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

Lookup NU author(s): Dr Amina Chaouch, Yasmin Issop, Daniel CoxORCiD, Dr Juliane Mueller, Dr Teresinha Evangelista, Dr Steven Laval, Dr Helen GriffinORCiD, Professor Hanns Lochmuller

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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 3Hz 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.

Publication metadata

Author(s): Nicole S, Chaouch A, Torbergsen T, Bauche S, de Bruyckere E, Fontenille MJ, Horn MA, van Ghelue M, Loseth S, Issop Y, Cox D, Muller JS, Evangelista T, Stalberg E, Ioos C, Barois A, Brochier G, Sternberg D, Fournier E, Hantai D, Abicht A, Dusl M, Laval SH, Griffin H, Eymard B, Lochmuller H

Publication type: Article

Publication status: Published

Journal: Brain

Year: 2014

Volume: 137

Issue: 9

Pages: 2429-2443

Print publication date: 01/09/2014

Online publication date: 20/06/2014

Acceptance date: 03/05/2014

ISSN (print): 0006-8950

ISSN (electronic): 1460-2156

Publisher: Oxford University Press

URL: http://dx.doi.org/10.1093/brain/awu160

DOI: 10.1093/brain/awu160

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