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Brain. 2014 Sep;137(Pt 9):2429-43. doi: 10.1093/brain/awu160. Epub 2014 Jun 20.

Agrin mutations lead to a congenital myasthenic syndrome with distal muscle weakness and atrophy.

Author information

1
1 Inserm, U1127, 75013 Paris, France2 Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, 75013 Paris, France3 CNRS, UMR 7225, 75013 Paris, France4 ICM, 75013 Paris, France.
2
5 Institute of Genetic Medicine, MRC Centre for Neuromuscular Diseases, Newcastle University, NE1 3BZ, Newcastle upon Tyne, UK.
3
6 Department of Clinical Neurophysiology, University Hospital of North Norway, 9038 Tromsø, Norway.
4
7 Department of Neurology, Oslo University Hospital, 0424 Oslo, Norway.
5
8 Department of Medical Genetics, University Hospital of North Norway, 9038 Tromsø, Norway.
6
9 Department of Clinical Neurophysiology, Uppsala University Hospital, 75185 Uppsala, Sweden.
7
10 AP-HP, University Hospital of Paris ïle-de-France ouest, Raymond Poincaré Hospital, 92380 Garches, France.
8
11 AP-HP, Pitié-Salpêtrière Hospital, centre national de référence des maladies neuromusculaires Paris-est, Myology Institute, Department of Neurophysiology, Federation of Biochemistry, 75013 Paris, France.
9
1 Inserm, U1127, 75013 Paris, France2 Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, 75013 Paris, France3 CNRS, UMR 7225, 75013 Paris, France4 ICM, 75013 Paris, France11 AP-HP, Pitié-Salpêtrière Hospital, centre national de référence des maladies neuromusculaires Paris-est, Myology Institute, Department of Neurophysiology, Federation of Biochemistry, 75013 Paris, France.
10
12 Friedrich-Baur-Institute, Department of Neurology, Ludwig Maximilians University, 80336 Munich, Germany.
11
5 Institute of Genetic Medicine, MRC Centre for Neuromuscular Diseases, Newcastle University, NE1 3BZ, Newcastle upon Tyne, UK hanns.lochmuller@ncl.ac.uk anne-marie.maronne@psl.aphp.fr.

Abstract

Congenital myasthenic syndromes are a clinically and genetically heterogeneous group of rare diseases resulting from impaired neuromuscular transmission. Their clinical hallmark is fatigable muscle weakness associated with a decremental muscle response to repetitive nerve stimulation and frequently related to postsynaptic defects. Distal myopathies form another clinically and genetically heterogeneous group of primary muscle disorders where weakness and atrophy are restricted to distal muscles, at least initially. In both congenital myasthenic syndromes and distal myopathies, a significant number of patients remain genetically undiagnosed. Here, we report five patients from three unrelated families with a strikingly homogenous clinical entity combining congenital myasthenia with distal muscle weakness and atrophy reminiscent of a distal myopathy. MRI and neurophysiological studies were compatible with mild myopathy restricted to distal limb muscles, but decrement (up to 72%) in response to 3 Hz repetitive nerve stimulation pointed towards a neuromuscular transmission defect. Post-exercise increment (up to 285%) was observed in the distal limb muscles in all cases suggesting presynaptic congenital myasthenic syndrome. Immunofluorescence and ultrastructural analyses of muscle end-plate regions showed synaptic remodelling with denervation-reinnervation events. We performed whole-exome sequencing in two kinships and Sanger sequencing in one isolated case and identified five new recessive mutations in the gene encoding agrin. This synaptic proteoglycan with critical function at the neuromuscular junction was previously found mutated in more typical forms of congenital myasthenic syndrome. In our patients, we found two missense mutations residing in the N-terminal agrin domain, which reduced acetylcholine receptors clustering activity of agrin in vitro. Our findings expand the spectrum of congenital myasthenic syndromes due to agrin mutations and show an unexpected correlation between the mutated gene and the associated phenotype. This provides a good rationale for examining patients with apparent distal myopathy for a neuromuscular transmission disorder and agrin mutations.

KEYWORDS:

agrin; congenital myasthenic syndrome; distal myopathy; neuromuscular junction; presynaptic

PMID:
24951643
DOI:
10.1093/brain/awu160
[Indexed for MEDLINE]

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