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

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.

Keywords: 3,4-Diaminopyridine (3,4-DAP); Congenital myasthenic syndrome; Neuromuscular junction; Synaptobrevin 1 (SYB1); Vesicle-associated membrane protein 1 (VAMP1).

Figure 1.

Clinical images of individuals with VAMP1-related congenital myasthenic syndrome. (a-e) Individual 3. Note congenital knee contractures at age 3 years (a), ptosis and facial weakness at age 12 years (b), and scoliosis at age 12 years (c-e). (f-j) Individual 4. Note facial weakness, high arched palate, and knee contractures. (k,l) Individuals 1 and 2. Note facial weakness. (m-o) Individual 5. Note facial weakness and the fluctuation of the ptosis, which is not present in the images.

Figure 2.

Pedigrees of the four families with VAMP1 variants included in this study. Circles indicate females, squares indicate males, filled in symbols denote affected individuals. Asterisks mark individuals from whom DNA samples were obtained.

Figure 3.

Muscle biopsy of individual 5. (A) Hematoxylin-eosin: moderate variability in the size of muscle fibers with some hypotrophic fibers. (B) and (C) Modified Gomori trichrome: no increase in connective tissue; occasional hypercontracted fibers were observed. Presence of isolated cytoplasmic bodies. (D) NADH, (E) SDH, and (F) COX staining did not reveal any defects in the myofibrillar pattern. (G) Slow and (H) Fast myosin reacted sections showed a predominance of type II fibers. (I) Neonatal myosin reacted section exhibited numerous small and normal-sized positive fibers.