Clinical and Genetic Heterogeneity of Paroxysmal Dyskinesias (S30.008)

OBJECTIVE: To explore the genetic and phenotypic spectrum of paroxysmal dyskinesias. BACKGROUND: Paroxysmal dyskinesia (PxDs) can be subdivided into paroxysmal kinesigenic dyskinesia (PKD), paroxysmal non-kinesigenic dyskinesia (PNKD), and paroxysmal exercise-induced dyskinesia (PED). Each subtype has been associated with PRRT2, MR-1 and SLC2A1 mutations, respectively. To date, there has been no study across all 3 genes in PxDs and little is known about PxDs pathogenesis. DESIGN/METHODS: We analysed all three genes in 145 patients with PxDs and in 53 patients with familial episodic ataxia (EA) and/or familial hemiplegic migraine (FHM). We further examined brain mRNA expression to investigate if selective vulnerability could explain the phenotypes. RESULTS: Out of 145 patients with paroxysmal movement disorders, a total of 47[percnt] had PRRT2 (35[percnt]), MR-1 (2[percnt]) or SLC2A1 (10[percnt]) mutations. Furthermore, PRRT2 mutations were found in 2 families with FHM or EA, one MR-1 family had FHM and one SLC2A1 family had EA. The phenotype associated with PRRT2 mutations frequently included FHM. SLC2A1 mutations were associated with variable phenotypes including PKD, PNKD, EA and myotonia and we identified a novel MR-1 gene deletion in FHM. We found that some PRRT2 loss-of-function mutations cause nonsense mediated decay, except when in the last exon, whereas missense mutations do not affect mRNA. In the family with a novel MR-1 deletion, mRNA was truncated likely leading to a reduction of the inhibition of exocytosis, and similar to PRRT2, an increase in vesicle release. CONCLUSIONS: This study highlights the frequency, novel mutations and clinical and molecular spectrum of PRRT2, MR-1, SLC2A1 and PNKD mutations as well as the phenotype-genotype overlap amongst these paroxysmal movement disorders. Investigation of PxDs should include the analysis of all three genes. Around half of our series remains genetically undefined implying that additional genes are yet to be identified. Disclosure: Dr. Bhatia has received personal compensation for activities with GlaxoSmithKline, Orion Corporation, Ipsen, Merz Pharmaceuticals, LLC., Sun Pharmaceutical Industries Ltd, Boehringer Ingelheim. Dr. Bhatia has received personal compensation in an editorial Dr. Erro has nothing to disclose. Dr. Gardiner has nothing to disclose. Dr. Jaffer has nothing to disclose. Dr. Stamelou has nothing to disclose. Dr. Walker has nothing to disclose. Dr. Kullman has nothing to disclose. Dr. Jarman has nothing to disclose. Dr. Kurian has nothing to disclose. Dr. Houlden has nothing to disclose.