DiagnosisClinical DiagnosisThe following findings support the clinical diagnosis of familial paroxysmal kinesigenic dyskinesia (PKD) [Bruno et al 2004]:Attacks of dystonia, chorea, ballismus, or athetosis triggered by sudden movement (e.g., having the individual stand up suddenly or walk briskly up and down the hall)Attack duration lasting seconds to minutesAttack frequency as high as 100 times/dayNo loss of consciousness during the attackReduction in attack frequency or prevention by the anticonvulsants phenytoin or carbamezepine
Note: The diagnosis of PKD can be further confirmed with a trial of low-dose phenytoin (100 mg) or carbamezepine (250 mg), which is usually sufficient to eliminate attacks.A normal interictal neurologic examinationA normal ictal and interictal EEGA normal MRIA family history consistent with autosomal dominant inheritanceMolecular Genetic TestingGene. Mutations in PRRT2 have been reported as causative of familial PKD in a subset of cases [Chen et al 2011, Wang et al 2011, Li et al 2012, Liu et al 2012]. Evidence for locus heterogeneity. Other, as yet unidentified, loci are still suspected as not all families with familial PKD have linked to the PRRT2 locus at 16q11.2-q12.1 [Spacey et al 2002, Zhou et al 2008]. Table 1. Summary of Molecular Genetic Testing Used in Familial Paroxysmal Kinesigenic DyskinesiaView in own windowGene Symbol Test MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilityPRRT2Sequence analysisSequence variants 2Unknown Clinical N/ALinkage analysisN/AN/AResearch only1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing Strategy To confirm/establish the diagnosis in a proband sequence analysis of PRRT2 may be considered. However, the diagnosis of familial PKD is based on clinical findings; failure to identify a mutation in PRRT2 does not exclude the diagnosis. Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersInfantile convulsions and choreoathetosis syndrome (ICCA syndrome). ICCA is characterized by afebrile convulsions at age three to 12 months and variable paroxysmal choreoathetosis. The familial form of ICCA is an autosomal dominant disorder with 80% penetrance. Mutations in PRRT2 have been identified in ICCA families [Heron et al 2012, Liu et al 2012]. Benign familial infantile epilepsy (BFIE) is an autosomal self-limiting seizure disorder of infancy. Mutations in PRRT2 have been identified in some BFIE families [Heron et al 2012].}

Natural HistoryFamilial paroxysmal kinesigenic dyskinesia (PKD) is characterized by unilateral or bilateral involuntary movements precipitated by sudden movements, being startled, or changes in velocity [Demirkiran & Jankovic 1995, Houser et al 1999, Tomita et al 1999]. The attacks include combinations of dystonia, choreoathetosis, and ballism. Many individuals experience an "aura"-like sensation (stiffness, tension, paresthesia, or crawling sensation in the affected limb) preceding the attacks [Bhatia 1999, Bhatia 2001]. The attacks do not involve a loss of consciousness.Attack frequency ranges from 100 per day to as few as one per month [Demirkiran & Jankovic 1995]. Most attacks last from a few seconds to five minutes [Houser et al 1999, Tomita et al 1999]; in a few instances, attacks can last several hours [Demirkiran & Jankovic 1995]. In most cases, the frequency of attacks decreases with age [Bhatia 1999, Tomita et al 1999, Bhatia 2001].Familial PKD has been associated with infantile seizures [Hattori et al 2000, Swoboda et al 2000], but not adult-onset seizures [Spacey et al 2002].Expressivity in familial PKD can be variable within as well as among families. Age of onset and severity of symptoms vary. Additionally, a variety of combinations (i.e., with respect to movement type and location) of symptoms are seen; for example, in one family member, an attack may manifest as mild dystonic symptoms on one half of the body, whereas another family member may experience severe bilateral chorea [Spacey et al 2002, Wang et al 2011].Age of onset is typically in childhood or adolescence but ranges from four months to 57 years [Demirkiran & Jankovic 1995, Li et al 2005].Familial PKD occurs more frequently in males than in females (~4:1 ratio) [Bhatia 1999].Precipitating factors. Attacks can be precipitated by sudden movement such as standing up from a seated position [Demirkiran & Jankovic 1995, Houser et al 1999, Tomita et al 1999]. However, cold, hyperventilation, and mental tension have also been reported to trigger attacks in individuals who have classic features of familial PKD [Spacey et al 2002].Neuroimaging: Resting state functional magnetic resonance imaging (fMRI) performed on seven individuals with PKD demonstrated significantly increased alteration of amplitude of low-frequency fluctuation bilaterally in the putamen when compared to controls, suggesting that there may be an abnormality in the cortico-striato-pallido-thalamic loop in people with PKD [Zhou et al 2010b].Diffusion tensor imaging, performed on seven individuals with PKD, demonstrated significantly higher fractional anisotropy in the right thalamus compared to controls. Persons with PKD also had lower mean diffusivity values in the left thalamus compared to controls, confirming ultrastructural abnormalities in the thalamus of individuals with PKD [Zhou et al 2010a].

Genotype-Phenotype CorrelationsNo genotype-phenotype correlations are known.

Differential DiagnosisParoxysmal dyskinesias can occur sporadically or as a feature of a number of hereditary disorders.Sporadic CausesSporadic causes of paroxysmal dyskinesias include lesions of the basal ganglia caused by multiple sclerosis [Roos et al 1991], tumors, and vascular lesions including Moyamoya disease [Demirkiran & Jankovic 1995, Gonzalez-Alegre et al 2003]. Lesions outside of the basal ganglia have been reported to cause symptoms resembling paroxysmal kinesigenic dyskinesia (PKD). An individual who sustained a right frontal penetrating injury with contusion and hemorrhage manifested PKD-like symptoms [Richardson et al 1987]. Central pontine myelinolysis has resulted in symptoms consistent with PKD [Baba et al 2003]. Neuroimaging (preferably MRI) is important to rule out these etiologies.Focal seizures can present with paroxysms of dystonia; EEG is an essential part of the investigation.Dyskinesias seen in association with rheumatic fever (Sydenham’s chorea) are associated with a raised anti-streptolysin O (ASO) titer and normal cerebrospinal fluid.Chorea gravidarum can present with paroxysms of chorea in the first trimester of pregnancy and usually resolves after delivery.Paroxysmal chorea can also be seen with systemic lupus erythematosus, diabetes mellitus, hypoparathyroidism, pseudohypoparathyroidism, and thyrotoxicosis. The relevant blood work should be done if these etiologies are being considered [Clark et al 1995, Yen et al 1998, Puri & Chaudhry 2004, Mahmud et al 2005, Thomas et al 2010].Autosomal Recessive CauseWilson disease is a disorder of copper metabolism that can present with hepatic, neurologic, or psychiatric disturbances, or a combination of these, in individuals ranging in age from three years to over 50 years. Neurologic presentations include movement disorders (tremors, poor coordination, loss of fine-motor control, chorea, choreoathetosis) or rigid dystonia (mask-like facies, rigidity, gait disturbance, pseudobulbar involvement). Treatment with copper-chelating agents or zinc can prevent the development of hepatic, neurologic, and psychiatric findings in asymptomatic affected individuals and can reduce findings in many symptomatic individuals. Diagnosis depends in part on the detection of low serum copper and ceruloplasmin concentrations and increased urinary copper excretion. Wilson disease is caused by mutations in ATP7B.Autosomal Dominant CausesMost of the hereditary causes of paroxysmal dyskinesias need to be considered:Paroxysmal exercise-induced dyskinesia (PED) is characterized by attacks of dystonia, chorea, and athetosis lasting five to 30 minutes. Attacks are triggered by prolonged exertion (e.g., walking or running) for five to 15 minutes. The body part involved in the exercise is usually the one that experiences the attacks [Bhatia et al 1997]. PED with epilepsy is observed in glucose transporter type 1 deficiency syndrome, caused by mutations in SLC2A1, encoding the glucose transporter GLUT1 on chromosome 1 [Schneider et al 2009, Suls et al 2008]. Inheritance is autosomal dominant; however, de novo mutations account for the majority of affected individuals. A single family with PED has been linked to the pericentric region of chromosome 16 [Münchau et al 2000]. The locus for autosomal recessive rolandic epilepsy with PED and writer’s cramp has been mapped to 16p12-11.2. Paroxysmal hypnogenic dyskinesia (PHD), now considered to be autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). Attacks associated with PHD/ADNFLE range dramatically, but include dystonia, chorea, and ballism. The episodes generally occur during non-REM sleep. The attacks often evoke arousal followed by sleep. Individuals are able to recall the episodes in the morning. Precipitating factors include increased activity, stress, and menses. Mutations in CHRNA4 [Rozycka et al 2003] and CHRNB2 [Duga et al 2002] have been found in some families with PHD/ADNFLE.Paroxysmal choreoathetosis/spasticity (CSE) is a movement disorder characterized by dystonia in the limbs, dysarthria, abnormal perioral and lower limb sensation, and double vision sometimes followed by headache. The distinguishing characteristic is persistent spasticity [Auburger et al 1996]. CSE appears to be inherited as an autosomal dominant disorder with onset before age five years. CSE has been linked to 1p34-p31 [Auburger et al 1996]. See Glucose Transporter Type 1 Deficiency Syndrome.Other hereditary causes of dyskinesias that can be considered include the following:Benign hereditary chorea is a rare autosomal dominant disorder characterized by non-progressive choreiform movements appearing in childhood without intellectual impairment. It does not shorten the life span of affected individuals, but severely affected individuals can be disabled by the chorea.Huntington disease (HD) is an autosomal dominant progressive disorder of motor, cognitive, and psychiatric disturbances. The mean age of onset is 35 to 44 years; the median survival time is 15 to 18 years after onset. The diagnosis of HD rests on positive family history, characteristic clinical findings, and the detection of an expansion in HTT of 36 or more CAG trinucleotide repeats [Warby et al 2010].X-linked paroxysmal dyskinesia and severe global retardation has been described in two unrelated boys with severe global retardation, an uncommon pattern of thyroid hormone abnormalities, and paroxysmal dyskinesia provoked by stimuli including changing of their clothes or diapers. These two boys have mutations in the thyroid hormone transporter gene, MCT8. Thyroid dysfunction has previously been identified as a cause for PKD [Yen et al 1998, Puri & Chaudhry 2004]. See MCT8 (SLC16A2)-Specific Thyroid Hormone Cell Transporter Deficiency.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with familial paroxysmal kinesigenic dyskinesia (PKD), the following evaluations are recommended:MRI to rule out secondary causes of PKDEEG to rule out seizures as a cause of the dyskinesiasTreatment of ManifestationsAttack frequency is reduced or prevented by the anticonvulsants phenytoin or carbamezepine, typically at lower doses than are used to treat epilepsy [Demirkiran & Jankovic 1995, McGrath & Dure 2003].Other anticonvulsants proven to be effective include oxcarbazepine [Tsao 2004], ethosuximide [Guerrini et al 2002], lamotrigine [Pereira et al 2000], and gabapentin [Chudnow et al 1997].SurveillanceIndividuals with PKD can be monitored every one to two years, particularly with respect to medication needs and doses Pregnancy Management Pregnant women who are on anticonvulsants therapy for PKD are recommended to take folic acid 5 mg/day. Because of the risk of teratogenic effects related to anticonvulsants, women with mild symptoms related to PKD may wish to consider discontinuing anticonvulsant therapy during pregnancy. Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Familial Paroxysmal Kinesigenic Dyskinesia: Genes and DatabasesView in own windowLocus NameGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDEKD1PRRT216p11​.2Proline-rich transmembrane protein 2PRRT2 @ LOVDPRRT2Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Familial Paroxysmal Kinesigenic Dyskinesia (View All in OMIM) View in own window 128200EPISODIC KINESIGENIC DYSKINESIA 1; EKD1 614386PROLINE-RICH TRANSMEMBRANE PROTEIN 2; PRRT2Normal allelic variants. The PRRT2 reference sequence NM_145239.2 has four exons Pathologic allelic variants. More than ten different PRRT2 mutations associated with familial PKD have been described [Chen et al 2011, Wang et al 2011, Li et al 2012, Liu et al 2012]. The most common mutation is c.649_650dupC (p.Arg217Profs*8); the duplication of a cytosine results in a frameshift and a premature stop [Chen et al 2011, Wang et al 2011, Li et al 2012, Liu et al 2012]. Table 2. Selected PRRT2 Pathologic Allelic VariantsView in own windowDNA Nucleotide Change
(Alias ¹) Protein Amino Acid Change
(Alias ¹)Reference Sequencesc.649_650dupC
(649_650insC)p.Arg217Profs*8
(p.P217fs*7)NM_145239​.2
NP_660282​.2See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). 1. Variant designation that does not conform to current naming conventionsNormal gene product. The protein encoded by PRRT2 (NP_660282.2) has 340 amino acids and is predicted to have two transmembrane segments. The function is unknown; however, yeast two-hybrid studies suggest that PRRT2 interacts with synaptosomal-associated protein 25kd (SNAP25) [Stelzl et al 2005]. High levels of PRRT2 mRNA have been identified in the globus pallidus, cerebellum, subthalamic nucleus, cerebellar peduncles, caudate nucleus, and cerebral cortex (www.ebi.ac.uk).Temporal expression patterns of mRNA PRRT2 in developing mouse brain were found to be relatively low before embryonic day 16, substantially increased in postnatal stages, peaking at postnatal day 14, and decreasing to low levels in adulthood [Chen et al 2011]. Abnormal gene product. The truncated PRRT2 protein results in altered subcellular localization [Chen et al 2011].