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GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. Information that appears in the Resources section of a GeneReview is current as of initial posting or most recent update of the GeneReview. Search GeneTests for this disorder and select
for the most up-to-date Resources information.—ED.
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.—ED.
Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.
Genetics clinics are a source of 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.
Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Disease 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, excitement, stress, fatigue, or chocolate. 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 50 years.
Diagnosis/testing. 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 known to be associated with familial PNKD. Molecular genetic testing of PNKD is available on a research basis only.
Management. 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 or tea, excitement, stress, fatigue, and chocolate, 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 gene mutation. Because PNKD demonstrates incomplete penetrance, approximately 10% of individuals with a PNKD mutation may be asymptomatic. Prenatal testing is possible for pregnancies at increased risk in families in which the disease-causing mutation is known.
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
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.—ED.
Gene. PNKD (previously known as MR1), the gene encoding paroxysmal nonkinesiogenic 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 Canadian family of European decent [Spacey et al 2006]. The family differs from those with PNKD gene mutations in that caffeine and alcohol do not trigger attacks in affected family members.
Six other PNKD pedigrees without PNKD gene 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 (RefSeq NM_015488; see Table 2) [Lee et al 2004, Rainier et al 2004, Bruno et al 2007].
Table 1 summarizes molecular genetic testing for this disorder.
Table 1. Molecular Genetic Testing Used in Familial Paroxysmal Nonkinesigenic Dyskinesia
| Test Method | Mutations Detected | Proportion of PNKD Attributed to Mutations in This Gene | Mutation Detection Frequency 1 | Test Availability |
|---|---|---|---|---|
| Sequence analysis | PNKD sequence variants | Unknown 2 | 57%-100% 3 | Clinical
 |
2. There is locus heterogeneity, but the proportion of familial PNKD that can be attributed to mutations in PNKD is unknown.
3. In a recent study eight of 14 PNKD pedigrees tested positive for PNKD mutations [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 10 minutes to 4 hours duration which could be precipitated by caffeine or alcohol, all affected individuals had a PNKD mutation.
Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.
No other phenotypes are known to be associated with mutations in PNKD.
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. Attacks 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].
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 has not been observed in individuals with PNKD mutations.
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.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Paroxysmal dyskinesias can occur sporadically or as a feature of a number of hereditary disorders.
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, hypoparathyriodism, pseudohypoparathyroidism, and thyrotoxicosis. The relevant blood work should be done if these etiologies are being considered [Mahmud et al 2005].
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 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 clinically available.
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]. 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 five to 15 minutes. The body part involved in the exercise is usually the one that experiences the attacks [Bhatia et al 1997]. The gene for PED has not been identified. However, the locus for PED in a single pedigree 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. No families with PED have been found to have PNKD mutations [Bruno et al 2007].
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 NREM 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 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 the HD gene of 36 or more CAG trinucleotide repeats [Warby et al 2007].
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
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].
Alcohol, coffee, tea, excitement, stress, fatigue, and chocolate are all known to precipitate attacks and thus should be avoided.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
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
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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Familial paroxysmal nonkinesigenic dyskinesia (PNKD) is inherited in an autosomal dominant manner.
Parents of a proband
Eighty to 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 gene 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 gene 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 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 or has a disease-causing mutation, his/her family members are at risk.
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 of having a disease-causing mutation.
DNA banking. DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA, particularly when the sensitivity of currently available testing is less than 100%. See
for a list of laboratories offering DNA banking.
Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15-18 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
.
Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.
| Gene Symbol | Chromosomal Locus | Protein Name |
|---|---|---|
| PNKD | 2q35 | Paroxysmal nonkinesiogenic dyskinesia protein |
Data are compiled from the following standard references: gene symbol from HUGO; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from Swiss-Prot.
| Gene Symbol | Entrez Gene | HGMD |
|---|---|---|
| PNKD | 25953 (MIM No. 609023) | PNKD |
For a description of the genomic databases listed, click here.
Note: HGMD requires registration.
Normal allelic variants. PNKD, also 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].
| DNA Nucleotide Change | Protein Amino Acid Change | Reference Sequence 1 |
|---|---|---|
| g.66C>T | p.Ala7Val | NM_015488 |
| g.72C>T | p.Ala9Val |
See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (http://www.hgvs.org).
1. Reference sequence (www.ncbi.nlm.nih.gov/Genbank/index.html)
Normal gene product. The function of paroxysmal nonkinesiogenic dyskinesia protein, the protein encoded by PNK, 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 is the larger of the two and codes for a 385-amino-acid protein; NM_022572 encodes for a 361-amino-acid protein. Expression detection by RT-PCR showed expression of PNKD NM_015488 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 [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 nonkinesiogenic dyskinesia protein. The substitutions are predicted to disrupt the alpha helix structure [Rainier et al 2004].
GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. Information that appears in the Resources section of a GeneReview is current as of initial posting or most recent update of the GeneReview. Search GeneTests for this disorder and select
for the most up-to-date Resources information.—ED.
Dystonia Medical Research Foundation
One East Wacker Drive Suite 2430
Chicago IL 60601-1905
Phone: 312-755-0198; 800-377-DYST (3978)
Fax: 312-803-0138
Email: dystonia@dystonia-foundation.org
Paroxysmal Dystonia and Dyskinesias
WE MOVE (Worldwide Education and Awareness for Movement Disorders)
204 West 84th Street
New York NY 10024
Phone: 800-437-MOV2 (800-437-6683)
Fax: 212-875-8389
Email: wemove@wemove.org
Dyskinesia (Paroxysmal)
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page.
No specific guidelines regarding genetic testing for this disorder have been developed.
26 August 2008 (cg) Comprehensive update posted live
24 June 2005 (ca) Review posted to live Web site
2 December 2004 (ss) Original submission
