Description of a new variant of the glutamine-fructose-6-phosphate transaminase 1 (GFPT1) gene causing congenital myasthenic syndrome (CMS) in 3 children from 2 unrelated families.

Muscle biopsies, EMG, and whole-exome sequencing were performed.

All 3 patients presented with congenital hypotonia, muscle weakness, respiratory insufficiency, head lag, areflexia, and gastrointestinal dysfunction. Genetic analysis identified a homozygous frameshift insertion in the GFPT1 gene (NM_001244710.1: c.686dupC; p.Arg230Ter) that was shared by all 3 patients. In one of the patients, inheritance of the variant was through uniparental disomy (UPD) with maternal origin. Repetitive nerve stimulation and single-fiber EMG was consistent with the clinical diagnosis of CMS with a postjunctional defect. Ultrastructural evaluation of the muscle biopsy from one of the patients showed extremely attenuated postsynaptic folds at neuromuscular junctions and extensive autophagic vacuolar pathology.

These results expand on the spectrum of known loss-of-function GFPT1 mutations in CMS12 and in one family demonstrate a novel mode of inheritance due to UPD.

描述谷氨酰胺-果糖-6-磷酸转氨酶 1 ( GFPT1 ) 基因的新变体导致来自 2 个无关家庭的 3 名儿童发生先天性肌无力综合征 (CMS)。

进行了肌肉活检、EMG 和全外显子组测序。

所有 3 名患者均出现先天性肌张力减退、肌肉无力、呼吸功能不全、头部滞后、反射消失和胃肠功能障碍。遗传分析确定了所有 3 名患者共有的GFPT1基因 (NM_001244710.1: c.686dupC; p.Arg230Ter) 中的纯合移码插入。在其中一名患者中，变异的遗传是通过具有母系起源的单亲二体性 (UPD)。重复神经刺激和单纤维肌电图与 CMS 的临床诊断一致，并伴有连接后缺损。对其中一名患者的肌肉活检进行的超微结构评估显示，神经肌肉接头处的突触后皱襞非常减弱，并且存在广泛的自噬性空泡病变。

这些结果扩展了 CMS12 中已知的功能丧失 GFPT1突变的范围，并且在一个家族中证明了由于 UPD 导致的一种新的遗传模式。