title: Distinct phenotypes of congenital acetylcholine receptor deficiency.
abstract: We contrast the phenotypes associated with hereditary acetylcholine receptor deficiency arising from mutations in either the acetylcholine receptor epsilon subunit or the endplate acetylcholine receptor clustering protein rapsyn. Mutational screening was performed by amplification of promoter and coding regions by PCR and direct DNA sequencing. We identified mutations in 37 acetylcholine receptor deficiency patients; 18 had acetylcholine receptor-epsilon mutations, 19 had rapsyn mutations. Mutated acetylcholine receptor-epsilon associated with bulbar symptoms, ptosis and ophthalmoplegia at birth, and generalized weakness. Mutated rapsyn caused either an early onset (rapsyn-EO) or late onset (rapsyn-LO) phenotype. Rapsyn-EO associated with arthrogryposis and life-threatening exacerbations during early childhood. Rapsyn-LO presented with limb weakness in adolescence or adulthood resembling seronegative myasthenia gravis. Awareness of distinct phenotypic features of acetylcholine receptor deficiency resulting from acetylcholine receptor-epsilon or rapsyn mutations should facilitate targeted genetic diagnosis, avoid inappropriate immunological therapy and, in some infants, prompt the rapid introduction of treatment that could be life saving.
authors.affiliation: Department of Clinical Neurology, Radcliffe Infirmary, Oxford, UK.
authors.forename: G
authors.initials: G
authors.lastname: Burke
authors.forename: J
authors.initials: J
authors.lastname: Cossins
authors.forename: S
authors.initials: S
authors.lastname: Maxwell
authors.forename: S
authors.initials: S
authors.lastname: Robb
authors.forename: M
authors.initials: M
authors.lastname: Nicolle
authors.forename: A
authors.initials: A
authors.lastname: Vincent
authors.forename: J
authors.initials: J
authors.lastname: Newsom-Davis
authors.forename: J
authors.initials: J
authors.lastname: Palace
authors.forename: D
authors.initials: D
authors.lastname: Beeson
mesh_terms: D015761:4-Aminopyridine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000293:Adolescent; D000328:Adult; D000368:Aged; D000077770:Amifampridine; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D002800:Cholinesterase Inhibitors / Q000627:therapeutic use; D004252:DNA Mutational Analysis / Q000379:methods; D004359:Drug Therapy, Combination; D004558:Electric Stimulation; D004576:Electromyography / Q000379:methods; D004594:Electrophysiology / Q000379:methods; D004622:Embryo, Mammalian; D004809:Ephedrine / Q000627:therapeutic use; D019054:Evoked Potentials, Motor / Q000187:drug effects / Q000528:radiation effects; D005260:Female; D005455:Fluorescent Antibody Technique / Q000379:methods; D006801:Humans; D007668:Kidney; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000235:genetics; D009132:Muscles; D009154:Mutation / Q000235:genetics; D020294:Myasthenic Syndromes, Congenital / Q000145:classification / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology*; D010641:Phenotype; D026902:Potassium Channel Blockers / Q000627:therapeutic use; D021122:Protein Subunits / Q000172:deficiency / Q000235:genetics; D011729:Pyridostigmine Bromide / Q000627:therapeutic use; D012333:RNA, Messenger / Q000096:biosynthesis; D011950:Receptors, Cholinergic / Q000172:deficiency* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D017422:Sequence Analysis, DNA / Q000379:methods; D012720:Severity of Illness Index; D013566:Sympathomimetics / Q000627:therapeutic use; D014162:Transfection / Q000379:methods
chemical_list: D002800:Cholinesterase Inhibitors; D009124:Muscle Proteins; D026902:Potassium Channel Blockers; D021122:Protein Subunits; D012333:RNA, Messenger; D011950:Receptors, Cholinergic; D013566:Sympathomimetics; C051609:peripheral membrane protein 43K; D015761:4-Aminopyridine; D004809:Ephedrine; D011729:Pyridostigmine Bromide; D000077770:Amifampridine