• Velina Guergueltcheva, Juliane S Müller, Marina Dusl, Jan Senderek, Anders Oldfors, Christopher Lindbergh, Susan Maxwell, Jaume Colomer, Cecilia Jimenez Mallebrera, Andres Nascimento, Juan J Vilchez, Nuria Muelas, Janbernd Kirschner, Shahriar Nafissi, Ariana Kariminejad, Yalda Nilipour, Bita Bozorgmehr, Hossein Najmabadi, Carmelo Rodolico, Jörn P Sieb, Beate Schlotter, Benedikt Schoser, Ralf Herrmann, Thomas Voit, Ortrud K Steinlein, Abdolhamid Najafi, Andoni Urtizberea, Doriette M Soler, Francesco Muntoni, Michael G Hanna, Amina Chaouch, Volker Straub, Kate Bushby, Jacqueline Palace, David Beeson, Angela Abicht, and Hanns Lochmüller.
• Department of Neurology, Friedrich-Baur-Institut, Ludwig Maximilians University, Munich, Germany.
• J. Neurol. 2012 May 1; 259 (5): 838-50.

AbstractCongenital 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).

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