Congenital myasthenic syndromes 2

Nathalie Smeets, Alexander Gheldof, Bart Dequeker, , Margaux Poleur , Sofia Maldonado Slootjes, Vinciane Van Parijs, Nicolas Deconinck, Pauline Dontaine,  Alicia Alonso-Jimenez, Jan De Bleecker, Willem De Ridder, Sarah Herdewyn, Stéphanie Paquay, Arnaud Vanlander, Liesbeth De Waele, Diane Beysen, Kristl G. Claeys, Nicolas Dubuisson, Isabelle Hansen, Gauthier Remiche, Sara Seneca, Véronique Bissay, Luc Régal. Congenital Myasthenic Syndromes in Belgium: Genetic and Clinical Characterization of Pediatric and Adult Patients. Pediatric Neurology, 2024-09-01, Volume 158, Pages 57-65.

Abstract

Background

Congenital myasthenic syndromes (CMS) are a group of genetic disorders characterized by impaired neuromuscular transmission. CMS typically present at a young age with fatigable muscle weakness, often with an abnormal response after repetitive nerve stimulation (RNS). Pharmacologic treatment can improve symptoms, depending on the underlying defect. Prevalence is likely underestimated. This study reports on patients with CMS followed in Belgium in 2022.

Methods

Data were gathered retrospectively from the medical charts. Only likely pathogenic and pathogenic variants were included in the analysis.

Results

We identified 37 patients, resulting in an estimated prevalence of 3.19 per 1,000,000. The patients harbored pathogenic variants in CHRNE, RAPSN, DOK7, PREPL, CHRNB1, CHRNG, COLQ , MUSK, CHRND, GFPT1, and GMPPB. CHRNE was the most commonly affected gene. Most patients showed disease onset at birth, during infancy, or during childhood. Symptom onset was at adult age in seven patients, caused by variants in CHRNE , DOK7 , MUSK , CHRND, and GMPPB . Severity and distribution of weakness varied, as did the presence of respiratory involvement, feeding problems, and extraneuromuscular manifestations. RNS was performed in 23 patients of whom 18 demonstrated a pathologic decrement. Most treatment responses were predictable based on the genotype.

Conclusions

This is the first pooled characterization of patients with CMS in Belgium. We broaden the phenotypical spectrum of pathogenic variants in CHRNE with adult-onset CMS. Systematically documenting larger cohorts of patients with CMS can aid in better clinical characterization and earlier recognition of this rare disease. We emphasize the importance of establishing a molecular genetic diagnosis to tailor treatment choices.


Daniel Natera-de Benito, Alessia Pugliese, Kiran Polavarapu, Velina Guergueltcheva, Ivailo Tournev, Albena Todorova, Joana Afonso Ribeiro, Daniel M. Fernández-Mayoralas, Carlos Ortez, Loreto Martorell, Berta Estévez-Arias, Leslie Matalonga, Steven Laurie, Cristina Jou, Jarred Lau, Rachel Thompson, Xinming Shen, Andrew G. Engel, Andres Nascimento, Hanns Lochmüller,
Duygu Selcen. 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. Pediatric Neurology, 2024-08-01, Volume 157, Pages 5-13.

Abstract

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.