title: Myasthenic syndrome due to defects in rapsyn: Clinical and molecular findings in 39 patients.
abstract: BACKGROUND
  Pathogenic mutations in rapsyn result in endplate acetylcholine receptor (AChR) deficiency and are a common cause of postsynaptic congenital myasthenic syndromes.
  
  
  METHODS
  Clinical, electrophysiologic, pathologic, and molecular studies were done in 39 patients.
  
  
  RESULTS
  In all but one patient, the disease presented in the first 2 years of life. In 9 patients, the myasthenic symptoms included constant or episodic ophthalmoparesis, and 1 patient had a pure limb-girdle phenotype. More than one-half of the patients experienced intermittent exacerbations. Long-term follow-up was available in 25 patients after start of cholinergic therapy: 21 became stable or were improved and 2 of these became asymptomatic; 3 had a progressive course; and 1 died in infancy. In 7 patients who had endplate studies, the average counts of AChR per endplate and the synaptic response to ACh were less reduced than in patients harboring low AChR expressor mutations. Eight patients were homozygous and 23 heterozygous for the common p.N88K mutation. Six mutations, comprising 3 missense mutations, an in-frame deletion, a splice-site mutation, and a nonsense mutation, are novel. Homozygosity for p.N88K was associated with varying grades of severity. No genotype-phenotype correlations were observed except in 8 Near-Eastern patients homozygous for the promoter mutation (c.-38A>G), who had a mild course.
  
  
  CONCLUSIONS
  All but 1 patient presented early in life and most responded to cholinergic agonists. With early diagnosis and therapy, rapsyn deficiency has a benign course in most patients. There was no consistent phenotype-genotype correlation except for an E-box mutation associated with jaw deformities.
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA. Milone.Margherita@mayo.edu
authors.forename: M
authors.initials: M
authors.lastname: Milone
authors.forename: X M
authors.initials: XM
authors.lastname: Shen
authors.forename: D
authors.initials: D
authors.lastname: Selcen
authors.forename: K
authors.initials: K
authors.lastname: Ohno
authors.forename: J
authors.initials: J
authors.lastname: Brengman
authors.forename: S T
authors.initials: ST
authors.lastname: Iannaccone
authors.forename: C M
authors.initials: CM
authors.lastname: Harper
authors.forename: A G
authors.initials: AG
authors.lastname: Engel
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D002648:Child; D002675:Child, Preschool; D018679:Cholinergic Agonists / Q000627:therapeutic use; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D005838:Genotype; D006720:Homozygote; D006801:Humans; D008297:Male; D009124:Muscle Proteins / Q000172:deficiency* / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D020294:Myasthenic Syndromes, Congenital / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D020511:Neuromuscular Junction Diseases / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D010641:Phenotype; D011950:Receptors, Cholinergic / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: D018679:Cholinergic Agonists; D009124:Muscle Proteins; D011950:Receptors, Cholinergic; C051609:peripheral membrane protein 43K