Identification of a new SYT2 variant validates an unusual distal motor neuropathy phenotype

Abstract

ObjectiveTo report a new SYT2 missense mutation causing distal hereditary motor neuropathy and presynaptic neuromuscular junction (NMJ) transmission dysfunction.MethodsWe report a multigenerational family with a new missense mutation, c. 1112T>A (p. Ile371Lys), in the C2B domain of SYT2, describe the clinical and electrophysiologic phenotype associated with this variant, and validate its pathogenicity in a Drosophila model.ResultsBoth proband and her mother present a similar clinical phenotype characterized by a slowly progressive, predominantly motor neuropathy and clear evidence of presynaptic NMJ dysfunction on nerve conduction studies. Validation of this new variant was accomplished by characterization of the mutation homologous to the human c. 1112T>A variant in Drosophila, confirming its dominant-negative effect on neurotransmitter release.ConclusionsThis report provides further confirmation of the role of SYT2 in human disease and corroborates the resultant unique clinical phenotype consistent with heriditary distal motor neuropathy. SYT2-related motor neuropathy is a rare disease but should be suspected in patients presenting with a combination of presynaptic NMJ dysfunction (resembling Lambert-Eaton myasthenic syndrome) and a predominantly motor neuropathy, especially in the context of a positive family history.

Identification of a Novel de Novo Variant in the SYT2 Gene Causing a Rare Type of Distal Hereditary Motor Neuropathy

“…The clinical signs found in our patient were similar to phenotypes described in previous studies [ 4 , 6 ]. He had a phenotype suggestive of motor neuropathy.…”

“…Previously, a group of authors identified a new type of dHMN caused by autosomal dominant pathogenic variants in synaptotagmin 2 ( SYT2 ) [ 3 ]. SYT2 is an integral membrane protein of synaptic vesicles and serves as a calcium sensor for neurotransmitter release, with calcium binding to its C2B domain, activating vesicle fusion [ 4 , 5 ]. This type of disease is associated with presynaptic neuromuscular junction dysfunction and characterized by foot deformities and fatigable ocular and lower limb weakness.…”

“…In the following study, a family, presenting with clear evidence of both presynaptic neuromuscular transmission impairment and distal motor neuropathy was described. This family carried a pathogenic variant c.1112T>A (p.Ile371Lys), which is also localized in the C2B domain of SYT2 [ 4 ]. Their data indicated that mutant I426K version forms mixed oligomers with WT synaptotagmin 1, thus dramatically reducing neurotransmitter release.…”

Biallelic loss of function variants in SYT2 cause a treatable congenital onset presynaptic myasthenic syndrome

“…To date, three independent dominantly acting heterozygous variants in SYT2 have been reported in five families as a rare cause of slowly progressive distal motor neuropathy and myasthenic syndrome (Herrmann et al, 2014;Montes-Chinea et al, 2018;Whittaker et al, 2015). Here we report a series of seven patients with recessive loss of function variants in SYT2, clinically manifesting with a severe presynaptic CMS.…”

“…At this time, three dominantly acting missense variants impacting the SYT2 C2B domain have been reported as a rare cause of distal motor neuropathy and myasthenic syndrome. Patients clinically manifest with relatively stable or slowly progressive distal weakness of variable severity with physiologic evidence of presynaptic NMJ impairment, responsive to 3,4 diaminopyridine treatment in some patients (Herrmann et al, 2014;Montes-Chinea et al, 2018;Whittaker et al, 2015). These heterozygous SYT2 variants are thought to impair Ca 2+ binding and disrupt synaptic transmission in a dominant-negative manner, however, their detailed mode of action remains to be fully explored.…”