Imaging Genetics of Laryngeal Dystonia

October 24, 2023 updated by: Kristina Simonyan
The contribution of genetic risk factors to the development of focal dystonias is evident. However, understanding of how variations in the causative gene expression lead to variations in brain abnormalities in different phenotypes of dystonia (e.g., familial, sporadic) remains limited. The research program of the investigators is set to determine the relationship between brain changes and genetic risk factors in laryngeal dystonia (or spasmodic dysphonia). The researchers use a novel approach of combined imaging genetics, next-generation DNA sequencing, and clinical-behavioral testing. The use of a cross-disciplinary approach as a tool for the discovery of the mediating neural mechanisms that bridge the gap from DNA sequence to the pathophysiology of dystonia holds a promise for the understanding of the mechanistic aspects of brain function affected by risk gene variants, which can be used reliably for the discovery of associated genes and neural integrity markers for this disorder. The expected outcome of this study may lead to better clinical management of this disorder, including its improved detection, accurate diagnosis, and assessment of the risk of developing dystonia in family members.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Laryngeal dystonia (LD), or spasmodic dysphonia, is an isolated focal dystonia characterized by selective impairment of speech production due to involuntary spasms in the laryngeal muscles. Despite the well-characterized clinical features of LD, its clinical management remains challenging due, in part, to the absence of objective measures (biomarkers) for early detection and differential diagnosis. This results in diagnostic inaccuracies, which have a negative impact on the patient's quality of life and healthcare costs. Importantly, delayed diagnosis leads to deferred treatment. The objective of this application is to conduct a series of studies that combine advanced machine-learning with neuroimaging and genetics to (1) identify the neural markers that accurately differentiate LD between its clinical phenotypes (adductor vs. abductor), genotypes (sporadic vs. familial), and comorbid disorders (voice tremor and muscle tension dysphonia); (2) determine the early predictive neural markers of LD development in at-risk individuals, and (3) validate associated LD gene mutations. Supported by our preliminary data, our central hypothesis is that brain abnormalities are shaped, in part, by underlying genetic factors and exhibit LD form-characteristic features, which can be used as differential diagnostic and early predictive biomarkers of this disorder. This research is innovative both conceptually and methodologically because it uses a cross-disciplinary approach to focus on the neural pathophysiology and genetic susceptibility factors for LD diagnostic and predictive biomarker discovery. The proposed research is significant because it will directly contribute to closing the critically existing gap in the clinical management of LD. Identification of LD neural and genetic markers is expected to have a positive translational impact by establishing enhanced criteria for accurate differential diagnosis and screening of persons at risk. In short, the successful completion of these studies will open new horizons for the clinical management of LD patients.

Study Type

Observational

Enrollment (Estimated)

410

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • United States
    • Massachusetts
      • Boston, Massachusetts, United States, 02114
        • Recruiting
        • Massachusetts Eye and Ear Infirmary
        • Contact:
        • Principal Investigator:
          • Kristina Simonyan, MD, PhD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Child
  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Sampling Method

Non-Probability Sample

Study Population

laryngeal dystonia unaffected relatives of laryngeal dystonia patients voice tremor muscle tension dysphonia

Description

Inclusion criteria:

  1. Males and females of diverse racial and ethnic background, with age across the lifespan;

  2. Laryngeal Dystonia patients

    • phenotype: adductor or abductor
    • genotype: familial or sporadic

  3. Voice Tremor patients

    • essential or
    • dystonic
  4. Muscle tension dysphonia patients

  5. Unaffected relatives of laryngeal dystonia patients with

    • familial laryngeal dystonia
    • early-onset laryngeal dystonia (onset at ≤ 35 y.o.)
    • typical onset laryngeal dystonia (onset at ≥ 40 y.o.)
  6. Native English speakers.
  7. Right-handedness.
  8. Normal cognitive status.

Exclusion criteria:

  1. Subjects who are incapable of giving informed consent.
  2. Pregnant or breastfeeding women until a time when they are no longer pregnant or breastfeeding.
  3. Subjects with past or present medical history of (a) major neurological problems, such as stroke, movement disorders (other than LD and VT in the patient groups), brain tumors, traumatic brain injury with loss of consciousness, ataxias, myopathies, myasthenia gravis, demyelinating diseases, alcoholism, drug dependence; (b) psychiatric problems, such as schizophrenia, bipolar depression, obsessive-compulsive disorder; (c) laryn¬geal problems, such as vocal fold paralysis, paresis, vocal fold nodules and polyps, carcinoma, chronic laryngitis.
  4. Patients who are not symptomatic due to treatment with botulinum toxin injections into the laryngeal muscles.
  5. Subjects who receive medication(s) affecting the central nervous system.
  6. Subjects with a history of major brain and/or laryngeal surgery.
  7. Subjects who have tattoos, ferromagnetic objects in their bodies that cannot be removed for imaging study participation.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Cohort
  • Time Perspectives: Cross-Sectional

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Laryngeal Dystonia
Patients with laryngeal dystonia will undergo an MRI of the brain and a blood draw.
Other: MRI
Functional and structural MRI of the brain will be conducted to identify disorder specific neural markers
Procedure: Blood draw
Blood samples will be collected, the DNA will be extracted and banked for genetic studies.
Unaffected relatives of laryngeal dystonia patients
Unaffected relatives of patients with laryngeal dystonia will undergo an MRI of the brain and a blood draw.
Other: MRI
Functional and structural MRI of the brain will be conducted to identify disorder specific neural markers
Procedure: Blood draw
Blood samples will be collected, the DNA will be extracted and banked for genetic studies.
Voice tremor
Patients with voice tremor will undergo an MRI of the brain and a blood draw.
Other: MRI
Functional and structural MRI of the brain will be conducted to identify disorder specific neural markers
Procedure: Blood draw
Blood samples will be collected, the DNA will be extracted and banked for genetic studies.
Muscle tension dysphonia
Patients with muscle tension dysphonia will undergo an MRI of the brain and a blood draw.
Other: MRI
Functional and structural MRI of the brain will be conducted to identify disorder specific neural markers
Procedure: Blood draw
Blood samples will be collected, the DNA will be extracted and banked for genetic studies.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Brain changes in laryngeal dystonia
Time Frame: 5 years
Identify imaging biomarker of laryngeal dystonia
5 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Genes responsible for laryngeal dystonia
Time Frame: 5 years
Identify genetic mutations responsible for laryngeal dystonia
5 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Kristina Simonyan

Collaborators

National Institute on Deafness and Other Communication Disorders (NIDCD)

Investigators

  • Principal Investigator: Kristina Simonyan, MD, PhD, Massachusetts Eye and Ear Infirmary

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

January 23, 2017

Primary Completion (Estimated)

July 31, 2027

Study Completion (Estimated)

July 31, 2027

Study Registration Dates

First Submitted

January 31, 2017

First Submitted That Met QC Criteria

February 1, 2017

First Posted (Estimated)

February 3, 2017

Study Record Updates

Last Update Posted (Actual)

October 25, 2023

Last Update Submitted That Met QC Criteria

October 24, 2023

Last Verified

October 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2019P001576
  • R01DC011805 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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