Imaging Genetics of Laryngeal Dystonia

NCT03042975 | Recruiting

• 2 other identifiers: 2019P001576R01DC011805
• Study Type: observational
• Target: 410
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Laryngeal Dystonia; Unaffected Relatives of Laryngeal Dystonia Patients; Voice Tremor; Muscle Tension Dysphonia

Keywords

dystonia; spasmodic dysphonia; imaging; genetics

Outcome Measures

Primary Outcomes (1)

• Brain changes in laryngeal dystonia

  Identify imaging biomarker of laryngeal dystonia

  5 years

Secondary Outcomes (1)

• Genes responsible for laryngeal dystonia

  5 years

Study Arms (4)

Laryngeal Dystonia

Patients with laryngeal dystonia will undergo an MRI of the brain and a blood draw.

Other: MRI; Procedure: Blood draw

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; Procedure: Blood draw

Voice tremor

Patients with voice tremor will undergo an MRI of the brain and a blood draw.

Other: MRI; Procedure: Blood draw

Muscle tension dysphonia

Patients with muscle tension dysphonia will undergo an MRI of the brain and a blood draw.

Other: MRI; Procedure: Blood draw

Interventions

MRI OTHER

Functional and structural MRI of the brain will be conducted to identify disorder specific neural markers

Laryngeal Dystonia; Muscle tension dysphonia; Unaffected relatives of laryngeal dystonia patients; Voice tremor

Blood draw PROCEDURE

Blood samples will be collected, the DNA will be extracted and banked for genetic studies.

Laryngeal Dystonia; Muscle tension dysphonia; Unaffected relatives of laryngeal dystonia patients; Voice tremor

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

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

You may qualify if:

• Males and females of diverse racial and ethnic background, with age across the lifespan;
• Laryngeal Dystonia patients
• phenotype: adductor or abductor
• genotype: familial or sporadic
• Voice Tremor patients
• essential or
• dystonic
• Muscle tension dysphonia patients
• 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.)
• Native English speakers.
• Right-handedness.
• Normal cognitive status.

You may not qualify if:

• Subjects who are incapable of giving informed consent.
• Pregnant or breastfeeding women until a time when they are no longer pregnant or breastfeeding.
• 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.
• Patients who are not symptomatic due to treatment with botulinum toxin injections into the laryngeal muscles.
• Subjects who receive medication(s) affecting the central nervous system.
• Subjects with a history of major brain and/or laryngeal surgery.
• Subjects who have tattoos, ferromagnetic objects in their bodies that cannot be removed for imaging study participation.

Sponsors & Collaborators

• Kristina Simonyan: lead
• National Institute on Deafness and Other Communication Disorders (NIDCD): collaborator

Study Sites (1)

Massachusetts Eye and Ear Infirmary

Boston, Massachusetts, 02114, United States

RECRUITING

Related Publications (11)

• Battistella G, Termsarasab P, Ramdhani RA, Fuertinger S, Simonyan K. Isolated Focal Dystonia as a Disorder of Large-Scale Functional Networks. Cereb Cortex. 2017 Feb 1;27(2):1203-1215. doi: 10.1093/cercor/bhv313.

  PMID: 26679193 RESULT

• Vulinovic F, Schaake S, Domingo A, Kumar KR, Defazio G, Mir P, Simonyan K, Ozelius LJ, Bruggemann N, Chung SJ, Rakovic A, Lohmann K, Klein C. Screening study of TUBB4A in isolated dystonia. Parkinsonism Relat Disord. 2017 Aug;41:118-120. doi: 10.1016/j.parkreldis.2017.06.001. Epub 2017 Jun 10.

  PMID: 28655586 RESULT

• Termsarasab P, Ramdhani RA, Battistella G, Rubien-Thomas E, Choy M, Farwell IM, Velickovic M, Blitzer A, Frucht SJ, Reilly RB, Hutchinson M, Ozelius LJ, Simonyan K. Neural correlates of abnormal sensory discrimination in laryngeal dystonia. Neuroimage Clin. 2015 Oct 30;10:18-26. doi: 10.1016/j.nicl.2015.10.016. eCollection 2016.

  PMID: 26693398 RESULT

• Fuertinger S, Horwitz B, Simonyan K. The Functional Connectome of Speech Control. PLoS Biol. 2015 Jul 23;13(7):e1002209. doi: 10.1371/journal.pbio.1002209. eCollection 2015 Jul.

  PMID: 26204475 RESULT

• Simonyan K, Fuertinger S. Speech networks at rest and in action: interactions between functional brain networks controlling speech production. J Neurophysiol. 2015 Apr 1;113(7):2967-78. doi: 10.1152/jn.00964.2014. Epub 2015 Feb 11.

  PMID: 25673742 RESULT

• Battistella G, Fuertinger S, Fleysher L, Ozelius LJ, Simonyan K. Cortical sensorimotor alterations classify clinical phenotype and putative genotype of spasmodic dysphonia. Eur J Neurol. 2016 Oct;23(10):1517-27. doi: 10.1111/ene.13067. Epub 2016 Jun 27.

  PMID: 27346568 RESULT

• Putzel GG, Fuchs T, Battistella G, Rubien-Thomas E, Frucht SJ, Blitzer A, Ozelius LJ, Simonyan K. GNAL mutation in isolated laryngeal dystonia. Mov Disord. 2016 May;31(5):750-5. doi: 10.1002/mds.26502. Epub 2016 Feb 1.

  PMID: 27093447 RESULT

• Rittiner JE, Caffall ZF, Hernandez-Martinez R, Sanderson SM, Pearson JL, Tsukayama KK, Liu AY, Xiao C, Tracy S, Shipman MK, Hickey P, Johnson J, Scott B, Stacy M, Saunders-Pullman R, Bressman S, Simonyan K, Sharma N, Ozelius LJ, Cirulli ET, Calakos N. Functional Genomic Analyses of Mendelian and Sporadic Disease Identify Impaired eIF2alpha Signaling as a Generalizable Mechanism for Dystonia. Neuron. 2016 Dec 21;92(6):1238-1251. doi: 10.1016/j.neuron.2016.11.012. Epub 2016 Dec 8.

  PMID: 27939583 RESULT

• Bianchi S, Battistella G, Huddleston H, Scharf R, Fleysher L, Rumbach AF, Frucht SJ, Blitzer A, Ozelius LJ, Simonyan K. Phenotype- and genotype-specific structural alterations in spasmodic dysphonia. Mov Disord. 2017 Apr;32(4):560-568. doi: 10.1002/mds.26920. Epub 2017 Feb 10.

  PMID: 28186656 RESULT

• Fuertinger S, Simonyan K. Connectome-Wide Phenotypical and Genotypical Associations in Focal Dystonia. J Neurosci. 2017 Aug 2;37(31):7438-7449. doi: 10.1523/JNEUROSCI.0384-17.2017. Epub 2017 Jul 3.

  PMID: 28674168 RESULT

• de Lima Xavier L, Simonyan K. The extrinsic risk and its association with neural alterations in spasmodic dysphonia. Parkinsonism Relat Disord. 2019 Aug;65:117-123. doi: 10.1016/j.parkreldis.2019.05.034. Epub 2019 May 24.

  PMID: 31153765 DERIVED

Biospecimen

Retention: SAMPLES WITH DNA

Brain images and blood samples will be collected. The DNA will be extracted and banked for genetic studies.

MeSH Terms

Conditions

Dysphonia; Dystonia

Interventions

Blood Specimen Collection

Condition Hierarchy (Ancestors)

Voice Disorders; Laryngeal Diseases; Respiratory Tract Diseases; Otorhinolaryngologic Diseases; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Dyskinesias

Intervention Hierarchy (Ancestors)

Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Investigative Techniques

Study Officials

• Kristina Simonyan, MD, PhD

  Massachusetts Eye and Ear Infirmary

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Kristina Simonyan, MD, PhD

CONTACT

617-573-6016; Simonyan_Lab@MEEI.HARVARD.EDU

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: CROSS SECTIONAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor of Otolaryngology - Head & Neck Surgery

Study Record Dates

• First Submitted: January 31, 2017
• First Posted: February 3, 2017
• Study Start: January 23, 2017
• Primary Completion (Estimated): July 31, 2028
• Study Completion (Estimated): July 31, 2028
• Last Updated: December 2, 2025

Record last verified: 2025-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)