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Rapid-Onset Dystonia-Parkinsonism

Synonym: DYT12

, MD, , PhD, and , PhD.

Author Information
, MD
Professor and Chair, Department of Neurology
Wake Forest University School of Medicine
Winston-Salem, North Carolina
, PhD
Associate Professor of Cellular and Molecular Physiology
Department of Surgery
Massachusetts General Hospital
Boston, Massachusetts
, PhD
Associate Professor, Departments of Genetics and Genomic Sciences and Neurology
Mount Sinai School of Medicine
New York, New York

Initial Posting: ; Last Revision: September 13, 2012.

Summary

Disease characteristics. Rapid-onset dystonia-parkinsonism (RDP) is characterized by abrupt onset of dystonia with parkinsonism (primarily bradykinesia and postural instability); a clear rostro-caudal (face>arm>leg) gradient of involvement; bulbar involvement; and absence of response to an adequate trial of L-dopa therapy. Often triggering events such as fever, physiologic stress, or alcoholic binges occur prior to the onset of symptoms. The symptoms often stabilize with little improvement after initial appearance with occasional second episodes of abrupt worsening of symptoms. Anxiety, depression, and seizures have been reported. The age of onset of symptoms ranges from four to 55 years.

Diagnosis/testing. Diagnosis of RDP is based on clinical findings. ATP1A3 is the only gene in which mutations are known to cause RDP; it is unclear if mutations in genes at other loci are also causative.

Management. Treatment of manifestations: High-dose benzodiazepines; standard treatment for seizures, depression and anxiety, and dysphagia.

Prevention of secondary complications: Physical therapy to prevent contractures in the hands and feet.

Agents/circumstances to avoid: Triggers of abrupt onset of RDP, such as alcohol, fever, psychological stress, excessive exercise.

Genetic counseling. RDP is inherited in an autosomal dominant manner with incomplete penetrance. Many individuals with RDP have an affected parent; however, de novo mutations are common. Each child of an individual with RDP has a 50% chance of inheriting the mutation. Prenatal diagnosis for pregnancies at increased risk is possible if the disease-causing mutation in the family is known.

Diagnosis

Clinical Diagnosis

Diagnosis of rapid-onset dystonia-parkinsonism (RDP) is based on clinical findings in individuals with mutations in ATP1A3, the only gene in which mutations are known to cause RDP.

Findings in 36 individuals from ten families with an ATP1A3 mutation established the following as the most common clinical features associated with molecularly confirmed RDP [Brashear et al 2007]:

  • Abrupt onset of dystonia with features of parkinsonism over a few minutes to 30 days [Dobyns et al 1993]
  • A clear rostro-caudal (face>arm>leg) gradient of involvement
  • Prominent bulbar findings on examination
  • Absence of response to an adequate trial of L-dopa therapy (e.g., carbidopa/levodopa 25/100 one pill 3x/day)
  • Family history consistent with autosomal dominant inheritance. Of note, de novo mutations are common [Anselm et al 2009, Blanco-Arias et al 2009, Tarsy et al 2010].

Additional features that suggest RDP:

  • Minimal or no tremor at onset
  • Occasional mild limb dystonia prior to the abrupt onset of dystonia
  • Triggers (e.g., running, childbirth, emotional stress, or alcoholic binges) associated with the abrupt onset of symptoms
  • Stabilization of symptoms within a month
  • Rare "second onsets" or abrupt worsening of symptoms later in life
  • Minimal improvement overall, but with limited improvement in gait

Although most people with RDP present with at least some of these typical features, exceptions have included:

  • Onset over age 60 years;
  • Onset of seizures after appearance of motor symptoms.

Testing

Brain imaging. When performed, clinical brain imaging (MRI, CT) is normal. Note: Detailed functional MRI has not been performed.

Position emission tomography (PET) studies using the dopamine transporter imaging agent [11C]β-CFT did not show a decrease in dopamine reuptake sites [Brashear et al 1999].

Striatal [123I]-FP-CIT uptake in one individual with RDP with a previously undescribed ATP1A3 mutation was just within the normal range. [99mTc]-HMPAO scan was also normal [Zanotti-Fregonara et al 2008].

Transcranial sonography in an individual with a previously undescribed ATP1A3 mutation revealed bilateral hyperechogenicity of the substantia nigra, the significance of which is unknown [Svetel et al 2010].

Cerebral blood flow was similar in persons with RDP when compared with age-matched controls [Brashear et al 1999].

Low cerebrospinal fluid concentration of the dopamine metabolite homovanillic acid in symptomatic individuals with an ATP1A3 mutation increased after L-dopa treatment, but did not correlate with clinical improvement [Brashear et al 1998a].

Molecular Genetic Testing

Gene. ATP1A3, which encodes the alpha 3 subunit of the Na,K-ATPase, is the only gene in which mutations are known to cause RDP [de Carvalho Aguiar et al 2004, Brashear et al 2007, McKeon et al 2007, Zanotti-Fregonara et al 2008, Anselm et al 2009, Blanco-Arias et al 2009, Svetel et al 2010, Tarsy et al 2010].

Evidence for locus heterogeneity. In a German family in which had eight members had RDP, none had a mutation in ATP1A3 and none showed linkage to the ATP1A3 locus on chromosome 19, suggesting the presence of at least one additional locus for RDP [Kabakci et al 2005]. Of note, five of the eight affected members had concurrent renal disease which has not been seen in families with an ATP1A3 mutation.

Clinical testing

  • Sequence analysis identified mutations in ten of 21 families referred with "possible" RDP, including four simplex cases (i.e., a single occurrence in a family) with a de novo mutation.

Table 1. Summary of Molecular Genetic Testing Used in Rapid-Onset Dystonia-Parkinsonism

Gene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1
ATP1A3 Sequence analysis of the coding region Sequence variants 2~50% 3

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.

3. Although no other genes or loci are known to be associated with RDP, not all individuals with a phenotype consistent with RDP have an ATP1A3 mutation; therefore, it is possible that mutation of another gene or genes causes RDP.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

Confirming/establishing the diagnosis in a proband. Diagnosis of RDP is based on clinical findings in an individual with a mutation in ATP1A3.

Predictive testing for at-risk asymptomatic adult family members requires prior confirmation of the diagnosis in the family.

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

Clinical Description

Natural History

The study of the clinical manifestations of rapid-onset dystonia-parkinsonism (RDP) has focused on the dystonia/parkinsonism [Dobyns et al 1993, Brashear et al 1996, Brashear et al 1997, Brashear et al 1998b, Kramer et al 1999, Pittock et al 2000, Linazasoro et al 2002, de Carvalho Aguiar et al 2004, Zaremba et al 2004, Kamphuis et al 2006, Lee et al 2007, McKeon et al 2007, Kamm et al 2008, Zanotti-Fregonara et al 2008, Anselm et al 2009, Blanco-Arias et al 2009, Svetel et al 2010, Tarsy et al 2010].

The clinical presentation of RDP includes the following:

  • Rapid onset of dystonia with parkinsonism (primarily bradykinesia and postural instability) over hours to days to weeks
  • Appearance of symptoms after triggering events such as running, childbirth, emotional stress, or alcoholic binges
  • Stability of the phenotype with little improvement after its initial appearance
  • Low concentration of dopamine metabolites in cerebrospinal fluid
  • Absence of other features, such as pill-rolling tremor, diurnal fluctuation, and responsiveness to standard medications for parkinsonism

To date, all known affected individuals have sought medical attention after developing motor symptoms. Of those with motor symptoms and an ATP1A3 mutation, most presented with a rostro-caudal gradient, rapid onset in less than 30 days, and no response to dopaminergic medications. Many had an identifiable trigger, such as fever, physiologic stress, or alcohol consumption. One individual had antecedent Parkinsonism; at least two had fluctuating symptoms before the deficit became permanent.

Motor findings. The clinical stages of RDP include: antecedent symptoms, primary onset, and occasional second episodes of worsening.

Antecedent symptoms have included nonspecific symptoms of dystonia, usually in the hands and arms. Some individuals reported mild limb cramping, most often involving the hands, prior to development of typical RDP following a physiologic stressor. One individual initially had one year of Parkinsonism, not dystonia, followed by abrupt onset of oromandibular dystonia with dysarthria.

The primary onset in individuals with an identified ATP1A3 mutation is usually paroxysmal or abrupt over hours to several weeks. In all affected individuals in two large US families, progression stopped at or before one month after onset. Many reported specific triggers consisting of either physical or psychological stress. Alcohol was a trigger in many but not all.

The bulbar and arm symptoms rarely improve after the primary onset; however, four individuals reported mild improvement in leg symptoms.

A few individuals report episodes of abrupt worsening of symptoms one to nine years after the initial onset. Because only a few affected individuals have been re-examined over time, documentation of the second events is incomplete. The second events resemble the primary onset, with worsening of bulbar, arm, and leg symptoms over a similar time course. Except for these second events, little change is reported over many years in those affected individuals for whom such information is available.

Non-motor features including anxiety, depression, and seizures have been reported. It is not clear whether these features are part of the phenotype.

Other. While RDP is the first human disease to be associated with mutations in ATP1A3, three neurologic diseases have been associated with mutations in the ATP1A2 subunit: infantile seizures, familial hemiplegic migraine (FHM), and familial common migraine [De Fusco et al 2003, Vanmolkot et al 2003, Bassi et al 2004, Kaunisto et al 2004, Swoboda et al 2004, Ambrosini et al 2005, Todt et al 2005], suggesting that the phenotypic spectrum associated with mutations in ATP1A3 may be broader.

Pathophysiology. The non-motor features of RDP may have a biochemical basis, given findings of abnormal dopamine, serotonin, and norepinephrine metabolites in cerebrospinal fluid of some affected individuals and asymptomatic individuals with an ATP1A3 mutation [Brashear et al 1998a].

Genotype-Phenotype Correlations

Genotype-phenotype correlations were reported by Brashear et al [2007] based on ATP1A3 sequence analysis in 49 persons from 21 families referred with "possible" RDP (Table 2, Table 3). Mutations were identified in 36 persons from ten families, including three de novo mutations and one mutation in a single individual whose family members were not tested. No mutations were found in 13 persons from 11 families.

Comparison of onset, gradient (i.e., rostro-caudal or vice versa), and presence of bulbar symptoms, tremor, and pain in mutation-positive and mutation-negative individuals revealed the following:

  • All 36 individuals with rapid-onset (p=0.002), rostro-caudal gradient (p<0.001), and bulbar symptoms (p<0.001) were mutation positive.

    Note: These three findings also characterized one of 13 mutation-negative persons. Unlike mutation-positive persons, this individual responded to anticholinergic therapy, making it likely that this person's findings represent a phenocopy.
  • None of the 36 mutation-positive individuals reported tremor (p=0.003) or severe pain (p=0.051).
  • Four of the 13 mutation-negative individuals reported tremor at onset; two of 11 reported pain (data available on 9 only). The presence of pain and tremor help distinguish those who are likely to be mutation negative from those likely to be mutation positive.

    Note: It is not clear if this is an absolute distinction because tremor was reported later in life in a few mutation-positive affected individuals in two families.

Several additional individuals with similar clinical features are also included in Table 2.

Table 2. Genotype-Phenotype Correlations

CitationNumber of Affected IndividualsMutationAverage Age at Onset (Age Range)Reported TriggersBulbar SymptomsF>A>L Gradient 1 Time Needed to Stabilize
Linazasoro et al [2002]2p.Thr613Met17 yrsNone++30 days
Zaremba et al [2004]4p.Thr613Met20 yrs (16-28)Head trauma++Hours
Pittock et al [2000], McKeon et al [2007]8p.Thr613Met22 yrs (4-55)Psychol. stress, minor fall++Days
Brashear et al [2007]2p.Thr613Met22 yrsPsychol. stress++4 days
Lee et al [2007]1p.Thr613Met21 yrsNone++30 days
de Carvalho Aguiar et al [2004]2p.Glu277Lys20 yrsFever, head trauma++1 week
Brashear et al [2007]1p.Glu277Lys22 yrsNone++Gradually progressive 3
Kamphuis et al [2006]1p.Ile274Thr37 yrsNone++24 hours
de Carvalho Aguiar et al [2004]13p.Ile758Ser23 yrs (14-43)Running, childbirth, fever++1 day - 1 year
de Carvalho Aguiar et al [2004]2p.Phe780Leu25 yrs (16-35)Running (1 person)++2 - 30 days
de Carvalho Aguiar et al [2004]4p.Asp801Tyr17 yrs (12-22)Overheating++30 mins - 3 days

Adapted from Brashear et al [2007]

+ = present

– = absent

1. Rostro-caudal gradient: face>arm>leg

2. De novo mutation

3. Abrupt onset

Penetrance

Penetrance is incomplete The small number of families studied to date limits the estimate of penetrance; however, several members of the larger reported families have had an ATP1A3 mutation but were asymptomatic [Kramer et al 1999, de Carvalho Aguiar et al 2004, Brashear et al 2007].

Anticipation

Anticipation has not been specifically observed in RDP. However, preliminary findings in one family warrant further study [Pittock et al 2000, McKeon et al 2007].

Nomenclature

Rapid-onset dystonia-parkinsonism was first recognized and named by Dobyns et al [1993] in a 15-year-old girl with an abrupt onset of dystonia with severe bulbar symptoms and some signs of Parkinson disease (postural instability with bradykinesia). Cerebrospinal fluid levels of dopamine metabolites were low; thus, the term RDP was used to describe what later came to be known as DYT12 caused by mutation of ATP1A3.

Because classic signs of Parkinson disease, such as tremor, are unusual in individuals with RDP, the term Parkinsonism in the designation RDP has been problematic. Thus, some have suggested that RDP be considered rapid-onset dystonia (ROD).

Prevalence

The prevalence of RDP is not known.

RDP has been described in individuals and families from the US, Europe, and Korea, and in an individual of African-Caribbean descent [Webb et al 1999; de Carvalho Aguiar et al 2004; Zaremba et al 2004; Brashear et al 2007; Lee et al 2007; Kamm et al 2008; Zanotti-Fregonara et al 2008; Anselm et al 2009; Blanco-Arias et al 2009; Svetel et al 2010; Tarsy et al 2010; Pekmezovic et al 2009].

Differential Diagnosis

The presence of tremor at onset of symptoms, a reversed rostro-caudal gradient, and significant limb pain exclude the diagnosis of rapid-onset dystonia-parkinsonism (RDP) [Brashear et al 2007].

The physician needs to exclude more common and treatable forms of dystonia-parkinsonism (see Dystonia Overview and Parkinson Disease Overview). Testing should include brain MRI, a trial of L-dopa, TOR1A (DYT1) testing, and evaluation for Wilson disease. In RDP, the MRI is normal and the response to L-dopa is minimal or none.

The differential diagnosis of RDP includes the following:

Dopa-responsive dystonia (DRD) differs from RDP in the response to L-dopa, which is minimal in those with RDP [Bressman et al 2002, Kabakci et al 2005, Geyer & Bressman 2006]. Furthermore, DRD typically presents in the leg and, in some reports, has been confused with cerebral palsy [Nygaard et al 1994].

DYT1 dystonia, unlike RDP, has a more caudal to rostral gradient. Onset of DYT1 dystonia in older individuals is rare, whereas RDP may present abruptly after age 30 years.

Young-onset parkinsonism. Individuals with young-onset parkinsonism may have limb dystonia as an early manifestation; however, unlike persons with RDP, they should have a significant and sustained response to L-dopa. Other recently described genetic forms of Parkinson disease including PINK1 type of young-onset Parkinson disease and Parkin type of juvenile Parkinson disease should be considered.

Other. A kindred of eight individuals with RDP who have neither mutation in ATP1A3 nor linkage to chromosome 19q in the DYT12 region is an apparent phenocopy [Kabakci et al 2005]. The proband presented at age six years with overnight onset of dysphonia, dysphagia, orofacial dystonia, and dystonia of all four limbs, findings which meet the diagnostic criteria for RDP. However, five of the eight affected individuals had renal disease consisting of renal hypoplasia, renal cysts, and/or end-stage renal disease, which has not been observed in individuals with RDP and ATP1A3 mutations. This suggests the existence of a second locus for RDP.

As in all persons with young-onset movement disorders, Wilson disease must be considered.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with rapid-onset dystonia-parkinsonism (RDP) evaluation using the RDP severity scale [de Carvalho Aguiar et al 2004] is recommended.

Treatment of Manifestations

Symptomatic benefit has been noted with high-dose benzodiazepines.

Standard therapies for the following are appropriate:

  • Seizures
  • Dysphagia
  • Depression and anxiety

Two individuals treated with deep brain stimulation [Kamm et al 2008] did not show marked improvement [personal communication with Dr. Brashear].

Prevention of Primary Manifestations

At-risk family members and asymptomatic individuals with an ATP1A3 mutation are cautioned to avoid alcohol or excessive exercise.

Prevention of Secondary Complications

Physical therapy to prevent contractures in the hands and feet is appropriate.

Agents/Circumstances to Avoid

Triggers associated with the abrupt onset of RDP that should be avoided include (but are not limited to) the following:

  • Alcohol
  • Fever
  • Psychological stress
  • Excessive exercise (such as running track)

Evaluation of Relatives at Risk

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

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

Levodopa and dopamine agonists provide little benefit.

The abrupt onset of symptoms cannot be prevented. During the abrupt onset, no acute treatment other than symptomatic relief of dystonia is available.

Genetic Counseling

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

Mode of Inheritance

Rapid-onset dystonia-parkinsonism (RDP) caused by mutation of ATP1A3 is inherited in an autosomal dominant manner with incomplete penetrance.

Risk to Family Members

Parents of a proband

  • Many individuals diagnosed with rapid-onset dystonia-parkinsonism (RDP) have an affected parent.
  • A proband with RDP may have the disorder as the result of a new mutation. In the 17 probands reported with mutations, eight occurred de novo [Brashear et al 2007, Kamm et al 2008, Anselm et al 2009, Blanco-Arias et al 2009, Tarsy et al 2010].
  • Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include obtaining a detailed medical and family history, examination by a movement disorder specialist, and molecular genetic testing of both parents for the ATP1A3 mutation identified in the proband.
  • Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of failure by health care professionals to recognize the syndrome, a milder phenotypic presentation, or complete lack of symptoms (reduced penetrance). Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations and genetic testing have been performed.

Note: If the parent is the individual in whom the mutation first occurred, s/he may have somatic mosaicism for the mutation and may be mildly/minimally affected.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband's parents.
  • If a parent of the proband is affected or has a disease-causing mutation, the risk to the sibs of inheriting the mutation is 50%.
  • The sibs of a proband with clinically unaffected parents are still at increased risk for the disorder because of the possibility of reduced penetrance in a parent. Because reduced penetrance is a possibility, parents who are clinically unaffected should undergo molecular testing to determine if they have the mutation.

Offspring of a proband. Each child of an individual with RDP has a 50% chance of inheriting the mutation.

Other family members of a proband. 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 or her family members may be at risk. A parent who is unaffected could still carry the mutation but not express the disorder.

Related Genetic Counseling Issues

Issues unique to RDP. Because of the sudden onset of RDP, at-risk individuals may become hypervigilant about symptoms. Serious psychological issues have been observed in families [Brashear, personal observation].

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has a disease-causing mutation it is likely that the proband has a de novo mutation. 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.

Prenatal Testing

If the disease-causing mutation has been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

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 such as RDP 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 most centers consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

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.

  • Alternating Hemiplegia of Childhood Foundation (AHCF)
    2000 Town Center
    Suite 1900
    Southfield MI 48075
    Phone: 650-796-1910
    Fax: 650-365-5798
    Email: lynn@ahckids.org
  • Alternating Hemiplegia of Childhood International Alliance
  • Dystonia Medical Research Foundation
    One East Wacker Drive
    Suite 2810
    Chicago IL 60601-1905
    Phone: 800-377-3978 (toll-free); 312-755-0198
    Fax: 312-803-0138
    Email: dystonia@dystonia-foundation.org
  • RDP (Rapid-onset Dystonia Parkinsonism) Study Web Site
    Phone: 336-716-3545
    Email: abrashea@wfubmc.edu
  • American Parkinson Disease Association (APDA)
    135 Parkinson Avenue
    Staten Island NY 10305
    Phone: 800-223-2732 (toll-free); 718-981-8001
    Fax: 718-981-4399
    Email: apda@apdaparkinson.org
  • National Parkinson Foundation
    1501 Northwest 9th Avenue
    Bob Hope Road
    Miami FL 33136-1494
    Phone: 800-327-4545 (toll-free); 305-243-6666
    Fax: 305-243-6073
    Email: contact@parkinson.org
  • Dystonia International Patient Registry (DIPR)
    Email: contact@dipregistry.com
  • US-International Alternating Hemiplegia of Childhood Registry
    Email: sharon@ahckids.org

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. Rapid-Onset Dystonia-Parkinsonism: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Rapid-Onset Dystonia-Parkinsonism (View All in OMIM)

128235DYSTONIA 12; DYT12
182350ATPase, Na+/K+ TRANSPORTING, ALPHA-3 POLYPEPTIDE; ATP1A3

Molecular Genetic Pathogenesis

The Na,K-ATPases convert metabolic energy by moving Na+ ions out of the cell and K+ ions into the cell, restoring the ion gradients reduced by the activity of ion channels and Na+-dependent carriers. In the central nervous system (CNS), the Na,K-ATPase is harnessed for reuptake of glutamate and other transmitters, extracellular K+ buffering, extrusion of Ca2+ by Na+:Ca2+ exchange, and the regulation of cell volume. Because it transports three Na+ ions out of the cell for every two K+ ions transported in, it is electrogenic and makes a small direct contribution to membrane potential.

Na,K-ATPase has three types of subunits (alpha, beta, and FXYD) and each subunit has multiple isoforms.

  • The catalytic alpha subunit has three isoforms (alpha 1, 2, and 3) that are expressed in the CNS by three distinct genes [Moseley et al 2003]. Although it is found in a few peripheral cell types, the alpha 3 isoform is expressed exclusively in neurons in the CNS.
  • Three beta subunits required for Na,K-ATPase function are also expressed in the CNS.
  • The FXYD subunit regulates and modifies the properties of the complex; at least three FXYD subunits are expressed in the CNS [McGrail et al 1991].

Of note, mutations in a gene for another alpha subunit of the Na,K-ATPase, ATP1A2, are associated with familial hemiplegic migraine [De Fusco et al 2003] and benign familial infantile convulsions [Vanmolkot et al 2003], as well as episodic events with severe intellectual disability [Vanmolkot et al 2006].

Click here for information on animal models of rapid-onset dystonia-parkinsonism.

Normal allelic variants. ATP1A3 comprises 23 exons. Several common coding SNPs are reported in dbSNP.

Pathologic allelic variants. The ten mutations described to date (Table 3) were identified in research laboratories and were missense changes or small insertions/deletions found in only six of the 23 exons (exons 8, 14, 15, 17, 20, and 23) [de Carvalho Aguiar et al 2004, Brashear et al 2007, Lee et al 2007, McKeon et al 2007, Kamm et al 2008, Zanotti-Fregonara et al 2008, Anselm et al 2009, Blanco-Arias et al 2009, Svetel et al 2010, Tarsy et al 2010].

Currently, a total of ten novel mutations (eight missense mutations, a 3bp in-frame deletion, and a 3 bp in-frame insertion) have been reported in 17 families, including eight de novo mutations [de Carvalho Aguiar et al 2004, Brashear et al 2007, Lee et al 2007, McKeon et al 2007, Kamm et al 2008, Zanotti-Fregonara et al 2008, Anselm et al 2009, Blanco-Arias et al 2009, Svetel et al 2010, Tarsy et al 2010]. (see Table 3).

Table 3. Selected ATP1A3 Pathologic Allelic Variants

DNA Nucleotide ChangeProtein Amino Acid Change Reference Sequence
c.821T>Cp.Ile274ThrNM_152296​.3
NP_689509​.1
c.829G>Ap.Glu277Lys
c.1838C>Tp.Thr613Met
c.2273T>Gp.Ile758Ser
c.2338T>Cp.Phe780Leu
c.2401G>Tp.Asp801Tyr
c.2767G>Ap.Asp923Asn
c.976-978delCTGp.Lys326del
c.3191_3193dupTACp.1013Ydup
c.2051C>Tp. Ser684Phe

Note: Information in the table is provided by the authors and has not been reviewed by GeneReviews staff.

Normal gene product. ATP1A3 encodes the alpha 3 subunit of the sodium/potassium-transporting ATPase (Na,K-ATPase), which comprises 1013 amino acid residues.

Abnormal gene product. Both functional studies and structural analysis of the alpha 3 subunit of the Na,K-ATPase suggest that missense mutations impair enzyme activity or stability [de Carvalho Aguiar et al 2004]; however, it is not known whether this loss of function occurs by haploinsufficiency or dominant-negative effects.

Functional biochemical studies with several pathogenic mutations all show reduced Na+ affinity suggesting that defects in the handling of Na+ may be a major factor in the development and pathology of RDP [Rodacker et al 2006, Blanco-Arias et al 2009, Einholm et al 2010].

References

Literature Cited

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Chapter Notes

Author Notes

Web site: rdpstudy.org

Acknowledgments

The authors would like to thank especially Dr William B Dobyns for his contributions to this research. In addition, we would like to thank Patricia de Carvalho Aguiar, Liu Liu, Marsha Caton, Seema Gollamudi, Geetha Senthil, Abby Rabinowitz, John T Penniston, Susan B Bressman, Deborah Raymond, Jacek Zaremba, Gurutz Linazasoro, Michel Borg, Andrew Green, David Webb, Sean J Pittock, David Riley, Marina AJ Tijssen, CjM Frijns, Gao Guimares, and all of the families and patients who participated in this research.

Revision History

  • 13 September 2012 (ab/tb) Revision: alternating hemiplegia of childhood added as a genetically related disorder
  • 25 August 2011 (me) Comprehensive update posted live
  • 19 March 2009 (cd) Revision: sequence analysis available clinically
  • 7 February 2008 (me) Review posted to live Web site
  • 5 October 2007 (ab) Original submission
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