Patient-reported outcomes and functional assessments of patients with Alkaptonuria in a 3-year Nitisinone treatment trial

IF 3.7 2区 生物学 Q2 ENDOCRINOLOGY & METABOLISM
Kathryn R. Spears , Francis Rossignol , Monique B. Perry , Michael A. Kayser , Pim Suwannarat , Kevin E. O'Brien , Joy C. Bryant , Wendy F. Greenwood , Steve Fuller , William A. Gahl , Wendy J. Introne
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引用次数: 0

Abstract

Alkaptonuria is a rare disorder of tyrosine catabolism caused by deficiency of homogentisate 1,2-dioxygenase that leads to accumulation of homogentisic acid (HGA). Deposition of HGA-derived polymers in connective tissue causes progressive arthropathy of the spine and large joints, cardiac valvular disease, and genitourinary stones beginning in the fourth decade of life. Nitisinone, a potent inhibitor of the upstream enzyme, 4-hydroxyphenylpyruvate dioxygenase, dramatically reduces HGA production. As such, nitisinone is a proposed treatment for alkaptonuria. A randomized clinical trial of nitisinone in alkaptonuria confirmed the biochemical efficacy and tolerability of nitisinone for patients with alkaptonuria but the selected primary outcome did not demonstrate significant clinical benefit. Given that alkaptonuria is a rare disease with slow progression and variable presentation, identifying outcome parameters that can detect significant change during a time-limited clinical trial is challenging. To gain insight into patient-perceived improvements in quality of life and corresponding changes in physical function associated with nitisinone use, we conducted a post-hoc per protocol analysis of patient-reported outcomes and a functional assessment. Analysis revealed that nitisinone-treated patients showed significant improvements in complementary domains of the 36-Item Short-Form Survey (SF-36) and 6-min walk test (6MWT). Together, these findings suggest that nitisinone improves both quality of life and function of patients with alkaptonuria. The observed trends support nitisinone as a therapy for alkaptonuria.

在为期 3 年的尼替西酮治疗试验中,对碱丙酮尿症患者进行了患者报告结果和功能评估。
钾胨尿症是一种罕见的酪氨酸分解障碍性疾病,因缺乏高戊酸 1,2-二氧 化酶而导致高戊酸(HGA)蓄积。HGA 衍生的聚合物沉积在结缔组织中,导致脊柱和大关节的渐进性关节病、心脏瓣膜病和泌尿生殖系统结石,这些病症始于患者生命的第四个十年。尼替西酮是上游酶--4-羟基苯基丙酮酸二加氧酶的强效抑制剂,能显著减少 HGA 的产生。因此,尼替西酮被建议用于治疗碱蛋白尿。尼替西酮治疗烷蛋白通尿症的随机临床试验证实,尼替西酮对烷蛋白通尿症患者具有生化疗效和耐受性,但所选的主要结果并未显示出显著的临床益处。鉴于碱蛋白胨尿症是一种进展缓慢、表现多变的罕见疾病,在有时间限制的临床试验中确定能检测出显著变化的结果参数具有挑战性。为了深入了解患者在使用尼替西酮后所感受到的生活质量改善和身体功能的相应变化,我们对患者报告的结果和功能评估进行了事后分析。分析结果显示,尼替西酮治疗的患者在 36 项短表调查 (SF-36) 和 6 分钟步行测试 (6MWT) 的互补领域均有显著改善。这些研究结果表明,尼替西酮能改善碱蛋白尿患者的生活质量和功能。观察到的趋势支持将尼替西酮作为碱蛋白尿的一种疗法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Molecular genetics and metabolism
Molecular genetics and metabolism 生物-生化与分子生物学
CiteScore
5.90
自引率
7.90%
发文量
621
审稿时长
34 days
期刊介绍: Molecular Genetics and Metabolism contributes to the understanding of the metabolic and molecular basis of disease. This peer reviewed journal publishes articles describing investigations that use the tools of biochemical genetics and molecular genetics for studies of normal and disease states in humans and animal models.
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