Genetic and clinical profile of 15 Chinese families with GDAP1-related Charcot–Marie–Tooth disease and identification of H256R as a frequent mutation

IF 3.9 3区 医学 Q1 CLINICAL NEUROLOGY Journal of the Peripheral Nervous System Pub Date : 2024-05-05 DOI:10.1111/jns.12628
Zhongzheng Li, Sen Zeng, Yongzhi Xie, Xiaobo Li, Shunxiang Huang, Huadong Zhao, Wanqian Cao, Lei Liu, Mengli Wang, Qiaoyu Gong, Jun Liu, Pengfei Rong, Ruxu Zhang
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Abstract

Background and Aims

Mutations in ganglioside-induced differentiation-associated protein 1 (GDAP1) cause axonal or demyelinating Charcot–Marie–Tooth disease (CMT) with autosomal dominant or recessive inheritance. In this study, we aim to report the genotypic and phenotypic features of GDAP1-related CMT in a Chinese cohort.

Methods

Clinical, neurophysiological, genetic data, and available muscle/brain imaging information of 28 CMT patients with GDAP1 variants were retrospectively collected.

Results

We identified 16 GDAP1 pathogenic variants, among which two novel variants c.980dup(p.L328FfsX25) and c.480+4T>G were first reported. Most patients (16/28) presented with AR or AD CMT2K phenotype. Clinical characteristics in our cohort demonstrated that the AR patients presented earlier onset, more severe phenotype compared with the AD patients. Considerable intra-familial phenotypic variability was observed among three AD families. Muscle atrophy and fatty infiltration in the lower extremity were detected by Muscle magnetic resonance imaging (MRI) scans in four patients. MRI showed two AR patients showed more severe muscle involvement of the posterior compartment than those of the anterolateral compartment in the calf. One patient carrying Q38*/H256R variants accompanied with mild periventricular leukoaraiosis.

Conclusions

In this study, we conducted an analysis of clinical features of the GDAP1-related CMT patients, expanded the mutation spectrum in GDAP1 by reporting two novel variants, and presented the prevalent occurrence of the H256R mutation in China. The screening of GDAP1 should be particularly emphasized in Chinese patients with CMT2, given the incomplete penetrance and pathogenic inheritance patterns involving dominant and recessive modes.

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15个中国GDAP1相关夏科-玛丽-牙病家族的遗传和临床概况,以及H256R作为一种常见突变的鉴定。
背景和目的:神经节苷脂诱导分化相关蛋白1(GDAP1)突变会导致轴索型或脱髓鞘型夏科-玛丽-牙病(CMT),具有常染色体显性或隐性遗传性。本研究旨在报告中国人群中 GDAP1 相关 CMT 的基因型和表型特征:方法:我们回顾性地收集了28例GDAP1变异型CMT患者的临床、神经电生理、遗传学数据以及现有的肌肉/脑成像信息:结果:我们发现了16个GDAP1致病变异,其中两个新变异c.980dup(p.L328FfsX25)和c.480+4T>G为首次报道。大多数患者(16/28)表现为 AR 或 AD CMT2K 表型。我们队列中的临床特征显示,与 AD 患者相比,AR 患者发病更早,表型更严重。在三个 AD 家系中观察到了相当大的家族内表型差异。四名患者的肌肉磁共振成像(MRI)扫描发现了下肢肌肉萎缩和脂肪浸润。核磁共振成像显示,两名AR患者的小腿后部肌肉受累比前外侧肌肉受累更严重。一名携带 Q38*/H256R 变体的患者伴有轻度脑室周围白化病:本研究对 GDAP1 相关 CMT 患者的临床特征进行了分析,报告了两个新的变异体,扩大了 GDAP1 的突变谱,并介绍了 H256R 突变在中国的流行情况。鉴于GDAP1的不完全渗透性以及显性和隐性遗传模式,中国的CMT2患者应特别重视GDAP1的筛查。
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来源期刊
CiteScore
6.10
自引率
7.90%
发文量
45
审稿时长
>12 weeks
期刊介绍: The Journal of the Peripheral Nervous System is the official journal of the Peripheral Nerve Society. Founded in 1996, it is the scientific journal of choice for clinicians, clinical scientists and basic neuroscientists interested in all aspects of biology and clinical research of peripheral nervous system disorders. The Journal of the Peripheral Nervous System is a peer-reviewed journal that publishes high quality articles on cell and molecular biology, genomics, neuropathic pain, clinical research, trials, and unique case reports on inherited and acquired peripheral neuropathies. Original articles are organized according to the topic in one of four specific areas: Mechanisms of Disease, Genetics, Clinical Research, and Clinical Trials. The journal also publishes regular review papers on hot topics and Special Issues on basic, clinical, or assembled research in the field of peripheral nervous system disorders. Authors interested in contributing a review-type article or a Special Issue should contact the Editorial Office to discuss the scope of the proposed article with the Editor-in-Chief.
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