New genotype-phenotype correlations in a large European cohort of patients with sarcoglycanopathy
New genotype-phenotype correlations in a large European cohort of patients with sarcoglycanopathy
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DOI：
10.1093/brain/awaa228
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发表时间：
2020-09-01
期刊：
影响因子：
14.5
通讯作者：
Diaz-Manera, Jordi
中科院分区：
文献类型：
--
作者：
Alonso-Perez, Jorge;Gonzalez-Quereda, Lidia;Diaz-Manera, Jordi
肌聚糖病包括四种常染色体隐性肢带型肌营养不良症亚型（LGMDR 3、LGMDR 4、LGMDR 5和LGMDR 6），分别由SGCA、SGCB、SGCG和SGCD基因突变引起。2016年，几位参与LGMDR 3 -6患者诊断、管理和护理的临床医生创建了欧洲肌聚糖病联盟。本研究的目的是确定欧洲一个大型肌聚糖病患者队列的临床和遗传谱。这是一项观察性回顾性研究。来自13个不同欧洲国家的共33个神经肌肉中心收集了在其中心随访的经基因证实的肌聚糖病患者的数据。本研究收集了人口统计学、遗传学和临床数据。收集了来自13个不同国家的439名患者的数据。43例患者因可用临床信息不足而未纳入分析。共有159名患者确诊为LGMDR 3，73名LGMDR 4，157名LGMDR 5和7名LGMDR 6。LGMDR 3患者发病较晚，疾病进展较慢。心脏受累在LGMDR 4中最常见。60%的LGMDR 3患者携带以下突变之一，无论是纯合状态还是杂合状态：Wc.229C>T、c.739G>A或c.850C>T。类似地，LMGDR 5患者中最常见的突变是c.525delT或c.848G>A。在LGMDR 4患者中，最常见的突变是c.341C>T。我们将LGMDR 3、LGMDR 4和LGMDR 5患者在10岁之前出现症状和残留蛋白表达低于30%确定为18岁之前失去行走能力的独立风险因素。本研究报告了一个大型欧洲肌聚糖病患者队列的临床、遗传和蛋白质数据。提高我们对这些极其罕见的常染色体隐性形式的LGMD的知识是通过欧洲各地的神经肌肉中心的合作努力帮助。我们的研究提供了基因型-表型相关性的重要数据，这些数据与肌聚糖病的自然史研究和即将进行的干预性试验的设计相关。
Sarcoglycanopathies comprise four subtypes of autosomal recessive limb-girdle muscular dystrophies (LGMDR3, LGMDR4, LGMDR5 and LGMDR6) that are caused, respectively, by mutations in the SGCA, SGCB, SGCG and SGCD genes. In 2016, several clinicians involved in the diagnosis, management and care of patients with LGMDR3-6 created a European Sarcoglycanopathy Consortium. The aim of the present study was to determine the clinical and genetic spectrum of a large cohort of patients with sarcoglycanopathy in Europe. This was an observational retrospective study. A total of 33 neuromuscular centres from 13 different European countries collected data of the genetically confirmed patients with sarcoglycanopathy followed-up at their centres. Demographic, genetic and clinical data were collected for this study. Data from 439 patients from 13 different countries were collected. Forty-three patients were not included in the analysis because of insufficient clinical information available. A total of 159 patients had a confirmed diagnosis of LGMDR3, 73 of LGMDR4, 157 of LGMDR5 and seven of LGMDR6. Patients with LGMDR3 had a later onset and slower progression of the disease. Cardiac involvement was most frequent in LGMDR4. Sixty per cent of LGMDR3 patients carried one of the following mutations, either in a homozygous or heterozygous state: Wc.229C>T, c.739G>A or c.850C>T. Similarly, the most common mutations in LMGDR5 patients were c.525delT or c.848G>A. In LGMDR4 patients the most frequent mutation was c.341C>T. We identified onset of symptoms before 10 years of age and residual protein expression lower than 30% as independent risk factors for losing ambulation before 18 years of age, in LGMDR3, LGMDR4 and LGMDR5 patients. This study reports clinical, genetic and protein data of a large European cohort of patients with sarcoglycanopathy. Improving our knowledge about these extremely rare autosomal recessive forms of LGMD was helped by a collaborative effort of neuromuscular centres across Europe. Our study provides important data on the genotype-phenotype correlation that is relevant for the design of natural history studies and upcoming interventional trials in sarcoglycanopathies.