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This Article Figures Only Full Text Full Text (PDF) CME: Take the course for this article: Volume 73, Number 3, July 21, 2009 Correspondence: Submit a response Alert me when this article is cited Alert me when Correspondence are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Milone, M. Articles by Engel, A. G. PubMed PubMed Citation Articles by Milone, M. Articles by Engel, A. G.

Myasthenic syndrome due to defects in rapsyn

Clinical and molecular findings in 39 patients

From the Department of Neurology (M.M., X.M.S., D.S., J.B., C.M.H., A.G.E.), Mayo Clinic, Rochester, MN; Division of Neurogenetics (K.O.), Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan; and Division of Pediatric Neurology (S.T.I.), Children’s Medical Center, University of Texas Southwestern Medical Center, Dallas.

Address correspondence and reprint requests to Dr. Margherita Milone, Department of Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905 Milone.Margherita{at}mayo.edu

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.

Abbreviations: 3,4-DAP = 3,4-diaminopyridine; -bgt = -bungarotoxin; AChR = acetylcholine receptor; CMAP = compound muscle action potential; CMS = congenital myasthenic syndrome; EP = endplate; MEPC = miniature endplate currents; MEPP = miniature endplate potentials; TPR = tetratricopeptide.

Supported by NIH grant 6277 and by a research grant from the Muscular Dystrophy Association to Dr. Engel.

Disclosure: Author disclosures are provided at the end of the article.

Received February 16, 2009. Accepted in final form April 13, 2009.