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Familial Paroxysmal Nonkinesigenic Dyskinesia

Synonyms: Paroxysmal Dystonic Choreoathetosis, Paroxysmal Nonkinesigenic Dyskinesia, PNKD

, MD, FRCPC and , PhD.

Author Information

Initial Posting: ; Last Update: May 3, 2011.


Clinical characteristics.

Familial paroxysmal nonkinesigenic dyskinesia (referred to as familial PNKD in this entry) is characterized by unilateral or bilateral involuntary movements; attacks are spontaneous or precipitated by alcohol, coffee or tea, chocolate, excitement, stress, or fatigue. Attacks involve dystonic posturing with choreic and ballistic movements, may be accompanied by a preceding aura, occur while the individual is awake, and are not associated with seizures. Attacks last minutes to hours and rarely occur more than once per day. Attack frequency, duration, severity, and combinations of symptoms vary within and among families. Age of onset is typically in childhood or early teens, but can be as late as age 50 years.


The clinical diagnosis of familial PNKD is based on the presence of attacks of dystonia, chorea, ballismus, or athetosis, often provoked by alcohol or caffeine. PNKD, the gene encoding myofibrillogenesis regulator 1, is the only gene in which pathogenic variants are known to cause familial PNKD.


Treatment of manifestations: Response to pharmacologic treatment is poor; clonazepam or diazepam can be effective. One individual responded to gabapentin.

Agents/circumstances to avoid: Alcohol, coffee and tea, chocolate, excitement, stress, and fatigue, which are known to precipitate attacks.

Genetic counseling.

Familial PNKD is inherited in an autosomal dominant manner. Offspring of an affected individual have a 50% chance of inheriting the PNKD pathogenic variant. Because PNKD demonstrates incomplete penetrance, approximately 10% of individuals with a PNKD pathogenic variant may be asymptomatic. Prenatal testing for pregnancies at increased risk is possible if the pathogenic variant in the family is known.


Clinical Diagnosis

The 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 athetosis
  • Attacks that can be provoked by alcohol or caffeine
  • Attacks not typically triggered by movement
  • Attacks lasting minutes to hours
  • Attacks rarely occurring more than once per day
  • No loss of consciousness during the attack
  • Poor response to pharmacologic treatment, although clonazepam or diazepam can be effective
  • A normal interictal neurologic examination
  • A normal ictal and interictal EEG
  • A normal MRI
  • A family history consistent with autosomal dominant inheritance

Molecular Genetic Testing

Gene. 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 pathogenic variants in that caffeine and alcohol do not trigger attacks in affected family members.

Six other PNKD pedigrees without PNKD pathogenic variants 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 pathogenic variants.

Clinical testing

Table 1.

Summary of Molecular Genetic Testing Used in Familial Paroxysmal Nonkinesigenic Dyskinesia

Gene 1Proportion of Familial PNKD Attributed to Mutation of This GeneTest MethodVariants Detected 2Variant Detection Frequency by Test Method 3
PNKDUnknown 4Sequence analysis 5Sequence variantsSee footnote 6
Deletion/duplication analysis 7Exon or whole-gene deletionsUnknown; none reported 8

See Molecular Genetics for information on allelic variants.


The ability of the test method used to detect a pathogenic variant that is present in the indicated gene


There is locus heterogeneity, but the proportion of familial PNKD that can be attributed to pathogenic variants in PNKD is unknown.


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


In one study eight of 14 families with PNKD tested positive for a PNKD pathogenic variant [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 pathogenic variant.


Testing that identifies exon or whole-gene deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.


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.)

Testing Strategy

To confirm/establish the diagnosis in a proband. Perform sequence analysis of PNKD 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 pathogenic variant in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the pathogenic variant in the family.

Clinical Characteristics

Clinical Description

Familial 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, chocolate, excitement, stress, and fatigue. 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 Correlations

Attacks in individuals in whom a PNKD pathogenic variant 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 pathogenic variant has not been identified are more variable in age at onset, clinical features, precipitants, and response to medications [Bruno et al 2007].


The penetrance for familial PNKD is greater than 90% in both males and females [Fink et al 1997, Jarman et al 1997, Tomita et al 1999, Lee et al 2004]. Lee et al [2004] determined that 50 of 52 individuals with a PNKD pathogenic variant had the phenotype; the remaining two individuals were too young for phenotype to be clarified. Bruno et al [2007] calculated the penetrance of PNKD in individuals with PNKD pathogenic variants to be 98%; the asymptomatic individual in the study was too young to be considered unaffected.


Anticipation has not been observed in individuals with PNKD pathogenic variants.


Familial PNKD is classified as paroxysmal dyskinesia. All of the disorders included in the dyskinesia category are characterized by intermittent occurrence of dystonia, chorea, and ballism of varying duration. The nomenclature used to classify the paroxysmal dyskinesias has been evolving over the past 60 years.

Recent classification. The classification of the paroxysmal dyskinesias is based on the duration of attacks and whether the attacks are precipitated by movement. Demirkiran and Jankovic [1995] studied 46 individuals identified with paroxysmal movement disorders and devised the following classification system:

  • Paroxysmal kinesigenic dyskinesia (PKD) defined as attacks of dyskinesia precipitated primarily by sudden movement and typically lasting less than five minutes
  • Paroxysmal nonkinesigenic dyskinesia (PNKD) defined as attacks of dyskinesia precipitated by stress, fatigue, menses, and heat, but not precipitated by exercise or movement, typically lasting minutes to hours
    A recent study [Bruno et al 2007] suggested further modifications to the classification system to identify PNKD with PNKD pathogenic variants:
    • Hyperkinetic involuntary movement attacks, with dystonia, chorea, or combination of these, typically lasting ten minutes to one hour, but potentially up to four hours
    • Normal neurologic examination results between attacks, and exclusion of secondary causes
    • Onset of attack in infancy or early childhood
    • Precipitation of attacks by caffeine and alcohol consumption
    • Family history of movement disorder meeting all preceding criteria
  • Paroxysmal exertion-induced dyskinesia (now referred to as paroxysmal exercise-induced dyskinesia) (PED) includes attacks of dyskinesia precipitated by five to 15 minutes of physical exertion, such as walking and running, typically lasting 15 to 30 minutes.
  • Paroxysmal hypnogenic dyskinesia is characterized by attacks of dyskinesia occurring primarily during sleep. This is now recognized to be a form of epilepsy, autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE).

Historical classification/nomenclature. Initial classification of "familial paroxysmal choreoathetosis" was made by Mount and Reback in 1940. They described an individual with attacks of chorea occurring three times per day and lasting five minutes to hours. The precipitating factors included coffee, tea, alcohol, smoking, and fatigue [Mount & Reback 1940].

Kertesz [1967] suggested the term paroxysmal kinesigenic choreoathetosis for disorders characterized by attacks precipitated by sudden movement.

Richards and Barnett [1968] introduced the term paroxysmal dystonic choreoathetosis for disorders characterized by long-lasting attacks that were not provoked by sudden movement.

Lance [1977] classified the paroxysmal dyskinesias into three groups based primarily on the duration of attacks and whether movement induced the attacks:

  • Paroxysmal dystonic choreoathetosis (PDC) included prolonged attacks (2 minutes to 4 hours) not precipitated by sudden movement or prolonged exertion.
  • Paroxysmal kinesigenic choreoathetosis (PKC) included short attacks (seconds to 5 minutes) induced by sudden movement.
  • An intermediate form included attacks (5-30 minutes in duration) precipitated by continued exertion rather than sudden movement.


Familial PNKD is extremely rare, but more common than the simplex form of PNKD (i.e., the occurrence of a single affected individual in a family).

Differential Diagnosis

Paroxysmal dyskinesias can occur sporadically or as a feature of a number of hereditary disorders.

Sporadic Causes

Sporadic 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 Cause

Wilson 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. Pathogenic variants in ATP7B are causative.

Autosomal Dominant Causes

Most 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 pathogenic variants 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].
  • 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]. Pathogenic variants 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.


Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with familial paroxysmal nonkinesigenic dyskinesia (PNKD), the following evaluations are recommended:

  • MRI to rule out secondary causes of PNKD
  • EEG to rule out seizures as a cause for the dyskinesias

Treatment of Manifestations

Response to pharmacologic treatment is poor; however, clonazepam or diazepam can be effective.


No long-term sequelae are associated with PNKD. Monitoring medication requirements and dosage is appropriate.

Agents/Circumstances to Avoid

Alcohol, coffee, tea, chocolate, excitement, stress, and fatigue are all known to precipitate attacks and thus should be avoided.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Pregnant women who are on anticonvulsants therapy for PNKD 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 PNKD may consider discontinuing anticonvulsant therapy during pregnancy.

Therapies Under Investigation

Search 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Familial paroxysmal nonkinesigenic dyskinesia (PNKD) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

Note: Although most individuals diagnosed with PNKD have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, late onset of the disease in the affected parent, or reduced penetrance.

Sibs of a proband. The risk to the sibs of a proband depends on the status of the parents:

Offspring of a proband. Each child of an individual who has a pathogenic variant or is clinically affected has a 50% chance of inheriting the pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents. If a parent is affected or has a pathogenic variant, his/her family members are at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant or clinical evidence of the disorder, it is possible that the proband has a de novo pathogenic variant or the disease is sporadic (see Differential Diagnosis). However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the PNKD pathogenic variant has been identified in an affected family member, prenatal diagnosis for a pregnancy at increased risk and preimplantation genetic diagnosis for PNKD are possible.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information 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 Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
PNKD2q35Probable hydrolase PNKDPNKD databasePNKDPNKD

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Familial Paroxysmal Nonkinesigenic Dyskinesia (View All in OMIM)


Gene structure. PNKD, previously known as MR-1, exists in three alternatively spliced forms of three, nine, and ten exons. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. In two recent studies including 62 affected individuals from ten families, one of the two pathogenic variants in Table 2 was found in all 62 individuals [Lee et al 2004, Rainier et al 2004].

Table 2.

Selected PNKD Pathogenic Variants

DNA Nucleotide Change
(Alias 1)
Predicted Protein ChangeReference Sequences

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​ See Quick Reference for an explanation of nomenclature.


Variant designation that does not conform to current naming conventions

Normal 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].


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Chapter Notes

Revision History

  • 3 May 2011 (me) Comprehensive update posted live
  • 26 August 2008 (cg) Comprehensive update posted live
  • 24 June 2005 (ca) Review posted to live Web site
  • 2 December 2004 (ss) Original submission
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