PRRT2 mutation correlated with phenotype of paroxysmal kinesigenic dyskinesia and drug response

Abstract

The Bruno et al. 1 criteria are commonly used to diagnose paroxysmal kinesigenic dyskinesia (PKD), listed as follows:• Identified kinesigenic trigger for the attacks • Short duration of attacks (1 minute) • No loss of consciousness or pain during attacks • Exclusion of other organic diseases and normal neurologic examination • Control of attacks with phenytoin or carbamazepine, if tried • Age at onset between 1 and 20 years, if no family history of PKD Our previous study has identified PRRT2 as a causative gene for PKD, 2 which was supported by several independent groups. 3-5 To date, many PRRT2 mutations in PKD have been reported, but the genotype-phenotype relationship of PKD has not been well-studied. Our objective was to investigate correlations of PRRT2 mutations with phenotypes of PKD and responses to carbamazepine in a cohort of patients with PKD.Classification of evidence. This study provides Class IV evidence of a correlation between phenotype and genotype in patients with PKD, the PRRT2 mutation, and response to carbamazepine. Methods.We recruited 81 patients with PKD, including 44 familial cases from 14 pedigrees and 37 possibly sporadic cases, from Huashan Hospital and First Affiliated Hospital during 2 periods, December 2005 to March 2011 (stage 1) and April 2011 to April 2012 (stage 2), prior to or after the discovery of PRRT2 mutations, respectively. All cases met Bruno et al. criteria. The study followed standard protocol approvals, registrations, and patient consents.Clinical evaluations were performed and patients were followed up. Sanger sequencing was performed to identify PRRT2 mutations. Differences in clinical characteristics between patients with PKD with and without PRRT2 mutations were tested using the 2-sample t test or the x 2 test. A generalized estimating equation (GEE) model was used to account for familial correlation. SAS version 9.2 (SAS Inc., Cary, NC) was used for statistical analyses.Results. Phenotypes of patients with PKD in this study were classified into 2 subtypes, choreoathetosis or dystonia, according to their main symptoms (detailed classifications seen in appendix e-1 on the Neurology ® Web site at www.neurology.org). Three cases had a positive history of infantile convulsions, and one had viral encephalitis before onset of PKD attacks. All others had no significant medical history. Available EEG and brain MRI showed unremarkable results.Four documented PRRT2 mutations, 2,6 including c.649dupC, c.514_517delTCTG, c.972delA, and c.649delC, were detected in 100% of familial cases and 11% of possibly sporadic cases (table e-1 and table e-2). The c.649dupC mutation was also detected in the asymptomatic parents of family 34 and 47, suggesting the incomplete penetrance of this mutation. Interestingly, we found a de novo mutation of c.649dupC in the patient with PKD of Mongolian ancestry. 7 Associations between PRRT2 mutations and the clinical presentation of PKD are shown in table 1. The mean age at onset in PRRT2 mutation carriers was significantly lower than that in non-P...

Clinical Manifestations in Paroxysmal Kinesigenic Dyskinesia Patients with Proline-Rich Transmembrane Protein 2 Gene Mutation

“…These findings correspond well with a previous study that found no difference between these two groups, with the exception of premonitory sensation 16. However, another study found a higher prevalence of the choreoathetotic phenotype and longer duration of paroxysmal dyskinesia in PKD patients with PRRT2 gene mutations 17. In the present study, there was no significant difference between the two groups, even when the duration of episodes was dichotomized into <5 s and >5 s ( p =0.580) just like the previous study.…”

“…Echoing previous studies,16,17 PKD patients with PRRT2 gene mutations were younger at disease onset in the present study. Assessment of the clinical data revealed that the clinical features of paroxysmal movement were highly typical and homogeneous, similar to previous studies 12,18.…”

“…Despite many reports of PRRT2 mutations in patients with PKD and other diseases, their clinical role in PKD remains unclear and debatable. Only a few studies have compared the clinical characteristics of PKD patients with and without PRRT2 gene mutations, and their results have been equivocal 16,17. PKD patients with PRRT2 gene mutations typically report an earlier age of symptom onset and are more likely to have non-dyskinetic symptoms than those without gene mutations.…”

Paroxysmal kinesigenic dyskinesia

“…5,8,9 Of note, PRRT2 gene mutations have also been identified in other paroxysmal disorders such as benign familial infantile seizures (BFIS), paroxysmal nonkinesigenic dyskinesia, paroxysmal exercise-induced dyskinesia, hemiplegic migraine, paroxysmal torticollis, episodic ataxia, childhood absence epilepsy, and febrile seizures. 18 Considering the remarkable pleiotropy of the PRRT2 gene with the still-expanding clinical spectrum and the limited researches into the genotype-phenotype analysis of PKD, [19][20][21][22] we analyzed the clinical manifestations and genetic features of our patients with PKD and conducted the genotype-phenotype correlation analysis. 18 Considering the remarkable pleiotropy of the PRRT2 gene with the still-expanding clinical spectrum and the limited researches into the genotype-phenotype analysis of PKD, [19][20][21][22] we analyzed the clinical manifestations and genetic features of our patients with PKD and conducted the genotype-phenotype correlation analysis.…”

Child Neurology: PRRT2 -associated movement disorders and differential diagnoses

“…Often, a dramatic improvement is seen with anticonvulsant treatment (sodium channel blockers) (particularly in PRRT2 mutation carriers 8 ), making this a possible way to confirm the diagnosis. 3 The overall prognosis of PKD is good as the frequency of attacks tends to decline with age and spontaneous remission occurs in a subset of patients.…”