背景:间隙连接蛋白β1(GJB1)的致病变体,编码连接蛋白32,已知会导致X连锁Charcot-Marie-Tooth病(CMTX),第二种最常见的CMT形式。CMTX具有以下五种中枢神经系统(CNS)表型:亚临床电生理异常,神经系统检查和/或影像学轻度固定异常,短暂性中枢神经系统功能障碍,认知障碍,和持续性中枢神经系统表现。
方法:一名40岁的日本男性出现中枢神经系统症状,包括眼球震颤,突出的痉挛性截瘫,轻度小脑共济失调,伴有亚临床周围神经病变。脑磁共振成像显示白质扩散加权图像中的高强度,尤其是沿着锥体束,从小就一直存在。神经传导评估显示运动传导速度轻度下降,并且没有II波以外的听觉脑干反应。刺激正中神经引起的体感诱发电位的外周和中枢传导时间延长。遗传分析确定了半合子GJB1变体,NM_000166.6:c.520C>Tp.Pro174Ser.
结论:此处描述的患者,使用GJB1p.Pro174Ser变体,呈现独特的中枢神经系统显性表型,以痉挛性截瘫和持续性广泛性白质脑病为特征,而不是CMTX。在GJC2和CLCN2变异的患者中也观察到类似的表型,可能是因为这些基因在调节离子和水平衡方面的共同功能,这对于维持白质功能至关重要。CMTX应考虑在GJB1相关疾病的范围内,其中可能包括有主要中枢神经系统症状的患者,其中一些可能被归类为一种新型的痉挛性截瘫。
BACKGROUND: Pathogenic variants in Gap junction protein beta 1 (GJB1), which encodes Connexin 32, are known to cause X-linked Charcot-Marie-Tooth disease (CMTX), the second most common form of CMT. CMTX presents with the following five central nervous systems (CNS) phenotypes: subclinical electrophysiological abnormalities, mild fixed abnormalities on neurological examination and/or imaging, transient CNS dysfunction, cognitive impairment, and persistent CNS manifestations.
METHODS: A 40-year-old Japanese male showed CNS symptoms, including nystagmus, prominent spastic paraplegia, and mild cerebellar ataxia, accompanied by subclinical peripheral neuropathy. Brain magnetic resonance imaging revealed hyperintensities in diffusion-weighted images of the white matter, particularly along the pyramidal tract, which had persisted since childhood. Nerve conduction assessment showed a mild decrease in motor conduction velocity, and auditory brainstem responses beyond wave II were absent. Peripheral and central conduction times in somatosensory evoked potentials elicited by stimulation of the median nerve were prolonged. Genetic analysis identified a hemizygous GJB1 variant, NM_000166.6:c.520C > T p.Pro174Ser.
CONCLUSIONS: The patient in the case described here, with a GJB1 p.Pro174Ser variant, presented with a unique CNS-dominant phenotype, characterized by spastic paraplegia and persistent extensive leukoencephalopathy, rather than CMTX. Similar phenotypes have also been observed in patients with GJC2 and CLCN2 variants, likely because of the common function of these genes in regulating ion and water balance, which is essential for maintaining white matter function. CMTX should be considered within the spectrum of GJB1-related disorders, which can include patients with predominant CNS symptoms, some of which can potentially be classified as a new type of spastic paraplegia.