Myasthenic syndrome due to defects in rapsyn Clinical and molecular findings in 39 patients
Myasthenic syndrome due to defects in rapsyn Clinical and molecular findings in 39 patients
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DOI：
10.1212/wnl.0b013e3181ae7cbc
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发表时间：
2009-07-21
期刊：
影响因子：
9.9
通讯作者：
Engel, A. G.
中科院分区：
文献类型：
--
作者：
Milone, M.;Shen, X. M.;Engel, A. G.
背景：rapsyn致病性突变导致终板乙酰胆碱受体（AChR）缺乏，是突触后先天性肌无力综合征的常见原因。方法：对39例患者进行临床、电生理、病理及分子检查。结果：除1例患者外，所有患者均在生命的前2年出现疾病。在9例患者中，肌无力症状包括持续或发作性眼轻症，1例患者为纯肢带型。超过一半的患者经历了间歇性恶化。25例患者在开始接受胆碱能治疗后进行长期随访：21例病情稳定或好转，2例无症状；3有一个渐进的过程；我在婴儿期就去世了。在进行终板研究的7例患者中，每个终板的AChR平均计数和对ACh的突触反应均低于AChR表达基因低突变的患者。常见的p. N88K突变8例为纯合，23例为杂合。6个突变是新的，包括3个错义突变，一个帧内缺失，一个剪接位点突变和一个无义突变。p. N88K的纯合性与不同程度的严重程度相关。除8例启动子纯合突变（c. -38A > G）的近东患者外，未观察到基因型与表型的相关性，这些患者病程轻微。结论：除1例患者外，所有患者均出现在生命早期，大多数患者对胆碱能激动剂有反应。通过早期诊断和治疗，rapsyn缺乏症在大多数患者中有良性病程。除了与颌骨畸形相关的E-box突变外，没有一致的表型-基因型相关性。神经病学(R) 2009；73: 228 - 235
Background: Pathogenic mutations in rapsyn result in endplate acetylcholine receptor (AChR) deficiency and are a common cause of postsynaptic congenital myasthenic syndromes.Methods: Clinical, electrophysiologic, pathologic, and molecular studies were done in 39 patients.Results: In all but one patient, the disease presented in the first 2 years of life. In 9 patients, the myasthenic symptoms included constant or episodic ophthalmoparesis, and 1 patient had a pure limb-girdle phenotype. More than one-half of the patients experienced intermittent exacerbations. Long-term follow-up was available in 25 patients after start of cholinergic therapy: 21 became stable or were improved and 2 of these became asymptomatic; 3 had a progressive course; and 1 died in infancy. In 7 patients who had endplate studies, the average counts of AChR per endplate and the synaptic response to ACh were less reduced than in patients harboring low AChR expressor mutations. Eight patients were homozygous and 23 heterozygous for the common p. N88K mutation. Six mutations, comprising 3 missense mutations, an in-frame deletion, a splice-site mutation, and a nonsense mutation, are novel. Homozygosity for p. N88K was associated with varying grades of severity. No genotype-phenotype correlations were observed except in 8 Near-Eastern patients homozygous for the promoter mutation (c. -38A > G), who had a mild course.Conclusions: All but 1 patient presented early in life and most responded to cholinergic agonists. With early diagnosis and therapy, rapsyn deficiency has a benign course in most patients. There was no consistent phenotype-genotype correlation except for an E-box mutation associated with jaw deformities. Neurology (R) 2009; 73: 228-235