Homozygous mutations in VAMP1 cause a presynaptic congenital myasthenic syndrome

We report 2 families with undiagnosed recessive presynaptic congenital myasthenic syndrome(CMS). Whole exomeor genome sequencing identified segregating homozygous variants in VAMP1: c.51_64delAGGTGGGGGTCCCC in a Kuwaiti family and c.146G>C in an Israeli family. VAMP1is crucial for vesicle fusionat presynaptic neuromuscular junction(NMJ). Electrodiagnostic examination showed severely low compound muscle action potentialsand presynaptic impairment. We assessed the effect of the nonsense mutationon mRNA levels and evaluated the NMJ transmission in VAMP1lew/lew mice, observing neurophysiological features of presynaptic impairment, similar to the patients. Taken together, our findings highlight VAMP1homozygous mutations as a cause of presynaptic CMS. Ann Neurol 2017;81:597–603