Abstract：
BACKGROUND: Inherited neuromuscular (NMD) and neurodegenerative diseases (NDD) belong to two distinct categories that disturb different components of the nervous system, leading to a variety of different symptoms and clinical manifestations. Both NMD and NDD are a heterogeneous group of genetic conditions. Genetic variations in the SGCA and SIL1 genes have been implicated in causing Limb Girdle Muscular Dystrophy (LGMD), a type of neuromuscular disorder, and Marinesco-Sjögren Syndrome (MSS) which is a neurodegenerative disorder.
METHODS: In the present study, we have investigated four patients presenting LGMD and five patients with MSS features. After collecting detailed clinical and family history, necessary laboratory investigations, including estimation of a skeletal muscle marker enzyme serum creatine kinase (CK), nerve conduction study (NCS), electromyography (EMG), echocardiography (Echo), Magnetic resonance imaging (MRI -brain), CT-brain and X-rays were performed. Whole exome followed by Sanger sequencing was employed to search for the disease-causing variants.
RESULTS: Physical examination in LGMD patients revealed poor muscle tone and facing difficulty in straightening up from the floor. Clinical history revealed frequent falls and strenuousness in climbing stairs. They started toe-walking in early childhood. Laboratory investigations confirmed elevated CK levels and abnormal NCS and EMG. The MSS patients showed abnormalities in gate and jerking movement, abnormal speech, and strabismus with cataract. MRI-brain showed cerebral atrophy in some MSS patients with elevated CK levels. Whole exome sequencing revealed a nonsense variant [c.C574T, p.(Arg192*)] in the SGCA gene and a frameshift [c.936dupG, p.(Leu313AlaFs*39)] in the SIL1 gene in LGMD and MSS patients, respectively.
CONCLUSIONS: Our study emphasizes the significance of integrating clinical and genetic analyses for precise diagnosis and tailored management strategies in inherited NMD and NDD disorders. To the best of our knowledge, this is the first study documenting SGCA and SIL1 recurrent variants in subcontinent populations with few rare clinical features. The recurrent mutations expanding the global understanding of the mutation\'s geographic and ethnic distribution and contributing valuable epidemiological data. The study will facilitate genetic counseling for families experiencing similar clinical features, both within Pakistani populations and in other regions.
METHODS: In the present study, we have investigated four patients presenting LGMD and five patients with MSS features. After collecting detailed clinical and family history, necessary laboratory investigations, including estimation of a skeletal muscle marker enzyme serum creatine kinase (CK), nerve conduction study (NCS), electromyography (EMG), echocardiography (Echo), Magnetic resonance imaging (MRI -brain), CT-brain and X-rays were performed. Whole exome followed by Sanger sequencing was employed to search for the disease-causing variants.
RESULTS: Physical examination in LGMD patients revealed poor muscle tone and facing difficulty in straightening up from the floor. Clinical history revealed frequent falls and strenuousness in climbing stairs. They started toe-walking in early childhood. Laboratory investigations confirmed elevated CK levels and abnormal NCS and EMG. The MSS patients showed abnormalities in gate and jerking movement, abnormal speech, and strabismus with cataract. MRI-brain showed cerebral atrophy in some MSS patients with elevated CK levels. Whole exome sequencing revealed a nonsense variant [c.C574T, p.(Arg192*)] in the SGCA gene and a frameshift [c.936dupG, p.(Leu313AlaFs*39)] in the SIL1 gene in LGMD and MSS patients, respectively.
CONCLUSIONS: Our study emphasizes the significance of integrating clinical and genetic analyses for precise diagnosis and tailored management strategies in inherited NMD and NDD disorders. To the best of our knowledge, this is the first study documenting SGCA and SIL1 recurrent variants in subcontinent populations with few rare clinical features. The recurrent mutations expanding the global understanding of the mutation\'s geographic and ethnic distribution and contributing valuable epidemiological data. The study will facilitate genetic counseling for families experiencing similar clinical features, both within Pakistani populations and in other regions.
摘要：
背景：遗传性神经肌肉（NMD）和神经退行性疾病（NDD）属于干扰神经系统不同成分的两个不同类别，导致各种不同的症状和临床表现。NMD和NDD都是一组异质性的遗传条件。SGCA和SIL1基因的遗传变异与导致四肢束腰肌营养不良（LGMD）有关，一种神经肌肉疾病,和Marinesco-Sjögren综合征（MSS），这是一种神经退行性疾病。
方法：在本研究中，我们调查了4例LGMD患者和5例具有MSS特征的患者.收集详细的临床和家族史后，必要的实验室调查，包括评估骨骼肌标记酶血清肌酸激酶（CK），神经传导研究（NCS），肌电图（EMG），超声心动图(Echo),磁共振成像（MRI-脑），进行CT脑和X线检查。采用全外显子组然后进行Sanger测序来搜索致病变体。
结果：LGMD患者的体格检查显示肌肉张力差，并且难以从地板上伸直。临床病史显示爬楼梯时经常跌倒和剧烈运动。他们从小就开始走路。实验室检查证实CK水平升高以及NCS和EMG异常。MSS患者表现出异常的门和抽搐运动，不正常的言语,斜视伴白内障。MRI脑显示一些CK水平升高的MSS患者发生脑萎缩。整个外显子组测序揭示了一个无义变体[c。C574T,p.(Arg192*)]在SGCA基因和移码中[c.936dupG，p.(Leu313AlaFs*39)]在LGMD和MSS患者的SIL1基因中，分别。
结论：我们的研究强调了整合临床和遗传分析对遗传性NMD和NDD疾病的精确诊断和定制管理策略的重要性。据我们所知,这是第一项研究记录了少有罕见临床特征的次大陆人群中SGCA和SIL1复发变异.复发突变扩大了全球对突变的地理和种族分布的理解，并提供了有价值的流行病学数据。这项研究将促进遗传咨询家庭经历类似的临床特征，在巴基斯坦人口和其他地区。
方法：在本研究中，我们调查了4例LGMD患者和5例具有MSS特征的患者.收集详细的临床和家族史后，必要的实验室调查，包括评估骨骼肌标记酶血清肌酸激酶（CK），神经传导研究（NCS），肌电图（EMG），超声心动图(Echo),磁共振成像（MRI-脑），进行CT脑和X线检查。采用全外显子组然后进行Sanger测序来搜索致病变体。
结果：LGMD患者的体格检查显示肌肉张力差，并且难以从地板上伸直。临床病史显示爬楼梯时经常跌倒和剧烈运动。他们从小就开始走路。实验室检查证实CK水平升高以及NCS和EMG异常。MSS患者表现出异常的门和抽搐运动，不正常的言语,斜视伴白内障。MRI脑显示一些CK水平升高的MSS患者发生脑萎缩。整个外显子组测序揭示了一个无义变体[c。C574T,p.(Arg192*)]在SGCA基因和移码中[c.936dupG，p.(Leu313AlaFs*39)]在LGMD和MSS患者的SIL1基因中，分别。
结论：我们的研究强调了整合临床和遗传分析对遗传性NMD和NDD疾病的精确诊断和定制管理策略的重要性。据我们所知,这是第一项研究记录了少有罕见临床特征的次大陆人群中SGCA和SIL1复发变异.复发突变扩大了全球对突变的地理和种族分布的理解，并提供了有价值的流行病学数据。这项研究将促进遗传咨询家庭经历类似的临床特征，在巴基斯坦人口和其他地区。
