Neurology. Genetics · 2020
Congenital myasthenic syndrome caused by a frameshift insertion mutation in GFPT1.
СтатьяНазвание и аннотация: Перевод в очереди
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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, UCLA Clinical Genomics Center
Аннотация
OBJECTIVE: 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.
METHODS: Muscle biopsies, EMG, and whole-exome sequencing were performed.
RESULTS: 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.
CONCLUSIONS: 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.
METHODS: Muscle biopsies, EMG, and whole-exome sequencing were performed.
RESULTS: 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.
CONCLUSIONS: 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.