title: Long-term follow-up in patients with congenital myasthenic syndrome due to RAPSN mutations.
abstract: Rapsyn (RAPSN) mutations are a common cause of postsynaptic congenital myasthenic syndromes. We present a comprehensive description of the clinical and molecular findings of ten patients with CMS due to mutations in RAPSN, mostly with a long-term follow-up. Two patients were homozygous and eight were heterozygous for the common p.Asn88Lys mutation. In three of the heterozygous patients we have identified three novel mutations (c.869T > C; p.Leu290Pro, c.1185delG; p.Thr396Profs*12, and c.358delC; p.Gln120Serfs*8). In our cohort, the RAPSN mutations lead to a relatively homogeneous phenotype, characterized by fluctuating ptosis, occasional bulbar symptoms, neck muscle weakness, and mild proximal muscle weakness with exacerbations precipitated by minor infections. Interestingly, episodic exacerbations continue to occur during adulthood. These were characterized by proximal limb girdle weakness and ptosis, and not so much by respiratory insufficiency after age 6. All patients presented during neonatal period and responded to cholinergic agonists. In most of the affected patients, additional use of 3,4-diaminopyridine resulted in significant clinical benefit. The disease course is stable except for intermittent worsening.
authors.affiliation: Department of Pediatrics, Hospital Universitario de Fuenlabrada, Madrid, Spain. Electronic address: daninatera@hotmail.com.
authors.forename: D
authors.initials: D
authors.lastname: Natera-de Benito
authors.affiliation: Department of Neurology, Hospital General San Jorge, Huesca, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Bestué
authors.affiliation: Department of Neurology, Hospital Universitari La Fe, Valencia, Spain.
authors.forename: J J
authors.initials: JJ
authors.lastname: Vilchez
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: T
authors.initials: T
authors.lastname: Evangelista
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: A
authors.initials: A
authors.lastname: Töpf
authors.affiliation: Department of Pediatrics, Hospital Universitario Cruces, Bilbao, Spain.
authors.forename: A
authors.initials: A
authors.lastname: García-Ribes
authors.affiliation: Department of Genetics, Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain.
authors.forename: M J
authors.initials: MJ
authors.lastname: Trujillo-Tiebas
authors.affiliation: Department of Genetics, Instituto de Medicina Genómica, Valencia, Spain.
authors.forename: M
authors.initials: M
authors.lastname: García-Hoyos
authors.affiliation: Department of Neuromuscular Diseases, Hospital Sant Joan de Déu, Barcelona, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Ortez
authors.affiliation: Department of Pediatric Neurology, Hospital Universitario 12 de Octubre, Madrid, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Camacho
authors.affiliation: Department of Pediatrics, Hospital Universitario Rey Juan Carlos, Madrid, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Jiménez
authors.affiliation: Friedrich-Baur-Institute, Ludwig-Maximilians-University Munich, Munich 80336,Germany.
authors.forename: M
authors.initials: M
authors.lastname: Dusl
authors.affiliation: Friedrich-Baur-Institute, Ludwig-Maximilians-University Munich, Munich 80336,Germany; Medical Genetics Center, Munich, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Abicht
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: H
authors.initials: H
authors.lastname: Lochmüller
authors.affiliation: Department of Neuromuscular Diseases, Hospital Sant Joan de Déu, Barcelona, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Colomer
authors.affiliation: Department of Neuromuscular Diseases, Hospital Sant Joan de Déu, Barcelona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Nascimento
mesh_terms: D015761:4-Aminopyridine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D000293:Adolescent; D000328:Adult; D000077770:Amifampridine; D002648:Child; D002675:Child, Preschool; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000235:genetics*; D009154:Mutation; D020294:Myasthenic Syndromes, Congenital / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology*; D010641:Phenotype; D026902:Potassium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology*; D011729:Pyridostigmine Bromide / Q000008:administration & dosage / Q000494:pharmacology; D055815:Young Adult
chemical_list: D002800:Cholinesterase Inhibitors; D009124:Muscle Proteins; D026902:Potassium Channel Blockers; C051609:peripheral membrane protein 43K; D015761:4-Aminopyridine; D011729:Pyridostigmine Bromide; D000077770:Amifampridine
keywords: 3,4-diaminopyridine; Congenital myasthenia; Congenital myasthenic syndrome; Neuromuscular junction; Pyridostigmine; Rapsyn