Genetic and phenotypic analyses of PRRT2 positive and negative paroxysmal kinesigenic dyskinesia

Paroxysmal kinesigenic dyskinesia (PKD) is a rare neurological disorder, characterized by attacks of involuntary movements triggered by sudden action. Variants in proline-rich transmembrane protein 2 ( ) are the most common genetic cause of PKD. The objective was to investigate the clinical and genetic characteristics of PKD and to establish genotype-phenotype correlations. We enrolled 219 PKD patients, documented their clinical information and performed screening using Sanger sequencing. Whole exome sequencing was performed on 49 PKD probands without variants. Genotype-phenotype correlation analyses were conducted on the probands. Among 219 PKD patients (99 cases from 39 families and 120 sporadic cases), 16 variants were identified. Nine variants (c.879+4A>G, c.879+5G>A, c.856G>A, c.955G>T, c.884G>C, c.649C>T, c.649dupC, c.649delC and c.696_697delCA) were previously known, while seven were novel (c.367_403del, c.347_348delAA, c.835C>T, c.116dupC, c.837_838insC, c.916_937del and c.902G>A). The mean interval from onset to diagnosis was 7.94 years. Compared to patients without variants, patients with the variants were more likely to have a positive family history, an earlier age of onset and a higher prevalence of falls during pre-treatment attacks (27.14% 8.99%, respectively). Patients with truncated variants tend to have bilateral attacks. We identified two transmembrane protein 151A ( ) variants including a novel variant (c.368G>C) and a reported variant (c.203C>T) in two PRRT2-negative probands with PKD. These findings provide insights on the clinical characteristics, diagnostic timeline and treatment response of PKD patients. PKD patients with truncated variants may tend to have more severe paroxysmal symptoms. This study expands the spectrum of and variants. Carbamazepine and oxcarbazepine are both used as a first-line treatment choice for PKD patients.