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Background Alkaptonuria, caused by mutations in the HGO gene and a deficiency of homogentisate 1,2-dioxygenase, results in an accumulation of homogentisic acid (HGA), ochronosis, and destruction of connective tissue. There is no effective therapy for this disorder, although nitisinone inhibits the enzyme that produces HGA. We performed a study to delineate the natural history of alkaptonuria.
Methods We evaluated 58 patients with alkaptonuria (age range, 4 to 80 years), using clinical, radiographic, biochemical, and molecular methods. A radiographic scoring system was devised to assess the severity of spinal and joint damage. Two patients were treated with nitisinone for 10 and 9 days, respectively.
Results Life-table analyses showed that joint replacement was performed at a mean age of 55 years and that renal stones developed at 64 years, cardiac-valve involvement at 54 years, and coronary-artery calcification at 59 years. Linear regression analysis indicated that the radiographic score for the severity of disease began increasing after the age of 30 years, with a more rapid increase in men than in women. Twenty-three new HGO mutations were identified. In a 51-year-old woman, urinary HGA excretion fell from 2.9 to 0.13 g per day after a 10-day course of nitisinone (7 days at a dose of 0.7 mg per day and 3 days at 2.8 mg per day). In a 59-year-old woman, urinary HGA fell from 6.4 g to 1.7 g per day after nine days of treatment with nitisinone (0.7 mg per day). Plasma tyrosine levels in these patients rose from approximately 1.1 mg per deciliter (60 µmol per liter) in both to approximately 12.8 mg per deciliter (700 µmol per liter) and 23.6 mg per deciliter (1300 µmol per liter), respectively, with no clinical signs or symptoms.
Conclusions The reported data on the natural history of alkaptonuria provide a basis for the evaluation of long-term therapies. Although nitisinone can reduce HGA production in humans with homogentisate 1,2-dioxygenase deficiency, the long-term safety and efficacy of this treatment require further evaluation.
Source Information
From the Section on Human Biochemical Genetics, Heritable Disorders Branch, National Institute of Child Health and Human Development, Bethesda, Md. (C.P., W.J.I., I.B., D.L.F., P.D.A., M.H., Y.A., W.A.G.); the Rehabilitation Medicine Department, National Institutes of Health Clinical Center, Bethesda, Md. (M.B.P., L.H.G.); the Department of Radiologic Pathology, Armed Forces Institute of Pathology, Washington, D.C.; the Department of Radiology, University of Maryland Medical Center, Baltimore; and the Departments of Radiology and Nuclear Medicine, Uniformed Services University of the Health Sciences, Bethesda, Md. (M.D.M.).
Address reprint requests to Dr. Gahl at 10 Center Dr., MSC 1851, Bldg. 10, Rm. 10C-103, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-1851, or at bgahl{at}helix.nih.gov.
Related Letters:
Alkaptonuria
Lorenzini S., Mannoni A., Selvi E., Phornphutkul C., Introne W. J., Gahl W. A.
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N Engl J Med 2003;
348:1408, Apr 3, 2003.
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