Abstract：
X-linked Myopathy with Excessive Autophagy (XMEA) is a rare autophagic vacuolar myopathy caused by mutations in the Vacuolar ATPase assembly factor VMA21 gene; onset usually occurs during childhood and rarely occurs during adulthood. We described a 22-year-old patient with XMEA, whose onset was declared at 11 through gait disorder. He had severe four-limb proximal weakness and amyotrophy, and his proximal muscle MRC score was between 2 and 3/5 in four limbs; creatine kinase levels were elevated (1385 IU/L), and electroneuromyography and muscle MRI were suggestive of myopathy. Muscle biopsy showed abnormalities typical of autophagic vacuolar myopathy. We detected a hemizygous, unreported, intronic, single-nucleotide substitution c.164-20T>A (NM_001017980.4) in intron 2 of the VMA21 gene. Fibroblasts derived from this patient displayed a reduced level of VMA21 transcripts (at 40% of normal) and protein, suggesting a pathogenicity related to an alteration of the splicing efficiency associated with an intron retention. This patient with XMEA displayed a severe phenotype (rapid weakness of upper and lower limbs) due to a new intronic variant of VMA21, related to an alteration in the splicing efficiency associated with intron retention, suggesting that phenotype severity is closely related to the residual expression of the VMA21 protein.
摘要：
具有过度自噬的X连锁肌病（XMEA）是一种罕见的自噬性空泡肌病，由空泡ATPase组装因子VMA21基因突变引起；发病通常发生在儿童期，很少发生在成年期。我们描述了一位22岁的XMEA患者，11岁时因步态障碍而宣布发病。他有严重的四肢近端无力和肌萎缩，他的四肢近端肌肉MRC评分在2和3/5之间；肌酸激酶水平升高（1385IU/L），神经肌电图和肌肉MRI提示肌病。肌肉活检显示典型的自噬空泡性肌病异常。我们发现了一个半合子，未报告,内含子,VMA21基因内含子2中的单核苷酸取代c.164-20T>A(NM_001017980.4)。来自该患者的成纤维细胞显示VMA21转录物（正常水平的40％）和蛋白质水平降低，提示与内含子保留相关的剪接效率改变有关的致病性。这位患有XMEA的患者由于VMA21的新内含子变体而表现出严重的表型（上肢和下肢快速无力），这与内含子保留相关的剪接效率的改变有关。提示表型严重程度与VMA21蛋白的残留表达密切相关。
