Alkaptonuria and Albinism
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Direct answer
Alkaptonuria is a deficiency of homogentisic acid oxidase in the tyrosine degradation pathway, so homogentisic acid accumulates and the urine blackens on standing — Garrod's founding example of an inborn error of metabolism from 1902. Albinism results from failure of melanin synthesis from that same tyrosine, most often through deficiency of tyrosinase, the copper-containing enzyme that converts tyrosine to DOPA and dopaquinone. One pathway therefore produces two classic autosomal recessive diseases: a benign black-urine syndrome with late arthritis, and a pigmentary disorder whose danger is photodamage and skin cancer.
What you must remember
- Tyrosine degradation: tyrosine transaminase to p-hydroxyphenylpyruvate, to homogentisic acid, then homogentisate 1,2-dioxygenase onward to fumarate plus acetoacetate — making tyrosine both glucogenic and ketogenic.
- Alkaptonuria: homogentisic acid oxidase deficiency; urine darkens on standing or with alkali as homogentisate oxidises to a black polymer; ferric chloride gives a transient blue-green colour.
- Ochronosis — bluish-black pigmentation of sclerae, ears, nose and cartilage — appears in adulthood, with degenerative arthritis of the spine and large joints and sometimes calcific aortic stenosis; life expectancy is near-normal and treatment is supportive (nitisinone remains investigational).
- Albinism types: OCA1 tyrosinase-null (no pigment ever, white hair, pink irides); OCA2 (P gene, commonest worldwide, some pigment develops); OCA3 (TRP-1, rufous); ocular albinism is X-linked (Nettleship–Falls).
- Ocular findings drive disability in all albinism: nystagmus, photophobia, strabismus, translucent irides, foveal hypoplasia with poor vision.
- Chediak–Higashi syndrome: partial albinism with giant neutrophil granules and recurrent infections; Hermansky–Pudlak syndrome: albinism with platelet storage-pool defect and bleeding tendency.
- Melanin pathway: tyrosine to L-DOPA to dopaquinone (tyrosinase, copper-dependent), then to eumelanin (black-brown) or, with cysteine, pheomelanin (red-yellow).
- Photoprotection is the management of albinism: sunscreens, clothing, sunglasses and regular skin examination, because squamous cell carcinoma of sun-exposed skin is the major long-term risk.
- Menkes disease illustrates copper-dependent pigmentation: defective copper transport cripples tyrosinase and lysyl oxidase, giving kinky, depigmented hair.
Two patients, one pathway
A father notices his infant son's diaper stained black where urine has pooled overnight; the child is thriving, and the urine is sterile but turns deeply black when a drop of alkali is added in the laboratory. That is alkaptonuria: nothing needs to be done in childhood beyond reassurance, but at forty he may return with slate-grey ears, dark-stained sclerae and back stiffness from ochronotic cartilage crumbling in his spine. Contrast a toddler from the same genetics ward: born with snow-white hair, grey-blue irises that transilluminate, and eyes that wander with rapid nystagmus. He is photophobic and squints in daylight. The diagnosis is oculocutaneous albinism; a hair-bulb incubation test with tyrosine (no darkening means tyrosinase-negative OCA1, darkening means tyrosinase-positive OCA2) traditionally separated the main types, with molecular testing now definitive. His care is preventive — broad-spectrum sunscreen from infancy, ultraviolet-protective glasses, low-vision support and annual skin checks, because in the Indian sun these children develop actinic damage and squamous cell carcinoma alarmingly early without protection. If the same child had recurrent pyogenic infections or a bruising tendency, the syndromic albinisms — Chediak–Higashi and Hermansky–Pudlak — would need exclusion.
Where students slip
Students label alkaptonuria "tyrosinosis" or confuse it with tyrosinaemia type I, which is fumarylacetoacetate hydrolase deficiency with liver failure and renal tubular dysfunction — a different and far more dangerous disease. The second slip is assuming all albinism is tyrosinase-negative: OCA2, the commonest form globally, retains enzyme and accumulates pigment with age, so a "darkening albino" is not a diagnostic error. Third, examiners ask why the urine blackens only on standing: homogentisic acid oxidises slowly in air (faster in alkali), so a fresh sample looks deceptively normal — always let it stand before concluding.
Frequently asked questions
Why does urine turn black in alkaptonuria?
Homogentisic acid, unable to be cleaved by homogentisate 1,2-dioxygenase, is excreted and oxidises on exposure to air and alkali to a benzoquinone polymer that is black; the change is gradual, which is why diapers stain overnight.
What is ochronosis?
Deposition of oxidised homogentisic acid polymer in cartilage, sclerae and other connective tissues, producing blue-black discolouration and progressive degenerative arthritis of the spine and large joints, sometimes with aortic valve calcification.
Which enzyme is deficient in the severe oculocutaneous albinism type OCA1?
Tyrosinase — the copper-containing enzyme catalysing tyrosine to DOPA and dopaquinone; complete loss (tyrosinase-negative) yields no melanin at any age, whereas OCA2 (P protein defect) is milder and the most frequent form worldwide.
Which syndromic albinisms must be remembered and why?
Chediak–Higashi (giant lysosomal granules, recurrent infections, partial albinism) and Hermansky–Pudlak (platelet storage-pool defect with bleeding diathesis) — both alter management beyond photoprotection.
Why is tyrosine called both glucogenic and ketogenic?
Its carbon skeleton splits into fumarate (glucogenic, feeding gluconeogenesis) and acetoacetate (ketogenic, a ketone body) — tyrosine and phenylalanine straddle both classes, a staple of metabolism vivas.