Familial Paroxysmal Nonkinesigenic Dyskinesia
Synonyms: Paroxysmal Dystonic Choreoathetosis, Paroxysmal Nonkinesigenic Dyskinesia, PNKD
Roberto Erro, MD, PhD.
Author Information and AffiliationsInitial Posting: June 24, 2005; Last Update: April 4, 2019.
Estimated reading time: 15 minutes
Summary
Clinical characteristics.
Familial paroxysmal nonkinesigenic dyskinesia (PNKD) is characterized by unilateral or bilateral involuntary movements. Attacks are typically precipitated by coffee, tea, or alcohol; they can also be triggered by excitement, stress, or fatigue, or can be spontaneous. 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.
Diagnosis/testing.
The clinical diagnosis of familial PNKD is suspected in a proband who presents with attacks of dystonia, chorea, and/or ballismus typically provoked by alcohol or caffeine. Identification of a heterozygous pathogenic variant in PNKD by molecular genetic testing confirms the diagnosis.
Management.
Treatment of manifestations: Avoid triggers (e.g., caffeine, alcohol, excitement, stress, fatigue). Response to pharmacologic treatment is poor; clonazepam or diazepam can be effective in some individuals. Some individuals have responded to gabapentin, levetiracetam, or acetazolamide.
Surveillance: Monitor medication requirements and dosage.
Genetic counseling.
Familial PNKD is inherited in an autosomal dominant manner. To date, all reported individuals with familial PNKD have inherited PNKD from an affected parent. Offspring of an affected individual have a 50% chance of inheriting the PNKD pathogenic variant. Once the PNKD pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Diagnosis
Suggestive Findings
Familial paroxysmal nonkinesigenic dyskinesia (PNKD) should be suspected in individuals with the following features:
Attacks:
Of dystonia, chorea, and/or ballismus, with onset during infancy
That can be provoked by alcohol or caffeine
Not typically triggered by sudden movement or sustained exercise
Lasting several minutes to hours
Rarely occurring more than once per day
No loss of consciousness during an attack
Poor response to pharmacologic treatment (although clonazepam or diazepam can be effective)
Normal:
Family history consistent with autosomal dominant inheritance
Establishing the Diagnosis
The diagnosis of familial PNKD is established in an individual with the above Suggestive Findings by identification of a heterozygous pathogenic variant in PNKD (formerly named MR-1) by molecular genetic testing (see Table 1).
Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive
genomic testing (exome sequencing, genome sequencing) depending on the phenotype.
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of PNKD is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of PNKD has not been considered are more likely to be diagnosed using genomic testing (see Option 2).
Option 1
When the phenotypic and laboratory findings suggest the diagnosis of PNKD, molecular genetic testing approaches can include single-gene testing or use of a multigene panel:
Single-gene testing. Sequence analysis of PNKD detects small intragenic deletions/insertions and missense, nonsense, and splice site variants.
Note: The usefulness of deletion/duplication analysis is unknown as no deletions or duplications involving PNKD as a cause of familial PNKD have been reported.
A multigene panel that includes
PNKD and other genes of interest (see
Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this
GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click
here. More detailed information for clinicians ordering genetic tests can be found
here.
Option 2
When the diagnosis of PNKD is not considered because an individual has atypical phenotypic features, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in Familial Paroxysmal Nonkinesigenic Dyskinesia
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| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|
|
PNKD
| Sequence analysis 3 | ~15 families 4 |
| Gene-targeted deletion/duplication analysis 5 | Unknown, none reported 6 |
- 1.
- 2.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or 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.
- 4.
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 6.
Clinical Characteristics
Clinical Description
Familial paroxysmal nonkinesigenic dyskinesia (PNKD) is characterized by unilateral or bilateral involuntary movements. Attacks are often precipitated by caffeinated beverages but can also be spontaneous or triggered by excitement, stress, fatigue, and very rarely by sudden movements or prolonged exercise [Erro et al 2014].
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], Erro et al [2014], Gardiner et al [2015].
Age of onset is typically in infancy or childhood but can in rare cases be as late as age 50 years.
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.
Attacks can occur as frequently as once or twice per day or as infrequently as once or twice per year. Although attacks can rarely be as short as 30 seconds, more frequently they last five minutes to six hours. In 50%-60% of individuals with familial PNKD, the frequency of attacks diminishes with age.
Expressivity is variable within and among families. Varying degrees of severity in symptoms occur; attacks involving respiratory muscles are potentially life threatening [Djarmati et al 2005, Bruno et al 2007, Zittel et al 2015].
Unlike familial paroxysmal kinesigenic dyskinesia (PKD), familial PNKD is not typically associated with seizures. When PNKD co-occurs with epilepsy, other genetic disorders should be considered (see Differential Diagnosis).
Genotype-Phenotype Correlations
There are currently no known genotype-phenotype correlations.
Penetrance
Bruno et al [2007] calculated the penetrance of familial PNKD in individuals with PNKD pathogenic variants to be 98%; the asymptomatic individual in the study was too young to be considered unaffected.
Nomenclature
Familial PNKD is classified as paroxysmal dyskinesia [Erro & Bhatia 2019]. 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.
Classification of the paroxysmal dyskinesias is based on the duration of attacks and whether the attacks are precipitated by movement, sustained exercise, or nonkinesigenic triggers. Before the discovery of the genes responsible for the paroxysmal dyskinesias, Demirkiran and Jankovic [1995] studied 46 individuals identified with both "idiopathic" and symptomatic 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 coffee, alcohol, stress, fatigue, menses, and heat, but not precipitated by exercise or movement, typically lasting minutes to hours
A study by
Bruno et al [2007] suggested further modifications to the clinical criteria to identify individuals with
PNKD pathogenic variants:
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 attacks 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 has been recognized in most cases to be a form of epilepsy:
autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). However, pathogenic variants in
PRRT2 and
ADCY5 have recently been associated with non-epileptic paroxysmal dyskinesias occurring during sleep.
Outdated terms for PNKD
Prevalence
Familial PNKD is extremely rare; exact prevalence is unknown.
Differential Diagnosis
Paroxysmal dyskinesias have been reported in individuals with the following disorders (brain MRI examination is important to rule out these etiologies):
Basal ganglia lesions caused by multiple sclerosis
Tumors
Vascular lesions including moyamoya disease
Penetrating brain injury (e.g., right frontal)
Central pontine myelinolysis
Focal seizures can present with paroxysms of dystonia; EEG is an essential part of the investigations.
Autoimmune disorders. 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.
Other. 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].
Inherited Causes of Paroxysmal Dyskinesia
Table 2.
Disorders to Consider in the Differential Diagnosis of Familial PNKD
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MOI /
Category | Disorder | Gene(s) | Age of Onset | Neurologic Presentation |
|---|
AD /
Paroxysmal dyskinesias | Familial paroxysmal kinesigenic dyskinesia
(See PRRT2-Associated Paroxysmal Movement Disorders.) | PRRT2 1 | Typically childhood & adolescence | Attacks of dyskinesia:
Are triggered by sudden movement; Last secs to mins; May occur 100x/day; Do not cause loss of consciousness, & persons have normal ictal EEG.
Clinical spectrum can incl:
Episodic ataxia; Hemiplegic migraine.
Some persons have personal or family history of afebrile convulsions. |
|
Glucose transporter type 1 deficiency syndrome
|
SLC2A1
| Infancy | PED:
|
|
Autosomal dominant nocturnal frontal lobe epilepsy
| Many | Infancy to adulthood | Incl dystonia, chorea, & ballism Episodes generally occur during non-REM sleep, often evoking arousal followed again by sleep. Persons are able to recall the episodes in the morning.
|
| KCNMA1-related paroxysmal dyskinesia (OMIM 609446) |
KCNMA1
| Childhood |
|
|
ADCY5-related dyskinesia
|
ADCY5
| Childhood | Choreiform, myoclonic, &/or dystonic movements w/attacks of paroxysmal dyskinesia, exacerbated by anxiety, not precipitated by startle, caffeine, or alcohol |
| Alternating hemiplegia of childhood (See ATP1A3-Related Neurologic Disorders.) |
ATP1A3
| Childhood | Alternating (i.e., from one side of the body to the other) attacks of dystonia w/a typical rostrocaudal distribution that may be triggered by fever, trauma, or stress |
AD /
Dyskinesias | Benign hereditary chorea (See NKX2-1-Related Disorders.) |
NKX2-1
| Childhood |
|
XL & AR /
Dyskinesias | Pyruvate dehydrogenase deficiency (See Primary Pyruvate Dehydrogenase Complex Deficiency Overview.) | Many | Childhood |
|
AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; MOI = mode of inheritance; PED = paroxysmal exercise-induced dyskinesia; XL = X-linked
- 1.
Heterozygous pathogenic variants in PRRT2 have been reported as causative of familial paroxysmal kinesigenic dyskinesia (PKD) in a subset of persons. The other gene(s) associated with PKD have not been identified.
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with familial paroxysmal nonkinesigenic dyskinesia (PNKD), the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:
Treatment of Manifestations
Avoid triggers (e.g., caffeine, alcohol).
Response to pharmacologic treatment is poor; however, clonazepam or diazepam can be effective in at least 50% of individuals with PNKD, although response may decrease over time.
Surveillance
Monitor medication requirements and dosage.
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 anticonvulsant therapy for familial PNKD are advised to take folic acid (5 mg/day). Because of the risk of teratogenic effects related to anticonvulsants, women with mild symptoms related to familial PNKD may consider discontinuing anticonvulsant therapy during pregnancy.
See MotherToBaby for access further information on medication use during pregnancy.
Therapies Under Investigation
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe 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, mode(s) of 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; it is not meant to address all personal, cultural, or
ethical issues that may arise 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
To date, all reported individuals with PNKD have an affected parent.
To date, no individuals diagnosed with PNKD have the disorder as the result of a de novo
PNKD pathogenic variant. The proportion of cases caused by de novo pathogenic variants is unknown.
Neurologic assessment and molecular genetic testing are recommended for the parents of a proband with an apparent de novo pathogenic variant.
If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a de novo variant in the proband or germline mosaicism in a parent (though theoretically possible, no instances of germline mosaicism have been reported).
Note: Although to date all individuals diagnosed with familial 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, or late onset of the disease in the affected parent.
Sibs of a proband. The risk to the sibs of a proband depends on the genetic status of the proband's parents:
If the parents have been tested for the PNKD pathogenic variant identified in the proband and:
A parent of the proband has the
PNKD pathogenic variant, the risk to the sibs of inheriting the variant is 50%; intrafamilial clinical variability has been observed (see
Clinical Description).
The
PNKD pathogenic variant cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [
Rahbari et al 2016].
If the parents have not been tested for the PNKD pathogenic variant but are clinically unaffected, the risk to sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for PNKD because of the possibility of reduced penetrance in a parent or the theoretic possibility of parental germline mosaicism.
Offspring of a proband. Each child of an individual with PNKD has a 50% chance of inheriting the PNKD pathogenic variant.
Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the PNKD pathogenic variant, his or her family members may be at risk.
Prenatal Testing and Preimplantation Genetic Testing
Once the PNKD pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
Resources
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.
Dystonia Medical Research Foundation
One East Wacker Drive
Suite 1730
Chicago IL 60601-1905
Phone: 800-377-3978 (toll-free); 312-755-0198
Fax: 312-803-0138
National Library of Medicine Genetics Home Reference
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
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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.
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 studies including 62 affected individuals from ten families, one of the two pathogenic variants in Table 3 was found in all 62 individuals [Lee et al 2004, Rainier et al 2004]. An additional pathogenic variant (p.Ala33Pro) was reported in one affected individual.
Table 3.
PNKD Variants Discussed in This GeneReview
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DNA Nucleotide Change
(Alias 1) | Predicted Protein Change | Reference Sequences |
|---|
c.20C>T
(66C>T) | p.Ala7Val |
NM_015488.4
NP_056303.3
|
c.26C>T
(72C>T) | p.Ala9Val |
| c.97G>C | p.Ala33Pro |
Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
- 1.
Variant designation that does not conform to current naming conventions
Normal gene product.
PNKD encodes probable hydrolase PNKD. PNKD function has not been fully characterized; however, based on approximately 40% homology between PNKD and HAGH, the gene encoding hydroxyacylglutathione hydrolase, which functions in detoxification of methylgloyoxal, a compound produced during oxidative stress and found in alcoholic beverages and coffee, it was thought that PNKD was also implicated in this detoxification pathway [Lee et al 2004]. However, in cultured cells and transgenic animals PNKD did not effectively restore absent HAGH activity, suggesting that it does not intervene in this pathway at appreciable levels in vivo [Shen et al 2011].
PNKD binds to Rab3-interacting molecules (RIMs), a group of proteins playing a role in vesicle priming and calcium-dependent neurotransmitter release, suggesting a possible role in synaptic regulation [Shen et al 2015, Erro et al 2017]. Given that caffeine stimulates calcium efflux from the endoplasmic reticulum at presynaptic terminals, the hypothesis would be that neurons might be more vulnerable to high concentration of calcium and hence could become hyperexcitable when challenged with caffeine [Shen et al 2015].
Two reported PNKD transcripts 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 (Table 3) [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].
References
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Chapter Notes
Author History
Paul Adams, PhD; University of British Columbia (2004-2019)
Roberto Erro, MD, PhD (2019-present)
Sian Spacey, MD, FRCPC; University of British Columbia (2004-2019)
Revision History
4 April 2019 (sw) Comprehensive update posted live
3 May 2011 (me) Comprehensive update posted live
26 August 2008 (cg) Comprehensive update posted live
24 June 2005 (ca) Review posted live
2 December 2004 (ss) Original submission
