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01-08-2017 | Original Communication

Mutations in GFPT1-related congenital myasthenic syndromes are associated with synaptic morphological defects and underlie a tubular aggregate myopathy with synaptopathy

Authors: Stéphanie Bauché, Geoffroy Vellieux, Damien Sternberg, Marie-Joséphine Fontenille, Elodie De Bruyckere, Claire-Sophie Davoine, Guy Brochier, Julien Messéant, Lucie Wolf, Michel Fardeau, Emmanuelle Lacène, Norma Romero, Jeanine Koenig, Emmanuel Fournier, Daniel Hantaï, Nathalie Streichenberger, Veronique Manel, Arnaud Lacour, Aleksandra Nadaj-Pakleza, Sylvie Sukno, Françoise Bouhour, Pascal Laforêt, Bertrand Fontaine, Laure Strochlic, Bruno Eymard, Frédéric Chevessier, Tanya Stojkovic, Sophie Nicole

Published in: Journal of Neurology | Issue 8/2017

Abstract

Mutations in GFPT1 (glutamine-fructose-6-phosphate transaminase 1), a gene encoding an enzyme involved in glycosylation of ubiquitous proteins, cause a limb-girdle congenital myasthenic syndrome (LG-CMS) with tubular aggregates (TAs) characterized predominantly by affection of the proximal skeletal muscles and presence of highly organized and remodeled sarcoplasmic tubules in patients’ muscle biopsies. We report here the first long-term clinical follow-up of 11 French individuals suffering from LG-CMS with TAs due to GFPT1 mutations, of which nine are new. Our retrospective clinical evaluation stresses an evolution toward a myopathic weakness that occurs concomitantly to ineffectiveness of usual CMS treatments. Analysis of neuromuscular biopsies from three unrelated individuals demonstrates that the maintenance of neuromuscular junctions (NMJs) is dramatically impaired with loss of post-synaptic junctional folds and evidence of denervation–reinnervation processes affecting the three main NMJ components. Moreover, molecular analyses of the human muscle biopsies confirm glycosylation defects of proteins with reduced O-glycosylation and show reduced sialylation of transmembrane proteins in extra-junctional area. Altogether, these results pave the way for understanding the etiology of this rare neuromuscular disorder that may be considered as a “tubular aggregates myopathy with synaptopathy”.

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Title: Mutations in GFPT1-related congenital myasthenic syndromes are associated with synaptic morphological defects and underlie a tubular aggregate myopathy with synaptopathy
Authors: Stéphanie Bauché
Geoffroy Vellieux
Damien Sternberg
Marie-Joséphine Fontenille
Elodie De Bruyckere
Claire-Sophie Davoine
Guy Brochier
Julien Messéant
Lucie Wolf
Michel Fardeau
Emmanuelle Lacène
Norma Romero
Jeanine Koenig
Emmanuel Fournier
Daniel Hantaï
Nathalie Streichenberger
Veronique Manel
Arnaud Lacour
Aleksandra Nadaj-Pakleza
Sylvie Sukno
Françoise Bouhour
Pascal Laforêt
Bertrand Fontaine
Laure Strochlic
Bruno Eymard
Frédéric Chevessier
Tanya Stojkovic
Sophie Nicole
Publication date: 01-08-2017
Publisher: Springer Berlin Heidelberg
Published in: Journal of Neurology / Issue 8/2017
Print ISSN: 0340-5354
Electronic ISSN: 1432-1459
DOI: https://doi.org/10.1007/s00415-017-8569-x

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Mutations in GFPT1-related congenital myasthenic syndromes are associated with synaptic morphological defects and underlie a tubular aggregate myopathy with synaptopathy

Abstract

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Abstract

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