot enter bile or caeruloplasmin: liver disease, Kayser–Fleischer rings, basal ganglia movement and psychiatric features; low caeruloplasmin, high urinary copper; penicillamine, trientine, zinc.
• Hereditary haemochromatosis (HFE C282Y): cirrhosis, bronze diabetes, cardiomyopathy, hypogonadism, 2nd and 3rd MCP arthropathy; venesection.

How FCPS asks about this

• Commonest lysosomal storage disease: Gaucher disease; glucocerebrosidase (β-glucosidase) deficiency, crumpled tissue-paper macrophages.
• Cherry-red spot without organomegaly: Tay–Sachs (hexosaminidase A); with organomegaly, Niemann–Pick.
• Infant with fasting hypoglycaemia, hepatomegaly and lactic acidosis: von Gierke disease; glucose-6-phosphatase.
• Exercise cramps, dark urine, second wind, no lactate rise: McArdle disease; muscle glycogen phosphorylase.
• Fair child with eczema and musty urine: phenylketonuria; phenylalanine hydroxylase; avoid aspartame.
• Well infant with cataracts and galactose in urine: galactokinase deficiency; classic GALT deficiency adds liver failure and E. coli sepsis.
• Organelle defective in Zellweger syndrome: peroxisome.