Objective: To describe a family with both congenital myasthenia and spastic ataxia

Background: The vesicle-associated membrane protein – VAMP1 is associated with synaptic activation in presynaptic terminals. Mono or biallelic variants on VAMP1 gene have been so far associated with the respective phenotypes: spastic ataxia type 1 and presynaptic congenital myasthenia. In this article, we describe a Brazilian family pedigree with compound heterozygous mutations in this gene, with a phenotype overlapping between the two aforementioned syndromes, an unprecedented description in the literature.

Method: The index case is a 46-year-old patient, third son of a nonconsanguineous marriage with a history of delayed milestones, hypotonia and proximal weakness. The patient had thick lips, short stature, kyphoscoliosis, flat and valgus feet, striatal hands, and joint deformities. Examination demonstrated cerebellar dysarthria, ptosis and ophthalmoparesis. Muscle strength was normal, and all tendon reflexes were absent. Mild dysmetria and gait ataxic were also present.

Results: Single fiber electromyography showed neuromuscular junction disease. Neuroimaging revealed cerebellar atrophy. The patient has three more siblings with a similar phenotype, Exome sequencing of the index patient and siblings revealed the presence of two biallelic variants on VAMP1 gene:  p.Ile114del -and c.340+26G>C.

Conclusion: The VAMP1 gene is responsible for encoding vesicle-associated membrane protein-1, also called synaptobrevin-1. It is a cell membrane protein that participates in the process of exocytosis. It plays this role in the presynaptic region, anchored in the synaptic vesicle membrane by the C-terminal. This gene consists of five exons and is located on chromosome 12p13.31. It aids in neuronal exocytosis, acting in the presynaptic region. Currently, mutations in VAMP1 are related to two distinct phenotypes. When in autosomal dominant pattern of inheritance, spastic ataxia type 1 (SPAX1), when in recessive inheritance, presynaptic congenital myasthenia. There is no description in the literature of a phenotypic presentation that encompasses both overlapping phenotypes. In the cases described above, we describe a family with the same phenotypic presentation and compound heterozygosity, an unprecedented fact to date. The final diagnosis was only possible through exome sequencing of the patient and other family members.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/spastic-ataxia-associated-with-congenital-myasthenia-related-to-the-vamp1-gene-report-of-an-affected-family-in-brazil/