title: Agrin mutations lead to a congenital myasthenic syndrome with distal muscle weakness and atrophy.
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.
authors.affiliation: 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.
authors.forename: Sophie
authors.initials: S
authors.lastname: Nicole
authors.affiliation: 5 Institute of Genetic Medicine, MRC Centre for Neuromuscular Diseases, Newcastle University, NE1 3BZ, Newcastle upon Tyne, UK.
authors.forename: Amina
authors.initials: A
authors.lastname: Chaouch
authors.affiliation: 6 Department of Clinical Neurophysiology, University Hospital of North Norway, 9038 Tromsø, Norway.
authors.forename: Torberg
authors.initials: T
authors.lastname: Torbergsen
authors.affiliation: 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.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Bauché
authors.affiliation: 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.
authors.forename: Elodie
authors.initials: E
authors.lastname: de Bruyckere
authors.affiliation: 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.
authors.forename: Marie-Joséphine
authors.initials: MJ
authors.lastname: Fontenille
authors.affiliation: 7 Department of Neurology, Oslo University Hospital, 0424 Oslo, Norway.
authors.forename: Morten A
authors.initials: MA
authors.lastname: Horn
authors.affiliation: 8 Department of Medical Genetics, University Hospital of North Norway, 9038 Tromsø, Norway.
authors.forename: Marijke
authors.initials: M
authors.lastname: van Ghelue
authors.affiliation: 6 Department of Clinical Neurophysiology, University Hospital of North Norway, 9038 Tromsø, Norway.
authors.forename: Sissel
authors.initials: S
authors.lastname: Løseth
authors.affiliation: 5 Institute of Genetic Medicine, MRC Centre for Neuromuscular Diseases, Newcastle University, NE1 3BZ, Newcastle upon Tyne, UK.
authors.forename: Yasmin
authors.initials: Y
authors.lastname: Issop
authors.affiliation: 5 Institute of Genetic Medicine, MRC Centre for Neuromuscular Diseases, Newcastle University, NE1 3BZ, Newcastle upon Tyne, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Cox
authors.affiliation: 5 Institute of Genetic Medicine, MRC Centre for Neuromuscular Diseases, Newcastle University, NE1 3BZ, Newcastle upon Tyne, UK.
authors.forename: Juliane S
authors.initials: JS
authors.lastname: Müller
authors.affiliation: 5 Institute of Genetic Medicine, MRC Centre for Neuromuscular Diseases, Newcastle University, NE1 3BZ, Newcastle upon Tyne, UK.
authors.forename: Teresinha
authors.initials: T
authors.lastname: Evangelista
authors.affiliation: 9 Department of Clinical Neurophysiology, Uppsala University Hospital, 75185 Uppsala, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Stålberg
authors.affiliation: 10 AP-HP, University Hospital of Paris ïle-de-France ouest, Raymond Poincaré Hospital, 92380 Garches, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Ioos
authors.affiliation: 10 AP-HP, University Hospital of Paris ïle-de-France ouest, Raymond Poincaré Hospital, 92380 Garches, France.
authors.forename: Annie
authors.initials: A
authors.lastname: Barois
authors.affiliation: 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.
authors.forename: Guy
authors.initials: G
authors.lastname: Brochier
authors.affiliation: 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.
authors.forename: Damien
authors.initials: D
authors.lastname: Sternberg
authors.affiliation: 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.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Fournier
authors.affiliation: 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.
authors.forename: Daniel
authors.initials: D
authors.lastname: Hantaï
authors.affiliation: 12 Friedrich-Baur-Institute, Department of Neurology, Ludwig Maximilians University, 80336 Munich, Germany.
authors.forename: Angela
authors.initials: A
authors.lastname: Abicht
authors.affiliation: 12 Friedrich-Baur-Institute, Department of Neurology, Ludwig Maximilians University, 80336 Munich, Germany.
authors.forename: Marina
authors.initials: M
authors.lastname: Dusl
authors.affiliation: 5 Institute of Genetic Medicine, MRC Centre for Neuromuscular Diseases, Newcastle University, NE1 3BZ, Newcastle upon Tyne, UK.
authors.forename: Steven H
authors.initials: SH
authors.lastname: Laval
authors.affiliation: 5 Institute of Genetic Medicine, MRC Centre for Neuromuscular Diseases, Newcastle University, NE1 3BZ, Newcastle upon Tyne, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Griffin
authors.affiliation: 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.
authors.forename: Bruno
authors.initials: B
authors.lastname: Eymard
authors.affiliation: 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.
authors.forename: Hanns
authors.initials: H
authors.lastname: Lochmüller
mesh_terms: D000328:Adult; D018171:Agrin / Q000235:genetics*; D000595:Amino Acid Sequence; D001284:Atrophy; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D018908:Muscle Weakness / Q000150:complications / Q000235:genetics* / Q000473:pathology; D009133:Muscular Atrophy / Q000150:complications / Q000235:genetics* / Q000473:pathology; D020294:Myasthenic Syndromes, Congenital / Q000150:complications / Q000235:genetics* / Q000473:pathology; D010375:Pedigree
chemical_list: D018171:Agrin
keywords: agrin; congenital myasthenic syndrome; distal myopathy; neuromuscular junction; presynaptic