title: Natural history of alkaptonuria.
abstract: 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 micromol per liter) in both to approximately 12.8 mg per deciliter (700 micromol per liter) and 23.6 mg per deciliter (1300 micromol 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.
authors.affiliation: Section on Human Biochemical Genetics, Heritable Disorders Branch, National Institute of Child Health and Human Development, Bethesda, Md 20892-1851, USA.
authors.forename: Chanika
authors.initials: C
authors.lastname: Phornphutkul
authors.forename: Wendy J
authors.initials: WJ
authors.lastname: Introne
authors.forename: Monique B
authors.initials: MB
authors.lastname: Perry
authors.forename: Isa
authors.initials: I
authors.lastname: Bernardini
authors.forename: Mark D
authors.initials: MD
authors.lastname: Murphey
authors.forename: Diana L
authors.initials: DL
authors.lastname: Fitzpatrick
authors.forename: Paul D
authors.initials: PD
authors.lastname: Anderson
authors.forename: Marjan
authors.initials: M
authors.lastname: Huizing
authors.forename: Yair
authors.initials: Y
authors.lastname: Anikster
authors.forename: Lynn H
authors.initials: LH
authors.lastname: Gerber
authors.forename: William A
authors.initials: WA
authors.lastname: Gahl
mesh_terms: D015111:4-Hydroxyphenylpyruvate Dioxygenase / Q000037:antagonists & inhibitors; D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000474:Alkaptonuria / Q000145:classification / Q000150:complications / Q000235:genetics / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D003240:Connective Tissue Diseases / Q000209:etiology; D003512:Cyclohexanones / Q000627:therapeutic use; D004252:DNA Mutational Analysis; D049308:Dioxygenases; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D006349:Heart Valve Diseases / Q000209:etiology; D050560:Homogentisate 1,2-Dioxygenase; D006801:Humans; D007592:Joint Diseases / Q000209:etiology; D007669:Kidney Calculi / Q000209:etiology; D015993:Life Tables; D016014:Linear Models; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009579:Nitrobenzoates / Q000627:therapeutic use; D010105:Oxygenases / Q000235:genetics*; D012720:Severity of Illness Index; D014443:Tyrosine / Q000378:metabolism
chemical_list: D003512:Cyclohexanones; D004791:Enzyme Inhibitors; D009579:Nitrobenzoates; D014443:Tyrosine; D010105:Oxygenases; D049308:Dioxygenases; D015111:4-Hydroxyphenylpyruvate Dioxygenase; D050560:Homogentisate 1,2-Dioxygenase; C077073:nitisinone