Asymmetric muscle weakness due to ACTA1 mosaic mutations
Asymmetric muscle weakness due to ACTA1 mosaic mutations
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DOI：
10.1212/wnl.0000000000010947
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发表时间：
2020-12-15
期刊：
影响因子：
9.9
通讯作者：
Bohm, Johann
中科院分区：
文献类型：
--
作者：
Lornage, Xaviere;Quijano-Roy, Susana;Bohm, Johann
目的 在临床、遗传、组织学和超微结构水平对2名患有不对称或单侧肌无力的无关患者进行特征描述。
方法 患者接受了全面的临床检查、全身磁共振成像（MRI）以及外显子组测序。通过组织学和电子显微镜评估肌肉形态。
结果 两名患者均表现出早发性肌张力减退、运动发育里程碑延迟、脊柱侧凸和肺功能降低。患者P1表现出单侧肌无力，仅影响身体左侧；患者P2的不对称性不太明显。两名患者的肌肉活检均显示杆状体为主要的组织病理学特征，MRI显示在选择性的头部、近端和远端肌肉中有大量脂肪浸润，与肌无力不对称程度相关。对两名患者血液DNA进行的外显子组测序在少数读段中发现了新生的ACTA1错义突变，提示存在突变嵌合现象。随后的桑格测序证实肌肉DNA上存在突变，而在血液DNA上几乎检测不到。
结论 新生突变可在胚胎发育的任何阶段发生，并可能导致受影响细胞和组织的嵌合模式，进而导致不对称临床表现的出现。本研究指出，嵌合突变在白细胞DNA上可能不易检测到，从而逃避常规的基因分析，并且可能是大量分子未确诊患者的原因。
ObjectiveTo characterize 2 unrelated patients with either asymmetric or unilateral muscle weakness at the clinical, genetic, histologic, and ultrastructural level.MethodsThe patients underwent thorough clinical examination, whole-body MRI, and exome sequencing. Muscle morphology was assessed by histology and electron microscopy.ResultsBoth patients presented with early-onset hypotonia, delayed motor milestones, scoliosis, and reduced pulmonary function. Patient P1 manifested unilateral muscle weakness exclusively affecting the left side of the body; the asymmetry was less pronounced in patient P2. Muscle biopsies from both patients showed nemaline rods as the main histopathologic hallmark, and MRI revealed major fatty infiltrations in selective head, proximal, and distal muscles, correlating with the degree of muscle weakness asymmetry. Exome sequencing on blood DNA from both patients identified de novo ACTA1 missense mutations in a small number of reads, suggesting mutation mosaicism. Subsequent Sanger sequencing confirmed the presence of the mutations on muscle DNA, while they were barely detectable on blood DNA.ConclusionsDe novo mutations can occur anytime during embryonic development and may result in a mosaic pattern of affected cells and tissues and lead to the development of an asymmetric clinical picture. The present study points out that mosaic mutations might not be easily detectable on leukocyte DNA and thereby escape routine genetic analysis, and possibly account for a significant number of molecularly undiagnosed patients.