Gene Of Paroxysmal Kinesigenic Dyskinesia Research Articles

Effects of PRRT2 mutation on brain gray matter networks in paroxysmal kinesigenic dyskinesia.

Although proline-rich transmembrane protein 2 is the primary causative gene of paroxysmal kinesigenic dyskinesia, its effects on the brain structure of paroxysmal kinesigenic dyskinesia patients are not yet clear. Here, we explored the influence of proline-rich transmembrane protein 2 mutations on similarity-based gray matter morphological networks in individuals with paroxysmal kinesigenic dyskinesia. A total of 51 paroxysmal kinesigenic dyskinesia patients possessing proline-rich transmembrane protein 2 mutations, 55 paroxysmal kinesigenic dyskinesia patients possessing proline-rich transmembrane protein 2 non-mutation, and 80 healthy controls participated in the study. We analyzed the structural connectome characteristics across groups by graph theory approaches. Relative to paroxysmal kinesigenic dyskinesia patients possessing proline-rich transmembrane protein 2 non-mutation and healthy controls, paroxysmal kinesigenic dyskinesia patients possessing proline-rich transmembrane protein 2 mutations exhibited a notable increase in characteristic path length and a reduction in both global and local efficiency. Relative to healthy controls, both patient groups showed reduced nodal metrics in right postcentral gyrus, right angular, and bilateral thalamus; Relative to healthy controls and paroxysmal kinesigenic dyskinesia patients possessing proline-rich transmembrane protein 2 non-mutation, paroxysmal kinesigenic dyskinesia patients possessing proline-rich transmembrane protein 2 mutations showed almost all reduced nodal centralities and structural connections in cortico-basal ganglia-thalamo-cortical circuit including bilateral supplementary motor area, bilateral pallidum, and right caudate nucleus. Finally, we used support vector machine by gray matter network matrices to classify paroxysmal kinesigenic dyskinesia patients possessing proline-rich transmembrane protein 2 mutations and paroxysmal kinesigenic dyskinesia patients possessing proline-rich transmembrane protein 2 non-mutation, achieving an accuracy of 73%. These results show that proline-rich transmembrane protein 2 related gray matter network deficits may contribute to paroxysmal kinesigenic dyskinesia, offering new insights into its pathophysiological mechanisms.

Cerebellum Dysfunction in Patients With PRRT2-Related Paroxysmal Dyskinesia.

The main culprit gene for paroxysmal kinesigenic dyskinesia, characterized by brief and recurrent attacks of involuntary movements, is PRRT2. The location of the primary dysfunction associated with paroxysmal dyskinesia remains a matter of debate and may vary depending on the etiology. While striatal dysfunction has often been implicated in these patients, evidence from preclinical models indicates that the cerebellum could also play a role. We aimed to investigate the role of the cerebellum in the pathogenesis of PRRT2-related dyskinesia in humans. We enrolled 22 consecutive right-handed patients with paroxysmal kinesigenic dyskinesia with a pathogenic variant of PRRT2 and their matched controls. Participants underwent a multimodal neuroimaging protocol. We recorded anatomic and diffusion-weighted MRI, as well as resting-state fMRI, during which we tested the aftereffects of sham and repetitive transcranial magnetic stimulation applied to the cerebellum on endogenous brain activity. We quantified the structural integrity of gray matter using voxel-based morphometry, the structural integrity of white matter using fixel-based analysis, and the strength and direction of functional cerebellar connections using spectral dynamic causal modeling. Patients with PRRT2 had decreased gray matter volume in the cerebellar lobule VI and in the medial prefrontal cortex, microstructural alterations of white matter in the cerebellum and along the tracts connecting the cerebellum to the striatum and the cortical motor areas, and dysfunction of cerebellar motor pathways to the striatum and the cortical motor areas, as well as abnormal communication between the associative cerebellum (Crus I) and the medial prefrontal cortex. Cerebellar stimulation modulated communication within the motor and associative cerebellar networks and tended to restore this communication to the level observed in healthy controls. Patients with PRRT2-related dyskinesia have converging structural alterations of the motor cerebellum and related pathways with a dysfunction of cerebellar output toward the cerebello-thalamo-striato-cortical network. We hypothesize that abnormal cerebellar output is the primary dysfunction in patients with a PRRT2 pathogenic variant, resulting in striatal dysregulation and paroxysmal dyskinesia. More broadly, striatal dysfunction in paroxysmal dyskinesia might be secondary to aberrant cerebellar output transmitted by thalamic relays in certain disorders. ClinicalTrials.gov identifier: NCT03481491.

TMEM151A Variants Cause Paroxysmal Kinesigenic Dyskinesia: A Large-Sample Study.

Paroxysmal kinesigenic dyskinesia (PKD) is the most common type of paroxysmal dyskinesias. Only one-third of PKD patients are attributed to proline-rich transmembrane protein 2 (PRRT2) mutations. We aimed to explore the potential causative gene for PKD. A cohort of 196 PRRT2-negative PKD probands were enrolled for whole-exome sequencing (WES). Gene Ranking, Identification and Prediction Tool, a method of case-control analysis, was applied to identify the candidate genes. Another 325 PRRT2-negative PKD probands were subsequently screened with Sanger sequencing. Transmembrane Protein 151 (TMEM151A) variants were mainly clustered in PKD patients compared with the control groups. 24 heterozygous variants were detected in 25 of 521 probands (frequency=4.80%), including 18 missense and 6 nonsense mutations. In 29 patients with TMEM151A variants, the ratio of male to female was 2.63:1 and the mean age of onset was 12.93 ± 3.15 years. Compared with PRRT2 mutation carriers, TMEM151A-related PKD were more common in sporadic PKD patients with pure phenotype. There was no significant difference in types of attack and treatment outcome between TMEM151A-positive and PRRT2-positive groups. We consolidated mutations in TMEM151A causing PKD with the aid of case-control analysis of a large-scale WES data, which broadens the genotypic spectrum of PKD. TMEM151A-related PKD were more common in sporadic cases and tended to present as pure phenotype with a late onset. Extensive functional studies are needed to enhance our understanding of the pathogenesis of TMEM151A-related PKD. © 2021 International Parkinson and Movement Disorder Society.

Cerebellar spreading depolarization mediates paroxysmal movement disorder.

Paroxysmal kinesigenic dyskinesia (PKD) is the most common paroxysmal dyskinesia, characterized by recurrent episodes of involuntary movements provoked by sudden changes in movement. Proline-rich transmembrane protein 2 (PRRT2) has been identified as the major causative gene for PKD. Here, we report that PRRT2 deficiency facilitates the induction of cerebellar spreading depolarization (SD) and inhibition of cerebellar SD prevents the occurrence of dyskinetic movements. Using Ca2+ imaging, we show that cerebellar SD depolarizes a large population of cerebellar granule cells and Purkinje cells in Prrt2-deficient mice. Electrophysiological recordings further reveal that cerebellar SD blocks Purkinje cell spiking and disturbs neuronal firing of the deep cerebellar nuclei (DCN). The resultant aberrant firing patterns in DCN are tightly, temporally coupled to dyskinetic episodes in Prrt2-deficient mice. Cumulatively, our findings uncover a pivotal role of cerebellar SD in paroxysmal dyskinesia, providing a potent target for treating PRRT2-related paroxysmal disorders.

Novel mutation of the PRRT2 gene in two cases of paroxysmal kinesigenic dyskinesia: Two case reports.

Paroxysmal kinesigenic dyskinesia (PKD) is a rare condition characterized by recurrent brief episodes of dystonia, chorea, athetosis or any combination of these, without alterations of consciousness. The proline-rich transmembrane protein 2 (PRRT2) gene has been widely investigated as a causative gene of PKD. To date, a cluster of pathogenic variants associated with PKD have been identified in the PRRT2 gene. In the present case report, two Chinese patients with sporadic PKD are discussed. Genetic analysis revealed a de novo heterozygous missense mutation, c.955G>T (p.Val319Leu) in exon 3 of the PRRT2 gene. Compared with the commonly reported clinical manifestation of PRRT2-associated PKD, the patients in this report showed several primary distinctive features. The mutations identified in the present analysis expand upon the mutation spectrum of the PRRT2 gene, and this newly found variant further reinforces the importance of the PRR2 gene in PKD.

Familial paroxysmal kinesigenic dyskinesia is associated with mutations in the KCNA1 gene.

Paroxysmal kinesigenic dyskinesia (PKD) is a heterogeneous movement disorder characterized by recurrent dyskinesia attacks triggered by sudden movement. PRRT2 has been identified as the first causative gene of PKD. However, it is only responsible for approximately half of affected individuals, indicating that other loci are most likely involved in the etiology of this disorder. To explore the underlying causative gene of PRRT2-negative PKD, we used a combination strategy including linkage analysis, whole-exome sequencing and copy number variations analysis to detect the genetic variants within a family with PKD. We identified a linkage locus on chromosome 12 (12p13.32-12p12.3) and detected a novel heterozygous mutation c.956 T>G (p.319 L>R) in the potassium voltage-gated channel subfamily A member 1, KCNA1. Whole-exome sequencing in another 58 Chinese patients with PKD who lacked mutations in PRRT2 revealed another novel mutation in the KCNA1 gene [c.765 C>A (p.255 N>K)] within another family. Biochemical analysis revealed that the L319R mutant accelerated protein degradation via the proteasome pathway and disrupted membrane expression of the Kv1.1 channel. Electrophysiological examinations in transfected HEK293 cells showed that both the L319R and N255K mutants resulted in reduced potassium currents and respective altered gating properties, with a dominant negative effect on the Kv1.1 wild-type channel. Our study suggests that these mutations in KCNA1 cause the Kv1.1 channel dysfunction, which leads to familial PKD. The current study further extended the genotypic spectrum of this disorder, indicating that Kv1.1 channel dysfunction maybe one of the underlying defects in PKD.

Familial paroxysmal kinesigenic dyskinesia is associated with mutations in the KCNA1 gene.

Paroxysmal kinesigenic dyskinesia (PKD) is a heterogeneous movement disorder characterized by recurrent dyskinesia attacks triggered by sudden movement. PRRT2 has been identified as the first causative gene of PKD. However, it is only responsible for approximately half of affected individuals, indicating that other loci are most likely involved in the etiology of this disorder. To explore the underlying causative gene of PRRT2-negative PKD, we used a combination strategy including linkage analysis, whole-exome sequencing and copy number variations analysis to detect the genetic variants within a family with PKD. We identified a linkage locus on chromosome 12 (12p13.32-12p12.3) and detected a novel heterozygous mutation c.956 T>G (p.319 L>R) in the potassium voltage-gated channel subfamily A member 1, KCNA1. Whole-exome sequencing in another 58 Chinese patients with PKD who lacked mutations in PRRT2 revealed another novel mutation in the KCNA1 gene [c.765 C>A (p.255 N>K)] within another family. Biochemical analysis revealed that the L319R mutant accelerated protein degradation via the proteasome pathway and disrupted membrane expression of the Kv1.1 channel. Electrophysiological examinations in transfected HEK293 cells showed that both the L319R and N255K mutants resulted in reduced potassium currents and respective altered gating properties, with a dominant negative effect on the Kv1.1 wild-type channel. Our study suggests that these mutations in KCNA1 cause the Kv1.1 channel dysfunction, which leads to familial PKD. The current study further extended the genotypic spectrum of this disorder, indicating that Kv1.1 channel dysfunction maybe one of the underlying defects in PKD.

Aberrant transcriptional networks in step-wise neurogenesis of paroxysmal kinesigenic dyskinesia-induced pluripotent stem cells.

Paroxysmal kinesigenic dyskinesia (PKD) is an episodic movement disorder with autosomal-dominant inheritance and marked variability in clinical manifestations.Proline-rich transmembrane protein 2 (PRRT2) has been identified as a causative gene of PKD, but the molecular mechanism underlying the pathogenesis of PKD still remains a mystery. The phenotypes and transcriptional patterns of the PKD disease need further clarification. Here, we report the generation and neural differentiation of iPSC lines from two familial PKD patients with c.487C>T (p. Gln163X) and c.573dupT (p. Gly192Trpfs*8) PRRT2 mutations, respectively. Notably, an extremely lower efficiency in neural conversion from PKD-iPSCs than control-iPSCs is observed by a step-wise neural differentiation method of dual inhibition of SMAD signaling. Moreover, we show the high expression level of PRRT2 throughout the human brain and the expression pattern of PRRT2 in other human tissues for the first time. To gain molecular insight into the development of the disease, we conduct global gene expression profiling of PKD cells at four different stages of neural induction and identify altered gene expression patterns, which peculiarly reflect dysregulated neural transcriptome signatures and a differentiation tendency to mesodermal development, in comparison to control-iPSCs. Additionally, functional and signaling pathway analyses indicate significantly different cell fate determination between PKD-iPSCs and control-iPSCs. Together, the establishment of PKD-specific in vitro models and the illustration of transcriptome features in PKD cells would certainly help us with better understanding of the defects in neural conversion as well as further investigations in the pathogenesis of the PKD disease.

Analysis of catechol-O-methyltransferase gene mutation and identification of new pathogenic gene for paroxysmal kinesigenic dyskinesia

We aimed to analyze the mutation site and frequency of catechol-O-methyltransferase (COMT) gene, to explore the relationship between COMT genotype and phenotype, and to find new pathogenic genes for paroxysmal kinesigenic dyskinesia (PKD). PKD patients who were treated from December 2011 to January 2014 were selected and subjected to genetic testing in the exon region of COMT. Two patients and one intrafamilial healthy control were subjected to exome sequencing using whole exome capture in combination with high-throughput sequencing to find candidate pathogenic gene sites. The results were verified by Sanger sequencing. A total of 11 familial PKD patients from 4 families and 9 sporadic patients without family history were included. Pathogenic c.634dupC(p.P220fsX7) mutation of COMT gene was found in 7 familial PKD patients and3 sporadic patients. Mutated COMT gene carriers suffered from PKD earlier (average age of onset: 11.61 ± 2.33 vs 16.21 ± 2.58, P = 0.001) with symmetric symptoms in most cases, while the mutation-negative group only showed unilateral symptoms (P = 0.001). The mutation-positive group also had more daily attacks (P = 0.038). Carbamazepine worked for all mutation-positive patients (10/10, 100%), but only for a part of mutation-negative patients (3/10, 30.0%). About 90000 single nucleotide polymorphisms and 2000 insertion-deletion polymorphisms were detected in each of the three samples. c.737C → T(p.T246 M) mutation of POC1B gene was a new pathogenic site for a selected family. COMT gene mutation, which was the pathogenesis of most familial PKD patients and a part of sporadic patients, predicted the response to carbamazepine. POC1B may be a novel pathogenic gene for PKD.

Five cases of paroxysmal kinesigenic dyskinesia by genetic diagnosis.

Paroxysmal kinesigenic dyskinesia (PKD) is an autosomal dominant disorder and PRRT2 is the causative gene of PKD. The aim of this study was to investigate PRRT2 mutations in patients who were clinically diagnosed with PKD. Nine PKD cases, including four familial cases and five sporadic cases, were selected. Peripheral blood was drawn after obtaining informed consent, and genomic DNA was extracted by a standard protocol. Sanger sequencing was performed for the screening of PRRT2 mutations. A total of five cases were detected to harbor PRRT2 mutations. Four familial cases carried a c.649dupC (p.Arg217Profs*8) mutation, while one sporadic case and his asymptomatic father carried a c.133-136delCCAG (p.Pro45Argfs*44) mutation. PRRT2 mutations were not identified in the remaining cases. The study further confirmed that PRRT2 was a causative gene of PKD and implied that PRRT2 mutation has incomplete penetrance.

PRRT2 truncated mutations lead to nonsense-mediated mRNA decay in Paroxysmal Kinesigenic Dyskinesia.

Paroxysmal Kinesigenic Dyskinesia (PKD) is an episodic involuntary movement disorder characterized by recurrent and brief involuntary movements. Proline-rich transmembrane protein 2 (PRRT2) has been identified as the causative gene for PKD, Benign familial infantile convulsions (BFIC) and Infantile convulsions with choreoathetosis (ICCA). As well, PRRT2 mutations have been detected in patients with PED or PNKD. To date, most of the mutations have been found to be nonsense. We used inhibitors of nonsense-mediated mRNA decay (NMD) pathway --emetine dihydrochloride hydrate and cycloheximide and silencing regulator of nonsense transcripts 1(UPF1) with immortalized lymphoblasts to detect whether the truncated mutations lead to NMD, a type of mRNA surveillance in every eukaryotic cell proved so far and that generally degrades mRNA containing premature translation termination codons (PTCs). In addition, we transfected the SH-SY5Y cells with wild-type and mutant PRRT2 plasmids to identify the PRRT2 protein's subcellular localization. We detected, low expression of truncated PRRT2 and was further rescued by applying the inhibitor of NMD pathway, suggesting that NMD plays an important role in the pathogenesis of PKD by haplo-insufficiency. Moreover, for the small portion of undegraded mutant PRRT2 that was translated into truncated proteins, their cellular localization changed from membrane to cytoplasm and nuclear, which might lead to a functional loss. We suggest that the NMD of truncated mutation of PRRT2 and altered cellular localization of undegraded of PRRT2, might lead to PKD.

Mutation analysis of PRRT2 in two Chinese BFIS families and nomenclature of PRRT2 related paroxysmal diseases

Benign familial infantile seizure (BFIS) and paroxysmal kinesigenic dyskinesia (PKD) are autosomal-dominant inherited self-limited neurological disorders. BFIS is characterized by clusters of epileptic seizures in infancy while, in some cases, infantile seizures and adolescent-onset paroxysmal kinesigenic choreoathetosis co-occurred, which is called infantile convulsions and choreoathetosis (ICCA) syndrome. We and other researchers have reported the proline-rich transmembrane protein 2 (PRRT2) as the causative gene of PKD. We and our collaborators also identified PRRT2 mutations in ICCA and other phenotypes. Here we collected two BFIS families of Chinese Han origin. The linkage analysis has mapped the BFIS-causing locus to 16p12.1–q12.2, where PRRT2 is located. We then performed mutation analysis of PRRT2 by direct sequencing and identified c.649–650insC mutation in all BFIS patients. We also noticed that paroxysmal diseases (such as BFIS, PKD and ICCA) with PRRT2 mutations, instead of other forms, share some characteristics like being responded well to anti-epiletic treatment, we thus suggest to name them as PRRT2-related paroxysmal diseases (PRPDs) in order to assist clinical diagnosis and treatment.

Progress in the research of genetics and clinical manifestation of paroxysmal kinesigenic dyskinesia

Paroxysmal kinesigenic dyskinesia (PKD) is a disorder characterized by recurrent and brief attacks that are induced by sudden voluntary movement with highly clinical and genetic heterogeneity. Familial PKD are mostly autosomal dominant inherited and proline-rich transmembrare protein 2 ( PRRT2 ) gene has been identified as the causative gene for PKD. So far 56 mutations have been documented and most of them are nonsense ones. No obvious genotype-phenotype correlation has been observed and the function of PRRT2 is still unclear, but the interaction between PRRT2 and synaptosomal-associated protein 25 (SNAP25) will shed the light on the research of PKD mechanism.

Altered intrinsic brain activity in patients with paroxysmal kinesigenic dyskinesia by PRRT2 mutation

The proline-rich transmembrane protein 2 (PRRT2) gene has been recently identified as a causative gene of paroxysmal kinesigenic dyskinesia (PKD), with an insertion mutation c.649_650insC (p.P217fsX7) reported as the most common mutation. However, the pathogenic mechanism of the mutation of PRRT2 remains largely unknown. Resting-state functional magnetic resonance imaging is a promising approach to assess cerebral function and reveals underlying functional changes. Resting-state functional magnetic resonance imaging was performed in 4 Chinese PKD patients with p.P217fsX7 mutation, 6 Chinese PKD patients without the mutation, and 10 healthy control subjects. Voxel-based analysis was used to characterize alterations in the amplitude of low-frequency fluctuation (ALFF). When compared with the healthy control subjects, both groups of PKD patients showed alterations in spontaneous brain activities within cortical-basal ganglia circuitry. Besides, the group of patients with p.P217fsX7 mutation also exhibited increased ALFF in the right postcenral gyrus and right rolandic operculum area, while the alteration of ALFF in group of patients without the mutation additionally involved the middle orbitofrontal cortex. Direct comparative analysis between these two patient groups revealed significantly increased ALFF in the right postcentral gyrus in the group with p.P217fsX7 mutation. Increased spontaneous brain activity in the cortical-basal ganglia circuitry, especially in the motor preparation areas, is a common pathophysiology in PKD. Differences in the spatial patterns of increased ALFF between patients with and those without the mutation might reflect the distinct pathological mechanism resulting from PRRT2 mutation.

PRRT2 mutation screening in patients with paroxysmal kinesigenic dyskinesia from Southwest China

Proline-rich transmembrane protein 2 (PRRT2) has recently been identified as a causative gene of paroxysmal kinesigenic dyskinesia (PKD). However, the frequencies of its mutations and their correlation with the clinical features of PKD remain largely unknown. Four exons of PRRT2 in 33 patients with PKD from Southwest China were screened by direct sequencing in this study. The mean onset age of the patients was 12.50 ± 2.70 years. Sixteen patients (48.48%) had sensory aura before their attacks. In total, 66.67% of the patients were running when the attacks occurred. c.649_650insC (p.P217fsX7), the most commonly reported insertion mutation, was identified in nine patients (27.27%). Other genes are involved in the development of PKD, but PRRT2 is a common causative gene for patients with PKD from Southwest China.

PRRT2 c.649dupC Mutation Derived from De Novo in Paroxysmal Kinesigenic Dyskinesia

PRRT2 was recently identified as a causative gene for paroxysmal kinesigenic dyskinesia (PKD), and the c.649dupC mutation was shown to be a "high frequency" mutation. This mutation was also identified in many sporadic cases. This might be attributed to the incomplete penetrance of c.649dupC. Alternatively, c.649dupC might derive from de novo. The aim of this study is to elucidate the possibility concerning de novo mutagenesis of PRRT2 mutations in PKD. Nine sporadic Chinese PKD patients including one Mongolian patient were recruited. Direct sequencing of PRRT2 was performed in them and their parents. Haplotype analysis was conducted to confirm the biological relationship. A novel mutation, c.133_136delCCAG, was identified in one Han patient and his unaffected mother. The c.649dupC mutation was detected in another Han patient and his unaffected father. To our interest, c.649dupC was detected in the Mongolian patient but not in his parents. Haplotype analysis confirmed the biological relationship among the trio. No mutations were identified in the remaining six patients. These findings demonstrate the heterogeneity of PKD, and the de novo mutagenesis of PRRT2 gene might indicate the genetic instability of this region.

PRRT2 mutation causes paroxysmal kinesigenic dyskinesia and hemiplegic migraine in monozygotic twins

PRRT2 gene mutations have recently been identified as a causative gene of Paroxysmal kinesigenic dyskinesia (PKD), a rare movement disorder characterised by the occurrence of chorea, dystonia or athetosis triggered by sudden action. Some patients have additional intermittent neurologic disorders like infantile convulsions. The association with migraine has been rarely reported in this condition. Here we report the coexistence of PKD and hemiplegic migraine in twins harbouring a heterozygous mutation in PRRT2.Two monozygotic twins manifesting PKD together with repeated episodes of migraine with some severe attacks of hemiplegic migraine have been followed and treated for more than 10 years.Molecular genetic analysis disclosed the c.649_650insC, p.R217Pfs*8 heterozygous mutation in both twins. This mutation was segregating from the mother who likewise harboured the same mutation c.649dupC although she had never manifested PKD but complained of rare common migraine attacks in her past history.The association of PKD and hemiplegic migraine has been previously reported in one large family, associated to febrile convulsions and afebrile seizures in some individuals, but our report relates this association of symptoms to a mutation in PRRT2. The co-occurrence of both hemiplegic migraine and PKD in monozygotic twins expands the phenotypic spectrum of intermittent manifestations related to PRRT2 and perhaps suggests an additional causing gene for hemiplegic migraine.

Identification of PRRT2 as the causative gene of paroxysmal kinesigenic dyskinesia

Identification of PRRT2 as the causative gene of paroxysmal kinesigenic dyskinesia