Alkaptonuria

Alkaptonuria (AKU), also known as black urine disease or ochronosis, is a rare autosomal recessive metabolic disorder caused by deficiency of the enzyme homogentisate 1,2-dioxygenase (HGD), which is involved in the breakdown of the amino acids tyrosine and phenylalanine. This enzyme deficiency leads to the accumulation of homogentisic acid (HGA) in the body. HGA and its oxidized polymers deposit in connective tissues throughout the body, a process known as ochronosis, causing progressive damage over decades. The hallmark early sign of alkaptonuria is darkening of urine upon standing or exposure to air, which may be noticed in infancy through dark staining of diapers. However, the most significant clinical manifestations typically develop in adulthood, usually after age 30. Ochronotic pigmentation causes a characteristic blue-black discoloration of cartilage, which can be visible in the ears and sclera of the eyes. The musculoskeletal system is most severely affected, with progressive ochronotic arthropathy involving the spine and large joints (particularly the hips, knees, and shoulders), leading to pain, stiffness, and significant disability. Cardiovascular complications include aortic and mitral valve calcification and stenosis, as well as coronary artery calcification. Renal and prostatic stones are also common. Other affected tissues include tendons, ligaments, and skin. There is currently no cure for alkaptonuria. Management has traditionally been supportive, including pain management, physical therapy, and joint replacement surgery when needed. Dietary restriction of phenylalanine and tyrosine has shown limited benefit. Nitisinone (Orfadin), a drug originally developed for hereditary tyrosinemia type 1, has been shown to effectively reduce HGA levels and was approved by the European Medicines Agency (EMA) in 2020 for the treatment of alkaptonuria in adults. High-dose vitamin C has been used as an antioxidant, though its clinical efficacy remains unproven. Genetic counseling is recommended for affected families.

Data sourced from FDA regulatory filings and ClinicalTrials.gov. Updated periodically.

Common questions about Alkaptonuria