Latour P, Vial C
Centre de référence maladies neuromusculaires rares Rhône-Alpes, 69677 Bron, France.
Rev Neurol (Paris). 2009 Dec;165(12):1122-6. doi: 10.1016/j.neurol.2009.10.002.
Charcot-Marie-Tooth (CMT) disease is the most common cause of inherited peripheral neuropathies with a frequency estimated at 1/2500. Electroneuromyographic examination distinguishes a myelinic form (CMT1) and an axonal form of the disease (CMT2). Significant genetic heterogeneity is found in CMT, with 15 genes or loci for CMT2. To date, a molecular diagnosis has not been established for most CMT2 patients and the distribution of identified mutations is wide spreading over nearly all genes. Simple guidelines for daily practice are difficult to establish from compilation of mutation reports or consultation of databases; little simplification can be expected from future findings. We present our results of molecular diagnosis for 251 CMT2 index cases characterized by their mode of inheritance (217 dominant and 34 recessive cases), and a motor conduction velocity in median nerve equal to or above to 38m/s. For each case, at least one of the genes known to date for CMT2 (MFN2, RAB7, GARS, NF-L, HSPB1, GDAP1, MPZ, HSPB8, GJB1, DNM2, YARS, LMNA, and MED25) was studied. Around 22% of diagnoses were established and efficiency was comparable for dominant or recessive cases. For dominant cases, the first objective was to search for mutations of proteins connexin32, mitofusin2 and P0. For recessive cases, GDAP1 provided the key to molecular diagnosis; lamin A/C mutations were only found for patients with an ethnic background from North Africa. Heat shock proteins HSPB1 and HSPB8 were implicated in a significant proportion of "spinal" (or pure motor) CMT2. NF-L or RAB7 mutations were rare. We did not identify any deleterious mutations in GARS, DNM2, YARS orMED2. We propose a simple decision tree for molecular diagnosis of CMT2.
夏科-马里-图斯（CMT）病是遗传性周围神经病最常见的病因，估计发病率为1/2500。神经电生理检查可区分脱髓鞘型（CMT1）和轴索性疾病（CMT2）。CMT存在显著的遗传异质性，CMT2有15个基因或基因座。迄今为止，大多数CMT2患者尚未建立分子诊断，已鉴定出的突变分布广泛，几乎涉及所有基因。从突变报告汇编或数据库查询中难以制定简单的日常实践指南；未来的研究结果也难以实现大幅简化。我们报告了251例CMT2先证者的分子诊断结果，这些患者以遗传方式（217例显性和34例隐性病例）以及正中神经运动传导速度等于或高于38m/s为特征。对于每例患者，至少研究了一个目前已知的CMT2相关基因（MFN2、RAB7、GARS、NF-L、HSPB1、GDAP1、MPZ、HSPB8、GJB1、DNM2、YARS、LMNA和MED25）。约22%的病例得以确诊，显性或隐性病例的诊断效率相当。对于显性病例，首要目标是寻找连接蛋白32、线粒体融合蛋白2和P0的突变。对于隐性病例，GDAP1是分子诊断的关键；仅在有北非种族背景的患者中发现了核纤层蛋白A/C突变。热休克蛋白HSPB1和HSPB8与相当一部分“脊髓型”（或纯运动型）CMT2有关。NF-L或RAB7突变罕见。我们在GARS、DNM2、YARS或MED2中未发现任何有害突变。我们提出了一个用于CMT2分子诊断的简单决策树。
