TY - JOUR
T1 - Myasthenic syndrome due to defects in rapsyn
T2 - Clinical and molecular findings in 39 patients
AU - Milone, M.
AU - Shen, X. M.
AU - Selcen, D.
AU - Ohno, K.
AU - Brengman, J.
AU - Iannaccone, S. T.
AU - Harper, C. M.
AU - Engel, A. G.
N1 - Funding Information:
Supported by NIH grant 6277 and by a research grant from the Muscular Dystrophy Association to Dr. Engel.
Funding Information:
Dr. Milone reports no disclosures. Dr. Shen reports no disclosures. D. Selcen receives research support from NIH/NINDS [K08, NS50106]. Dr. Ohno reports no disclosures. Mrs. Brengman reports no disclosures. Dr. Iannaccone served on the Muscular Dystrophy Advisory Board of NicOx; serves on the Editorial Boards of Neuromuscular Disorders, Journal of Clinical Neuromuscular Disease, and Journal of Pediatric Rehabilitation Medicine; receives research support from PTC Therapeutics for clinical trial of PTC124 in Duchenne muscular dystrophy [Site PI], from NIH for clinical trial of phenylbutyrate in spinal muscular atrophy [Site PI], and from the SMA Foundation, North American Charcot-Marie Tooth Network, and the Muscular Dystrophy Association. Dr. Harper reports no disclosures. Dr. Engel serves as Associate Editor for Neurology®; receives royalties from McGraw-Hill for editing the 3rd edition of Myology; received honorarium for editing volume 91 of the Handbook of Clinical Neurology, 3rd series; and receives research support from NIH [NS6277] and the Muscular Dystrophy Association.
PY - 2009/7/21
Y1 - 2009/7/21
N2 - 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.
AB - 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.
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U2 - 10.1212/WNL.0b013e3181ae7cbc
DO - 10.1212/WNL.0b013e3181ae7cbc
M3 - Article
C2 - 19620612
AN - SCOPUS:68949173752
SN - 0028-3878
VL - 73
SP - 228
EP - 235
JO - Neurology
JF - Neurology
IS - 3
ER -