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J Neurol. 2012 May;259(5):838-50. doi: 10.1007/s00415-011-6262-z. Epub 2011 Oct 6.

Congenital myasthenic syndrome with tubular aggregates caused by GFPT1 mutations.

Author information

1
Department of Neurology, Friedrich-Baur-Institut, Ludwig Maximilians University, Munich, Germany.
2
Clinic of Neurology, University Hospital Alexandrovska, Sofia, Bulgaria.
3
Institute of Genetic Medicine, Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK.
4
Institute of Neuropathology, RWTH Aachen University, Aachen, Germany.
5
Institute of Human Genetics, RWTH Aachen University, Aachen, Germany.
6
Department of Pathology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
7
Neuromuscular Center, Sahlgrenska University Hospital, Gothenburg, Sweden.
8
Neurosciences Group, Department of Clinical Neurology, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
9
Unitat de Patologia Neuromuscular, Servei de Neurologia, Hospital Sant Joan de Deu, Esplugues, Barcelona, Spain.
10
Servicio de Neurología, Hospital Universitario y Politécnico La Fe and CIBER de Enfermedades Neurodegenerativas (CIBERNED), Valencia, Spain.
11
Division of Neuropaediatrics and Muscle Disorders, University Medical Center, Freiburg, Germany.
12
Department of Neurology, Tehran University of Medical Sciences, Tehran, Iran.
13
Kariminejad-Najmabadi Pathology and Genetics Center, Tehran, Iran.
14
Neuropathology Lab, Toos Hospital, Tehran, Iran.
15
Departments of Neurosciences, Psychiatry and Anaesthesiology, A.O.U. "G. Martino", Messina, Italy.
16
Department of Neurology, Geriatric Medicine and Palliative Care, Hanse-Klinikum, Stralsund, Germany.
17
Department of Paediatrics I, University Hospital Essen, Essen, Germany.
18
Institut de Myologie, Unité Mixte de Recherche UPMC-INSERM-CNRS-AIM UM 76, U974, UMR 7215, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
19
Institute of Human Genetics, Ludwig Maximilians University, Munich, Germany.
20
Azad University Medical Branch, Tehran, Iran.
21
Hôpital Marin, Hendaye, France.
22
Department of Paediatrics, Mater Dei Hospital, Tal-Qroqq, Msida, Malta.
23
The Dubowitz Neuromuscular Centre, UCL Institute of Child Health, London, UK.
24
MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London, UK.
25
CMS NCG Group, Department of Clinical Neurology, John Radcliffe Hospital, Oxford, UK.
26
Institute of Genetic Medicine, Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK. hanns.lochmuller@ncl.ac.uk.

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).

KEYWORDS:

Congenital myasthenic syndromes; Dok-7; GFPT1; Limb-girdle myasthenia; Tubular aggregates

PMID:
21975507
DOI:
10.1007/s00415-011-6262-z
[Indexed for MEDLINE]

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