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 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 testing

• Sequence 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. Although available clinically, 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 Dyskinesia

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Gene Symbol	Proportion of Familial PNKD Attributed to Mutations in This Gene	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
PNKD	Unknown 2	Sequence analysis	Sequence variants 3	See footnote 4	Clinical
		Deletion / duplication analysis 5	Exonic or whole-gene deletions	Unknown; none reported 6

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. 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. See array GH.

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.

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

No other phenotypes are known to be associated with mutations in PNKD.

Natural History

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, 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 Correlations

Attacks 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].

Penetrance

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 mutation 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 mutations to be 98%; the asymptomatic individual in the study was too young to be considered unaffected.

Anticipation

Anticipation has not been observed in individuals with PNKD mutations.

Nomenclature

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 mutations:

  • 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.

Prevalence

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).

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. Molecular genetic testing of ATP7B is clinically available.

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 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 2011].

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).

Evaluations Following Initial Diagnosis

To 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 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.

• 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.

Surveillance

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

Agents/Circumstances to Avoid

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

Testing 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 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 Investigation

Search 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.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

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

Risk to Family Members

Parents of a proband

• Approximately 80%-90% of individuals diagnosed with familial PNKD have an affected parent.

• A proband with familial PNKD may have the disorder as the result of a new gene mutation. The proportion of cases caused by de novo mutations is unknown.

• Recommendations for the evaluation of parents of an individual with apparent de novo mutation include neurologic assessment and molecular genetic testing if the mutation has been identified in the 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.

• If a parent of a proband is affected or has a PNKD mutation, the risk to the sibs of inheriting the mutation is 50%.

• Since familial PNKD demonstrates incomplete penetrance, a clinically unaffected parent may have a mutation and sibs of the proband may still be at 50% risk of inheriting the disease-causing mutation.

Offspring of a proband. Each child of an individual who has a disease-causing mutation or is clinically affected has a 50% chance of inheriting the mutation.

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 disease-causing mutation, his/her family members are at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is possible that the proband has a de novo mutation 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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. The disease-causing allele of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

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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