Abstract：
OBJECTIVE: 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.
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.
摘要：
目的：神经节苷脂诱导的分化相关蛋白1（GDAP1）的突变会导致轴突或脱髓鞘Charcot-Marie-Tooth病（CMT）常染色体显性或隐性遗传。在这项研究中,我们旨在报道一个中国队列中GDAP1相关CMT的基因型和表型特征.
方法：临床，神经生理学，遗传数据,回顾性收集28例有GDAP1变异的CMT患者的可用肌肉/脑影像学信息.
结果：我们确定了16种GDAP1致病变体，其中两个新的变体c.980dup(p.L328FfsX25）和c.480+4T>G首次报道。大多数患者（16/28）表现为AR或ADCMT2K表型。我们队列的临床特征表明，AR患者发病较早，与AD患者相比，表型更严重。在三个AD家族中观察到相当大的家族内表型变异性。通过肌肉磁共振成像（MRI）扫描发现4例患者的下肢肌肉萎缩和脂肪浸润。MRI显示，两名AR患者的后室肌肉受累比小腿前外侧室更严重。1例患者携带Q38*/H256R变异，伴有轻度脑室周围白质疏松。
结论：在这项研究中，我们对GDAP1相关CMT患者的临床特征进行了分析，通过报告两个新的变异扩大了GDAP1的突变谱，并介绍了H256R突变在中国的普遍发生。鉴于外显率不完全和致病遗传模式涉及显性和隐性模式，应在中国CMT2患者中特别强调GDAP1的筛查。
方法：临床，神经生理学，遗传数据,回顾性收集28例有GDAP1变异的CMT患者的可用肌肉/脑影像学信息.
结果：我们确定了16种GDAP1致病变体，其中两个新的变体c.980dup(p.L328FfsX25）和c.480+4T>G首次报道。大多数患者（16/28）表现为AR或ADCMT2K表型。我们队列的临床特征表明，AR患者发病较早，与AD患者相比，表型更严重。在三个AD家族中观察到相当大的家族内表型变异性。通过肌肉磁共振成像（MRI）扫描发现4例患者的下肢肌肉萎缩和脂肪浸润。MRI显示，两名AR患者的后室肌肉受累比小腿前外侧室更严重。1例患者携带Q38*/H256R变异，伴有轻度脑室周围白质疏松。
结论：在这项研究中，我们对GDAP1相关CMT患者的临床特征进行了分析，通过报告两个新的变异扩大了GDAP1的突变谱，并介绍了H256R突变在中国的普遍发生。鉴于外显率不完全和致病遗传模式涉及显性和隐性模式，应在中国CMT2患者中特别强调GDAP1的筛查。
