DiagnosisClinical DiagnosisThe diagnosis of familial paroxysmal nonkinesigenic dyskinesia (PNKD) is most commonly made on clinical grounds. The following findings support the clinical diagnosis:Attacks of dystonia, chorea, ballismus, or athetosisAttacks that can be provoked by alcohol or caffeineAttacks not typically triggered by movementAttacks lasting minutes to hoursAttacks rarely occurring more than once per dayNo loss of consciousness during the attackPoor response to pharmacologic treatment, although clonazepam or diazepam can be effectiveA normal interictal neurologic examinationA normal ictal and interictal EEGA normal MRIA family history consistent with autosomal dominant inheritanceMolecular Genetic TestingGene. PNKD, the gene encoding paroxysmal nonkinesigenic dyskinesia protein (myofibrillogenesis regulator 1), is the only gene known to be associated with familial PNKD [Lee et al 2004, Rainier et al 2004, Chen et al 2005].Other loci. A second locus for familial PNKD has been identified on chromosome 2q31 in a family of European decent [Spacey et al 2006]. The family differs from those with PNKD mutations in that caffeine and alcohol do not trigger attacks in affected family members.Six other PNKD pedigrees without PNKD mutations have been described [Bruno et al 2007], although further loci have not been identified. Alcohol does not trigger attacks in affected members of these pedigrees, a finding that distinguishes them from families with PNKD mutations.Clinical testingSequence analysis. In three studies sequence analysis of PNKD identified either an alanine-to-valine substitution at codon 7 or an alanine-to-valine substitution at codon 9 (see Table 2) [Lee et al 2004, Rainier et al 2004, Bruno et al 2007].Deletion/duplication analysis. The usefulness of deletion/duplication analysis is unknown as no deletions or duplications involving PNKD as a cause of familial paroxysmal nonkinesigenic dyskinesia have been reported.Table 1. Summary of Molecular Genetic Testing Used in Familial Paroxysmal Nonkinesigenic DyskinesiaView in own windowGene SymbolProportion of Familial PNKD Attributed to Mutations in This GeneTest MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilityPNKDUnknown 2Sequence analysisSequence variants 3See footnote 4ClinicalDeletion / duplication analysis 5Exonic or whole-gene deletionsUnknown; none reported 61. The ability of the test method used to detect a mutation that is present in the indicated gene2. There is locus heterogeneity, but the proportion of familial PNKD that can be attributed to mutations in PNKD is unknown.3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.4. In one study eight of 14 families with PNKD tested positive for a PNKD mutation [Bruno et al 2007]. When the clinical criteria were restricted to individuals with a positive family history, onset in infancy or childhood, no secondary cause for their events, normal interictal examinations, and spontaneous hyperkinetic events of ten minutes’ to four hours’ duration which could be precipitated by caffeine or alcohol, all affected individuals had a PNKD mutation.5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment. 6. No deletions or duplications involving PNKD as a cause of familial paroxysmal nonkinesigenic dyskinesia have been reported. (Note: By definition, deletion/duplication analysis identifies rearrangements that are not identifiable by sequence analysis of genomic DNA.)Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing Strategy To confirm/establish the diagnosis in a proband. Perform sequence analysis of PKND in individuals with a history of spontaneous involuntary attacks of dystonia, chorea, or ballismus triggered by caffeine and alcohol and a family history of similar findings consistent with autosomal dominant inheritance.Predicative testing for at-risk adult relatives requires prior identification of the disease-causing mutations in the family.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) DisordersNo other phenotypes are known to be associated with mutations in PNKD.}

Natural HistoryFamilial paroxysmal nonkinesigenic dyskinesia (PNKD) is characterized by unilateral or bilateral involuntary movements. Attacks are often spontaneous, but can be precipitated by alcohol, coffee or tea, excitement, stress, fatigue, and chocolate. Familial PNKD is not precipitated by sudden movement [Bruno et al 2007].The clinical description of this disorder is based on the following citations, unless otherwise noted: Demirkiran & Jankovic [1995], Bhatia [1999], Bhatia [2001], Bruno et al [2007].The attacks predominantly involve dystonic posturing with some choreic and ballistic movements. Individuals often experience an "aura"-like sensation preceding the attacks. Attacks are never associated with a loss of consciousness and never occur during sleep.Unlike familial paroxysmal kinesigenic dyskinesia (PKD), familial PNKD is not associated with seizures.Attacks can occur as frequently as once to twice per day or as infrequently as once to twice per year. Although attacks can be as short as 30 seconds, more frequently they last five minutes to six hours. In some individuals, the frequency of attacks diminishes with age.Expressivity is variable within and among families. Varying degrees of severity in symptoms occur, as well as a variety of combinations of symptoms in terms of movement type and location [Djarmati et al 2005, Bruno et al 2007].Age of onset is typically in infancy or childhood but can be as late as age 50 years.The male-to-female ratio is 1:1 [Lee et al 2004, Bruno et al 2007].

Genotype-Phenotype CorrelationsAttacks in individuals in whom a PNKD mutation has been identified begin in infancy and early childhood. Typical attacks consist of a mixture of chorea and dystonia in the limbs, face, and trunk; a typical attack lasts from ten minutes to one hour. Caffeine, alcohol, and emotional stress are prominent precipitants. Attacks respond favorably to benzodiazepines (e.g., clonazepam, diazepam). Attacks in individuals in whom a PNKD mutation has not been identified are more variable in age at onset, clinical features, precipitants, and response to medications [Bruno et al 2007].

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 the basal ganglia have been reported as causing symptoms resembling paroxysmal kinesigeneic 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 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 investigations.Dyskinesias seen in association with rheumatic fever (Sydenham’s chorea) are associated with a raised anti-streptolysin O (ASO) titer and normal cerebrospinal fluid. PNKD has also been reported as a manifestation of antiphospholipid antibody syndrome [Engelen & Tijssen 2005].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 laboratory testing should be done if these etiologies are being considered [Mahmud et al 2005].Autosomal Recessive CauseWilson disease. Wilson disease is a disorder of copper metabolism that can present with hepatic, neurologic, and/or psychiatric disturbances in individuals ranging from age three years to more than 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. Mutations in ATP7B are causative.Autosomal Dominant CausesMost of the hereditary causes of paroxysmal dyskinesias need to be considered:Familial paroxysmal kinesigenic dyskinesia (PKD) is characterized by attacks of dyskinesia, triggered by sudden movement. Attacks are seconds to minutes in duration and can occur as frequently as 100 times a day [Bruno et al 2004, Mehta et al 2009]. During attacks, individuals do not lose consciousness and have a normal ictal EEG. PKD is associated with infantile seizures [Swoboda et al 2000, Spacey et al 2002]. PKD has been linked to 16q11.2-q22.1 [Tomita et al 1999, Bennett et al 2000, Valente et al 2000].Infantile convulsions and choreoathetosis syndrome (ICCA syndrome) 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. It has been linked to 16p12-q12 in four families from northwestern France [Szepetowski et al 1997] and one family of Chinese origin [Lee et al 1998]. The locus for ICCA overlaps the locus for PKD; thus, it is possible that they are the same condition caused by mutations in the same gene. In some families, it appears that variable expressivity could be manifesting as either infant convulsions or dyskinesia. Identification of the gene will clarify.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 5-15 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 [Seidner et al 1998, Suls et al 2009]. 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. Episodes generally occur during non-REM sleep. 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 [Crowell & Anders 1985, Lee et al 1985]. 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 sensation periorally and in the lower limbs, and double vision sometimes followed by headache. The distinguishing characteristic is persistent spasticity [Auburger et al 1996]. CSE appears to be inherited in an autosomal dominant manner with onset before age five years. CSE has been linked to 1p34-p31 [Auburger et al 1996].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].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 nonkinesigenic dyskinesia (PNKD), the following evaluations are recommended:MRI to rule out secondary causes of PNKDEEG to rule out seizures as a cause for the dyskinesiasTreatment of ManifestationsResponse to pharmacologic treatment is poor; however, clonazepam or diazepam can be effective. A four-year-old child with familial PNKD responded to gabapentin [Chudnow et al 1997]. Szczałuba et al [2009] reported individuals from a family with PKND who responded favorably to levetiracetam.SurveillanceNo long-term sequelae are associated with PKND. Monitoring medication requirements and dosage is appropriate.Agents/Circumstances to AvoidAlcohol, coffee, tea, excitement, stress, fatigue, and chocolate are all known to precipitate attacks and thus should be avoided.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy ManagementPregnant women who are on anticonvulsants therapy for PKND 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 PKND may 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 Nonkinesigenic Dyskinesia: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDPNKD2q35Probable hydrolase PNKDPNKD homepage - Mendelian genesPNKDData 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 Nonkinesigenic Dyskinesia (View All in OMIM) View in own window 118800PAROXYSMAL NONKINESIGENIC DYSKINESIA 1; PNKD1 609023MYOFIBRILLOGENESIS REGULATOR 1Normal allelic variants. PNKD, previously known as MR-1, exists in three alternatively spliced forms of three, nine, and ten exons.Pathologic allelic variants. In two recent studies including 62 affected individuals from ten families, one of the two mutations in Table 2 was found in all 62 individuals [Lee et al 2004, Rainier et al 2004].Table 2. Selected PNKD Pathologic Allelic VariantsView in own windowDNA Nucleotide Change
(Alias ¹) Protein Amino Acid Change Reference Sequencesc.20C>T
(66C>T)p.Ala7ValNM_015488​.4
NP_056303​.3c.26C>T
(72C>T)p.Ala9ValSee 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 function of probable hydrolase paroxysmal nonkinesigenic dyskinesia protein, the protein encoded by PNKD, has not been characterized at this point; however, there is significant sequence homology between PNKD and HAGH, the gene encoding hydroxyacylglutathione hydrolase, which is known to function in detoxification of methylgloyoxal, a compound produced during oxidative stress and also found in alcoholic beverages and coffee [Lee et al 2004]. Two PNKD transcript variants are listed by the National Center for Biotechnology Information database. The two variants are identical in their last eight exons, but differ in the first two exons. NM_015488.4 is the larger of the two and codes for a 385-amino-acid protein; NM_022572.4 encodes for a 361-amino-acid protein. Expression detection by RT-PCR showed expression of PNKD NM_015488.4 in brain and none in the liver, kidney, skeletal muscle, heart, or lung [Lee et al 2004, Rainier et al 2004].Abnormal gene product: In three studies, all affected individuals studied had either an alanine-to-valine substitution at codon 7 or an alanine-to-valine substitution at codon 9 in the PNKD transcript NM_015488.4 [Lee et al 2004, Rainier et al 2004, Bruno et al 2007]. Both of these amino acid substitutions are in a predicted amino-terminal alpha helix domain of the paroxysmal nonkinesigenic dyskinesia protein. The substitutions are predicted to disrupt the alpha helix structure [Rainier et al 2004].