title: Novel truncating RAPSN mutations causing congenital myasthenic syndrome responsive to 3,4-diaminopyridine.
abstract: Rapsyn is essential for clustering the acetylcholine receptor at the postsynaptic membrane of the neuromuscular junction. Direct sequencing of RAPSN in two children with congenital myasthenic syndromes with no mutation in any of the AChR subunits identified two heterozygous recessive mutations in each: a previously characterized N88K mutation in both, and a second frameshifting mutation in Patient (Pt) 1 and a nonsense mutation in Pt 2. An intercostal muscle biopsy in Pt 1 revealed decreased AChRs per endplate and decreased amplitude of the miniature endplate potential, predicted consequences of rapsyn deficiency. Clinically, both children manifested with hypomotility in utero, fatigable ocular and limb weakness since birth, decreased strength during viral illness, decremental response on electromyography, and absence of AChR antibodies. Pt 1, however, had a more severe clinical course with recurrent episodes of respiratory failure, contractures, and craniofacial malformations. In both patients, treatment with pyridostigmine was of some benefit, but the addition of 3,4-diaminopyridine led to significant clinical improvement. Thus, rapsyn deficiency predicting similar consequences at the cellular level can result in phenotypes with marked differences in severity of symptoms, risk of respiratory failure, and presence of contractures and craniofacial malformations.
authors.affiliation: Department of Pediatrics (Neurology), The Hospital for Sick Children, University of Toronto, Canada.
authors.forename: Brenda L
authors.initials: BL
authors.lastname: Banwell
authors.forename: Kinji
authors.initials: K
authors.lastname: Ohno
authors.forename: Joern P
authors.initials: JP
authors.lastname: Sieb
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Engel
mesh_terms: D015761:4-Aminopyridine / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D000109:Acetylcholine / Q000378:metabolism; D000200:Action Potentials / Q000187:drug effects; D000293:Adolescent; D000077770:Amifampridine; D001706:Biopsy / Q000379:methods; D002352:Carrier Proteins / Q000378:metabolism; D002648:Child; D002802:Cholinesterases / Q000378:metabolism; D004252:DNA Mutational Analysis / Q000379:methods; D004553:Electric Conductivity; D004576:Electromyography; D005260:Female; D017353:Gene Deletion; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D026901:Membrane Transport Proteins; D008854:Microscopy, Electron / Q000379:methods; D009045:Motor Endplate / Q000187:drug effects / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics* / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology / Q000648:ultrastructure; D009154:Mutation; D020294:Myasthenic Syndromes, Congenital / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology; D009469:Neuromuscular Junction / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000627:therapeutic use; D011950:Receptors, Cholinergic / Q000378:metabolism; D050494:Vesicular Acetylcholine Transport Proteins; D033921:Vesicular Transport Proteins
chemical_list: D002352:Carrier Proteins; D026901:Membrane Transport Proteins; D009124:Muscle Proteins; D026902:Potassium Channel Blockers; D011950:Receptors, Cholinergic; C493459:SLC18A3 protein, human; D050494:Vesicular Acetylcholine Transport Proteins; D033921:Vesicular Transport Proteins; C051609:peripheral membrane protein 43K; D015761:4-Aminopyridine; D002802:Cholinesterases; D000109:Acetylcholine; D000077770:Amifampridine