Paroxysmal Kinesigenic Dyskinesia Research Articles

PRRT2 Mutations are the major cause of benign familial infantile seizures

Mutations in PRRT2 have been described in paroxysmal kinesigenic dyskinesia (PKD) and infantile convulsions with choreoathetosis (PKD with infantile seizures), and recently also in some families with benign familial infantile seizures (BFIS) alone. We analyzed PRRT2 in 49 families and three sporadic cases with BFIS only of Italian, German, Turkish, and Japanese origin and identified the previously described mutation c.649dupC in an unstable series of nine cytosines to occur in 39 of our families and one sporadic case (77% of index cases). Furthermore, three novel mutations were found in three other families, whereas 17% of our index cases did not show PRRT2 mutations, including a large family with late-onset BFIS and febrile seizures. Our study further establishes PRRT2 as the major gene for BFIS alone.

Erratum: Mutations in PRRT2 responsible for paroxysmal kinesigenic dyskinesias also cause benign familial infantile convulsions

Erratum: Mutations in PRRT2 responsible for paroxysmal kinesigenic dyskinesias also cause benign familial infantile convulsions

Trusting new age weapons to tackle titin

The advent of next-generation sequencing technologies available at an increasingly affordable price is revolutionizing the discovery and diagnosis of human disease genes. We are without doubt, witnessing the dawn of a new era of disease gene discovery that will radically impact the field of human genetics. Next-generation sequencing technologies are already having a significant impact on neurological disorders, with huge further potential for improved clinical service delivery. In late 2010, Brain first published a paper (Wang et al. , 2010) detailing the identification of a disease gene for spinocerebellar ataxia by sequencing the exomes of four affected family members. An exome comprises ∼1% of the entire genome, encompassing all coding and coding-flanking regions, and is estimated to account for ∼85% of all disease-causing mutations. Notably, Wang et al . (2010) demonstrated that when they allied linkage data with their exome sequencing results, exome data from only one affected individual were sufficient to find the mutation. There have been further illustrations of the power of next-generation sequencing technologies in the past 2 years. Combining linkage and exome sequencing data was again effectively harnessed to identify mutations for familial amyotrophic lateral sclerosis (Johnson et al. , 2010), a dominant form of limb girdle muscular dystrophy with a vacuolar pathology (Harms et al. , 2012 b ), and paroxysmal kinesigenic dyskinesias (Wang et al. , 2011). Homozygosity mapping in consanguineous families can also be partnered with exome sequencing for successful gene discovery, for example, for an autosomal recessive spinocerebellar ataxia (Doi et al. , 2011), and also in the mammoth efforts of Najmabadi et al. (2011), who studied 136 consanguineous families leading to identification of 50 novel genes for intellectual disability or related neurological disorders. Targeted capture and next-generation sequencing of the …

Identification of PRRT2 as the causative gene of paroxysmal kinesigenic dyskinesia

Identification of PRRT2 as the causative gene of paroxysmal kinesigenic dyskinesia

Mutations in the Novel Protein PRRT2 Cause Paroxysmal Kinesigenic Dyskinesia with Infantile Convulsions (IN10-2.005)

Objective: To find the gene responsible for paroxysmal kinesigenic dyskinesia (PKD). Background Paroxysmal Kinesigenic Dyskinesia with Infantile Convulsions (PKD/IC) is an episodic movement disorder with autosomal dominant inheritance and high penetrance, but the causative gene is unknown. Design/Methods: PKD/IC patients and families were collected, and whole-genome sequencing (WGS) was carried out. When PRRT2 was found linked with PKD/IC, basic biochemical experiments and cell cultures were performed to test its expression and localization. Results: We have now identified four truncating mutations involving the PRRT2 gene in the vast majority (24/25) of well characterized families with PKD/IC. PRRT2 truncating mutations were also detected in 28 of 78 additional families. The PRRT2 gene encodes a proline-rich transmembrane protein of unknown function that has been reported to interact with the t-SNARE, SNAP25 . PRRT2 localizes to axons but not to dendritic processes in primary neuronal culture. Conclusions: We believe that PRRT2 mutations associated with PKD/IC lead to dramatically reduced PRRT2 protein level leading ultimately to neuronal hyperexcitability that manifests in vivo as PKD/IC. Supported by: Grants from the Dystonia Medical Research Foundation, the Bachmann-Strauss Dystonia Parkinson Foundation, NIH grant U54 RR19481, the Sandler Neurogenetics Fund (Y-HF and LP), NIH grant NS043533 (LP), ANR grant EPILAND (PS), and INSERM. L.J.P. is an investigator of the Howard Hughes Medical Institute. Disclosure: Dr. Lee has nothing to disclose. Dr. Huang has nothing to disclose. Dr. Edwards has nothing to disclose. Dr. Hanna has nothing to disclose. Dr. Bowcock has nothing to disclose. Dr. Szepetowski has nothing to disclose. Dr. Fu has nothing to disclose. Dr. Ptacek has nothing to disclose.

Mutations in the Novel Protein PRRT2 Cause Paroxysmal Kinesigenic Dyskinesia with Infantile Convulsions (P05.082)

Mutations in the Novel Protein PRRT2 Cause Paroxysmal Kinesigenic Dyskinesia with Infantile Convulsions (P05.082)

Microdeletions detected using chromosome microarray in children with suspected genetic movement disorders: a single‐centre study

Chromosome microarray (CMA) can determine copy number variants such as microdeletions or microduplications. Microdeletions of movement disorder genes including epsilon-sarcoglycan (SGCE) and thyroid transcription factor-1 (TITF1) have been described in patients with myoclonus dystonia and benign hereditary chorea respectively. We examined whether CMA is a valuable tool in the investigation of children with suspected genetic movement disorders. A genetic movement disorder was suspected if there was a positive first-degree family history, or two or more of the following factors: normal or near-normal magnetic resonance imaging, negative history of brain injury, and negative investigations for metabolic disorders. Tic disorders were excluded. Twenty-five patients (18 males, seven females) with a mean age at movement disorder onset of 4 years 5 month (range 1 mo-14 y) were prospectively recruited with the following primary movement disorders: dystonia (n=10), paroxysmal kinesigenic dyskinesia (n=5), tremor (n=4), chorea (n=3), myoclonus (n=2), and paroxysmal non-kinesigenic dyskinesia (n=1). Comorbid associated features were common, particularly developmental delay or intellectual disability (19 out of 25) and attention-deficit-hyperactivity disorder (six out of 25). CMA was performed using Agilent aCGH 60K array. Seven out of twenty-five patients had a microdeletion determined by CMA. None of the microdeletions were considered benign variants. Four patients had a deletion of a known movement disorder gene including paroxysmal kinesigenic dyskinesia (PRRT2; n=2), SGCE (myoclonus dystonia, n=1), and TITF1 (benign hereditary chorea, n=1). Three patients had novel microdeletions of unknown but potential significance including 14q13.3 (chorea, n=1), 19p13.12 (tremor, n=1), and 19q13.12 (progressive dystonia). All seven patients had associated neurodevelopmental or behavioural problems. Assays that determine copy number variants may be a valuable first-tier investigation in patients with suspected genetic movement disorders, particularly when associated with intellectual disability or developmental disorders. Microdeletion syndromes may help the search for new movement disorder genes.

Paroxysmal kinesigenic dyskinesias of epileptic origin abolished by temporal lobectomy

Paroxysmal kinesigenic dyskinesias of epileptic origin abolished by temporal lobectomy

Paroxysmal kinesigenic dyskinesia: Cortical or non-cortical origin

Paroxysmal kinesigenic dyskinesia (PKD) is characterized by involuntary dystonia and/or chorea triggered by a sudden movement. Cases are usually familial with an autosomal dominant inheritance. Hypotheses regarding the pathogenesis of PKD focus on the controversy whether PKD has a cortical or non-cortical origin. A combined familial trait of PKD and benign familial infantile seizures has been reported as the infantile convulsions and paroxysmal choreoathetosis (ICCA) syndrome. Here, we report a family diagnosed with ICCA syndrome with an Arg217STOP mutation. The index patient showed interictal EEG focal changes compatible with paroxysmal dystonic movements of his contralateral leg. This might support cortical involvement in PKD.

Mutations in PRRT2 responsible for paroxysmal kinesigenic dyskinesias also cause benign familial infantile convulsions

Paroxysmal kinesigenic dyskinesia (PKD (MIM128000)) is a neurological disorder characterized by recurrent attacks of involuntary movements. Benign familial infantile convulsion (BFIC) is also one of a neurological disorder characterized by clusters of epileptic seizures. The BFIC1 (MIM601764), BFIC2 (MIM605751) and BFIC4 (MIM612627) loci have been mapped to chromosome 19q, 16p and 1p, respectively, while BFIC3 (MIM607745) is caused by mutations in SCN2A on chromosome 2q24. Furthermore, patients with BFIC have been observed in a family concurrently with PKD. Both PKD and BFIC2 are heritable paroxysmal disorders and map to the same region on chromosome 16. Recently, the causative gene of PKD, the protein-rich transmembrane protein 2 (PRRT2), has been detected using whole-exome sequencing. We performed mutation analysis of PRRT2 by direct sequencing in 81 members of 17 families containing 15 PKD families and two BFIC families. Direct sequencing revealed that two mutations, c.649dupC and c.748C>T, were detected in all members of the PKD and BFIC families. Our results suggest that BFIC2 is caused by a truncated mutation that also causes PKD. Thus, PKD and BFIC2 are genetically identical and may cause convulsions and involuntary movements via a similar mechanism.

Paroxysmal Kinesigenic Dyskinesia as the Initial Symptom of Hashimoto Encephalopathy

Paroxysmal Kinesigenic Dyskinesia as the Initial Symptom of Hashimoto Encephalopathy

Exacerbation of idiopathic paroxysmal kinesigenic dyskinesia in remission state caused by secondary hypoparathyroidism with hypocalcemia after thyroidectomy: Evidence for ion channelopathy

Most reported cases of paroxysmal kinesigenic dyskinesia (PKD) are idiopathic or familial; however, hypoparathyroidism is another unusual cause of secondary PKD. The pathomechanism of PKD remains poorly understood, and the association between idiopathic and secondary PKD remains an enigma, and has yet to be clearly elucidated. We recently encountered a patient with idiopathic PKD whose symptoms were aggravated by secondary hypoparathyroidism with hypocalcemia after having undergone a thyroidectomy. The patient’s paroxysms were ameliorated by the normalization of serum calcium levels. The results discussed herein may provide support for the hypothesis that PKD is associated with neuronal ion regulation.

New Mutation Implicated in Paroxysmal Kinesigenic Dyskinesia

New Mutation Implicated in Paroxysmal Kinesigenic Dyskinesia

Mutations in the Gene PRRT2 Cause Paroxysmal Kinesigenic Dyskinesia with Infantile Convulsions

Paroxysmal kinesigenic dyskinesia with infantile convulsions (PKD/IC) is an episodic movement disorder with autosomal-dominant inheritance and high penetrance, but the causative genetic mutation is unknown. We have now identified four truncating mutations involving the gene PRRT2 in the vast majority (24/25) of well-characterized families with PKD/IC. PRRT2 truncating mutations were also detected in 28 of 78 additional families. PRRT2 encodes a proline-rich transmembrane protein of unknown function that has been reported to interact with the t-SNARE, SNAP25. PRRT2 localizes to axons but not to dendritic processes in primary neuronal culture, and mutants associated with PKD/IC lead to dramatically reduced PRRT2 levels, leading ultimately to neuronal hyperexcitability that manifests invivo as PKD/IC.

PRRT2 Mutations Cause Benign Familial Infantile Epilepsy and Infantile Convulsions with Choreoathetosis Syndrome

Benign familial infantile epilepsy (BFIE) is a self-limited seizure disorder that occurs in infancy and has autosomal-dominant inheritance. We have identified heterozygous mutations in PRRT2, which encodes proline-rich transmembrane protein 2, in 14 of 17 families (82%) affected by BFIE, indicating that PRRT2 mutations are the most frequent cause of this disorder. We also report PRRT2 mutations in five of six (83%) families affected by infantile convulsions and choreoathetosis (ICCA) syndrome, a familial syndrome in which infantile seizures and an adolescent-onset movement disorder, paroxysmal kinesigenic choreoathetosis (PKC), co-occur. These findings show that mutations in PRRT2 cause both epilepsy and a movement disorder. Furthermore, PRRT2 mutations elicit pleiotropy in terms of both age of expression (infancy versus later childhood) and anatomical substrate (cortex versus basal ganglia).

Paroxysmal Kinesigenic Dyskinesia-like Symptoms in a Patient with Tourette Syndrome.

Paroxysmal kinesigenic dyskinesia (PKD) is characterized by episodic dystonia or choreiform movements provoked by sudden voluntary movement. PKD is not commonly reported in Tourette syndrome (TS). We describe a unique case of TS with PKD-like episodic dyskinesia that responded to carbamazepine. A 36-year-old male with long-standing TS developed paroxysmal "cramping". Attacks were provoked by quick, sudden arm movements, which induced dystonic cramping, or by reaching overhead, which caused painful contraction of truncal muscles. The spells typically lasted 5-20 seconds and occurred multiple times daily. The patient's mother suffered from intermittent dystonic toe curling. In view of the similarity of symptoms to PKD, carbamazepine was prescribed at 400 mg daily. The symptoms resolved completely. Inadvertent discontinuation led to relapse, and resumption led to recapture of benefit. This case demonstrates the possibility that PKD-like symptoms may co-occur with TS and may be responsive to carbamazepine.

Unlocking the genetics of paroxysmal kinesigenic dyskinesia

Paroxysmal kinesigenic dyskinesia (PKD, or paroxysmal kinesigenic choreoathetosis) is a rare and remarkable hereditary disorder that was recognized as early as 1892 and defined more precisely during the 20th century (Mount and Reback, 1940; Kertesz, 1967; Richards and Barnett, 1968; Lance, 1977; Kato et al ., 2006). Patients with PKD experience recurrent and brief episodes of dystonic or choreoathetotic involuntary movements that are induced by sudden motion, such as standing up quickly or being startled (Bruno et al ., 2004; Bhatia, 2011). Although this disorder can be very disabling if undiagnosed, its outcome is usually benign when treated with low doses of anti-convulsants such as carbamazepine or phenytoin. Most patients with primary idiopathic forms of PKD report a family history of the disease compatible with autosomal dominant inheritance. The first locus for PKD, identified in 1999 on chromosome 16p11.2-q12.1 (EKD1, Fig. 1) overlaps with another locus identified for infantile convulsions and paroxysmal choreoathetosis (ICCA) (Szepetowski et al ., 1997; Tomita et al ., 1999). ICCA is also inherited in an autosomal dominant fashion and is characterized by benign afebrile infantile convulsions that start within the first year of life and usually stop by 3 years of age, variably associated with paroxysmal dyskinesia (Table 1). Benign familial infantile convulsions, ICCA and PKD have thus been proposed to be different expressions of the same disorder or allelic disorders (Caraballo et al ., 2001). Linkage of families with PKD, ICCA and benign familial infantile convulsions to the same region on chromosome 16 has been confirmed by many groups, but despite the sequencing of the 157 genes contained in the region, the causative one has remained a mystery for more than a decade (Kikuchi et al ., 2007). Figure 1 Schematic representation of chromosome 16, showing the overlapping loci …

Identification of PRRT2 as the causative gene of paroxysmal kinesigenic dyskinesias

Paroxysmal kinesigenic dyskinesias is a paroxysmal movement disorder characterized by recurrent, brief attacks of abnormal involuntary movements induced by sudden voluntary movements. Although several loci, including the pericentromeric region of chromosome 16, have been linked to paroxysmal kinesigenic dyskinesias, the causative gene has not yet been identified. Here, we identified proline-rich transmembrane protein 2 (PRRT2) as a causative gene of paroxysmal kinesigenic dyskinesias by using a combination of exome sequencing and linkage analysis. Genetic linkage mapping with 11 markers that encompassed the pericentromeric of chromosome 16 was performed in 27 members of two families with autosomal dominant paroxysmal kinesigenic dyskinesias. Then, the whole-exome sequencing was performed in three patients from these two families. By combining the defined linkage region (16p12.1–q12.1) and the results of exome sequencing, we identified an insertion mutation c.649_650InsC (p.P217fsX7) in one family and a nonsense mutation c.487C>T (p.Q163X) in another family. To confirm our findings, we sequenced the exons and flanking introns of PRRT2 in another three families with paroxysmal kinesigenic dyskinesias. The c.649_650InsC (p.P217fsX7) mutation was identified in two of these families, whereas a missense mutation, c.796C>T (R266W), was identified in another family with paroxysmal kinesigenic dyskinesias. All of these mutations completely co-segregated with the phenotype in each family. None of these mutations was identified in 500 normal unaffected individuals of matched geographical ancestry. Thus, we have identified PRRT2 as the first causative gene of paroxysmal kinesigenic dyskinesias, warranting further investigations to understand the pathogenesis of this disorder.

Exome sequencing identifies truncating mutations in PRRT2 that cause paroxysmal kinesigenic dyskinesia

Paroxysmal kinesigenic dyskinesia is the most common type of paroxysmal movement disorder and is often misdiagnosed clinically as epilepsy. Using whole-exome sequencing followed by Sanger sequencing, we identified three truncating mutations within PRRT2 (NM_145239.2) in eight Han Chinese families with histories of paroxysmal kinesigenic dyskinesia: c.514_517delTCTG (p.Ser172Argfs*3) in one family, c.649dupC (p.Arg217Profs*8) in six families and c.972delA (p.Val325Serfs*12) in one family. These truncating mutations co-segregated exactly with the disease in these families and were not observed in 1,000 control subjects of matched ancestry. PRRT2 is a newly discovered gene consisting of four exons encoding the proline-rich transmembrane protein 2, which encompasses 340 amino acids and contains two predicted transmembrane domains. PRRT2 is highly expressed in the developing nervous system, and a truncating mutation alters the subcellular localization of the PRRT2 protein. The function of PRRT2 and its role in paroxysmal kinesigenic dyskinesia should be further investigated.

Alteration of Ictal and Interictal Perfusion in Patients with Paroxysmal Kinesigenic Dyskinesia

Although previous cerebral blood flow studies have suggested that the basal ganglia or thalamus are involved in the pathogenesis of paroxysmal kinesigenic dyskinesia (PKD), the precise anatomic substrate or pathophysiological networks associated with PKD remain unclear. Here, ictal and interictal single photon emission computed tomography (SPECT) in 2 patients with idiopathic PKD compared to 6 age-matched normal controls and the perfusion findings of subtraction ictal SPECT co-registered to MRI (SISCOM) in 1 patient are reported. The interictal and ictal perfusion changes were different in each of the patients and there were no consistent anatomic substrates observed. 2 patients had significant perfusion changes in the left frontal/temporal cortices compared to controls, whereas the others showed an increased uptake of 99mTc-ethyl cysteinate dimer (ECD) in the left occipital area on subtraction SPECT imaging. The results of this study suggest that the pathophysiology of PKD cannot be simply explained by lesions of the basal ganglia or thalamus, and that other associated areas of the cortex are likely involved in these movement disorders.