DiagnosisClinical DiagnosisDiagnosis 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 examinationAbsence 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.TestingBrain 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 TestingGene. 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-ParkinsonismView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilityATP1A3 Sequence analysis of the coding region Sequence variants 2~50% 3Clinical 1. The ability of the test method used to detect a mutation that is present in the indicated gene2. 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 StrategyConfirming/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.Genetically Related (Allelic) DisordersSeveral de novo mutations in ATP1A3 associated with alternating hemiplegia of childhood (AHC) have been reported [Heinzen et al 2012, Rosewich et al 2012]. See Ozelius [2012] for discussion and comparison of these two different phenotypes (DYT12 and AHC).}

Natural HistoryThe 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 CorrelationsGenotype-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 CorrelationsView in own windowCitationNumber of Affected IndividualsMutationAverage Age at Onset (Age Range)Reported TriggersBulbar SymptomsF>A>L Gradient ¹ Time Needed to StabilizeLinazasoro et al [2002]1 ^{2p.Thr613Met17 yrsNone++30 daysZaremba et al [2004]4p.Thr613Met20 yrs (16-28)Head trauma++HoursPittock et al [2000], McKeon et al [2007]8p.Thr613Met22 yrs (4-55)Psychol. stress, minor fall++DaysBrashear et al [2007]1 2p.Thr613Met22 yrsPsychol. stress++4 daysLee et al [2007]1p.Thr613Met21 yrsNone++30 daysde Carvalho Aguiar et al [2004]1 2p.Glu277Lys20 yrsFever, head trauma++1 weekBrashear et al [2007]1p.Glu277Lys22 yrsNone++Gradually progressive 3Kamphuis et al [2006]1p.Ile274Thr37 yrsNone++24 hoursde Carvalho Aguiar et al [2004]13p.Ile758Ser23 yrs (14-43)Running, childbirth, fever++1 day - 1 yearde Carvalho Aguiar et al [2004]2p.Phe780Leu25 yrs (16-35)Running (1 person)++2 - 30 daysde Carvalho Aguiar et al [2004]4p.Asp801Tyr17 yrs (12-22)Overheating++30 mins - 3 daysAdapted from Brashear et al [2007] + = present – = absent 1. Rostro-caudal gradient: face>arm>leg2. De novo mutation 3. Abrupt onset}

Differential DiagnosisThe 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 , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations Following Initial DiagnosisTo 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 ManifestationsSymptomatic benefit has been noted with high-dose benzodiazepines.Standard therapies for the following are appropriate:Seizures Dysphagia Depression and anxietyTwo individuals treated with deep brain stimulation [Kamm et al 2008] did not show marked improvement [personal communication with Dr. Brashear]. Prevention of Primary ManifestationsAt-risk family members and asymptomatic individuals with an ATP1A3 mutation are cautioned to avoid alcohol or excessive exercise. Prevention of Secondary ComplicationsPhysical therapy to prevent contractures in the hands and feet is appropriate.Agents/Circumstances to AvoidTriggers 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 RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch 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.OtherLevodopa 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.

Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDATP1A319q13​.2Sodium/potassium-transporting ATPase subunit alpha-3ATP1A3 homepage - Mendelian genesATP1A3Data 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) View in own window 128235DYSTONIA 12; DYT12 182350ATPase, Na+/K+ TRANSPORTING, ALPHA-3 POLYPEPTIDE; ATP1A3Molecular Genetic PathogenesisThe 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]. The p.Glu277Lys mutation in exon 8, the p.Thr613Met mutation in exon 14, and the p.Asp923Asn are recurrent. All three occurrences of p.Glu277Lys were de novo [de Carvalho Aguiar et al 2004, Brashear et al 2007, Tarsy et al 2010]. The p.Thr613Met mutation occurred as both a de novo mutation and an inherited mutation [de Carvalho Aguiar et al 2004, Brashear et al 2007, Lee et al 2007, McKeon et al 2007]In both instances the p.Asp923Asn mutation arose de novo [Zanotti-Fregonara et al 2008, Anselm et al 2009].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 View in own windowDNA Nucleotide ChangeProtein Amino Acid Change Reference Sequencec.821T>Cp.Ile274ThrNM_152296​.3
NP_689509​.1 c.829G>Ap.Glu277Lysc.1838C>Tp.Thr613Metc.2273T>Gp.Ile758Serc.2338T>Cp.Phe780Leuc.2401G>Tp.Asp801Tyrc.2767G>Ap.Asp923Asnc.976-978delCTGp.Lys326delc.3191_3193dupTACp.1013Ydupc.2051C>Tp. Ser684PheNote: 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].