title: Congenital myasthenic syndrome with tubular aggregates caused by GFPT1 mutations.
abstract: 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).
authors: Department of Neurology, Friedrich-Baur-Institut, Ludwig Maximilians University, Munich, Germany.|Clinic of Neurology, University Hospital Alexandrovska, Sofia, Bulgaria.
authors: Velina
authors: V
authors: Guergueltcheva
authors: Institute of Genetic Medicine, Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK.
authors: Juliane S
authors: JS
authors: Müller
authors: Department of Neurology, Friedrich-Baur-Institut, Ludwig Maximilians University, Munich, Germany.
authors: Marina
authors: M
authors: Dusl
authors: Institute of Neuropathology, RWTH Aachen University, Aachen, Germany.|Institute of Human Genetics, RWTH Aachen University, Aachen, Germany.
authors: Jan
authors: J
authors: Senderek
authors: Department of Pathology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
authors: Anders
authors: A
authors: Oldfors
authors: Neuromuscular Center, Sahlgrenska University Hospital, Gothenburg, Sweden.
authors: Christopher
authors: C
authors: Lindbergh
authors: Neurosciences Group, Department of Clinical Neurology, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
authors: Susan
authors: S
authors: Maxwell
authors: Unitat de Patologia Neuromuscular, Servei de Neurologia, Hospital Sant Joan de Deu, Esplugues, Barcelona, Spain.
authors: Jaume
authors: J
authors: Colomer
authors: Unitat de Patologia Neuromuscular, Servei de Neurologia, Hospital Sant Joan de Deu, Esplugues, Barcelona, Spain.
authors: Cecilia Jimenez
authors: CJ
authors: Mallebrera
authors: Unitat de Patologia Neuromuscular, Servei de Neurologia, Hospital Sant Joan de Deu, Esplugues, Barcelona, Spain.
authors: Andres
authors: A
authors: Nascimento
authors: Servicio de Neurología, Hospital Universitario y Politécnico La Fe and CIBER de Enfermedades Neurodegenerativas (CIBERNED), Valencia, Spain.
authors: Juan J
authors: JJ
authors: Vilchez
authors: Servicio de Neurología, Hospital Universitario y Politécnico La Fe and CIBER de Enfermedades Neurodegenerativas (CIBERNED), Valencia, Spain.
authors: Nuria
authors: N
authors: Muelas
authors: Division of Neuropaediatrics and Muscle Disorders, University Medical Center, Freiburg, Germany.
authors: Janbernd
authors: J
authors: Kirschner
authors: Department of Neurology, Tehran University of Medical Sciences, Tehran, Iran.
authors: Shahriar
authors: S
authors: Nafissi
authors: Kariminejad-Najmabadi Pathology and Genetics Center, Tehran, Iran.
authors: Ariana
authors: A
authors: Kariminejad
authors: Neuropathology Lab, Toos Hospital, Tehran, Iran.
authors: Yalda
authors: Y
authors: Nilipour
authors: Kariminejad-Najmabadi Pathology and Genetics Center, Tehran, Iran.
authors: Bita
authors: B
authors: Bozorgmehr
authors: Kariminejad-Najmabadi Pathology and Genetics Center, Tehran, Iran.
authors: Hossein
authors: H
authors: Najmabadi
authors: Departments of Neurosciences, Psychiatry and Anaesthesiology, A.O.U. "G. Martino", Messina, Italy.
authors: Carmelo
authors: C
authors: Rodolico
authors: Department of Neurology, Geriatric Medicine and Palliative Care, Hanse-Klinikum, Stralsund, Germany.
authors: Jörn P
authors: JP
authors: Sieb
authors: Department of Neurology, Friedrich-Baur-Institut, Ludwig Maximilians University, Munich, Germany.
authors: Beate
authors: B
authors: Schlotter
authors: Department of Neurology, Friedrich-Baur-Institut, Ludwig Maximilians University, Munich, Germany.
authors: Benedikt
authors: B
authors: Schoser
authors: Department of Paediatrics I, University Hospital Essen, Essen, Germany.
authors: Ralf
authors: R
authors: Herrmann
authors: Institut de Myologie, Unité Mixte de Recherche UPMC-INSERM-CNRS-AIM UM 76, U974, UMR 7215, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
authors: Thomas
authors: T
authors: Voit
authors: Institute of Human Genetics, Ludwig Maximilians University, Munich, Germany.
authors: Ortrud K
authors: OK
authors: Steinlein
authors: Azad University Medical Branch, Tehran, Iran.
authors: Abdolhamid
authors: A
authors: Najafi
authors: Hôpital Marin, Hendaye, France.
authors: Andoni
authors: A
authors: Urtizberea
authors: Department of Paediatrics, Mater Dei Hospital, Tal-Qroqq, Msida, Malta.
authors: Doriette M
authors: DM
authors: Soler
authors: The Dubowitz Neuromuscular Centre, UCL Institute of Child Health, London, UK.
authors: Francesco
authors: F
authors: Muntoni
authors: MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London, UK.
authors: Michael G
authors: MG
authors: Hanna
authors: Institute of Genetic Medicine, Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK.
authors: Amina
authors: A
authors: Chaouch
authors: Institute of Genetic Medicine, Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK.
authors: Volker
authors: V
authors: Straub
authors: Institute of Genetic Medicine, Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK.
authors: Kate
authors: K
authors: Bushby
authors: CMS NCG Group, Department of Clinical Neurology, John Radcliffe Hospital, Oxford, UK.
authors: Jacqueline
authors: J
authors: Palace
authors: Neurosciences Group, Department of Clinical Neurology, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
authors: David
authors: D
authors: Beeson
authors: Department of Neurology, Friedrich-Baur-Institut, Ludwig Maximilians University, Munich, Germany.
authors: Angela
authors: A
authors: Abicht
authors: Institute of Genetic Medicine, Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK. hanns.lochmuller@ncl.ac.uk.
authors: Hanns
authors: H
authors: Lochmüller
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D004252:DNA Mutational Analysis; D005945:Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing) / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D020294:Myasthenic Syndromes, Congenital / Q000150:complications* / Q000235:genetics*; D020914:Myopathies, Structural, Congenital / Q000150:complications* / Q000235:genetics*; D012720:Severity of Illness Index; D055815:Young Adult
chemical_list: C497511:GFPT1 protein, human; D005945:Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing)