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The neural substrates of rapid-onset Dystonia-Parkinsonism.

ABSTRACT: Although dystonias are a common group of movement disorders, the mechanisms by which brain dysfunction results in dystonia are not understood. Rapid-onset Dystonia-Parkinsonism (RDP) is a hereditary dystonia caused by mutations in the ATP1A3 gene. Affected individuals can be free of symptoms for years, but rapidly develop persistent dystonia and Parkinsonism-like symptoms after a stressful experience. Using a mouse model, we found that an adverse interaction between the cerebellum and basal ganglia can account for the symptoms of these individuals. The primary instigator of dystonia was the cerebellum, whose aberrant activity altered basal ganglia function, which in turn caused dystonia. This adverse interaction between the cerebellum and basal ganglia was mediated through a di-synaptic thalamic pathway that, when severed, alleviated dystonia. Our results provide a unifying hypothesis for the involvement of cerebellum and basal ganglia in the generation of dystonia and suggest therapeutic strategies for the treatment of RDP.

SUBMITTER: Calderon DP

PROVIDER: S-EPMC3430603 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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The neural substrates of rapid-onset Dystonia-Parkinsonism.

Calderon D Paola DP Fremont Rachel R Kraenzlin Franca F Khodakhah Kamran K

Nature neuroscience 20110206 3

Although dystonias are a common group of movement disorders, the mechanisms by which brain dysfunction results in dystonia are not understood. Rapid-onset Dystonia-Parkinsonism (RDP) is a hereditary dystonia caused by mutations in the ATP1A3 gene. Affected individuals can be free of symptoms for years, but rapidly develop persistent dystonia and Parkinsonism-like symptoms after a stressful experience. Using a mouse model, we found that an adverse interaction between the cerebellum and basal gang ...[more]

PMID: 21297628

Similar Datasets

Revising rapid-onset dystonia-parkinsonism: Broadening indications for ATP1A3 testing.

Project description:Background and objectivesRapid-onset dystonia-parkinsonism (RDP) is caused by mutations in the ATP1A3 gene, which codes for the α-3 subunit of the Na+ /K+ ATPase. It has been characterized by rapid-onset bulbar dysfunction, limb dystonia, bradykinesia, and a rostrocaudal spatial gradient of expression, usually after a physiologic trigger. We reexamined whether these features were in fact characteristic.MethodsWe characterized phenotypic variation within a cohort of 50 ATP1A3 mutation-positive individuals (carriers) and 44 mutation-negative family members (noncarriers). Potential participants were gathered through referral for clinical suspicion of RDP or alternating hemiplegia of childhood. Inclusion criteria were having a ATP1A3 mutation or being a family member of such an individual.ResultsWe found RDP is underdiagnosed if only "characteristic" patients are tested. Rapid onset and bulbar predominance were not universally present in carriers. Among those with at least mild symptoms of dystonia, rostrocaudal severity gradient was rare (7%). Symptoms began focally but progressed to be generalized (51%) or multifocal (49%). Arm (41%) onset was most common. Arms and voice were typically most severely affected (48% and 44%, respectively). Triggers preceded onset in 77% of the participants. Rapid onset, dystonia, parkinsonism, bulbar symptoms, headaches, seizures, frontal impairment, and a history of mood disorder and a history of psychosis were more common in carriers. Approximately half of the proband mutations occurred de novo (56%).ConclusionsOur findings suggest that patients should not be excluded from ATP1A3 testing because of slow onset, limb onset, absent family history, or onset in middle adulthood. RDP should be strongly considered in the differential for any bulbar dystonia. © 2019 International Parkinson and Movement Disorder Society.

| S-EPMC6879786 | biostudies-literature

A case of rapid-onset dystonia-parkinsonism accompanied by pyramidal tract impairment.

Project description:BACKGROUND:Rapid-onset dystonia-parkinsonism (RDP) is a rare autosomal dominant disorder that is caused by mutations in the ATP1A3 gene and is characterized by an acute onset of asymmetric dystonia and parkinsonism. To date, fewer than 75 RDP cases have been reported worldwide. Clinical signs of pyramidal tract involvement have been reported in several RDP cases, and none of them included the Babinski sign. CASE PRESENTATION:We report a 24-year-old Chinese female with RDP who exhibited a strikingly asymmetric, predominantly dystonic movement disorder with a rostrocaudal gradient of involvement and parkinsonism. Physical examiniations revealed hyperactive reflexes, bilateral ankle clonus and positive Babinski sign in the right. DTI showed reduced white matter integrity of the corticospinal tract in the frontal lobe and subpontine plane. Genetic testing revealed a missense mutation of the ATP1A3-gene (E277K) in the patient. CONCLUSION:We suggest that pyramidal tract impairment could be involved in rapid-onset dystonia-parkinsonism and the pyramidal tract impairment in RDP needs to be differentiated from HSP.

| S-EPMC5105251 | biostudies-literature

An Elderly Woman with Reversal of Clinical Presentation Mimicking Rapid-Onset Dystonia-Parkinsonism.

Project description: Not available

| S-EPMC6031980 | biostudies-literature

New triggers and non-motor findings in a family with rapid-onset dystonia-parkinsonism.

Project description:A woman from Italy presented with dystonic leg symptoms at the age of 59. Rapid-onset dystonia-parkinsonism (RDP) was not suspected until 3 affected children (2 male, 1 female) with presentations consistent with the disorder were recognized.The mother and four of her children (3 with and 1 without dystonia) were evaluated with an extensive battery including standardized history questionnaire and rating scales. In addition, all four children had cognitive testing and three of the four children had psychiatric interviews.In this family, a T613M mutation in the ATP1A3 gene was confirmed, the most common mutation present in patients with RDP. The proband's limb dystonia was atypical of RDP, symptoms of the others affected included dysarthria, asymmetric limb dystonia, and dysphagia more consistent with RDP. The two sons developed dystonia-parkinsonism in adolescence after consuming large amounts of alcohol. All 3 of those with psychiatric interviews reached diagnosable thresholds for mood disorder (bipolar or dysthymia) and some form of anxiety disorder.The phenotype and age of onset is broader than previously reported in RDP, suggesting that it could be under-reported. Prior to this study, neuropsychologic symptoms associated with RDP were under-appreciated. Those patients who are at risk or suspected of having RDP should be cautioned to avoid excessive alcohol intake. Further study is needed to assess if the cognitive and psychiatric features are part of a broader RDP phenotype and this may have implications for future research into genetic susceptibility for psychiatric disease.

| S-EPMC3753404 | biostudies-other

Characterization of Atp1a3 mutant mice as a model of rapid-onset dystonia with parkinsonism.

Project description:Rapid-onset dystonia with parkinsonism (RDP) or DYT12 dystonia is a rare form of primary, generalized dystonia. Patients do not present with any symptoms until triggered by a physiological stressor. Within days, patients will show both dystonia and parkinsonism. Mutations resulting in a loss of function in the ATP1A3 gene have been identified as the cause of RDP. ATP1A3 encodes the ?3 subunit of the Na(+)/K(+)-ATPase, which is exclusively expressed in neurons and cardiac cells. We have previously created a line of mice harboring a point mutation of the Atp1a3 gene (mouse homolog of the human ATP1A3 gene) that results in a loss of function of the ?3 subunit. The Atp1a3 mutant mice showed hyperactivity, spatial learning and memory deficits, and increased locomotion induced by methamphetamine. However, the full spectrum of the motor phenotype has not been characterized in the mutant mice and it is not known whether triggers such as restraint stress affect the motor phenotype. Here, we characterized the motor phenotype in normal heterozygous Atp1a3 mutant mice and heterozygous Atp1a3 mutant mice that have been exposed to a restraint stress. We found that this type of trigger induced significant deficits in motor coordination and balance in the mutant mice, characteristic of other genotypic dystonia mouse models. Furthermore, stressed mutant mice also had a decreased thermal sensitivity and alterations in monoamine metabolism. These results suggest that the Atp1a3 mutant mouse models several characteristics of RDP and further analysis of this mouse model will provide great insight into pathogenesis of RDP.

| S-EPMC2981691 | biostudies-literature

Failure of Pallidal Deep Brain Stimulation in a Case of Rapid-Onset Dystonia Parkinsonism (DYT12).

Project description: Not available

| S-EPMC6353499 | biostudies-literature

X linked dystonia parkinsonism

Project description:Investigation of expression profile in XDP brains. Keywords: an XDP patient and neurologically normal control

2006-02-03 | GSE3064 | GEO

ATP1A3 mutations in infants: a new rapid-onset dystonia-Parkinsonism phenotype characterized by motor delay and ataxia.

Project description:We report new clinical features of delayed motor development, hypotonia, and ataxia in two young children with mutations (R756H and D923N) in the ATP1A3 gene. In adults, mutations in ATP1A3 cause rapid-onset dystonia-Parkinsonism (RDP, DYT12) with abrupt onset of fixed dystonia. The parents and children were examined and videotaped, and samples were collected for mutation analysis. Case 1 presented with fluctuating spells of hypotonia, dysphagia, mutism, dystonia, and ataxia at 9 months. After three episodes of hypotonia, she developed ataxia, inability to speak or swallow, and eventual seizures. Case 2 presented with hypotonia at 14 months and pre-existing motor delay. At age 4 years, he had episodic slurred speech, followed by ataxia, drooling, and dysarthria. He remains mute. Both children had ATP1A3 gene mutations. To our knowledge, these are the earliest presentations of RDP, both with fluctuating features. Both children were initially misdiagnosed. RDP should be considered in children with discoordinated gait, and speech and swallowing difficulties.

| S-EPMC3465467 | biostudies-literature

Rapid-Onset Dystonia-Parkinsonism in a Chinese Girl with a De Novo ATP1A3 c.2267G>A (p.R756H) Genetic Mutation.

Project description: Not available

| S-EPMC6353356 | biostudies-literature

Mutations in SLC39A14 disrupt manganese homeostasis and cause childhood-onset parkinsonism-dystonia.

Project description:Although manganese is an essential trace metal, little is known about its transport and homeostatic regulation. Here we have identified a cohort of patients with a novel autosomal recessive manganese transporter defect caused by mutations in SLC39A14. Excessive accumulation of manganese in these patients results in rapidly progressive childhood-onset parkinsonism-dystonia with distinctive brain magnetic resonance imaging appearances and neurodegenerative features on post-mortem examination. We show that mutations in SLC39A14 impair manganese transport in vitro and lead to manganese dyshomeostasis and altered locomotor activity in zebrafish with CRISPR-induced slc39a14 null mutations. Chelation with disodium calcium edetate lowers blood manganese levels in patients and can lead to striking clinical improvement. Our results demonstrate that SLC39A14 functions as a pivotal manganese transporter in vertebrates.

| S-EPMC4894980 | biostudies-literature

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