Clinical Diagnosis

The 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 minutes

• Attack frequency as high as 100 times/day

• No loss of consciousness during the attack

• Reduction 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 examination

• A normal ictal and interictal EEG

• A normal MRI

• A family history consistent with autosomal dominant inheritance

Molecular Genetic Testing

Gene. 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 Dyskinesia

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
PRRT2	Sequence analysis	Sequence variants 2	Unknown	Clinical
N/A	Linkage analysis	N/A	N/A	Research only

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. 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.

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any 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

Infantile 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 History

Familial 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 Correlations

No genotype-phenotype correlations are known.

Penetrance

The penetrance for familial PKD has been reported to be between 80% and 90% in both males and females [Tomita et al 1999, Spacey et al 2002].

Anticipation

Anticipation has not been observed.

Nomenclature

Familial PKD is classified as a 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 & 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 a 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 four 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 for 15 to 30 minutes.

  • Paroxysmal hypnogenic dyskinesia is characterized by attacks of dyskinesia occurring primarily during sleep. This is now recognized to be autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), a form of epilepsy.

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 & 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

PKD is rare; prevalence is estimated at 1:150,000. The autosomal dominantly inherited form (familial form) is more common than the simplex form (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 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 Cause

Wilson 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. Molecular genetic testing of ATP7B is available clinically.

Autosomal Dominant Causes

Most 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].

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).

Evaluations Following Initial Diagnosis

To 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 PKD

• EEG to rule out seizures as a cause of the dyskinesias

Treatment of Manifestations

Attack 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].

Surveillance

Individuals 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 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 kinesigenic dyskinesia (PKD) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• More than 90% of individuals with familial PKD have an affected parent.

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

• Recommendations for the evaluation of parents of an individual with an apparent de novo mutation include a thorough history and neurologic examination.

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, the risk to the sibs of inheriting the mutation is 50%.

• Because familial PKD demonstrates incomplete penetrance, a clinically unaffected parent may still have a gene mutation, in which case the sibs of the proband are at a 50% risk of inheriting the mutation.

Offspring of a proband. Offspring of affected individuals with familial PKD have a 50% chance of inheriting the gene mutation.

Other family members. The risk to other family members depends on the status of the proband's parents. If a parent is affected, his or 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 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 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 for a PRRT2 mutation associated with familial PKD 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 mutation of an affected family member must be identified in the family 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.

Requests for prenatal testing for conditions which (like familial PKD) do not affect intellect and have some treatment available are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although decisions about prenatal testing are the choice of the parents, discussion of these issues is appropriate.

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 in GeneReviews™ chapters any 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

• 15 March 2012 (cd) Revision: prenatal testing available clinically for PRRT2 mutations

• 16 February 2012 (cd) Revision: mutations in PRRT2 identified as causative of a subset of cases of familial PKD

• 31 March 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