Novel truncating RAPSN mutations causing congenital myasthenic syndrome responsive to 3,4-diaminopyridine

被引:41
作者
Banwell, BL
Ohno, K
Sieb, JP
Engel, AG
机构
[1] Mayo Clin & Mayo Fdn, Dept Neurol, Rochester, MN 55905 USA
[2] Mayo Clin & Mayo Fdn, Neuromuscular Res Lab, Rochester, MN 55905 USA
[3] Gen Hosp, D-18410 Stralsund, Germany
[4] Univ Toronto, Hosp Sick Children, Dept Pediat Neurol, Toronto, ON, Canada
关键词
congenital myasthenic syndrome; human rapsyn deficiency; therapy; 3,4-diaminopyridine;
D O I
10.1016/j.nmd.2003.11.004
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
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 frame-shifting 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. (C) 2003 Elsevier B.V. All rights reserved.
引用
收藏
页码:202 / 207
页数:6
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