Agrin mutations lead to a congenital myasthenic syndrome with distal muscle weakness and atrophy
Agrin mutations lead to a congenital myasthenic syndrome with distal muscle weakness and atrophy
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DOI：
10.1093/brain/awu160
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发表时间：
2014-09-01
期刊：
影响因子：
14.5
通讯作者：
Lochmueller, Hanns
中科院分区：
文献类型：
--
作者：
Nicole, Sophie;Chaouch, Amina;Lochmueller, Hanns
先天性肌无力综合征是由神经肌肉传递受损引起的一组临床和遗传异质性罕见疾病。其临床特征是疲劳性肌无力，与对重复神经刺激的肌肉反应递减相关，并且经常与突触后缺陷相关。远端肌病形成另一组临床和遗传异质性的原发性肌肉疾病，其中虚弱和萎缩仅限于远端肌肉，至少最初是这样。在先天性肌无力综合征和远端肌病中，有相当数量的患者在遗传学上仍未被诊断。在这里，我们报告了5例来自三个不相关的家庭，一个惊人的同质性临床实体结合先天性肌无力与远端肌无力和萎缩，让人想起远端肌病。MRI和神经生理学研究与局限于远端肢体肌肉的轻度肌病相一致，但对3 Hz重复神经刺激的响应减少（高达72%）指向神经肌肉传递缺陷。运动后的增量（高达285%），观察到在所有情况下，提示突触前先天性肌无力综合征的远端肢体肌肉。肌肉终板区的免疫荧光和超微结构分析显示，与失神经再支配事件的突触重建。我们在两个亲属中进行了全外显子组测序，在一个孤立的病例中进行了桑格测序，并在编码聚集蛋白的基因中发现了五个新的隐性突变。这种在神经肌肉接头处具有关键功能的突触蛋白聚糖先前在更典型的先天性肌无力综合征中被发现突变。在我们的患者中，我们发现两个错义突变存在于N-末端聚集蛋白结构域，这降低了聚集蛋白在体外的乙酰胆碱受体聚集活性。我们的研究结果扩展了由于聚集蛋白突变引起的先天性肌无力综合征的范围，并显示了突变基因与相关表型之间意想不到的相关性。这为检查明显远端肌病患者的神经肌肉传递障碍和聚集蛋白突变提供了一个很好的理由。
Congenital myasthenic syndromes are a clinically and genetically heterogeneous group of rare diseases resulting from impaired neuromuscular transmission. Their clinical hallmark is fatigable muscle weakness associated with a decremental muscle response to repetitive nerve stimulation and frequently related to postsynaptic defects. Distal myopathies form another clinically and genetically heterogeneous group of primary muscle disorders where weakness and atrophy are restricted to distal muscles, at least initially. In both congenital myasthenic syndromes and distal myopathies, a significant number of patients remain genetically undiagnosed. Here, we report five patients from three unrelated families with a strikingly homogenous clinical entity combining congenital myasthenia with distal muscle weakness and atrophy reminiscent of a distal myopathy. MRI and neurophysiological studies were compatible with mild myopathy restricted to distal limb muscles, but decrement (up to 72%) in response to 3Hz repetitive nerve stimulation pointed towards a neuromuscular transmission defect. Post-exercise increment (up to 285%) was observed in the distal limb muscles in all cases suggesting presynaptic congenital myasthenic syndrome. Immunofluorescence and ultrastructural analyses of muscle end-plate regions showed synaptic remodelling with denervation-reinnervation events. We performed whole-exome sequencing in two kinships and Sanger sequencing in one isolated case and identified five new recessive mutations in the gene encoding agrin. This synaptic proteoglycan with critical function at the neuromuscular junction was previously found mutated in more typical forms of congenital myasthenic syndrome. In our patients, we found two missense mutations residing in the N-terminal agrin domain, which reduced acetylcholine receptors clustering activity of agrin in vitro. Our findings expand the spectrum of congenital myasthenic syndromes due to agrin mutations and show an unexpected correlation between the mutated gene and the associated phenotype. This provides a good rationale for examining patients with apparent distal myopathy for a neuromuscular transmission disorder and agrin mutations.