Natural history of alkaptonuria
Natural history of alkaptonuria
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DOI：
10.1056/nejmoa021736
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发表时间：
2002-12-26
影响因子：
158.5
通讯作者：
Gahl, WA
中科院分区：
文献类型：
--
作者：
Phornphutkul, C;Introne, WJ;Gahl, WA
背景资料：由HGO基因突变和尿黑酸1，2-双加氧酶缺乏引起的尿黑酸尿症导致尿黑酸（HGA）蓄积、褐变和结缔组织破坏。虽然尼替西酮抑制产生HGA的酶，但对这种疾病没有有效的治疗方法。我们进行了一项研究，以描绘黑酸尿症的自然史。方法：我们评估了58例黑酸尿症（年龄范围，4至80岁），采用临床，放射学，生化和分子方法。设计了一个放射学评分系统来评估脊柱和关节损伤的严重程度。两名患者接受了nitisinone为10和9 days.Results：生命表分析表明，关节置换术进行了平均年龄为55岁，肾结石在64岁，心脏瓣膜参与在54岁，和冠状动脉钙化在59岁。线性回归分析表明，疾病严重程度的放射学评分在30岁后开始增加，男性比女性增加得更快。发现了23个新的HGO突变。在一名51岁的女性中，尿HGA排泄量在尼替西酮10天疗程后从2.9 g/天降至0.13 g/天（7天剂量为0.7 mg/天，3天剂量为2.8 mg/天）。在一名59岁的妇女，尿HGA从6.4克下降到1.7克/天后，9天的治疗与尼替西酮（0.7毫克/天）。这些患者的血浆酪氨酸水平从约1.1 mg/dl（每升60微摩尔），每分升约12.8毫克（700微摩尔/升）和23.6毫克/分升（1300微摩尔/升），没有临床体征或症状。黑酸尿症自然史的报告数据为长期治疗的评价提供了基础。虽然尼替西酮可以减少尿黑酸1，2-双加氧酶缺乏症患者的HGA产生，但这种治疗的长期安全性和有效性需要进一步评估。
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.