Proline-rich Transmembrane Protein 2 Gene Research Articles

A new genetic diagnosis strategy for paroxysmal kinesigenic dyskinesia: Targeted high-throughput detection of PRRT2 gene c.649 locus.

Paroxysmal kinesigenic dyskinesia (PKD) is the most prevalent kind type of paroxysmal Dyskinesia, characterized by recurrent and transient episodes of involuntary movements. Most PKD cases were attributed to the proline-rich transmembrane protein 2 (PRRT2) gene, in which the c.649 region is a hotspot for known mutations. Even though some patients with PKD have been genetically diagnosed using whole-exome sequencing (WES) and Sanger sequencing, there are still cases of missed diagnoses due to the limitations of sequencing technology and analytic methods on throughput. Patients meeting the diagnosis criteria of PKD with negative results of PRRT2-Sanger sequencing and WES were included in this study. Mutation screening and targeted high-throughput sequencing were performed to analyze and verify the sequencing results of the potential mutations. Six patients with PKD with high mutation ratios of c.649dupC were screened using our targeted high-throughput sequencing from 26 PKD patients with negative results of PRRT2-Sanger sequencing and WES (frequency = 23.1%), which compensated for the comparatively shallow sequencing depth and statistical flaws in this region. Compared with the local normal population and other patients with PKD, the mutation ratios of c.649dupC of these six patients with PKD were much higher and also had truncated protein structures and differentially altered mRNA expression. Based on the above studies, we emphasize the routine targeted high-throughput sequencing of the c.649 site in the PRRT2 gene in so-called genetic-testing-negative patients with PKD, and manually calculate the deletion and duplication mutations depth and ratios to lower the rate of clinical misdiagnosis.

Clinical and genetic analysis of benign familial infantile epilepsy caused by PRRT2 gene variant.

This study presents the clinical phenotypes and genetic analysis of seven patients with benign familial infantile epilepsy (BFIE) diagnosed by whole-exome sequencing. The clinical data of seven children with BFIE diagnosed at the Department of Neurology, Children's Hospital Affiliated to Zhengzhou University between December 2017 and April 2022 were retrospectively analyzed. Whole-exome sequencing was used to identify the genetic causes, and the variants were verified by Sanger sequencing in other family members. The seven patients with BFIE included two males and five females ranging in age between 3 and 7 months old. The main clinical phenotype of the seven affected children was the presence of focal or generalized tonic-clonic seizures, which was well controlled by anti-seizure medication. Cases 1 and 5 exhibited predominantly generalized tonic-clonic seizures accompanied by focal seizures while cases 2, 3, and 7 displayed generalized tonic-clonic seizures, and cases 4 and 6 had focal seizures. The grandmother and father of cases 2, 6, and 7 had histories of seizures. However, there was no family history of seizures in the remaining cases. Case 1 carried a de novo frameshift variant c.397delG (p.E133Nfs*43) in the proline-rich transmembrane protein 2 (PRRT2) gene while case 2 had a nonsense variant c.46G > T (p.Glu16*) inherited from the father, and cases 3-7 carried a heterozygous frameshift variant c.649dup (p.R217Pfs*8) in the same gene. In cases 3 and 4, the frameshift variant was de novo, while in cases 5-7, the variant was paternally inherited. The c.397delG (p.E133Nfs*43) variant is previously unreported. This study demonstrated the effectiveness of whole-exome sequencing in the diagnosis of BFIE. Moreover, our findings revealed a novel pathogenic variant c.397delG (p.E133Nfs*43) in the PRRT2 gene that causes BFIE, expanding the mutation spectrum of PRRT2.

INFANTILE CONVULSIONS AND CHOREOATHETOSIS (ICCA) SYNDROME WITH PRRT2 MUTATION-A CASE REPORT

Infantile convulsions and choreoathetosis (ICCA) syndrome is a rare autosomal dominant disorder characterised by convulsions during infancy with paroxysmal choreoathetosis at a later age. Mutations in proline rich transmembrane protein 2 (PRRT2) gene have been identified as a cause for ICCA syndrome. Carbamazepine or phenytoin is effective in preventing seizure recurrence and controlling dyskinesias. Here, we report a child with ICCA syndrome with homozygous mutation in PRRT2 gene.

PRRT2 Gene Analysis of Paroxysmal Kinesigenic Dyskinesia (PKD) in Thai Children

Objective: To examine the frequency of the proline-rich transmembrane protein-2 (PRRT2) gene mutation in Thai patients with paroxysmal kinesigenic dyskinesia (PKD). Material and Methods: A retrospective study of children aged 0-18 years with a diagnosis of PKD at Siriraj Hospital. The genetic analyses of the PRRT2 gene were done by bidirectional Sanger sequencing.Results: Twelve patients with PKD were included. The known PRRT2 mutation, c.649dupC (p.Arg217Profs*8), was identified in three of the patients (25.0%), one of the nine sporadic cases (11.1%) and two of the three familial cases (66.6%), all from different families. PKD had a complete response to carbamazepine treatment regardless of PRRT2 mutation status. Conclusion: Our study provided the new details of the clinical phenotypes and PRRT2 gene analysis findings for Thai PKD. PRRT2 mutations were identified in our Thai PKD patients with increased detection rates in the familial PKD cases. The c.649dupC (p.Arg217Profs*8) was also found to be a hot-spot mutation in our Thai PKD patients. Furthermore, this study demonstrates the importance of PRRT2 gene analysis in order to properly diagnose and treat these patients.

Novel PRRT2 gene variants identified in paroxysmal kinesigenic dyskinesia and benign familial infantile epilepsy in Chinese families.

The present study was performed to investigate the clinical manifestations and pathogenic variants in three large families with autosomal dominant paroxysmal kinesigenic dyskinesia (PKD) and/or benign familial infantile epilepsy (BFIE) in China. Detailed clinical data and family history were collected. Genomic DNA was isolated from the peripheral blood samples of all available members. The genetic diagnosis was made by whole-exome sequencing on the three probands and the candidate variants were verified by PCR-Sanger sequencing. The pathogenicity of variants was predicted by bioinformatics analyses and classified according to the American College of Medical Genetics criteria. A total of three causative heterozygous variants were identified in the proline-rich transmembrane protein 2 (PRRT2) gene by DNA sequencing: A novel c.324_334del(p.Val109Argfs*21) deletion variant in Family A, as well as the previously known c.510_513del(p.Ser172Argfs*3) deletion variant in Family B and c.649dupC(p.Arg217Profs*8) duplication variant in Family C. The three variants of PRRT2 co-segregated with the phenotype and genotype in the family members. The present results deepen the current understanding of PKD/BFIE and extend the genotypic-phenotypic spectrum of PKD/BFIE.

The Spectrum of PRRT2-Associated Disorders: Update on Clinical Features and Pathophysiology.

Mutations in the PRRT2 (proline-rich transmembrane protein 2) gene have been identified as the main cause of an expanding spectrum of disorders, including paroxysmal kinesigenic dyskinesia and benign familial infantile epilepsy, which places this gene at the border between epilepsy and movement disorders. The clinical spectrum has largely expanded to include episodic ataxia, hemiplegic migraine, and complex neurodevelopmental disorders in cases with biallelic mutations. Prior to the discovery of PRRT2 as the causative gene for this spectrum of disorders, the sensitivity of paroxysmal kinesigenic dyskinesia to anticonvulsant drugs regulating ion channel function as well as the co-occurrence of epilepsy in some patients or families fostered the hypothesis this could represent a channelopathy. However, recent evidence implicates PRRT2 in synapse functioning, which disproves the “channel hypothesis” (although PRRT2 modulates ion channels at the presynaptic level), and justifies the classification of these conditions as synaptopathies, an emerging rubric of brain disorders. This review aims to provide an update of the clinical and pathophysiologic features of PRRT2-associated 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.

Co-existence of Mutations in PRRT2 and ABCC6 Genes in a Turkish Family

Paroxysmal kinesigenic choreoathetosis (PKC) is an inherited disorder with an autosomal dominant mode of inheritance, caused mostly by the mutations in PRRT2 (proline-rich transmembrane protein-2) gene, located on chromosome 16. Pseudoxanthoma elasticum (PXE) is a hereditary metabolic disease with autosomal recessive inheritance resulting from the mutations in the ABCC6 (ATP-Binding Cassette, Subfamily C, Member 6) gene, located also on chromosome 16. Here we present a female patient with familial paroxysmal kinesigenic dyskinesia and benign familial infantile convulsions (BFIC), in whom both a heterozygous truncating frameshift mutation in the PRRT2 gene and a heterozygous missense mutation in the ABCC6 gene were demonstrated. The co-existence of these two mutations has not been reported in the literature. Although the clinical symptomatology of PXE was not present in our patient, some family members of our index case had. Here we present a Turkish family with two different mutations on the same chromosome, namely PRRT2 and ABCC6 mutations. However, because these two mutations have separate parental inheritance and are not in linkage disequilibrium, the co-existence was reported as co-incidental.

PRRT2 gene variant in a child with dysmorphic features, congenital microcephaly, and severe epileptic seizures: genotype-phenotype correlation?

BackgroundMutations in Proline-rich Transmembrane Protein 2 (PRRT2) have been primarily associated with individuals presenting with infantile epilepsy, including benign familial infantile epilepsy, benign infantile epilepsy, and benign myoclonus of early infancy, and/or with dyskinetic paroxysms such as paroxysmal kinesigenic dyskinesia, paroxysmal non-kinesigenic dyskinesia, and exercise-induced dyskinesia. However, the clinical manifestations of this disorder vary widely. PRRT2 encodes a protein expressed in the central nervous system that is mainly localized in the pre-synaptic neurons and is involved in the modulation of synaptic neurotransmitter release. The anomalous function of this gene has been proposed to cause dysregulation of neuronal excitability and cerebral disorders.Case presentationWe hereby report on a young child followed-up for three years who presents with a spectrum of clinical manifestations such as congenital microcephaly, dysmorphic features, severe intellectual disability, and drug-resistant epileptic encephalopathy in association with a synonymous variant in PRRT2 gene (c.501C > T; p.Thr167Ile) of unknown clinical significance variant (VUS) revealed by diagnostic exome sequencing.ConclusionSeveral hypotheses have been advanced on the specific role that PRRT2 gene mutations play to cause the clinical features of affected patients. To our knowledge, the severe phenotype seen in this case has never been reported in association with any clinically actionable variant, as the missense substitution detected in PRRT2 gene. Intriguingly, the same mutation was reported in the healthy father: the action of modifying factors in the affected child may be hypothesized. The report of similar observations could extend the spectrum of clinical manifestations linked to this mutation.

Constitutive Inactivation of the PRRT2 Gene Alters Short-Term Synaptic Plasticity and Promotes Network Hyperexcitability in Hippocampal Neurons.

Mutations in PRoline-Rich Transmembrane protein 2 (PRRT2) underlie a group of paroxysmal disorders including epilepsy, kinesigenic dyskinesia and migraine. Most of the mutations lead to impaired PRRT2 expression and/or function, emphasizing the pathogenic role of the PRRT2 deficiency. In this work, we investigated the phenotype of primary hippocampal neurons obtained from mouse embryos in which the PRRT2 gene was constitutively inactivated. Although PRRT2 is expressed by both excitatory and inhibitory neurons, its deletion decreases the number of excitatory synapses without significantly affecting the number of inhibitory synapses or the nerve terminal ultrastructure. Analysis of synaptic function in primary PRRT2 knockout excitatory neurons by live imaging and electrophysiology showed slowdown of the kinetics of exocytosis, weakened spontaneous and evoked synaptic transmission and markedly increased facilitation. Inhibitory neurons showed strengthening of basal synaptic transmission, accompanied by faster depression. At the network level these complex synaptic effects resulted in a state of heightened spontaneous and evoked activity that was associated with increased excitability of excitatory neurons in both PRRT2 knockout primary cultures and acute hippocampal slices. The data indicate the existence of network instability/hyperexcitability as the possible basis of the paroxysmal phenotypes associated with PRRT2 mutations.

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

ABSTRACTPurpose 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.

The PRRT2 knockout mouse recapitulates the neurological diseases associated with PRRT2 mutations

Heterozygous and rare homozygous mutations in PRoline-Rich Transmembrane protein 2 (PRRT2) underlie a group of paroxysmal disorders including epilepsy, kinesigenic dyskinesia episodic ataxia and migraine. Most of the mutations lead to impaired PRRT2 expression and/or function. Recently, an important role for PRTT2 in the neurotransmitter release machinery, brain development and synapse formation has been uncovered. In this work, we have characterized the phenotype of a mouse in which the PRRT2 gene has been constitutively inactivated (PRRT2 KO). β-galactosidase staining allowed to map the regional expression of PRRT2 that was more intense in the cerebellum, hindbrain and spinal cord, while it was localized to restricted areas in the forebrain. PRRT2 KO mice are normal at birth, but display paroxysmal movements at the onset of locomotion that persist in the adulthood. In addition, adult PRRT2 KO mice present abnormal motor behaviors characterized by wild running and jumping in response to audiogenic stimuli that are ineffective in wild type mice and an increased sensitivity to the convulsive effects of pentylentetrazol. Patch-clamp electrophysiology in hippocampal and cerebellar slices revealed specific effects in the cerebellum, where PRRT2 is highly expressed, consisting in a higher excitatory strength at parallel fiber-Purkinje cell synapses during high frequency stimulation. The results show that the PRRT2 KO mouse reproduces the motor paroxysms present in the human PRRT2-linked pathology and can be proposed as an experimental model for the study of the pathogenesis of the disease as well as for testing personalized therapeutic approaches.

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.

Clinical features and PRRT2 gene mutation in paroxysmal kinesigenic dyskinesia

To investigate the clinical features and proline-rich transmembrane protein 2 (PRRT2) gene mutation in patients with paroxysmal kinesigenic dyskinesia (PKD). Clinical information was collected at Peking University First Hospital from January 2004 to July 2014. In total, 10 patients with PKD were recruited, and all were males. Among them, four patients were the probands from four PKD families and the other six patients were sporadic cases. Clinical information was analyzed. Peripheral blood samples for DNA study were collected from PKD patients and their family members. Genomic DNA was extracted using standard procedures. Mutation analysis of PRRT2 was performed by Sanger sequencing after PCR. Of the 10 patients, the median age of dyskinesias onset was 10 years, ranging from 4 to 13 years. The description of their attacks were abnormal involuntary movements provoked by sudden movements, without loss of consciousness. Five patients exhibited dystonia, two patients exhibited choreoathetosis, and three patients had mixed (dystonia and choreoathetosis) dyskinesias. The duration of the attacks lasted for 3 to 30 seconds. The frequency ranged from once per month to twenty times per day. PRRT2 mutations, c. 649_650insC (p. R217PfsX8), were found in all the four PKD families. Mutation c. 649_650insC was also detected in two of the six sporadic PKD cases, inheriting from their asymptomatic mother. The onset age of PKD could be in the early childhood. The clinical features of the familial cases and sporadic cases showed no difference. The attacks manifested as dystonia, choreathetosis, or mixed. PRR2 mutations could be identified in familial or sporadic cases with PKD. Mutation c. 649_650insC is the hotspot mutation of PRRT2 gene.

Novel loss-of-function PRRT2 mutation causes paroxysmal kinesigenic dyskinesia in a Han Chinese family.

BackgroundMutations in proline-rich transmembrane protein 2 (PRRT2) are a cause of paroxysmal kinesigenic dyskinesia (PKD). In this study, we investigated the PRRT2 gene mutation in a Chinese Han family with PKD and study the pathogenesis of the mutation with PRRT2 gene.MethodsPeripheral venous blood was taken from the family members. Sanger sequencing was used for novel mutation sequencing. For the pathogenesis with the novel mutation was analyzed by bioinformatics, real-time PCR, subcellular localization and Western blot.ResultsThe Sanger sequencing showed a novel mutation, c.186-187delGC, a deletion mutation, in exon 2 of the PRRT2 gene, the frameshift mutation generated a truncated protein that was stably expressed in transfected Human embryonic kidney (HEK) 293 cells. A subcellular localization assay in COS-7 cells with GFP-tagged protein showed nuclear localization for the mutant protein while the wild-type protein was localized in membranes. Co-transfection of HEK293 cells with wild-type and mutant expression plasmids cells did not influence mRNA or protein expression from the wild-type plasmid.ConclusionsOur findings demonstrated that the c.186-187delGC mutation resulted in a truncated protein from the PRRT2 gene to involve in PKD pathogenesis with haploinsufficiency. The results extend the mutation spectrum of the PRRT2 gene and provide a new example for studying the pathogenesis of the mutated PRRT2 gene.

Unusual variability of PRRT2 linked phenotypes within a family

BackgroundMutations in the proline-rich transmembrane protein 2 (PRRT2) gene on chromosome 16p11.2 have recently been identified as a cause of paroxysmal kinesigenic dyskinesias (PKD), infantile convulsions and choreoathetosis (ICCA) syndrome or infantile convulsions (IC). AimsHere, we describe a family with four affected members. They all suffer from different diseases: febrile convulsion, epileptic seizures, PKD or headache. MethodsThe whole coding region of PRRT2 gene has been analyzed. ResultsMolecular testing revealed the PRRT2 gene mutation c649.delC in exon 2 for all three sibs as well as for the mother. ConclusionOur presented family case shows the great variability within PRRT2 linked phenotypes even within the same family. Further and more detailed studies will be needed before genetic findings enter into the daily diagnostic and the daily genetic counseling with all its consequences.

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

Background and PurposeGiven the diverse phenotypes including combined non-dyskinetic symptoms in patients harboring mutations of the gene encoding proline-rich transmembrane protein 2 (PRRT2), the clinical significance of these mutations in paroxysmal kinesigenic dyskinesia (PKD) is questionable. In this study, we investigated the clinical characteristics of PKD patients with PRRT2 mutations.MethodsFamilial and sporadic PKD patients were enrolled and PRRT2 gene sequencing was performed. Demographic and clinical data were compared between PKD patients with and without a PRRT2 mutation.ResultsAmong the enrolled PKD patients (8 patients from 5 PKD families and 19 sporadic patients), PRRT2 mutations were detected in 3 PKD families (60%) and 2 sporadic cases (10.5%). All familial patients with a PRRT2 gene mutation had the c.649dupC mutation, which is the most commonly reported mutation. Two uncommon mutations (c.649delC and c.629dupC) were detected only in the sporadic cases. PKD patients with PRRT2 mutation were younger at symptom onset and had more non-dyskinetic symptoms than those without PRRT2 mutation. However, the characteristics of dyskinetic movement did not differ between the two groups.ConclusionsThis is the first study of PRRT2 mutations in Korea. The presence of a PRRT2 mutation was more strongly related to familial PKD, and was clinically related with earlier age of onset and common non-dyskinetic symptoms in PKD patients.

PRRT2-related disorders: further PKD and ICCA cases and review of the literature

Recent studies reported mutations in the gene encoding the proline-rich transmembrane protein 2 (PRRT2) to be causative for paroxysmal kinesigenic dyskinesia (PKD), PKD combined with infantile seizures (ICCA), and benign familial infantile seizures (BFIS). PRRT2 is a presynaptic protein which seems to play an important role in exocytosis and neurotransmitter release. PKD is the most common form of paroxysmal movement disorder characterized by recurrent brief involuntary hyperkinesias triggered by sudden movements. Here, we sequenced PRRT2 in 14 sporadic and 8 familial PKD and ICCA cases of Caucasian origin and identified three novel mutations (c.919C>T/p.Gln307, c.388delG/p.Ala130Profs 46, c.884G>A/p.Arg295Gln) predicting two truncated proteins and one probably damaging point mutation. A review of all published cases is also included. PRRT2 mutations occur more frequently in familial forms of PRRT2-related syndromes (80-100 %) than in sporadic cases (33-46 %) suggesting further heterogeneity in the latter. PRRT2 mutations were rarely described in other forms of paroxysmal dyskinesias deviating from classical PKD, as we report here in one ICCA family without kinesigenic triggers. Mutations are exclusively found in two exons of the PRRT2 gene at a high rate across all syndromes and with one major mutation (c.649dupC) in a mutational hotspot of nine cytosines, which is responsible for 57 % of all cases in all phenotypes. We therefore propose that genetic analysis rapidly performed in early stages of the disease is highly cost-effective and can help to avoid further unnecessary diagnostic and therapeutic interventions.