Twelve patients from seven unrelated South Indian families with a limb-girdle muscular dystrophy-congenital myasthenic syndrome (LGMD/CMS) phenotype and recessive inheritance underwent deep clinical phenotyping, electrophysiological evaluation, muscle histopathology, and next-generation sequencing/Sanger sequencing–based identification of the genetic defect. Homozygosity mapping was performed using high-throughput genome-wide genotyping for mapping the mutation and to evaluate the founder effect. The age of disease onset among patients ranged from childhood to 40 years of age. The key clinical manifestations observed were progressive fatigable limb-girdle weakness, muscle hypertrophy/atrophy, and preferential weakness in a dystrophic pattern. The ages at last follow-up ranged from 30 to 64 years; nine were independently ambulant, two required assistance, and one was wheelchair-bound. Lower limb muscle MRI showed varying degrees of fat replacement in the glutei, hamstrings, anterior leg muscles, and medial gastrocnemius. All patients showed significant decrement on repetitive nerve stimulation (RNS). Muscle biopsy in 7 patients revealed varying degrees of dystrophic and neurogenic changes. Treatment with pyridostigmine and/or salbutamol resulted in variable improvement in 10 patients. Genetic analysis showed an identical homozygous GMPPB mutation c.1000G > A (p.Asp334Asn) in all affected patients. A region of homozygosity (6Mbp) was observed flanking the c.1000G > A change in carrier chromosomes. This study identifies c.1000G > A in GMPPB as a common founder mutation in an ethnic community of South Indian descent with milder yet variable degree of clinical presentation of GMPPB-associated LGMD-CMS.

来自 7 个不相关的南印度家庭的 12 名具有肢带型肌营养不良症-先天性肌无力综合征 (LGMD/CMS) 表型和隐性遗传的患者接受了深度临床表型分析、电生理评估、肌肉组织病理学和基于下一代测序/Sanger 测序的鉴定的遗传缺陷。使用高通量全基因组基因分型进行纯合性作图，以绘制突变图并评估创始人效应。患者发病年龄从儿童期到 40 岁不等。观察到的主要临床表现是进行性易疲劳的肢带无力、肌肉肥大/萎缩和营养不良模式的优先虚弱。末次随访年龄为 30 至 64 岁；九人独立行走，两人需要帮助，一名需要坐轮椅。下肢肌肉 MRI 显示臀肌、腘绳肌、前腿肌肉和内侧腓肠肌有不同程度的脂肪替代。所有患者的重复神经刺激（RNS）均显着下降。7 名患者的肌肉活检显示不同程度的营养不良和神经源性变化。吡啶斯的明和/或沙丁胺醇治疗导致 10 名患者出现不同程度的改善。遗传分析显示在所有受影响的患者中存在相同的纯合 GMPPB 突变 c.1000G > A (p.Asp334Asn)。在 c.1000G 两侧观察到纯合子区域 (6Mbp) > 载体染色体的变化。本研究确定了 c.1000G >