Congenital myasthenic syndrome caused by novel COL13A1 mutations
Congenital myasthenic syndrome caused by novel COL13A1 mutations
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DOI：
10.1007/s00415-019-09239-7
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发表时间：
2019-05-01
影响因子：
6
通讯作者：
Senderek, Jan
中科院分区：
文献类型：
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作者：
Dusl, Marina;Moreno, Teresa;Senderek, Jan
XIII胶原蛋白是一种非纤维性跨膜型胶原蛋白，长期以来一直被认为在神经肌肉接头突触成熟过程中起着关键作用。最近，在三名先天性肌无力综合征(CMS)患者中发现了双等位基因COL13A1功能丧失突变，CMS是一种罕见的遗传性疾病，具有神经肌肉传递缺陷，导致异常疲劳性和波动性肌肉无力，经常成功地使用乙酰胆碱酯酶抑制剂治疗。在这里，我们报告了另外6名CMS患者，他们来自三个此前未报道的COL13A1纯合子功能丧失突变(p.Tyr216*，p.Glu543fs和p.Thr629fs)。我们的病例的表型与以前报道的患者相似，包括出生时的呼吸窘迫和严重的吞咽困难，通常在生命的头几天或几周内缓解或改善。所有患者都有明显的眼睑下垂，仅有轻微的眼球麻痹和全身肌肉无力，主要影响面部、球、呼吸和轴肌。对乙酰胆碱酯酶抑制剂治疗的反应通常是负面的，而沙丁胺醇被证明是有益的。我们的数据进一步支持COL13A1变异与CMS的因果关系，并提示这种类型的CMS可能在临床上是同源的，需要替代的药物治疗。
Collagen XIII is a non-fibrillar transmembrane collagen which has been long recognized for its critical role in synaptic maturation of the neuromuscular junction. More recently, biallelic COL13A1 loss-of-function mutations were identified in three patients with congenital myasthenic syndrome (CMS), a rare inherited condition with defective neuromuscular transmission, causing abnormal fatigability and fluctuating muscle weakness and often successfully treated with acetylcholinesterase inhibitors. Here we report six additional CMS patients from three unrelated families with previously unreported homozygous COL13A1 loss-of-function mutations (p.Tyr216*, p.Glu543fs and p.Thr629fs). The phenotype of our cases was similar to the previously reported patients including respiratory distress and severe dysphagia at birth that often resolved or improved in the first days or weeks of life. All individuals had prominent eyelid ptosis with only minor ophthalmoparesis as well as generalized muscle weakness, predominantly affecting facial, bulbar, respiratory and axial muscles. Response to acetylcholinesterase inhibitor treatment was generally negative while salbutamol proved beneficial. Our data further support the causality of COL13A1 variants for CMS and suggest that this type of CMS might be clinically homogenous and requires alternative pharmacological therapy.