Clinical Features And Molecular Pathogenesis Of Paroxysmal Kinesigenic Dyskinesia

Paroxysmal kinesigenic dyskinesia(PKD)is a rare movement disorder characterized by transient and recurrent dystonic or choreoathetoid attacks triggered by sudden voluntary movements.In 2011,genome-wide linkage analyses confirmed PRRT2(Proline-rich transmembrane protein 2)as the causative gene of PKD.In the present study,we aimed to investigate the clinical and genetic features of PKD in a large population and to analyze the genotype-phenotype correlation.Besides,we primarily researched into the role of PRRT2 protein in the pathogenesis of PKD.130 PKD patients were enrolled in the present study,including 29 patients from 19 PKD families and 101 sporadic cases.The mean age at onset was 11.8±3.8 years and the clinical manifestation was characterized by dystonia mostly precipitated by sudden movements.Attacks usually lasted less than 1 minute,and the consciousness remained intact during the episode.The MRI and EEG examinations were normal.A total of 81 patients required antiepileptic treatment,including 51 patients with carbamazepine,17 patients with oxcarbazepine,and 13 patients with other antiepileptics(phenytoin,valproate,lamotrigine,topiramate and clonazepam),of which 96.3% reported a good benefit from the treatment.Approximately 98.0% of the patients who received carbamazepine showed a good response.Among the 120 PKD probands,we detected 8 PRRT2 mutations,accounting for 30% of the study population,with 78.9%(15/19)in patients with familial PKD and 20.8%(21/101)in sporadic cases respectively.Five mutations(c.487C>T,c.573 dupT,c.649 dupC,c.649 delC and c.981C>G)were already reported,while 3 mutations(c.787C>T,c.797G>A and c.931C>T)were undocumented in the SNP Database or 1000 Genomes Project,neither were detected in 200 healthy controls.A complicated PKD patient harboring a homozygous c.931 C>T mutation was shown to have inherited the mutation via uniparental disomy.Compared with non-carriers,the PRRT2 mutation carriers were younger at onset,experienced longer attacks,and tended to present with complicated PKD and a positive family history.PRRT2 protein exclusively expressed in the central nervous system,according to an age-dependent expression pattern.The immunofluorescence study demonstrated PRRT2 protein mainly located in granular cells and Purkinje cells in cerebellum,but not in striatum or substantia nigra.In conclusion,PRRT2 mutations are common in PKD patients,and are significantly associated with an earlier age at onset,longer duration of attacks,a complicated form of PKD and a tendency for a positive family history.When treatment is needed,a small dosage of carbamazepine is recommended as the first-choice drug.The expression pattern of PRRT2 protein gives insight into the pathogenesis of PKD,in which the abnormal PRRT2 protein may disturb the synapse of parallel fiber-Purkinje cell(PF-PC),resulting in dysfunction of neurotransmission releasing,thus leading to the onset of PKD.