Genes that affect synaptic excitability and transmission identified by rare variant analyses in episodic ataxias

The episodic ataxias are a heterogeneous group of paroxysmal neurological disorders characterized by intermittent attacks of unsteadiness and incoordination, often associated with additional neurological features including migraine or hemiplegic migraine, epilepsy, fluctuating weakness, or progressive ataxia. There are at least ten causative genes reported, with some of these only identified in isolated cases or families. Although separate screening studies have been carried out on each of the episodic ataxia genes, so far there has been no report of large study using a next generation sequencing approach in the analysis of these disorders, thus little is known about their molecular heterogeneity. The identification in the present study of rare variants in genes implicated in synaptic excitability and transmission highlight overlapping molecular pathways and pleiotropic clinical presentations in paroxysmal neurological disorders.