Novel truncating RAPSN mutations causing congenital myasthenic syndrome responsive to 3,4-diaminopyridine
Novel truncating RAPSN mutations causing congenital myasthenic syndrome responsive to 3,4-diaminopyridine
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DOI：
10.1016/j.nmd.2003.11.004
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发表时间：
2004-03-01
影响因子：
2.8
通讯作者：
Engel, AG
中科院分区：
文献类型：
--
作者：
Banwell, BL;Ohno, K;Engel, AG
Rapsyn 对于将乙酰胆碱受体聚集在神经肌肉接头的突触后膜上至关重要。对两名患有先天性肌无力综合征且任何 AChR 亚基均无突变的儿童进行 RAPSN 直接测序，确定了其中的两种杂合隐性突变：两者均具有先前鉴定的 N88K 突变，以及患者 (Pt) 1 中的第二个移码突变和 Pt 2 中的无义突变。Pt 1 的肋间肌活检显示每个终板的 AChR 减少，并且微型终板电位的幅度降低，预测rapsyn 缺乏的后果。临床上，两个孩子均表现出子宫内运动能力低下、出生后眼睛和四肢易疲劳、病毒感染期间体力下降、肌电图反应减弱以及缺乏AChR抗体。然而，1 号患者的临床病程更为严重，反复发作呼吸衰竭、挛缩和颅面畸形。对于这两名患者，吡斯的明治疗有一定效果，但添加 3,4-二氨基吡啶可带来显着的临床改善。因此，rapsyn 缺乏在细胞水平上预测类似的后果，可能会导致在症状严重程度、呼吸衰竭风险以及挛缩和颅面畸形方面存在显着差异的表型。 (C) 2003 Elsevier B.V. 保留所有权利。
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.