Congenital myasthenic syndrome caused by a frameshift insertion mutation in GFPT1

Szabolcs Szelinger; Jonida Krate; Keri Ramsey; Samuel P Strom; Perry B Shieh; Hane Lee; Newell Belnap; Chris Balak; Ashley L Siniard; Megan Russell; Ryan Richholt; Matt De Both; Ana M Claasen; Isabelle Schrauwen; Stanley F Nelson; Matthew J Huentelman; David W Craig; Samuel P Yang; Steven A Moore; Kumaraswamy Sivakumar; Vinodh Narayanan; Sampathkumar Rangasamy; UCLA Clinical Genomics Center

doi:10.1212/NXG.0000000000000468

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Congenital myasthenic syndrome caused by a frameshift insertion mutation in GFPT1

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Congenital myasthenic syndrome caused by a frameshift insertion mutation in GFPT1

Szabolcs Szelinger, Jonida Krate, Keri Ramsey, Samuel P Strom, Perry B Shieh, Hane Lee, Newell Belnap, Chris Balak, Ashley L Siniard, Megan Russell, …

Neurology. Genetics, Vol.6(4), pp.e468-e468

08/2020

DOI: 10.1212/NXG.0000000000000468

PMCID: PMC7357421

PMID: 32754643

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Abstract

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 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 mutations in CMS12 and in one family demonstrate a novel mode of inheritance due to UPD.

Details

Title: Subtitle: Congenital myasthenic syndrome caused by a frameshift insertion mutation in GFPT1
Creators: Szabolcs Szelinger - Translational Genomics Research Institute
Jonida Krate - Translational Genomics Research Institute
Keri Ramsey - Translational Genomics Research Institute
Samuel P Strom
Perry B Shieh - University of California, Los Angeles
Hane Lee - University of California, Los Angeles
Newell Belnap - Translational Genomics Research Institute
Chris Balak - Translational Genomics Research Institute
Ashley L Siniard - Translational Genomics Research Institute
Megan Russell - Translational Genomics Research Institute
Ryan Richholt - Translational Genomics Research Institute
Matt De Both - Translational Genomics Research Institute
Ana M Claasen - Translational Genomics Research Institute
Isabelle Schrauwen - Columbia University
Stanley F Nelson - University of California, Los Angeles
Matthew J Huentelman - Translational Genomics Research Institute
David W Craig - University of California, Los Angeles
Samuel P Yang - Providence Sacred Heart Medical Center
Steven A Moore - University of Iowa
Kumaraswamy Sivakumar
Vinodh Narayanan - Translational Genomics Research Institute
Sampathkumar Rangasamy - Translational Genomics Research Institute
UCLA Clinical Genomics Center
Resource Type: Journal article
Publication Details: Neurology. Genetics, Vol.6(4), pp.e468-e468
DOI: 10.1212/NXG.0000000000000468
PMID: 32754643
PMCID: PMC7357421
NLM abbreviation: Neurol Genet
ISSN: 2376-7839
eISSN: 2376-7839
Grant note: P50 NS053672 / NINDS NIH HHS U54 NS053672 / NINDS NIH HHS
Language: English
Date published: 08/2020
Academic Unit: Pathology
Record Identifier: 9984186501102771

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