| Paroxysmal kinesigenic dyskinesia?PKD?is an episodic neurological movement disorder manifesting as episodes of dystonia,chorea or ballism induced by sudden movements.In 2011,Chinese researchers confirmed PRRT2?Proline-rich transmembrane protein 2?as one of the causative genes of PKD.Approximately 27%-65% of the cases of PKD worldwide are attributable to PRRT2 mutations,indicating that additional causative genes are yet to be identified or that genotype-phenotype overlap between PKD and other paroxysmal disorders might exist.In this research,we aimed to analyze and summarize the clinical manifestations as well as genetic features of PKD in a large population.Furthermore,the potential causative genes in PRRT2 negative PKD patients were also explored.At the same time,we also investigated the psychological characteristics and social behaviors of PKD patients in order to analyze the main factors influencing the quality of life among these.Firstly,a total of 284 PKD patients from our study center were enrolled in the first part of the study,including 127 familial patients?from 46 families?and 157 sporadic ones.The average age of onset was 11.9±4.0 years old,and the major phenotype was dystonia attacks triggered by sudden autonomic movement.Patients had episodic attacks usually lasted no more than 60 seconds with intact consciousness remained during the attack period.The frequency of PKD attacks per day varied greatly from several times to hundreds of times.During interval period,they were completely normal.One hundred and seventy-six patients needed antiepileptic therapy,and 97.7% of them benefited from the therapy.One hundred and eighteen patients received carbamazepine,and 98.3% of them benefited from this.Among 46 PKD families and 157 sporadic patients,a total of 16 PRRT2 mutations were detected,which accounted for 67.4%?31/46?of familial cases and 24.2%?38/157?of sporadic cases respectively.Eleven mutations?c.487C>T,c.649 delC,c.649 dupC,c.573 dupT,c.787C>T,c.797G>A,c.931C>T,c.981C>G,c.439G>C,c.859G>A and c.433delC?were already documented,while the other 5 mutations?c.511515delinsT,c.971972insG,c.761C>T,c.955G>T and c.959C>T?were novel.The 5 novel variants were not found in 1000 genome database,SNP database,or the 500 healthy controls.Aiming to investigate the potential causative genes of PKD,we further performed whole exome sequencing and Sanger sequencing in 163 PRRT2-negative probands with PKD from China Paroxysmal Dyskinesia Multicenter Network.As a result,we found mutations in 6 different genes which might cause the phenotype of PKD,including 3 de novo mutations?KCNMA1 c.1534A>G,SLC2A1 c.418G>A and SCN8 A c.3640G>A?and 3 variations cosegregated in 3 PKD families respectively?PNKD c.956 dupA,KCNA1 c.765C>A and DEPDC5 c.3311C>T?.According to the American College of Medical Genetics Standards and Guidelines,these 6 genetic variants were classified as "pathogenic" or "likely pathogenic".Eventually,a cross-sectional survey of psychological and quality of life were further performed using Symptom Check List-90-Revised?SCL-90-R?,Self-Rating Anxiety Scale?SAS?,World Health Organization Quality of Life-100?WHOQoL-100?,as well as Self-Rating Depression Scale?SDS?.For this part,we enrolled a total of 165 PKD patients,including 138 males and 27 females.Among these patients,149?90.3%?finished high school.There were 26 cases?15.8%?from rural areas and the other 139?84.2%?from urban areas.Among all of the factors analyzed,non-remission of PKD?P = 0.011?and higher score in depression?P = 0.000?were associated with lower levels of quality of life.In conclusion,PRRT2 mutation is still the main cause of PKD.For PRRT2-negative patients,the 6 genes identified in this study should be further tested.Sporadic PKD might be associated with de novo variants.In order to help PKD patients to be effectively diagnosed and treated,we need to standardize the process of diagnosis and treatment,strengthen clinical training and social science propaganda,as well as provide patients with comprehensive social support. |
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