title: Electrophysiological and morphological characterization of a case of autosomal recessive congenital myasthenic syndrome with acetylcholine receptor deficiency due to a N88K rapsyn homozygous mutation.
abstract: Congenital myasthenic syndromes are rare heterogeneous hereditary disorders, which lead to defective neuromuscular transmission resulting in fatigable muscle weakness. Post-synaptic congenital myasthenic syndromes are caused by acetylcholine receptor kinetic abnormalities or by acetylcholine receptor deficiency. Most of the congenital myasthenic syndromes with acetylcholine receptor deficiency are due to mutations in acetylcholine receptor subunit genes. Some have recently been attributed to mutations in the rapsyn gene. Here, we report the case of a 28-year-old French congenital myasthenic syndrome patient who had mild diplopia and fatigability from the age of 5 years. His muscle biopsy revealed a marked reduction in rapsyn and acetylcholine receptor at neuromuscular junctions together with a simplification of the subneural apparatus structure. In this patient, we excluded mutations in the acetylcholine receptor subunit genes and identified the homozygous N88K rapsyn mutation, which has already been shown by cell expression to impair rapsyn and acetylcholine receptor aggregation at the neuromuscular junction. The detection of the N88K mutation at the heterozygous state in five of 300 unrelated control subjects shows that this mutation is not infrequent in the healthy population. Electrophysiological measurements on biopsied intercostal muscle from this patient showed that his rapsyn mutation-induced fatigable weakness is expressed not only in a diminution in acetylcholine receptor membrane density but also in a decline of endplate potentials evoked at low frequency.
authors.affiliation: INSERM U.582, Institut de Myologie, Hôpital de la Salpêtrière, 47 Boulevard de l'Hôpital, 75651 Cedex 13, Paris, France
authors.forename: Eriko
authors.initials: E
authors.lastname: Yasaki
authors.forename: Cassandra
authors.initials: C
authors.lastname: Prioleau
authors.forename: Julien
authors.initials: J
authors.lastname: Barbier
authors.forename: Pascale
authors.initials: P
authors.lastname: Richard
authors.forename: Frédéric
authors.initials: F
authors.lastname: Andreux
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Leroy
authors.forename: Philippe
authors.initials: P
authors.lastname: Dartevelle
authors.forename: Jeanine
authors.initials: J
authors.lastname: Koenig
authors.forename: Jordi
authors.initials: J
authors.lastname: Molgó
authors.forename: Michel
authors.initials: M
authors.lastname: Fardeau
authors.forename: Bruno
authors.initials: B
authors.lastname: Eymard
authors.forename: Daniel
authors.initials: D
authors.lastname: Hantaï
mesh_terms: D000328:Adult; D001706:Biopsy; D025063:Chromosome Disorders / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D004252:DNA Mutational Analysis; D015536:Down-Regulation / Q000235:genetics; D004594:Electrophysiology; D005260:Female; D005787:Gene Frequency; D005808:Genes, Recessive / Q000235:genetics; D006239:Haplotypes / Q000235:genetics; D006720:Homozygote; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000235:genetics; D009124:Muscle Proteins / Q000172:deficiency* / Q000235:genetics; D018482:Muscle, Skeletal / Q000294:innervation / Q000473:pathology / Q000503:physiopathology*; D009154:Mutation / Q000235:genetics; D020294:Myasthenic Syndromes, Congenital / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D009469:Neuromuscular Junction / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D010375:Pedigree; D011940:Receptor Aggregation / Q000235:genetics; D011978:Receptors, Nicotinic / Q000172:deficiency* / Q000235:genetics; D013570:Synaptic Membranes / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D009435:Synaptic Transmission / Q000235:genetics
chemical_list: D009124:Muscle Proteins; D011978:Receptors, Nicotinic; C051609:peripheral membrane protein 43K