■亨廷顿病(HD)是常染色体显性遗传,全渗透剂,神经退行性疾病最常见于中年成年人。HD是由HTT基因中的CAG重复扩增引起的,导致突变型亨廷顿(mHTT)的表达。我们的目的是检测和量化泪液中的mHTT,据我们所知,这是以前从未测量过的。
■我们招募了20个清单,13个显眼的HD基因扩增携带者(HDGECs)和20个年龄匹配的对照。所有患者都接受了详细的评估,包括统一亨廷顿病评定量表(UHDRS)总运动评分(TMS)和总功能能力评分。使用纸Schirmer's条收集泪液。使用单分子计数SMCxPRO技术测定泪液mHTT的水平。
■显色患者(67,223±80,360fM)和显色前患者(55,561±45,931fM)的平均泪液mHTT水平显着高于对照组(1622±2179fM)。我们注意到泪液mHTT水平和CAG重复长度之间的显著相关性,\'估计诊断年限\',疾病负担评分和UHDRSTMS和TFC。当比较对照与明显患者时,ROC曲线显示几乎完美的得分(AUC=0.9975)。同样,对照组和入组患者之间的AUC为0.9846.区分对照组和明显患者的最佳临界值为4544fM,而对照组和显见前患者之间的区别为6596fM。
■泪液mHTT水平具有早期和非侵入性检测HD改变的潜力,可以整合到临床试验和临床诊断中。
OBJECTIVE: Huntington\'s disease (HD) is an autosomal dominant, fully penetrant, neurodegenerative disease that most commonly affects middle-aged adults. HD is caused by a CAG repeat expansion in the HTT gene, resulting in the expression of mutant huntingtin (mHTT). Our aim was to detect and quantify mHTT in tear fluid, which, to our knowledge, has never been measured before.
METHODS: We recruited 20 manifest and 13 premanifest HD gene expansion carriers, and 20 age-matched controls. All patients underwent detailed assessments, including the Unified Huntington\'s Disease Rating Scale (UHDRS) total motor score (TMS) and total functional capacity (TFC) score. Tear fluid was collected using paper Schirmer\'s strips. The level of tear mHTT was determined using single-molecule counting SMCxPRO technology.
RESULTS: The average tear mHTT levels in manifest (67,223 ± 80,360 fM) and premanifest patients (55,561 ± 45,931 fM) were significantly higher than those in controls (1,622 ± 2,179 fM). We noted significant correlations between tear mHTT levels and CAG repeat length, \"estimated years to diagnosis,\" disease burden score and UHDRS TMS and TFC. The receiver operating curve demonstrated an almost perfect score (area under the curve [AUC] = 0.9975) when comparing controls to manifest patients. Similarly, the AUC between controls and premanifest patients was 0.9846. The optimal cutoff value for distinguishing between controls and manifest patients was 4,544 fM, whereas it was 6,596 fM for distinguishing between controls and premanifest patients.
CONCLUSIONS: Tear mHTT has potential for early and noninvasive detection of alterations in HD patients and could be integrated into both clinical trials and clinical diagnostics.