Advancing the Understanding of Vesicle-Associated Membrane Protein 1-Related Congenital Myasthenic Syndrome: Phenotypic Insights, Favorable Response to 3,4-Diaminopyridine, and Clinical Characterization of Five New Cases
Por:
Natera-de Benito D, Pugliese A, Polavarapu K, Guergueltcheva V, Tournev I, Todorova A, Afonso Ribeiro J, Fernández-Mayoralas DM, Ortez-Gonzalez CI, Martorell-Sampol L, Estévez-Arias B, Matalonga L, Laurie S, Jou-Munoz C, Lau J, Thompson R, Shen X, Engel AG, Nascimento-Osorio A, Lochmüller H and Selcen D
Publicada:
1 ago 2024
Ahead of Print:
1 jun 2024
Resumen:
Background: 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. Methods: This study presents a characterization of five new individuals with VAMP1-related CMS, providing insights into the phenotype. Results: 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. Conclusions: 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. (c) 2024 Elsevier Inc. All rights reserved.
Filiaciones:
Natera-de Benito D:
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
Pugliese A:
IRCCS Centro Neurolesi "Bonino-Pulejo", Neurology Unit, Messina, Italy
Polavarapu K:
Children' s Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada
Guergueltcheva V:
Clinic of Neurology, University Hospital Sofiamed, Sofia University St. Kliment Ohridski, Sofia, Bulgaria
Tournev I:
Department of Neurology, University Hospital "Alexandrovska", Medical University, Sofia, Bulgaria
Department of Cognitive Science and Psychology, New Bulgarian University, Sofia, Bulgaria
Todorova A:
Genetic Medico-Diagnostic Laboratory "Genica", Sofia, Bulgaria
Department of Medical Chemistry and Biochemistry, Sofia Medical University, Sofia, Bulgaria
Afonso Ribeiro J:
Neurology Department, Coimbra University Hospital Centre, Coimbra, Portugal
Fernández-Mayoralas DM:
Department of Pediatric Neurology, Hospital Universitario Quirónsalud, Madrid, Spain
Ortez-Gonzalez CI:
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
Martorell-Sampol L:
Department of Genetic and Molecular Medicine-IPER, Hospital Sant Joan de Déu and Institut de Recerca Sant Joan de Déu, Barcelona, Spain
Estévez-Arias B:
Neuromuscular Unit, Department of Neurology, Hospital Sant Joan de Déu, Barcelona, Spain
Laboratory of Neurogenetics and Molecular Medicine-IPER, Sant Joan de Deu Research Institute, Barcelona, Spain
Matalonga L:
Centro Nacional de Análisis Genómico, Barcelona, Spain
Laurie S:
Centro Nacional de Análisis Genómico, Barcelona, Spain
Jou-Munoz C:
Applied Research in Neuromuscular Diseases, Institut de Recerca Sant Joan de Déu, Barcelona, Spain
Department of Pathology, Hospital Sant Joan de Déu, Barcelona, Spain
Lau J:
Children' s Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada
Thompson R:
Children' s Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada
Shen X:
Department of Neurology and Neuromuscular Research Laboratory, Mayo Clinic, Rochester, Minnesota
Engel AG:
Department of Neurology and Neuromuscular Research Laboratory, Mayo Clinic, Rochester, Minnesota
Nascimento-Osorio A:
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
Lochmüller H:
Children' s Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada
Laboratory of Neurogenetics and Molecular Medicine-IPER, Sant Joan de Deu Research Institute, Barcelona, Spain
Brain and Mind Research Institute, University of Ottawa, Ottawa, Canada
Department of Neuropediatrics and Muscle Disorders, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany
Selcen D:
Department of Neurology and Neuromuscular Research Laboratory, Mayo Clinic, Rochester, Minnesota
Green Submitted
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