Giant axonal neuropathy: cross-sectional analysis of a large natural history cohort.
Giant axonal neuropathy: cross-sectional analysis of a large natural history cohort.
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DOI：
10.1093/brain/awab179
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发表时间：
2021-11-29
期刊：
影响因子：
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通讯作者：
Bonnemann, Carsten G
中科院分区：
文献类型：
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作者：
Bharucha-Goebel, Diana X;Norato, Gina;Bonnemann, Carsten G
巨轴突神经病（GAN）是一种非常罕见的常染色体隐性遗传、进行性神经退行性疾病，在儿童早期发病，表现为突出的感觉运动神经病，通常进展为影响PNS和CNS。该疾病是由位于16q23.2上的GAN基因中的双等位基因突变引起的，导致功能性gigaxonin的丧失，gigaxonin是调节中间丝周转所必需的底物特异性泛素连接酶衔接蛋白。在这里，我们报告了一项前瞻性收集的45名年龄范围为3- 21岁的遗传学证实的GAN患者的自然史研究的首次研究访视的横断面数据，以描述和交叉关联基线临床和功能队列特征。我们回顾了这一队列中分布在整个GAN基因中的致病变异，并确定了墨西哥血统GAN个体以及复发性单亲同二体病例中的复发性创始人突变。通过对力量、运动功能和疾病严重程度的电生理标志物的测量进行交叉相关分析，我们确定了运动功能测量32在GAN患者中具有最强的跨测量和年龄相关性。我们分析了运动功能测量32评分，因为它们对应于年龄和行走状态。重要的是，我们确定并表征了一个亚组的个体，其具有较温和的GAN形式，并且具有类似于Charcot-Marie-Tooth病的表现。这样的临床表现是不同的GAN的经典介绍，我们展示了如何在运动功能测量32和其他功能运动量表的性能两组分歧。我们进一步提供了关于GAN自主神经功能损害的第一次系统性临床分析的数据，这些分析是在自然史队列的一个子集上进行的。我们的基因证实的GAN个体队列是迄今为止报道的最大的，并突出了GAN与疾病状态相关的临床异质性和独特的表型和功能特征。目前的工作旨在作为前瞻性自然史研究的基础，并与正在进行的GAN儿童基因治疗试验相一致。
Giant axonal neuropathy (GAN) is an ultra-rare autosomal recessive, progressive neurodegenerative disease with early childhood onset that presents as a prominent sensorimotor neuropathy and commonly progresses to affect both the PNS and CNS. The disease is caused by biallelic mutations in the GAN gene located on 16q23.2, leading to loss of functional gigaxonin, a substrate specific ubiquitin ligase adapter protein necessary for the regulation of intermediate filament turnover. Here, we report on cross-sectional data from the first study visit of a prospectively collected natural history study of 45 individuals, age range 3-21years with genetically confirmed GAN to describe and cross-correlate baseline clinical and functional cohort characteristics. We review causative variants distributed throughout the GAN gene in this cohort and identify a recurrent founder mutation in individuals with GAN of Mexican descent as well as cases of recurrent uniparental isodisomy. Through cross-correlational analysis of measures of strength, motor function and electrophysiological markers of disease severity, we identified the Motor Function Measure 32 to have the strongest correlation across measures and age in individuals with GAN. We analysed the Motor Function Measure 32 scores as they correspond to age and ambulatory status. Importantly, we identified and characterized a subcohort of individuals with a milder form of GAN and with a presentation similar to Charcot-Marie-Tooth disease. Such a clinical presentation is distinct from the classic presentation of GAN, and we demonstrate how the two groups diverge in performance on the Motor Function Measure 32 and other functional motor scales. We further present data on the first systematic clinical analysis of autonomic impairment in GAN as performed on a subset of the natural history cohort. Our cohort of individuals with genetically confirmed GAN is the largest reported to date and highlights the clinical heterogeneity and the unique phenotypic and functional characteristics of GAN in relation to disease state. The present work is designed to serve as a foundation for a prospective natural history study and functions in concert with the ongoing gene therapy trial for children with GAN.