Tyrosinaemia type I (fumarylacetoacetase deficiency) produces succinylacetone, a potent inhibitor of delta-aminolevulinic acid dehydratase (ALAD). The resultant biochemical and clinical consequence is:

• A Elevated homogentisate causing ochronosis and arthropathy
• B Excess tyrosine causes melanin overproduction and skin hyperpigmentation
• C Elevated succinylacetone activates gluconeogenesis causing hyperglycaemia
• D Accumulation of delta-aminolevulinic acid (ALA) causing acute neurological crises resembling porphyria, plus hepatorenal disease ✓

Explanation

Fumarylacetoacetase (FAH) deficiency (tyrosinaemia type I) causes accumulation of maleylacetoacetate and fumarylacetoacetate, which spontaneously form succinylacetone. Succinylacetone is a structural analogue of delta-ALA and irreversibly inhibits ALAD (porphobilinogen synthase), the second enzyme of haem biosynthesis. This causes ALA accumulation in urine and blood, producing acute porphyria-like neurological crises (abdominal pain, motor neuropathy) in addition to progressive hepatic dysfunction and renal tubular Fanconi syndrome. Treatment is NTBC (nitisinone, inhibits HPPD upstream). Homogentisate accumulation occurs in alkaptonuria (AKU, type III tyrosinaemia-related).

Reference: Harper's Illustrated Biochemistry, 32nd ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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