Dystonia Genotype-Phenotype Correlation

Study Overview
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Brief Summary
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The purpose of this study is to (1) investigate the effect of known dystonia-causing mutations on brain structure and function, to (2) identify structural brain changes that differ between clinical phenotypes of dystonia, and to (3) collect DNA, detailed family history, and clinical phenotypes from patients with idiopathic dystonia with the goal of identifying new dystonia-related genes. Investigators will be recruiting both healthy control subjects and subjects with any form of dystonia. For this study there will be a maximum of two study visit involving a clinical assessment, collection of medical and family history, task training session, an MRI using the learned tasks, and finally a blood draw for genetic analysis. In total, these visits will take 3-5 hours. If the dystonia subjects receive botulinum toxin injections for treatment, the participants and their matched controls will be asked to come for a second visit.

Detailed Description
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Identify a cohort of individuals with known dystonia-related gene mutations, and individuals with idiopathic but presumed-genetic dystonia. Some of these individuals may receive botulinum toxin injections to treat their dystonia per standard of care; in these patients, investigators will image before and after injections to assess for imaging correlates of treatment response. Analyze DNA samples from both the dystonia and healthy individual cohorts to detect the presence of mutations and/or polymorphisms in genes associated with dystonia Collect systematic clinical information, including Tsui Torticollis, Burke-Fahn-Marsden, Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS), Voice Disability Index, Unified Myoclonus Rating Scale, Beck Depression Inventory, Beck Anxiety Inventory and Spielberg Trait Anxiety scales. Scales will be tailored to the type of dystonia, as determined by the clinician referring into the study (i.e., torticollis scales will only be performed on patients with cervical dystonia). Use functional MRI (fMRI), diffusion tensor imaging (DTI), and structural MRI to a) analyze brain activity and structure pre- and post-botulinum toxin injections, b) determine how different stages of movement (execution, preparation, sequencing) influence dystonia and the underlying neural mechanisms, c) identify structural abnormalities shared between clinical sub-types of dystonia. As new MR imaging methods are introduced that may improve the investigators ability to identify or distinguish these abnormalities, the investigator will incorporate these novel sequences into the imaging protocol. Correlate brain activity and structural data with ratings of dystonia severity, location of dystonia, genetic status, and response to treatment (medications and/or botulinum toxin injections). Correlate polymorphism data with dystonia severity, response to botulinum toxin, depression/anxiety severity, and brain activity/structure.

Official Title
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Dystonia Genotype-Phenotype Correlation: A Study to Identify Additional Genetic Associations That Contribute to Specific Dystonic Phenotypes

Conditions
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Dystonia 19, Dystonia, Dystonia; Idiopathic, Dystonia, Primary, Dystonia, Secondary, Dystonia, Familial, Dystonia Disorder, Dystonias, Sporadic, Dystonia; Orofacial, Dystonia Lenticularis, Dystonia, Paroxysmal, Dystonia 6, Dystonia 5, Dystonia 8, Dystonia 9, Dystonia 10, Dystonia 11, Dystonia 20, Dystonia 12, Dystonia, Focal, Dystonia of Head, Dystonia, Diurnal

Intervention / Treatment
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* Other: Magnetic Resonance Imaging


Participation Criteria
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Eligibility Criteria
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General Exclusion (both Dystonia and Control groups): Metal in any part of the body (including metal injury to the eye) OR carrying a medical device incompatible with MRI (e.g., metal implants such as surgical clips or pacemakers) OR positive screening per UTSW MRI screening form Claustrophobia Non-fluent English Weight incompatible with MRI safety History of head trauma with neurological sequelae, including multiple concussions and/or history of stroke Pregnancy Serious medical illness or history of serious medical illness, including cancer that was treated with radiation or chemotherapy, heart attack, or a known history of HIV-1 + status Subjects with Hepatitis C (by Hepatitis C+ titer) Subjects with insulin dependent diabetes mellitus (IDDM) Severe respiratory compromise In the opinion of the investigator, not able to safely participate in this study Inclusion Criteria: Dystonia group Previous diagnosis of dystonia which include but is not limited to: cervical dystonia (50 subjects) blepharospasm (25 subjects) limb dystonia (50 subjects) spasmodic dysphonia (25 subjects) segmental dystonia multi-focal dystonia Any childhood-onset dystonia (25 subjects) Age > 11 years Control group: No prior dystonia diagnosis (175 subjects) Age > 11 years Exclusion Criteria: Dystonia group Prior history of or concurrent neurological or psychiatric diagnosis - depression and/or anxiety accepted Current use of non-dystonia neuroactive medications - SSRI/medication for depression and/or anxiety accepted Current use of cervical brace designed for dystonia treatment Prior structural brain injury Control group: History of or current neurological or psychiatric diagnosis - depression and/or anxiety accepted, but must not be in active phase Current use of any neuroactive medication, SSRI/medication for depression and/or anxiety accepted

Ages Eligible for Study
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Minimum Age: 11 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Dystonia group<br>Both groups will have blood drawn, undergo clinical assessments, the collection of medical and family history, and an Magnetic Resonance Imaging. This is an observational study and there is no intervention. | Other: Magnetic Resonance Imaging<br>* Study interventions are minimal risk.<br>* Other names: Clinical Assessments;|
| Control Group<br>Both groups will have blood drawn, undergo clinical assessments, the collection of medical and family history, and an Magnetic Resonance Imaging. This is an observational study and there is no intervention. | Other: Magnetic Resonance Imaging<br>* Study interventions are minimal risk.<br>* Other names: Clinical Assessments;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Structural or functional imaging of dystonia and control groups | Identify structural or functional imaging measures that distinguish (a) dystonia patients from matched controls, (b) between clinically-defined forms of dystonia | 3-5 hours at each study visit | 
| Genetic Analysis of dystonia and control groups | Identify polymorphisms in genes known to cause dystonia that affect the structural or functional imaging measures in dystonia patients and to identify new genes associated with dystonia. | 30 min | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dystonia, Control, Magnetic Resonance Imagine, Genotype, Phenotype