Failure of Sequential Pallidal and Motor Thalamus DBS for Rapid-Onset Dystonia-Parkinsonism (DYT12).
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ABSTRACT:
SUBMITTER: Fearon C
PROVIDER: S-EPMC6336187 | biostudies-literature | 2018 Jul-Aug
REPOSITORIES: biostudies-literature
Publications
Failure of Sequential Pallidal and Motor Thalamus DBS for Rapid-Onset Dystonia-Parkinsonism (DYT12).
Fearon Conor C McKinley John J McCarthy Allan A Rebelo Pedro P Goggin Carole C Magennis Brian B Aziz Tipu T Green Alexander L AL Lynch Timothy T
Movement disorders clinical practice 20171204 4
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Project description: Not available
| S-EPMC6353499 | biostudies-literature
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
Project description: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.
| S-EPMC3430603 | biostudies-literature
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
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
Project description:Biallelic mutations in GBA1 cause the lysosomal storage disorder Gaucher disease, and carriers of GBA1 variants have an increased risk of Parkinson's disease (PD). It is still unknown whether GBA1 variants are also associated with other movement disorders. We present the case of a woman with type 1 Gaucher disease who developed acute dystonia and parkinsonism at 35 years of age during a recombinant enzyme infusion treatment. She developed severe dystonia in all extremities and a bilateral pill-rolling tremor that did not respond to levodopa treatment. Despite the abrupt onset of symptoms, neither Sanger nor whole genome sequencing revealed pathogenic variants in ATP1A3 associated with rapid-onset dystonia-parkinsonism (RDP). Further examination showed hyposmia and presynaptic dopaminergic deficits in [18F]-DOPA PET, which are commonly seen in PD but not in RDP. This case extends the spectrum of movement disorders reported in patients with GBA1 mutations, suggesting an intertwined phenotype.
| S-EPMC10548083 | biostudies-literature
Project description:BackgroundRapid-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 presentationWe 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.ConclusionWe 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
Project description:ImportanceAnecdotal evidence suggests that deep brain stimulation (DBS) of the internal globus pallidus (GPi) is effective in ameliorating dystonia in X-linked dystonia parkinsonism (XDP), a disease that is usually refractive to medical therapy.ObjectiveTo determine the efficacy of GPi-DBS in a cohort of patients with XDP in a prospective study and identify predictors of postoperative outcomes.Design, setting, and participantsThis observational prospective cohort study enrolled patients in February 2013 and was completed in December 2014. The patients were followed up for up to 46 months. Patients from the Philippines were treated in a single center in Lübeck, Germany and followed up in the Philippines. Sixteen men with XDP (mean [SD] age, 40.9 [7.3] years; disease duration, 1-6 years) from the Philippines with predominant dystonia were selected.ExposuresAll patients underwent bilateral GPi-DBS in Lübeck, Germany.Main outcomes and measuresClinical assessment included the motor parts of the Burke-Fahn-Marsden scale (BFMDRS-M) and the Unified Parkinson's Disease Rating Scale (UPDRS-III). T1-based basal ganglia volumetry was performed and correlated with postoperative outcomes.ResultsThe study participants included 16 Filipino men (mean age, 40.9 years). Masked video ratings revealed significant improvements of dystonia severity 1 week (-55%; range, -94% to 59%; P < .01) and 6 months (-59%; range, -100% to 22%; P < .001) after surgery. The UDPRS-III score also improved, albeit to a lesser extent (-19%; range, -54% to 95%; and -27%; range, -70% to 124%; respectively). Unmasked long-term follow-up confirmed the continued efficacy of GPi-DBS up to 46 months after surgery. Important secondary end points improved, including activities of daily living, pain severity, weight, and quality of life. Caudate atrophy was a predictor of a less beneficial outcome (r = 0.817, P = .004).Conclusions and relevanceInternal globus pallidus DBS had a positive association in XDP with predominant dystonia (the primary end point) and contributed to an improved quality of life (the secondary end point). The response to DBS occurred within 1 week. Given the inverse correlation of postoperative benefit and caudate atrophy, GPi-DBS should be considered early during the disease course. Close international collaboration, training, and funding from multiple sources enabled the sustainable follow-up of patients with XDP in the Philippines.
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| S-EPMC6031980 | biostudies-literature