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Congenital myasthenic syndrome with tubular aggregates caused by GFPT1 mutations

Lookup NU author(s): Dr Nuria Muelas Gomez, Professor Michael Hanna, Dr Amina Chaouch, Professor Volker StraubORCiD, Emerita Professor Katherine Bushby, Professor Hanns Lochmuller


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Congenital myasthenic syndrome (CMS) is a clinically and genetically heterogeneous group of inherited disorders of the neuromuscular junction. A difficult to diagnose subgroup of CMS is characterised by proximal muscle weakness and fatigue while ocular and facial involvement is only minimal. DOK7 mutations have been identified as causing the disorder in about half of the cases. More recently, using classical positional cloning, we have identified mutations in a previously unrecognised CMS gene, GFPT1, in a series of DOK7-negative cases. However, detailed description of clinical features of GFPT1 patients has not been reported yet. Here we describe the clinical picture of 24 limb-girdle CMS (LG-CMS) patients and pathological findings of 18 of them, all carrying GFPT1 mutations. Additional patients with CMS, but without tubular aggregates, and patients with non-fatigable weakness with tubular aggregates were also screened. In most patients with GFPT1 mutations, onset of the disease occurs in the first decade of life with characteristic limb-girdle weakness and fatigue. A common feature was beneficial and sustained response to acetylcholinesterase inhibitor treatment. Most of the patients who had a muscle biopsy showed tubular aggregates in myofibers. Analysis of endplate morphology in one of the patients revealed unspecific abnormalities. Our study delineates the phenotype of CMS associated with GFPT1 mutations and expands the understanding of neuromuscular junction disorders. As tubular aggregates in context of a neuromuscular transmission defect appear to be highly indicative, we suggest calling this condition congenital myasthenic syndrome with tubular aggregates (CMS-TA).

Publication metadata

Author(s): Guergueltcheva V, Muller J, Dusl M, Senderek J, Oldfors A, Lindbergh C, Maxwell S, Colomer J, Mallebrera C, Nascimento A, Vilchez J, Muelas N, Kirschner J, Nafissi S, Kariminejad A, Nilipour Y, Bozorgmehr B, Najmabadi H, Rodolico C, Sieb J, Schlotter B, Schoser B, Herrmann R, Voit T, Steinlein O, Najafi A, Urtizberea A, Soler D, Muntoni F, Hanna M, Chaouch A, Straub V, Bushby K, Palace J, Beeson D, Abicht A, Lochmuller H

Publication type: Article

Publication status: Published

Journal: Journal of Neurology

Year: 2012

Volume: 259

Issue: 5

Pages: 838-850

Print publication date: 06/10/2011

ISSN (print): 0340-5354

ISSN (electronic): 1432-1459

Publisher: Springer


DOI: 10.1007/s00415-011-6262-z


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Funder referenceFunder name
Myasthenia Gravis Association
Faculty of Medical Sciences, Newcastle University
Instituto de Salud Carlos III
Medical Research Council
Muscular Dystrophy Campaign
Ab 130/2-1Deutsche Forschungsgemeinschaft
CM06/00154Fundacion para la Investigacion del Hospital Universitario La Fe
MD-NET 01GM0601German Ministry of Education and Research (BMBF, Bonn, Germany)