Shy M E, Siskind C, Swan E R, Krajewski K M, Doherty T, Fuerst D R, Ainsworth P J, Lewis R A, Scherer S S, Hahn A F
Department of Neurology, Wayne State University, 421 E. Canfield, Detroit, MI 48201, USA.
Neurology. 2007 Mar 13;68(11):849-55. doi: 10.1212/01.wnl.0000256709.08271.4d.
To investigate possible genotype-phenotype correlations and to evaluate the natural history of patients with Charcot-Marie-Tooth disease type 1X (CMT1X).
CMT1X is caused by over 260 distinct mutations in the gap junction beta 1 (GJB1) gene, located on the X chromosome, which encodes the gap junction protein connexin 32 (Cx32). The natural history of CMT1X is poorly understood, and it remains unknown whether particular mutations cause more severe neuropathies through abnormal gain-of-function mechanisms.
We evaluated 73 male patients with CMT1X, who each have 1 of 28 different GJB1 mutations predicted to affect nearly all domains of Cx32. Disability was evaluated quantitatively by the CMT Neuropathy Score (CMTNS) as well as by the CMT Symptom Score (CMTSS) and the CMT Examination Score (CMTES), which are both based on the CMTNS. Patients were also evaluated by neurophysiology.
In all patients, disability increased with age, and the degree of disability was comparable with that observed in patients with a documented GJB1 deletion. Disability correlated with a loss of motor units as assessed by motor unit number estimates.
Taken together, these data suggest that most GJB1 mutations cause neuropathy by a loss of normal connexin 32 function. Therefore, treatment of male patients with Charcot-Marie-Tooth disease type 1X may prove amenable to gene replacement strategies.
研究1X型腓骨肌萎缩症（CMT1X）患者可能存在的基因型-表型相关性，并评估其自然病史。
CMT1X由位于X染色体上的缝隙连接蛋白β1（GJB1）基因中的260多种不同突变引起，该基因编码缝隙连接蛋白连接蛋白32（Cx32）。CMT1X的自然病史了解甚少，特定突变是否通过异常功能获得机制导致更严重的神经病变仍不清楚。
我们评估了73例男性CMT1X患者，他们分别携带28种不同的GJB1突变中的一种，这些突变预计会影响Cx32的几乎所有结构域。通过CMT神经病变评分（CMTNS）以及基于CMTNS的CMT症状评分（CMTSS）和CMT检查评分（CMTES）对残疾程度进行定量评估。患者还接受了神经生理学评估。
在所有患者中，残疾程度随年龄增加，且与记录有GJB1缺失的患者所观察到的残疾程度相当。根据运动单位数量估计，残疾程度与运动单位的丧失相关。
综上所述，这些数据表明，大多数GJB1突变通过正常连接蛋白32功能的丧失导致神经病变。因此，1X型腓骨肌萎缩症男性患者的治疗可能适用于基因替代策略。
