Charcot-Marie-Tooth disease type 1A with 17p11.2 duplication - Clinical and electrophysiological phenotype study and influencing disease severity in 119 cases
Charcot-Marie-Tooth disease type 1A with 17p11.2 duplication - Clinical and electrophysiological phenotype study and influencing disease severity in 119 cases
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DOI：
10.1093/brain/120.5.813
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发表时间：
1997-05-01
期刊：
影响因子：
14.5
通讯作者：
Bouche, P
中科院分区：
文献类型：
--
作者：
Birouk, N;Gouider, R;Bouche, P
对 119 名已证实 17p11.2 重复的 1A 型腓骨肌萎缩症 (CMT1A) 患者进行了一项临床和电生理学研究。 50% 的病例首次出现功能性表现是在 10 岁以内，70% 的病例是在 20 岁之前出现。主要的临床症状是下肢肌肉无力和消瘦。所有患者的临床检查均未正常，且均至少出现高弓足或踝反射消失。所有神经的运动神经传导速度（MNCV）均一致降低，所有患者正中神经的运动神经传导速度均小于或等于 33 m/s。所有病例的感觉电位均异常，即使没有临床感觉丧失。所有患者远端肌肉的针肌电图募集均减少。即使在临床无症状个体或儿童中，MNCV 减慢也与重复的存在完全一致，证实了 17p11.2 重复的完整电生理外显率，并使正中神经 MNCV 成为筛查受影响的高危个体的可靠工具。功能障碍程度较轻。百分之九十六的患者能够自主； 25% 是无症状的，是通过系统的家庭调查，特别是根据正中神经 MNCV 减少来诊断的。发病年龄早和正中神经 MNCV 大大降低预示着更严重的病程；发病越早，正中神经 MNCV 减少得越多，并且在同等病程后功能障碍往往越高。根据病程对神经功能缺损、功能缺损和 MNCV 进行横断面分析表明，无论发病年龄如何，17p12.2 重复的 CMT1A 疾病都是一种临床进展性疾病，神经功能缺损和功能障碍增加，而正中神经 MNCV 和复合肌肉动作电位（CMAP）振幅不随病程变化。在大家庭中研究了父母与子女之间以及兄弟姐妹之间的家庭内表型变异。功能障碍和神经功能缺损差异较大，家系内正中神经MNCV最高范围达到23 m/s。与外周髓磷脂Po蛋白点突变的CMT1B患者的临床和电生理数据进行比较。研究发现，CMT1A 患者因移动远端运动潜伏期延长和 CMAP 振幅降低而受到更严重的影响，而 MNCV 没有显着差异，表明外周髓磷脂 Po 蛋白点突变并不总是与严重表型相关。相同的遗传缺陷（17p11.2重复）会导致表型内的不同表达，即使在发病年龄、临床严重程度和 MNCV 减慢方面存在差异的兄弟姐妹中也是如此。这种表型变异可能是由于与外周髓磷脂蛋白 22 表达相关的其他遗传因素以及其他内源性或环境因素造成的。
A clinical and electrophysiological study was performed in 119 Type 1A Charcot-Marie-Tooth disease (CMT1A) patients with proven 17p11.2 duplication. Onset of the first functional manifestations was in the first decade in 50% of cases and before the age of 20 years in 70% of cases. The predominant clinical signs were muscle weakness and wasting in the lower limbs. None of the patients was normal on clinical examination and all presented at least pes cavus or ankle jerk areflexia. Motor nerve conduction velocity (MNCV) was uniformly reduced in all nerves, and was less than or equal to 33 m/s in the median nerve for all patients. Sensory potentials were abnormal in all cases, even where there was no clinical sensory loss. Needle electromyography recruitment was reduced in distal muscles for all patients. MNCV slowing was fully consistent with the presence of duplication even in clinically asymptomatic individuals or in children, confirming the complete electrophysiological penetrance of 17p11.2 duplication and making median nerve MNCV a reliable tool for screening affected at-risk individuals. Functional disability was mild. Ninety-six percent of patients were autonomous; 25% were asymptomatic and diagnosed by systematic family investigation especially on the basis of median nerve MNCV reduction. Early age at onset and greatly reduced median nerve MNCV were predictive of a more severe disease course; the earlier the onset the more reduced the median nerve MNCV and the higher the functional disability tended to be after an equivalent disease duration. Cross-sectional analysis of neurological deficit, functional deficit and MNCV according to disease duration showed that, regardless of age at onset, CMT1A disease with 17p12.2 duplication is a clinically progressive disorder Neurological deficit and functional disability increased, whereas median nerve MNCV and compound muscle action potential (CMAP) amplitude did not change with disease course. Intrafamilial phenotype variation between parents and children and between siblings was studied in large families. Functional disability and neurological deficit differed widely and the highest range of median nerve MNCV within a family reached 23 m/s. Clinical and electrophysiological data were compared with those of CMT1B patients with peripheral myelin Po protein point mutation. CMT1A patients were found to be more severely affected with move prolonged distal motor latency and more reduced CMAP amplitude, whereas MNCV did not significantly differ indicating that peripheral myelin Po protein point mutation is not always associated with a severe phenotype. The same genetic defect (17p11.2 duplication) results in variable expression within the phenotype, even in siblings with variations in age at onset, clinical severity and MNCV slowing. This phenotypic variation could be due to additional genetic factors related to peripheral myelin protein 22 expression as well as to other endogenous or environmental factors.