Alkaptonuria is a rare autosomal recessive disorder of metabolism caused by deficiency of
homogentisic acid oxidase and resulting in accumulation of
homogentisic acid in collagenous structures. It is characterized by homogentisic aciduria, bluish-black discoloration of connective tissues (
ochronosis) and
arthropathy of large joints. Less common manifestations include
cardiovascular abnormalities, renal, urethral and prostate
calculi.
Bone fractures are unusual in
ochronosis. In this report, we describe a woman, 69 years of age, with a history of dark urine since childhood and progressive pigmentation of the skin, sclera, and auricular cartilages. She had severe
arthropathy requiring
total joint replacement in both of her knees and right hip. She also had severe
aortic stenosis requiring valve replacement, and asymptomatic
nephrolithiasis. She presented with a low
trauma fracture of the distal femur despite two years of alendroate
therapy. We review the etiology, pathogenesis, clinical presentation, diagnosis and treatment of
alkaptonuric ochronosis. Early detection is important for prevention and treatment of multiple systems.
Nitisinone, a potent inhibitor of
4-hydroxyphenylpyruvate dioxygenase, dramatically reduces production and urinary excretion of
homogentisic acid; however, the long-term efficacy and side effects of such
therapy are unknown. Identifying the gene for
alkaptonuria offers the potential for a new therapeutic approach (replacement
therapy with a recombinant
enzyme) in the treatment of
alkaptonuric ochronosis.