Szelinger Szabolcs, Krate Jonida, Ramsey Keri, Strom Samuel P, Shieh Perry B, Lee Hane, Belnap Newell, Balak Chris, Siniard Ashley L, Russell Megan, Richholt Ryan, Both Matt De, Claasen Ana M, Schrauwen Isabelle, Nelson Stanley F, Huentelman Matthew J, Craig David W, Yang Samuel P, Moore Steven A, Sivakumar Kumaraswamy, Narayanan Vinodh, Rangasamy Sampathkumar
theNeurogenomics Division (S.S., J.K., K.R., N.B., C.B., A.L.S., M.R., R.R., M.D.B., A.M.C., M.J.H, V.N., S.R.), Translational Genomics Research Institute, Center for Rare Childhood Disorders, Phoenix, AZ; Fulgent Genetics (S.P.S.), Temple City, CA; Department of Neurology (P.B.S.), University of California Los Angeles; David Geffen School of Medicine (P.B.S.), Los Angeles; Department of Pathology and Laboratory Medicine (H.L., S.F.N.), University of California, Los Angeles; Department of Human Genetics (H.L., S.F.N.), David Geffen School of Medicine; Department of Neurology (I.S.), Columbia University, Center for Statistical Genetics, New York; Department of Translational Genomics (D.W.C.), University of Southern California, Los Angeles; Providence Sacred Heart Medical Center and Children's Hospital (S.P.Y.), Spokane, WA; Department of Pathology (S.A.M), University of Iowa, Carver College of Medicine; and Neuromuscular Clinic and Research Center (K.S.), Phoenix, AZ.
Neurol Genet. 2020 Jun 30;6(4):e468. doi: 10.1212/NXG.0000000000000468. eCollection 2020 Aug.
Description of a new variant of the glutamine-fructose-6-phosphate transaminase 1 () 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 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 mutations in CMS12 and in one family demonstrate a novel mode of inheritance due to UPD.
描述一种新的谷氨酰胺-果糖-6-磷酸转氨酶1（）基因突变体，该突变体在来自2个无血缘关系家庭的3名儿童中导致先天性肌无力综合征（CMS）。
进行了肌肉活检、肌电图检查和全外显子组测序。
所有3例患者均表现为先天性肌张力减退、肌无力、呼吸功能不全、头后仰、无反射和胃肠功能障碍。基因分析确定在基因（NM_001244710.1：c.686dupC；p.Arg230Ter）中存在一个纯合移码插入，这一突变在所有3例患者中均存在。在其中1例患者中，该突变体通过母源单亲二倍体（UPD）遗传。重复神经刺激和单纤维肌电图检查结果与诊断为突触后缺陷的CMS临床诊断一致。对其中1例患者的肌肉活检进行超微结构评估，结果显示神经肌肉接头处突触后褶皱极度变薄，并存在广泛的自噬空泡病理改变。
这些结果扩展了已知的CMS12功能丧失突变谱，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。
