P.380: Bi-allelic loss of function mutations in SYT2 cause a congenital onset severe presynaptic myasthenic syndrome

Abstract

Synaptotagmins are integral membrane proteins of the synaptic vesicles that function as calcium sensors and regulate neurotransmitter release at the presynaptic nerve. Synaptotagmin II, encoded by SYT2, is the major isoform expressed at the neuromuscular junction. Syt2 deficient mice are known to develop a lethal impairment in synaptic transmission with a reduction in evoked release of neurotransmitters at the neuromuscular junction, manifesting with progressive motor degeneration. Recently dominant missense mutations in SYT2 have been reported as a rare cause of distal motor neuropathy and myasthenic syndrome, clinically manifesting as a relatively stable or slowly progressive, distal weakness of variable expressivity with presynaptic NMJ impairment, responsive to 3,4 diaminopyridine treatment in some patients. While the exact pathogenic mechanism of these dominantly-acting SYT2 missense mutations remains largely unknown, they all impact the C2B calcium-binding domain and are thought to have a dominant-negative effect on synaptic vesicle exocytosis. Here we report four patients, of three independent families, with bi-allelic loss-of-function mutations in SYT2, clinically manifesting with a remarkably consistent phenotype of severe congenital-onset hypotonia and weakness, with electrodiagnostic findings consistent with a presynaptic congenital myasthenic syndrome (CMS). This case series further establishes SYT2 as a CMS-disease gene and expands its clinical and genetic spectrum to include recessive loss-of-function mutations, manifesting as a severe congenital-onset presynaptic CMS with potential treatment implications, thus warranting an early genetic diagnosis.