PDF(Pubmed)
Abstract：
Fukutin-related protein (FKRP) mutations cause a broad spectrum of muscular dystrophies, from a relatively mild limb-girdle muscular dystrophy type 9 (LGMDR9) to severe congenital muscular dystrophy (CMD). This study aims to report two siblings belonging to a non-consanguineous Tunisian family harboring a novel compound heterozygous FKRP variant and presenting a mild LGDMR9 phenotype. For mutation screening, massive parallel sequencing was performed, followed by Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA) to validate the existence of the discovered variants. The absence of alpha-dystroglycan was determined by immunohistochemistry. Brain and thigh magnetic resonance imaging (MRI) were performed to detect thigh and brain abnormalities. The two siblings had a late age at onset and clinical examination showed that the pelvic girdles had a predominantly proximal and symmetrical distribution of weakness without cardiac or respiratory involvement. They both had a modified Gardner-Medwin Walton Scale mGMWS grade of 4 and a modified Rankin Scale (mRS) score of 1. The DNA sequencing revealed a novel deletion of exons 2 and 3 in one allele and a missense mutation c.1364C > A, which has been reported to be responsible for congenital muscular dystrophy and mental retardation on the second allele. The simultaneous presence of the two variations in the two cases suggests that the variants segregate with the pathophysiology.
摘要：
Fukutin相关蛋白（FKRP）突变导致广泛的肌营养不良，从相对轻度的9型肢带肌营养不良（LGMDR9）到严重的先天性肌营养不良（CMD）。这项研究旨在报告两个属于非近亲突尼斯家族的兄弟姐妹，他们拥有一种新型的复合杂合FKRP变体，并表现出轻度的LGDMR9表型。对于突变筛选，进行大规模平行测序，然后进行Sanger测序和多重连接依赖性探针扩增(MLPA)以验证发现的变体的存在。通过免疫组织化学确定不存在α-营养不良聚糖。进行脑部和大腿磁共振成像（MRI）以检测大腿和脑部异常。这两个兄弟姐妹的发病年龄较晚，临床检查显示，骨盆带主要是近端和对称分布的无力，没有心脏或呼吸道的参与。他们的改良Gardner-MedwinWalton量表mGMWS评分均为4级，改良Rankin量表（mRS）评分均为1分。DNA测序揭示了一个等位基因中外显子2和3的新缺失和一个错义突变c.1364C>A，据报道，这是在第二个等位基因上导致先天性肌营养不良和智力低下的原因。在两种情况下同时存在两种变异表明变异与病理生理学分离。
