alkaptonuria

Alkaptonuria is a rare inherited metabolic disorder caused by deficient activity of the enzyme homogentisate 1,2-dioxygenase (HGD) in the tyrosine degradation pathway. As a result, homogentisic acid (HGA) accumulates in the body and is excreted in urine; oxidation of HGA gives urine its characteristic dark color when exposed to air. Over time, HGA deposits in connective tissues (ochronosis), leading to discoloration and degeneration of cartilage and other tissues.

Clinical features include dark urine that darkens on standing or exposure to air, and ochronosis, which becomes evident in adulthood as bluish-black pigmentation of the sclerae, ear cartilage, and other connective tissues. This is associated with progressive wear and tear of joints and the spine, resulting in early-onset osteoarthritis. Cardiac valvular disease and kidney stones may also occur.

Genetically, alkaptonuria is autosomal recessive and caused by biallelic mutations in the HGD gene. Carriers are typically asymptomatic. The condition remains very rare, with higher reported frequencies in some isolated populations due to founder effects.

Diagnosis is suggested by the combination of dark urine and ochronosis and confirmed by elevated homogentisic acid in urine or serum and/or molecular testing of the HGD gene.

Management is supportive, as there is no widely available cure. Treatments focus on symptom relief and slowing progression. This may include pain control, physical therapy, and, in severe cases, joint replacement. Nitisinone (NTBC) reduces HGA production by inhibiting HPPD and can slow ochronosis but raises tyrosine levels, requiring monitoring and dietary considerations. Dietary restriction of phenylalanine and tyrosine is used variably. Patients require regular monitoring for cardiovascular, renal, and ocular complications. The condition was first described by Archibald Garrod in 1902.