Autosomal recessive axonal Charcot-Marie-Tooth disease (ARCMT2): phenotype-genotype correlations in 13 Moroccan families
Autosomal recessive axonal Charcot-Marie-Tooth disease (ARCMT2): phenotype-genotype correlations in 13 Moroccan families
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DOI：
10.1093/brain/awm014
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发表时间：
2007-04-01
期刊：
影响因子：
14.5
通讯作者：
LeGuern, Eric
中科院分区：
文献类型：
--
作者：
Bouhouche, Ahmed;Birouk, Nazha;LeGuern, Eric
Charcot-Marie-Tooth病是一组遗传异质性的运动神经病和感觉神经病。轴突常染色体隐性亚群(ARCMT2)的3个基因座分别位于1q21(CMT2B1，LMNA)、8q21(CMT4A和CMT2K，GDAP1)和19q13(CMT2B2)。我们报告了13个具有ARCMT2表型的摩洛哥家庭的临床、电生理、病理和遗传学研究。对所有指征病例和的高危亲属进行临床和电生理检查。临床受累患者31例。对3例患者进行了腓神经活检。有4个家系与1q21基因连锁，均有LMNA R298C突变。有6个家系与8q21基因座连锁，均有GDAP1 S194X突变。这两个突变的创始人效应是通过分析靠近基因的微卫星标记而提出的。剩下的三个家庭被排除在三个已知的基因座之外。电生理检查结果与轴索神经病变相一致。临床资料表明，在CMT2B1中，该病最常在第二个十年开始，并从远端肌肉向近端肌肉逐渐发展。我们的三名病程最长(24年)的患者也有严重的肩胛肌损伤。这可能是CMT2B1的一个特征。CMT4A/2K患者发病年龄多在2岁以前。大多数人从一开始就有严重的马蹄内翻足，这是CMT4A/2K的特征之一。本组CMT4A/2K患者均未发生声带麻痹。与这三个已知基因座没有关联的三个家系的临床表型呈现出一些在那些具有已知遗传缺陷的家系中没有的特殊性。一个家庭的特点是起病晚(>；20年)或轻微的神经病变，只有在检查时才能诊断出来。在第二个家庭中，背侧弯是最突出的症状。在第三个家庭中，症状开始于第二个十年，伴随着明显的脊柱侧弯的中度神经病变。这些家系说明了ARCMT2的临床和遗传异质性的程度。
Charcot-Marie-Tooth disease is a genetically heterogeneous group of hereditary motor and sensory neuropathies. Three loci for the axonal autosomal recessive subgroup (ARCMT2) have been reported in 1q21 (CMT2B1, LMNA), 8q21 (CMT4A and CMT2K, GDAP1) and 19q13 (CMT2B2). We report here a clinical, electrophysiological, pathological and genetic study in 13 Moroccan families with ARCMT2 phenotypes. Clinical and electrophysiological examinations were performed in all index cases and 64 'at-risk' relatives. Thirty-one patients were clinically affected. A peroneal nerve biopsy was obtained from three patients. Four families were linked to the 1q21 locus, all had the LMNA R298C mutation. Six families were linked to the 8q21 locus, all had the GDAP1 S194X mutation. Founder effects for both mutations were suggested by the analysis of microsatellite markers close to the genes. The three remaining families were excluded from the three known loci. The electrophysiological findings were consistent with an axonal neuropathy. The clinical data show that in CMT2B1 the disease began most often in the second decade and progressed gradually from distal to proximal muscles. Three of our patients with the longest disease durations (> 24 years) had also severe impairment in the scapular muscles. Reported here for the first time, this might be a hallmark of CMT2B1. Patients with CMT4A/2K had onset most often before the age of 2 years. Most had severe clubfoot from the beginning, one of the hallmarks of CMT4A/2K. None of our patients with CMT4A/2K had vocal cord paralysis. The clinical phenotype of the three families that are not linked to the three known loci presented some particularities that were not seen in those with known genetic defects. One family was characterized by late onset of the disease (> 20 years) or a mild neuropathy that was diagnosed only when the family was examined. In a second family, dorsal scoliosis was the most prominent symptom. In the third family, symptoms began in the second decade with a moderate neuropathy associated with a pronounced scoliosis. These families illustrate the extent of clinical and genetic heterogeneity in ARCMT2.