Natera-de Benito Daniel, Pugliese Alessia, Polavarapu Kiran, Guergueltcheva Velina, Tournev Ivailo, Todorova Albena, Afonso Ribeiro Joana, Fernández-Mayoralas Daniel M, Ortez Carlos, Martorell Loreto, Estévez-Arias Berta, Matalonga Leslie, Laurie Steven, Jou Cristina, Lau Jarred, Thompson Rachel, Shen Xinming, Engel Andrew G, Nascimento Andres, Lochmüller Hanns, Selcen Duygu
Neuromuscular Unit, Department of Neurology, Hospital Sant Joan de Déu, Barcelona, Spain; Applied Research in Neuromuscular Diseases, Institut de Recerca Sant Joan de Déu, Barcelona, Spain.
IRCCS Centro Neurolesi "Bonino-Pulejo", Neurology Unit, Messina, Italy.
Pediatr Neurol. 2024 Aug;157:5-13. doi: 10.1016/j.pediatrneurol.2024.04.027. Epub 2024 May 9.
Congenital myasthenic syndromes (CMS) are a group of inherited neuromuscular junction (NMJ) disorders arising from gene variants encoding diverse NMJ proteins. Recently, the VAMP1 gene, responsible for encoding the vesicle-associated membrane protein 1 (VAMP1), has been associated with CMS.
This study presents a characterization of five new individuals with VAMP1-related CMS, providing insights into the phenotype.
The individuals with VAMP1-related CMS exhibited early disease onset, presenting symptoms prenatally or during the neonatal period, alongside severe respiratory involvement and feeding difficulties. Generalized weakness at birth was a common feature, and none of the individuals achieved independent walking ability. Notably, all cases exhibited scoliosis. The clinical course remained stable, without typical exacerbations seen in other CMS types. The response to anticholinesterase inhibitors and salbutamol was only partial, but the addition of 3,4-diaminopyridine (3,4-DAP) led to significant and substantial improvements, suggesting therapeutic benefits of 3,4-DAP for managing VAMP1-related CMS symptoms. Noteworthy is the identification of the VAMP1 (NM_014231.5): c.340delA; p.Ile114SerfsTer72 as a founder variant in the Iberian Peninsula and Latin America.
This study contributes valuable insights into VAMP1-related CMS, emphasizing their early onset, arthrogryposis, facial and generalized weakness, respiratory involvement, and feeding difficulties. Furthermore, the potential efficacy of 3,4-DAP as a useful therapeutic option warrants further exploration. The findings have implications for clinical management and genetic counseling in affected individuals. Additional research is necessary to elucidate the long-term outcomes of VAMP1-related CMS.
先天性肌无力综合征（CMS）是一组由编码多种神经肌肉接头（NMJ）蛋白的基因变异引起的遗传性神经肌肉接头疾病。最近，负责编码囊泡相关膜蛋白1（VAMP1）的VAMP1基因已被证实与CMS相关。
本研究对5例与VAMP1相关的CMS患者进行了特征描述，以深入了解其表型。
与VAMP1相关的CMS患者发病较早，在产前或新生儿期出现症状，伴有严重的呼吸功能受累和喂养困难。出生时全身无力是常见特征，所有患者均未获得独立行走能力。值得注意的是，所有病例均出现脊柱侧弯。临床病程保持稳定，无其他类型CMS所见的典型病情加重。抗胆碱酯酶抑制剂和沙丁胺醇的反应仅为部分有效，但添加3,4-二氨基吡啶（3,4-DAP）可导致显著且实质性的改善，表明3,4-DAP对治疗VAMP1相关的CMS症状具有治疗益处。值得注意的是，VAMP1（NM_014231.5）：c.340delA；p.Ile114SerfsTer72被鉴定为伊比利亚半岛和拉丁美洲的一个奠基者变异。
本研究为VAMP1相关的CMS提供了有价值的见解，强调了其发病早、关节挛缩、面部及全身无力、呼吸功能受累和喂养困难等特点。此外，3,4-DAP作为一种有用的治疗选择的潜在疗效值得进一步探索。这些发现对受影响个体的临床管理和遗传咨询具有重要意义。有必要进行更多研究以阐明VAMP1相关的CMS的长期预后。
