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.

Rare Missense Variants in KCNJ10 Are Associated with Paroxysmal Kinesigenic Dyskinesia.

BACKGROUND: Although the group of paroxysmal kinesigenic dyskinesia (PKD) genes is expanding, the molecular cause remains elusive in more than 50% of cases. OBJECTIVE: The aim is to identify the missing genetic causes of PKD. METHODS: Phenotypic characterization, whole exome sequencing and association test were performed among 53 PKD cases. RESULTS: We identified four causative variants in KCNJ10, already associated with EAST syndrome (epilepsy, cerebellar ataxia, sensorineural hearing impairment and renal tubulopathy). Homozygous p.(Ile209Thr) variant was found in two brothers from a single autosomal recessive PKD family, whereas heterozygous p.(Cys294Tyr) and p.(Thr178Ile) variants were found in six patients from two autosomal dominant PKD families. Heterozygous p.(Arg180His) variant was identified in one additional sporadic PKD case. Compared to the Genome Aggregation Database v2.1.1, our PKD cohort was significantly enriched in both rare heterozygous (odds ratio, 21.6; P = 9.7 × 10-8) and rare homozygous (odds ratio, 2047; P = 1.65 × 10-6) missense variants in KCNJ10. CONCLUSIONS: We demonstrated that both rare monoallelic and biallelic missense variants in KCNJ10 are associated with PKD. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Missense mutations in the membrane domain of PRRT2 affect its interaction with Nav1.2 voltage-gated sodium channels.

PRRT2 is a neuronal protein that controls neuronal excitability and network stability by modulating voltage-gated Na+ channel (Nav). PRRT2 pathogenic variants cause pleiotropic syndromes including epilepsy, paroxysmal kinesigenic dyskinesia and episodic ataxia attributable to loss-of-function pathogenetic mechanism. Based on the evidence that the transmembrane domain of PRRT2 interacts with Nav1.2/1.6, we focused on eight missense mutations located within the domain that show expression and membrane localization similar to the wild-type protein. Molecular dynamics simulations showed that the mutants do not alter the structural stability of the PRRT2 membrane domain and preserve its conformation. Using affinity assays, we found that the A320V and V286M mutants displayed respectively decreased and increased binding to Nav1.2. Accordingly, surface biotinylation showed an increased Nav1.2 surface exposure induced by the A320V mutant. Electrophysiological analysis confirmed the lack of modulation of Nav1.2 biophysical properties by the A320V mutant with a loss-of-function phenotype, while the V286M mutant displayed a gain-of-function with respect to wild-type PRRT2 with a more pronounced left-shift of the inactivation kinetics and delayed recovery from inactivation. The data confirm the key role played by the PRRT2-Nav interaction in the pathogenesis of the PRRT2-linked disorders and suggest an involvement of the A320 and V286 residues in the interaction site. Given the similar clinical phenotype caused by the two mutations, we speculate that circuit instability and paroxysmal manifestations may arise when PRRT2 function is outside the physiological range.

The Pathogenesis of Paroxysmal Kinesigenic Dyskinesia: Current Concepts.

Paroxysmal kinesigenic dyskinesia (PKD) is a movement disorder characterized by recurrent and transient episodes of involuntary movements, including dystonia, chorea, ballism, or a combination of these, which are typically triggered by sudden voluntary movement. Disturbance of the basal ganglia-thalamo-cortical circuit has long been considered the cause of involuntary movements. Impairment of the gating function of the basal ganglia can cause an aberrant output toward the thalamus, which in turn leads to excessive activation of the cerebral cortex. Structural and functional abnormalities in the basal ganglia, thalamus, and cortex and abnormal connections between these brain regions have been found in patients with PKD. Recent studies have highlighted the role of the cerebellum in PKD. Insufficient suppression from the cerebellar cortex to the deep cerebellar nuclei could lead to overexcitation of the thalamocortical pathway. Therefore, this literature review aims to provide a comprehensive overview of the current research progress to explore the neural circuits and pathogenesis of PKD and promote further understanding and outlook on the pathophysiological mechanism of movement disorders. © 2023 International Parkinson and Movement Disorder Society.

Novel missense variant in the TMEM151A gene causing paroxysmal kinesigenic dyskinesia: a case report with literature review.

BACKGROUND: Paroxysmal kinesigenic dyskinesia (PKD) is a rare movement disorder with high clinical and genetic heterogeneity. Proline-rich transmembrane protein 2 (PRRT2) was identified as the first causative gene for PKD in 2011. Recently, heterozygous variants in transmembrane protein 151A (TMEM151A) were identified as another pathogenic cause of PKD. CASE DESCRIPTION: A 16-year-old man diagnosed with PKD exhibited hemidystonia triggered by sudden voluntary movements. His mother also had similar symptoms since the age of 20. Whole-exome sequencing revealed a likely pathogenic missense variant (c.892 T > C) in the TMEM151A gene. At the same time, we reviewed the literature focusing on the molecular characteristics and the clinical phenotypes in patients with TMEM151A variants, especially within the same family. CONCLUSION: This case further validated the pathogenic role of TMEM151A variants in PKD. The findings of interfamilial and intrafamilial variability in the phenotypes expanded our understanding of TMEM151A-related PKD.

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

BACKGROUND: 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. OBJECTIVE: We aimed to explore the potential causative gene for PKD. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Features Differ Between Paroxysmal Kinesigenic Dyskinesia Patients with PRRT2 and TMEM151A Variants.

BACKGROUND: Mutations in proline-rich transmembrane protein 2 (PRRT2) are the major cause of paroxysmal kinesigenic dyskinesia (PKD). We recently reported transmembrane protein 151A (TMEM151A) mutations caused PKD. Herein, we aimed to conduct phenotypic comparisons of patients with PKD carrying PRRT2 variants, carrying TMEM151A variants, and carrying neither the PRRT2 nor TMEM151A variant. METHODS: Sanger sequencing of PRRT2 and TMEM151A was performed, and phenotypic characteristics were analyzed. RESULTS: In a cohort of 131 PKD probands (108 without PRRT2 variants and 23 newly recruited), five novel TMEM151A variants were identified and one (c.647C > A) occurred de novo. Together with our previous studies, PRRT2 and TMEM151A variants accounted for 34.7% (85/245) and 6.9% (17/245) of PKD probands, respectively. Compared with patients carrying PRRT2 variants, those with TMEM151A variants tended to exbibit dystonia with shorter durations, have no history of benign infantile epilepsy, and have residual attacks/aura when treated with carbamazepine/oxcarbazepine. CONCLUSIONS: Patients with TMEM151A variants have different features from patients with PRRT2 variants. © 2022 International Parkinson and Movement Disorder Society.

TMEM151A phenotypic spectrum includes paroxysmal kinesigenic dyskinesia with infantile convulsions.

In a three-generation family, five individuals exhibited the typical phenotype of paroxysmal kinesigenic dyskinesia (PKD). Intriguingly, one of the individuals also showed benign familial infantile convulsions (BFIC) at age 4 months and spontaneously resolved at age 18 months. At age 12, she developed a typical PKD, and was gradually relieved at age 21. Therefore, the clinical phenotype was consistent with PKD with infantile convulsions (PKD/IC). Whole exome sequence and co-segregation analysis revealed a novel heterozygous variant c.1085A > G in the TMEM151A gene. Our study suggests that the TMEM151A gene may be associated with the disease spectrum of PKD-PKD/IC-BFIC.

Disruption of gray matter morphological networks in patients with paroxysmal kinesigenic dyskinesia.

This study explores the topological properties of brain gray matter (GM) networks in patients with paroxysmal kinesigenic dyskinesia (PKD) and asks whether GM network features have potential diagnostic value. We used 3D T1-weighted magnetic resonance imaging and graph theoretical approaches to investigate the topological organization of GM morphological networks in 87 PKD patients and 115 age- and sex-matched healthy controls. We applied a support vector machine to GM morphological network matrices to classify PKD patients versus healthy controls. Compared with the HC group, the GM morphological networks of PKD patients showed significant abnormalities at the global level, including an increase in characteristic path length (Lp) and decreases in local efficiency (Eloc ), clustering coefficient (Cp), normalized clustering coefficient (γ), and small-worldness (σ). The decrease in Cp was significantly correlated with disease duration and age of onset. The GM morphological networks of PKD patients also showed significant changes in nodal topological characteristics, mainly in the basal ganglia-thalamus circuitry, default-mode network and central executive network. Finally, we used the GM morphological network matrices to classify individuals as PKD patients versus healthy controls, achieving 87.8% accuracy. Overall, this study demonstrated disruption of GM morphological networks in PKD, which might extend our understanding of the pathophysiology of PKD; further, GM morphological network matrices might have the potential to serve as network neuroimaging biomarkers for the diagnosis of PKD.

Exercise test for patients with new-onset paroxysmal kinesigenic dyskinesia.

The pathogenesis of primary paroxysmal kinesigenic dyskinesia (PKD) remains unclear, and channelopathy is a possibility. In a pilot study, we found that PKD patients had abnormal exercise test (ET) results. To investigate the ET performances in patients affected by PKD, and the role of the channelopathies in the pathogenesis of PKD, we compared the ET results of PKD patients, control subjects, and hypokalemic periodic paralysis (HoPP) patients, and we analyzed ET changes in 32 PKD patients before and after treatment. Forty-four PKD patients underwent genetic testing for the PRRT2, SCN4A, and CLCN1 genes. Sixteen of 59 (27%) patients had abnormal ET results in the PKD group, while 28 of 35 (80%) patients had abnormal ET results in the HoPP group. Compared with the control group, the PKD group showed a significant decrease in the compound muscle action potential (CMAP) amplitude and area after the long ET (LET), while the HoPP group showed not only greater decreases in the CMAP amplitude and area after the LET but also greater increases in the CMAP amplitude and area immediately after the LET. The ET parameters before and after treatment were not significantly different. Nine of 44 PKD patients carried PRRT2 mutations, but the gene abnormalities were unrelated to any ET parameter. The PKD group demonstrated an abnormal LET result by electromyography (EMG), and this abnormality did not seem to correlate with the PRRT2 variant or sodium channel blocker therapy.

Brain structural connectome in relation to PRRT2 mutations in paroxysmal kinesigenic dyskinesia.

This study explored the topological characteristics of brain white matter structural networks in patients with Paroxysmal Kinesigenic Dyskinesia (PKD), and the potential influence of the brain network stability gene PRRT2 on the structural connectome in PKD. Thirty-five PKD patients with PRRT2 mutations (PKD-M), 43 PKD patients without PRRT2 mutations (PKD-N), and 40 demographically-matched healthy control (HC) subjects underwent diffusion tensor imaging. Graph theory and network-based statistic (NBS) approaches were performed; the topological properties of the white matter structural connectome were compared across the groups, and their relationships with the clinical variables were assessed. Both disease groups PKD-M and PKD-N showed lower local efficiency (implying decreased segregation ability) compared to the HC group; PKD-M had longer characteristic path length and lower global efficiency (implying decreased integration ability) compared to PKD-N and HC, independently of the potential effects of medication. Both PKD-M and PKD-N had decreased nodal characteristics in the left thalamus and left inferior frontal gyrus, the alterations being more pronounced in PKD-M patients, who also showed abnormalities in the left fusiform and bilateral middle temporal gyrus. In the connectivity characteristics assessed by NBS, the alterations were more pronounced in the PKD-M group versus HC than in PKD-N versus HC. As well as the white matter alterations in the basal ganglia-thalamo-cortical circuit related to PKD with or without PRRT2 mutations, findings in the PKD-M group of weaker small-worldness and more pronounced regional disturbance show the adverse effects of PRRT2 gene mutations on brain structural connectome.

The Phenotypic and Genetic Spectrum of Paroxysmal Kinesigenic Dyskinesia in China.

BACKGROUND: Paroxysmal kinesigenic dyskinesia is a spectrum of involuntary dyskinetic disorders with high clinical and genetic heterogeneity. Mutations in proline-rich transmembrane protein 2 have been identified as the major pathogenic factor. OBJECTIVES: We analyzed 600 paroxysmal kinesigenic dyskinesia patients nationwide who were identified by the China Paroxysmal Dyskinesia Collaborative Group to summarize the clinical phenotypes and genetic features of paroxysmal kinesigenic dyskinesia in China and to provide new thoughts on diagnosis and therapy. METHODS: The China Paroxysmal Dyskinesia Collaborative Group was composed of departments of neurology from 22 hospitals. Clinical manifestations and proline-rich transmembrane protein 2 screening results were recorded using unified paroxysmal kinesigenic dyskinesia registration forms. Genotype-phenotype correlation analyses were conducted in patients with and without proline-rich transmembrane protein 2 mutations. High-knee exercises were applied in partial patients as a new diagnostic test to induce attacks. RESULTS: Kinesigenic triggers, male predilection, dystonic attacks, aura, complicated forms of paroxysmal kinesigenic dyskinesia, clustering in patients with family history, and dramatic responses to antiepileptic treatment were the prominent features in this multicenter study. Clinical analysis showed that proline-rich transmembrane protein 2 mutation carriers were prone to present at a younger age and have longer attack duration, bilateral limb involvement, choreic attacks, a complicated form of paroxysmal kinesigenic dyskinesia, family history, and more forms of dyskinesia. The new high-knee-exercise test efficiently induced attacks and could assist in diagnosis. CONCLUSIONS: We propose recommendations regarding diagnostic criteria for paroxysmal kinesigenic dyskinesia based on this large clinical study of paroxysmal kinesigenic dyskinesia. The findings offered some new insights into the diagnosis and treatment of paroxysmal kinesigenic dyskinesia and might help in building standardized paroxysmal kinesigenic dyskinesia clinical evaluations and therapies. © 2020 International Parkinson and Movement Disorder Society.

PRRT2 missense mutations cluster near C-terminus and frequently lead to protein mislocalization.

OBJECTIVE: Variants in human PRRT2 cause paroxysmal kinesigenic dyskinesia (PKD) and other neurological disorders. Most reported variants resulting in truncating proteins failed to localize to cytoplasmic membrane. The present study identifies novel PRRT2 variants in PKD and epilepsy patients and evaluates the functional consequences of PRRT2 missense variations. METHODS: We investigated two families with PKD and epilepsies using Sanger sequencing and a multiple gene panel. Subcellular localization of mutant proteins was investigated using confocal microscopy and cell surface biotinylation assay in Prrt2-transfected cells. RESULTS: Two novel PRRT2 variants, p.His232Glnfs*10 and p.Leu298Pro, were identified, and functional study revealed impaired localization of both mutant proteins to the plasma membrane. Further investigation of other reported missense variants revealed decreased protein targeting to the plasma membrane in eight of the 13 missense variants examined (p.Trp281Arg, p.Ala287Thr, p.Ala291Val, p.Arg295Gln, p.Leu298Pro, p.Ala306Asp, p.Gly324Glu, and p.Gly324Arg). In contrast, all benign variants we tested exhibited predominant localization to the plasma membrane similar to wild-type Prrt2. Most likely pathogenic variants were located at conserved amino acid residues near the C-terminus, whereas truncating variants spread throughout the gene. SIGNIFICANCE: PRRT2 missense variants clustering at the C-terminus often lead to protein mislocalization. Failure in protein targeting to the plasma membrane by PRRT2 variants may be a key mechanism in causing PKD and related neurological disorders.

Paroxysmal Movement Disorders: Recent Advances.

PURPOSE OF REVIEW: Recent advancements in next-generation sequencing (NGS) have enabled techniques such as whole exome sequencing (WES) and whole genome sequencing (WGS) to be used to study paroxysmal movement disorders (PMDs). This review summarizes how the recent genetic advances have altered our understanding of the pathophysiology and treatment of the PMDs. Recently described disease entities are also discussed. RECENT FINDINGS: With the recognition of the phenotypic and genotypic heterogeneity that occurs amongst the PMDs, an increasing number of gene mutations are now implicated to cause the disorders. PMDs can also occur as part of a complex phenotype. The increasing complexity of PMDs challenges the way we view and classify them. The identification of new causative genes and their genotype-phenotype correlation will shed more light on the underlying pathophysiology and will facilitate development of genetic testing guidelines and identification of novel drug targets for PMDs.

Proline-rich transmembrane protein 2-negative paroxysmal kinesigenic dyskinesia: Clinical and genetic analyses of 163 patients.

BACKGROUND: Paroxysmal kinesigenic dyskinesia is the most common type of paroxysmal dyskinesia. Approximately half of the cases of paroxysmal kinesigenic dyskinesia worldwide are attributable to proline-rich transmembrane protein 2 mutations. OBJECTIVE: The objective of this study was to investigate potential causative genes and clinical characteristics in proline-rich transmembrane protein 2-negative patients with paroxysmal kinesigenic dyskinesia. METHODS: We analyzed clinical manifestations and performed exome sequencing in a cohort of 163 proline-rich transmembrane protein 2-negative probands, followed by filtering data with a paroxysmal movement disorders gene panel. Sanger sequencing, segregation analysis, and phenotypic reevaluation were used to substantiate the findings. RESULTS: The clinical characteristics of the enrolled 163 probands were summarized. A total of 39 heterozygous variants were identified, of which 33 were classified as benign, likely benign, and uncertain significance. The remaining 6 variants (3 novel, 3 documented) were pathogenic and likely pathogenic. Of these, 3 were de novo (potassium calcium-activated channel subfamily M alpha 1, c.1534A>G; solute carrier family 2 member 1, c.418G>A; sodium voltage-gated channel alpha subunit 8, c.3640G>A) in 3 sporadic individuals, respectively. The other 3 (paroxysmal nonkinesiogenic dyskinesia protein, c.956dupA; potassium voltage-gated channel subfamily A member 1, c.765C>A; Dishevelled, Egl-10, and Pleckstrin domain containing 5, c.3311C>T) cosegregated in 3 families. All 6 cases presented with typical paroxysmal kinesigenic dyskinesia characteristics, except for the Dishevelled, Egl-10, and Pleckstrin domain containing 5 family, where the proband's mother had abnormal discharges in her temporal lobes in addition to paroxysmal kinesigenic dyskinesia episodes. CONCLUSIONS: Our findings extend the genotypic spectrum of paroxysmal kinesigenic dyskinesia and establish the associations between paroxysmal kinesigenic dyskinesia and genes classically related to other paroxysmal movement disorders. De novo variants might be a cause of sporadic paroxysmal kinesigenic dyskinesia. © 2018 International Parkinson and Movement Disorder Society.

A PRRT2 variant in a Chinese family with paroxysmal kinesigenic dyskinesia and benign familial infantile seizures results in loss of interaction with STX1B.

OBJECTIVE: To identify the causative gene of autosomal dominant paroxysmal kinesigenic dyskinesia and benign familial infantile seizures (PKD/BFIS) in a large Chinese family and explore the potential pathogenic mechanism of a PRRT2 (proline-rich transmembrane protein 2) variant. METHODS: Genetic testing was performed via whole exome sequencing. Western blotting and immunofluorescence were used to analyze the protein expression level and subcellular localization of the PRRT2 mutant in HeLa cells and N2A cells. Coimmunoprecipitation was conducted to investigate the interaction of the PRRT2 mutant with syntaxin 1B (STX1B). RESULTS: In a large Chinese family with autosomal dominant PKD/BFIS showing wide phenotypic heterogeneity, including patients suffering from PKD, BFIS, or epilepsy and asymptomatic variant carriers, a c.621dupA variant in PRRT2 was identified in the proband and was shown to cosegregate with the phenotype in this family. This variant results in premature termination at codon 224, producing a truncated protein (p.Ser208Ilefs*17) in which the two conserved hydrophobic segments and the cytoplasmic loop are missing. Both the expression and subcellular localization of PRRT2 are strongly affected by the c.621dupA variant. In addition, we found that PRRT2 directly interacts with STX1B, a SNARE protein critical for neurotransmitter release, whereas the truncated variant p.Ser208Ilefs*17 lacking the helix-loop-helix domain fails to bind to STX1B. SIGNIFICANCE: Our findings identified a PRRT2 variant in a family with PKD/BFIS and confirmed STX1B as a new binding partner of PRRT2, which suggested that the loss of the interaction between PRRT2 and STX1B may contribute to the pathogenesis of PKD/BFIS.

PRRT2 mutations in a cohort of Chinese families with paroxysmal kinesigenic dyskinesia and genotype-phenotype correlation reanalysis in literatures.

PURPOSE OF THE STUDY: Though rare, children are susceptible to paroxysmal dyskinesias such as paroxysmal kinesigenic dyskinesia, and infantile convulsions and choreoathetosis. Recent studies showed that the cause of paroxysmal kinesigenic dyskinesia or infantile convulsions and choreoathetosis could be proline-rich transmembrane protein 2 (PRRT2) gene mutations. MATERIAL AND METHODS: This study analysed PRRT2 gene mutations in 51 families with paroxysmal kinesigenic dyskinesia or infantile convulsions and choreoathetosis by direct sequencing. In particular, we characterize the genotype-phenotype correlation between age at onset and the types of PRRT2 mutations in all published cases. RESULTS: Direct sequencing showed that 12 out of the 51 families had three different pathogenic mutations (c.649dupC, c.776dupG, c.649C>T) in the PRRT2 gene. No significant difference of age at onset between the patients with and without PRRT2 mutations was found in this cohort of patients. A total of 97 different PRRT2 mutations have been reported in 87 studies till now. The PRRT2 mutation classes are wide, and most mutations are frameshift mutations but the most common mutation remains c.649dupC. Comparisons of the age at onset in paroxysmal kinesigenic dyskinesia or infantile convulsions patients with different types of mutations showed no significant difference. CONCLUSIONS: This study expands the clinical and genetic spectrums of Chinese patients with paroxysmal kinesigenic dyskinesia and infantile convulsions and choreoathetosis. No clear genotype-phenotype correlation between the age at onset and the types of mutations has been determined.

Thalamocortical dysconnectivity in paroxysmal kinesigenic dyskinesia: Combining functional magnetic resonance imaging and diffusion tensor imaging.

BACKGROUND: Paroxysmal kinesigenic dyskinesia is associated with macrostructural and microstructural abnormalities in the thalamus. OBJECTIVES: To examine functional and structural connectivity of thalamocortical networks in paroxysmal kinesigenic dyskinesia and to further investigate the effect of mutation of the proline-rich transmembrane protein 2 on thalamocortical networks. METHODS: Patients with paroxysmal kinesigenic dyskinesia (n = 20), subdivided into proline-rich transmembrane protein 2-mutated (n = 8) and nonmutated patients (n = 12) and healthy controls (n = 20) underwent resting-state functional MRI and diffusion imaging scan. The functional properties of correlations in neural activity (functional connectivity) and the structural properties of white matter probabilistic tractography (structural connectivity) were analyzed to characterize thalamocortical networks. Furthermore, the effect of proline-rich transmembrane protein 2 mutation on functional and structural connectivity of thalamocortical networks were examined using one-way analysis of variance among three groups. RESULTS: Patients had increased functional and structural connectivity between ventral lateral/anterior thalamic nuclei and a lateral motor area, as compared to controls. This functional connectivity positively correlated with disease duration. Interestingly, proline-rich transmembrane protein 2-mutated patients showed decreased functional connectivity and preserved structural connectivity, between mediodorsal nucleus and prefrontal cortex, compared to nonmutated patients and controls. CONCLUSIONS: Thalamomotor/premotor hyperconnectivity suggests abnormal communication between thalamus and motor cortex in patients. Furthermore, thalamoprefrontal hypoconnectivity in proline-rich transmembrane protein 2-mutated patients might indicate that proline-rich transmembrane protein 2 mutations result in inefficient thalamoprefrontal integration. Our findings facilitate a deeper understanding of the crucial role of thalamocortical dysconnectivity in the pathophysiological mechanisms of paroxysmal kinesigenic dyskinesia. © 2017 International Parkinson and Movement Disorder Society.

Transcallosal conduction in paroxysmal kinesigenic dyskinesia.

OBJECTIVES: Detecting whether a possible disequilibrium between the excitatory and inhibitory interhemispheric interactions in paroxysmal kinesigenic dyskinesia (PKD) exists. METHODS: This study assessed measures of motor threshold, motor evoked potential latency, the cortical silent period, the ipsilateral silent period and the transcallosal conduction time (TCT) in PKD patients. Data were compared between the clinically affected hemisphere (aH) and the fellow hemisphere (fH). RESULTS: The transcallosal conduction time from the aH to the fH was 11.8 ms (range = 2.3-20.7) and 13.6 ms (range = 2.8-67.7) from the fH to the aH. The difference in TCT in the affected side was significant (p = .019). CONCLUSION: The findings demonstrated that, although inhibitory interneurons act normally and symmetrically between the motor cortices and transcallosal inhibition was normal and symmetrical between both sides, the onset of transcallosal inhibition was asymmetrical. The affected hemisphere's inhibition toward the unaffected hemisphere is faster compared to the inhibition provided by the fellow hemisphere. These results are consistent with an inhibitory deficit in the level of interhemispheric interactions. SIGNIFICANCE: This study revealed a defect in inhibition of the motor axis could be responsible in the pathological mechanisms of kinesigenic dyskinesia.

The evolving spectrum of PRRT2-associated paroxysmal diseases.

Next-generation sequencing has identified mutations in the PRRT2 (proline-rich transmembrane protein 2) gene as the leading cause for a wide and yet evolving spectrum of paroxysmal diseases. PRRT2 mutations are found in the majority of patients with benign familial infantile epilepsy, infantile convulsions and choreoathetosis and paroxysmal kinesigenic dyskinesia, confirming a common disease spectrum that had previously been suggested based on gene linkage analyses and shared clinical features. Beyond these clinical entities, PRRT2 mutations have been described in other childhood-onset movement disorders, different forms of seizures, headache disorders, and intellectual disability. PRRT2 encodes a protein that is expressed in the central nervous system and is thought to be involved in the modulation of synaptic neurotransmitter release. The vast majority of mutations lead to a truncated protein or no protein at all and thus to a haploinsufficient state. The subsequent reduction of PRRT2 protein may lead to altered synaptic neurotransmitter release and dysregulated neuronal excitability in various regions of the brain, resulting in paroxysmal movement disorders and seizure phenotypes. In this review, we examine the genetics and neurobiology of PRRT2 and summarize the evolving clinical and molecular spectrum of PRRT2-associated diseases. Through a comprehensive review of 1444 published cases, we provide a detailed assessment of the demographics, disease characteristics and genetic findings of patients with PRRT2 mutations. Benign familial infantile epilepsy (41.7%; n = 602), paroxysmal kinesigenic dyskinesia (38.7%; n = 560) and infantile convulsions and choreoathetosis (14.3%; n = 206) constitute the vast majority of PRRT2-associated diseases, leaving 76 patients (5.3%) with a different primary diagnosis. A positive family history is present in 89.1% of patients; and PRRT2 mutations are familial in 87.1% of reported cases. Seventy-three different disease-associated PRRT2 mutations (35 truncating, 22 missense, three extension mutations, six putative splice site changes, and seven changes that lead to a complete PRRT2 deletion) have been described to date, with the c.649dupC frameshift mutation accounting for the majority of cases (78.5%). Expanding the genetic landscape, 15 patients with biallelic PRRT2 mutations and six patients with 16p11.2 microdeletions and a paroxysmal kinesigenic dyskinesia phenotype have been reported. Probing the phenotypic boundaries of PRRT2-associated disorders, several movement, seizure and headache disorders have been linked to PRRT2 mutations in a subset of patients. Of these, hemiplegic migraine emerges as a novel PRRT2-associated phenotype. With this comprehensive review of PRRT2-associated diseases, we hope to provide a scientific resource for informing future research, both in laboratory models and in clinical studies.