肢带型肌营养不良2I型的临床、病理和基因突变特点

Clinical, myopathological and genetic mutations features of limb girdle muscular dystrophy 2I

目的总结9例肢带型肌营养不良2I型（limb girdle muscular dystrophy 2I, LGMD2I）患者的病理及基因特点。方法回顾性收集于2011—2016年就诊于北京大学第一医院的LGMD2I患者共9例，均来自无血缘关系的不同家系，平均发病年龄（8.2±5.2）岁（2～19岁），平均病程（10.4±6.1）年（1～24年），男女比例6∶3。全部患者均表现为隐匿起病的肢带肌无力，4例伴随腓肠肌肥大，3例翼状肩胛，血清肌酸肌酶964～23 131 U/L（正常值25～190 U/L）。5例行肌电图检查的患者均为肌源性损害。对患者进行肌肉活体组织检查，同时提取患者及其父母的外周血DNA，采用二代测序技术进行遗传性肌病相关基因检测，通过一代测序验证突变位点及进行家系验证。结果9例患者中有6例出现肌病样病理改变，1例呈肌营养不良样改变，2例为轻微病理改变。9例患者中6例存在主要组织相容性复合物－Ⅰ阳性表达，2例镶边空泡。共发现7个fukutin相关蛋白基因错义突变位点，其中c.545A〉G（p.Y182C）和c.1067T〉C（p.Ile356Thr）突变为已知突变，前者出现在8例患者中（包括3例纯合和5例复合杂合突变）。c.1263C〉A （p.Tyr421X）、c.534G〉T （p.Thr178Cys）、c.1027G〉C （p.Glu343Gln）、c.1027G〉T（p.Glu343X）、c.1448A〉G （p.Tyr483Cys）为新发突变。结论LGMD2I患者的骨骼肌病理改变具有较大变异性，A545G（Y182C）错义突变是该组患者的热点突变。

ObjectiveTo summary the pathological and genetic features in nine Chinese limb girdle muscular dystrophy 2I （LGMD2I） patients.MethodsNine LGMD2I patients were recruited from Peking University First Hospital between 2011 and 2016, who came from nine unrelated and non-consanguineous families. The mean age of onset was （8.2±5.2） years （2 to 19 years）, and the mean disease duration was （10.4±6.1） years （1 to 24 years）. There were six males and three females, present with weakness in limb girdle muscles, four of whom accompanied with calf hypertrophy and three with scapular winging. Serum creatine kinase was 964-23 131 U/L （normal 25-190 U/L）. Five of them who conducted electromyogram showed myogenic pattern. Muscle biopsy and next generation sequencing were performed in these patients, then sanger sequencing was performed to determine whether the variants co-segregated with the phenotype in these families.ResultsMuscle biopsy revealed myopathy features in six patients, dystrophic change in one, and only mild changes in two. Major histocompatibility complex-Ⅰ was positive in six cases, and rimmed vacuoles were found in two. There were seven mutations in fukutin-related protein （FKRP） gene. A reported mutation of c. 545A〉G （p.Y182C） appeared in eight cases, including three homozygotes and five compound heterozygotes. The mutation of c. 1067T〉C （p.Ile356Thr） was reported too. And c. 1263C〉A （p.Tyr421X）, c. 534G〉T（p.Thr178Cys）, c. 1027G〉C （p.Glu343Gln）, c. 1027G〉T（p.Glu343X）, c. 1448A〉G （p.Tyr483Cys） were found to be novel mutations.ConclusionsLGMD2I showed large variation in myopathology. The missense mutation A545G（Y182C） is a hot spot of FKRP gene in our series.