Agrin mutations lead to a congenital myasthenic syndrome with distal muscle weakness and atrophy
| Autor: | Daniel Hantaï, Sophie Nicole, Yasmin Issop, Teresinha Evangelista, Marie-Joséphine Fontenille, Angela Abicht, Helen Griffin, Emmanuel Fournier, Damien Sternberg, Marina Dusl, A. Barois, Elodie De Bruyckere, Christine Ioos, Bruno Eymard, Amina Chaouch, Erik Stålberg, Dan Cox, Guy Brochier, S. Bauche, Hanns Lochmüller, Steven H. Laval, S. Løseth, Marijke Van Ghelue, Juliane S. Müller, T. Torbergsen, Morten Andreas Horn |
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| Přispěvatelé: | Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Newcastle University [Newcastle], University Hospital of North Norway [Tromsø] (UNN), Oslo University Hospital [Oslo], Uppsala University Hospital, Hôpital Raymond Poincaré [Garches], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Ludwig-Maximilians University [Munich] (LMU), godard-bauché, Stéphanie |
| Rok vydání: | 2014 |
| Předmět: |
Adult
Male medicine.medical_specialty presynaptic Molecular Sequence Data Neuromuscular transmission distal myopathy Biology Muscle disorder Neuromuscular junction [SHS]Humanities and Social Sciences Internal medicine medicine Humans Agrin Amino Acid Sequence Myopathy Myasthenic Syndromes Congenital Muscle Weakness neuromuscular junction Muscle weakness Congenital myasthenic syndrome Middle Aged medicine.disease Pedigree Muscular Atrophy medicine.anatomical_structure Endocrinology congenital myasthenic syndrome Distal Myopathies Female Neurology (clinical) [SHS] Humanities and Social Sciences medicine.symptom Atrophy |
| Zdroj: | Brain-A Journal of Neurology Brain-A Journal of Neurology, 2014, 137 (9), pp.2429-2443. ⟨10.1093/brain/awu160⟩ |
| ISSN: | 1460-2156 0006-8950 |
| DOI: | 10.1093/brain/awu160⟩ |
| Popis: | International audience; 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. |
| Databáze: | OpenAIRE |
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