Natural History of Alkaptonuria

Alkaptonuria is caused by mutations in the HGO gene and a deficiency of homogentisate 1,2-dioxygenase, which lead to an accumulation of homogentisic acid (HGA), ochronosis, and connective-tissue destruction. There is no effective therapy for the disorder. This study of the natural history of alkaptonuria examines findings in 58 patients, 57 of whom had detectable HGO mutations. The data are intended to serve as a base line for future trials of therapy. Nitisinone, which inhibits the enzyme that produces HGA, was administered briefly in two patients; urinary HGA levels decreased and plasma tyrosine levels increased without apparent adverse effects. This year marks the 100th anniversary of Sir Archibald Garrod's description of alkaptonuria (Mendelian Inheritance in Man number 203500) as the first disorder in humans to be found to conform to the principles of mendelian autosomal recessive inheritance. 1 In his Croonian lectures of 1908, 2 Garrod coined the term “inborn error of metabolism” and proposed that alkaptonuria results from a deficiency of an enzyme that normally splits the aromatic ring of homogentisic acid (HGA) (Figure 1), a tyrosine-degradation product known to accumulate in patients with alkaptonuria. 3 Indeed, alkaptonuria is associated with deficient homogentisate 1,2-dioxygenase (HGO) activity in the liver, 4 and the . . .