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Congenital myasthenic syndrome caused by a frameshift insertion mutation in GFPT1
Szabolcs Szelinger1, Jonida Krate1, Keri Ramsey1
1theNeurogenomics 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.
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.
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