PRRT2 Mutation and Serum Cytokines in Paroxysmal Kinesigenic Dyskinesia

Objective Paroxysmal kinesigenic dyskinesia(PKD)is a rare movement disorder PRRT2 gene mutations have been reported to cause PKD.However,the pathophysiological mechanism of PKD remains unclear,and it is unknown whether an inflammatory response is involved in the occurrence of this disease.We aimed to investigate the symptomatology,genotype,and serum cytokines of patients with PKD.Methods We recruited 21 patients with PKD,including 7 with familial PKD and 14 with sporadic PKD.Their clinical features were investigated,and blood samples were collected,and PRRT2 mutations and cytokine levels were detected.Results The mean age at PKD onset was 12.3±2.2 years old.Dystonia was the most common manifestation of dyskinesia,and the limbs were the most commonly affected parts.All attacks were induced by identifiable kinesigenic triggers,and the attack durations were brief(<1 min).Four different mutations from 9 probands were identified in 7 familial cases(71.4%)and 14 sporadic cases(28.6%).Two of these mutations(c.649dupC,c.620_621delAA)had already been reported,while other 2(c.1018_1019delAA,c.1012+1G>A)were previously undocumented.The tumor necrosis factor(TNF)-αlevel in the PKD group was significantly higher than that in the age-and sex-matched control group(P=0.025).There were no significant differences in the interleukin(IL)-1β,IL-2R,IL-6,IL-8,or IL-10 levels between the two groups.Conclusion In this study,we summarized the clinical and genetic characteristics of PKD.We found that the serum TNF-αlevels were elevated in patients clinically diagnosed with PKD,suggesting that an inflammatory response is involved in the pathogenesis of PKD.

Paroxysmal kinesigenic dyskinesia presenting with transient involuntary twitching movements involving right leg in a 24-year-old man responding well to topiramate

Paroxysmal kinesigenic dyskinesia(PKD)is presented as a short paroxysmal attack of focal or generalized involuntary movement.The most common treatments for PKD are carbamazepine and phenytoin.Though the cases of clinically diagnosed PKD with a good response to topiramate have been already reported,this patient was unique in several ways.Here,we reported the case of a 24-year-old patient with PKD for one year,and described the pathogenesis of PKD.

Mutation Analysis of MR-1, SLC2A 1, and CLCN1 in 28 PRRT2-negative Paroxysmal Kinesigenic Dyskinesia Patients

Background： Paroxysmal kinesigenic dyskinesia （PKD） is the most common subtype of paroxysmal dyskinesias and is caused by mutations in PRRT2 gene. The majority of familial PKD was identified to harbor PRRT2 mutations. However, over two-third of sporadic PKD patients did not carry anyPRRT2 mutation, suggesting an existence of additional genetic mutations or possible misdiagnosis due to clinical overlap. Methods： A cohort of 28 Chinese patients clinically diagnosed with sporadic PKD and excluded PRRT2 mutations were recruited, Clinical features were evaluated, and all subjects were screened for MR-l, SLC2A1, and CLCN1 genes, which are the causative genes of paroxysmal nonkinesigenic dyskinesia （PNKD）, paroxysmal exertion-induced dyskinesia, and myotonia congenita （MC）, respectively, In addition, 200 genetically matched healthy individuals were recruited as controls. Results： A total of 16 genetic variants including 4 in MR-1 gene, 8 in SLC2A1 gene, and 4 in CLCN1 gene were detected. Among them, SLC2A1 c.363G〉A mutation was detected in one case, and CLCN1 c. 1205C〉T mutation was detected in other two cases. Neither of them was found in 200 controls as well as 1000 Genomes database and ExAC database. Both mutations were predicted to be pathogenic by SIFT and PolyPhen2. The SLC2A 1 c.363G〉A mutation was novel. Conclusions： The phenotypic overlap may lead to the difficulty in distinguishing PKD from PNKD and MC. For those PRRT2-negative PKD cases, screening of SLC2A1 and CLCN1 genes are useful in confirming the diagnosis.

Paroxysmal kinesigenic dyskinesia and myotonia congenita in the same family:coexistence of a PRRT2 mutation and two CLCN1 mutations

Paroxysmal kinesigenic dyskinesia（PKD） and myotonia congenita（MC） are independent disorders that share some clinical features. We aimed to investigate the sequences of PRRT2 and CLCN1 in a proband diagnosed with PKD and suspected MC. Clinical evaluation and auxiliary examinations were performed. Direct sequencing of the entire coding regions of the PRRT2 and CLCN1 genes was conducted. Haplotype analysis confirmed the relationships among the family members. The proband suffered choreoathetosis attacks triggered by sudden movements, and lower-limb weakness a n d s t i ff n e s s t h a t w o r s e n e d i n c o l d w e a t h e r. Carbamazepine monotherapy completely controlled his choreoathetosis and significantly relieved his limb weakness and stiffness. His father, when young, had similar limb stiffness, while his mother and brother were asymptomatic. Genetic analysis revealed that the proband and his father harbored a PRRT2 c.649 dup C mutation, and CLCN1 c.1723C〉T and c.2492A〉G mutations. His brother carried only the two CLCN1 mutations. None of these mutations were identified in his mother and 150 unrelated controls. This is the first report showing the coexistence ofPRRT2 and CLCN1 mutations. Our results also indicate that both the PRRT2 and CLCN1 genes need to be screened if we fail to identify PRRT2 mutations in PKD patients or CLCN1 mutations in MC patients.

Somatosensory disinhibition in patients with paroxysmal kinesigenic dyskinesia

Background Paroxysmal kinesigenic dyskinesia （PKD） is characterized by recurrent brief episodes of chorea and dystonia induced by sudden movement. Whether the central nervous system is hyper- or hypoexcitable in PKD remains undetermined. The aim of our study was to compare the somatosensory evoked potential （SEP） recovery cycle, a marker of somatosensory system excitability, in PKD patients and controls.

Penetrance estimation of PRRT2 variants in paroxysmal kinesigenic dyskinesia and infantile convulsions

Proline-rich transmembrane protein 2(PRRT2)is the leading cause of paroxysmal kinesigenic dyskinesia(PKD),benign familial infantile epilepsy(BFIE),and infantile convulsions with choreoathetosis(ICCA).Reduced penetrance of PRRT2 has been observed in previous studies,whereas the exact penetrance has not been evaluated well.The objective of this study was to estimate the penetrance of PRRT2 and determine its influencing factors.We screened 222 PKD index patients and their available relatives,identified 39 families with pathogenic or likely pathogenic(P/LP)PRRT2 variants via Sanger sequencing,and obtained 184 PKD/BFIE/ICCA families with P/LP PRRT2 variants from the literature.Penetrance was estimated as the proportion of affected variant carriers.PRRT2 penetrance estimate was 77.6%(95%confidence interval(CI)74.5%–80.7%)in relatives and 74.5%(95%CI 70.2%–78.8%)in obligate carriers.In addition,we first observed that penetrance was higher in truncated than in non-truncated variants(75.8%versus 50.0%,P=0.01),higher in Asian than in Caucasian carriers(81.5%versus 68.5%,P=0.004),and exhibited no difference in gender or parental transmission.Our results are meaningful for genetic counseling,implying that approximately three-quarters of PRRT2 variant carriers will develop PRRT2-related disorders,with patients from Asia or carrying truncated variants at a higher risk.

Clinical Analysis of Nine Cases of Paroxysmal Exercise-induced Dystonia

This study was aimed to analyze the clinical features of paroxysmal kinesigenic dyskinesia (PKD) and extend the understanding of this disease. From August, 2008 to October, 2010, 9 patients were diagnosed with PKD in the Department of Neurology of the First Affiliated Hospital of Zhejiang University, China. The data involving clinical demographic characteristics, somatosensory evoked potentials, results of electromyography, video electroencephalography (EEG), brain magnetic resonance imaging (MRI) and computerized tomography (CT) were collected. All PKD patients exhibited unilat-eral or bilateral recurrent episodic dyskinetic attacks triggered by sudden voluntary movements. The duration of the attacks ranged from several seconds to one minute. The attack frequency ranged from approximately once in several months to more than 10 times in a day. Patients suffered from no conscious disorders during the attack, and no neurological signs were found during the period between attacks. No abnormal somatosensory evoked potentials were found. Routine EEG, video EEG monitoring or brain imaging showed normal findings. Classical treatment for anti-epilepsy, including car-bamazepine and topiramate, was administered to the patients and proved to be effective. It was concluded that PKD is characteristically triggered by sudden voluntary movement; no abnormal elec-troneurophysiological findings are observed in PKD, and antiepileptic drugs are effective in treating the disorder.

Recommendations for the diagnosis and treatment of paroxysmal kinesigemc dyskinesia: an expert consensus in China

Paroxysmal dyskinesias are a group of neurological diseases characterized by intermittent episodes of involuntary movements with different causes.Paroxysmal kinesigenic dyskinesia(PKD)is the most common type of paroxysmal dyskinesia and can be divided into primary and secondary types based on the etiology.Clinically,PKD is characterized by recurrent and transient attacks of involuntary movements precipitated by a sudden voluntary action.The major cause of primary PKD is genetic abnormalities,and the inheritance pattern of PKD is mainly autosomal-dominant with incomplete penetrance.The proline-rich transmembrane protein 2(PRRT2)was the first identified causative gene of PKD,accounting for the majority of PKD cases worldwide.An increasing number of studies has revealed the clinical and genetic characteristics,as well as the underlying mechanisms of PKD.By seeking the views of domestic experts,we propose an expert consensus regarding the diagnosis and treatment of PKD to help establish standardized clinical evaluation and therapies for PKD.In this consensus,we review the clinical manifestations,etiology,clinical diagnostic criteria and therapeutic recommendations for PKD,and results of genetic analyses in PKD patients performed in domestic hospitals.

Characteristics of infantile convulsions and choreoathetosis syndrome caused by PRRT2 mutation

Importance:Infantile convulsions and choreoathetosis(ICCA)is a rare neurological disorder.Many affected patients are either misdiagnosed or prescribed multiple antiepileptic drugs.Objective:To explore therapeutic drug treatments and dosages for ICCA in children.Methods:Detailed clinical features(e.g.,past medical history and family history),genetic features,and treatment outcomes were collected from the records of six patients with ICCA.Results:Mean age at paroxysmal kinesigenic dyskinesia(PKD)onset was 8 years 8 months(range,3-12 years);the clinical presentation was characterized by daily short paroxysmal episodes of dystonia/dyskinesia.All patients had infantile convulsions at less than 1 year of age,and the mean onset age was 5.5 months(range,4-7 months).Two patients had a family history of ICCA,PKD,or benign familial infantile epilepsy.Whole exome sequencing identified the c.649-650insC mutation in PRRT2 in six patients;three mutations were inherited and three were de novo.All patients were prescribed low-dose carbamazepine and showed dramatic improvement with the complete disappearance of dyskinetic episodes after 3 days.They attended follow-up for 5-17 months and were attack-free until the final follow-up.Interpretation:PRRT2 mutations are the primary cause of ICCA.Lowdose carbamazepine monotherapy is effective and well-tolerated in children.