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Dystonia, An Attractive Field of Research

What is Dystonia?

Dystonia is an umbrella term for a group of movement disorders in which sustained muscle contractions cause twisting and repetitive movements or abnormal postures. It is the third most common movement disorder, after Parkinson’s disease and tremor. The movements are involuntary, sometimes painful and can be incapacitating.

Symptoms may affect a single muscle, a muscle group (such as the arm, leg, or the neck), or the entire body including limbs, trunk, head, and face.  Dystonia can affect several parts of the body. Early symptoms may include a deterioration in handwriting, foot cramps, and/or an abnormal gait often due to posture of the foot. The neck may turn or pull involuntarily, especially with fatigue or stress. Sometimes the eyes will blink uncontrollably or be involuntarily closed for a sustained period, causing functional blindness. Other possible symptoms are voice or speech difficulties due to muscle contractions of the larynx. Some patients develop a tremor. Initial symptoms of dystonia may be mild. The symptoms may intensify over time and spread to additional, often adjacent, areas of the body. In other cases, there is little or no progression. The earlier the age of onset, the more likely the form will be severe.

Several areas of the brain have been implicated in dystonia including the basal ganglia, cerebellum, thalamus, and cortex.  Several neurotransmitters have also been implicated including GABA, dopamine, and acetylcholine. Secondary dystonia can result from environmental or disease-related damage to the basal ganglia. Birth injury, infection, drug exposure, heavy-metal or carbon monoxide poisoning, trauma, or stroke can cause dystonic symptoms. Dystonia can also occur as the symptom of other diseases, some of which may be hereditary. Many cases of dystonia have no connection to disease or injury and are classified as primary or idiopathic dystonia. Of the primary dystonias, some cases appear to be inherited in a dominant manner and with reduced penetrance. Several forms of dystonia have multiple genes or multiple mutations that are associated with symptoms. Some dystonias may have different types of hereditary patterns, including recessive and x-linked.

At the moment there is no cure for dystonia. Current pharmacological treatments are aimed at lessening the symptoms of muscle contractions, pain, and abnormal postures. In the most common and severe form of inherited dystonias (early-onset generalized dystonia), pharmacological treatment is often ineffective.  However, clinical research has shown that deep brain stimulation (DBS) of the globus pallidus internus (GPi) nuclei is highly effective for these patients (first reports in the late 90′s). DBS surgery consists in the implantation of electrodes in the GPi, connected to a battery, implanted under the skin in the chest or abdomen. DBS treatment involves delivering high-frequency, low-voltage current in the grey nuclei. Recent studies have shown that benefits may be maintained over 10 years after initial surgery. The mechanism of action of DBS on dystonia remains unknown.

What is the Dystonia Coalition?

The Dystonia Coalition is a collaboration of medical researchers and patient advocacy groups supported by the Office of Rare Diseases and The National Institute of Neurological Disorders and Stroke at the NIH. The mission is to advance the pace of clinical and translational research in the dystonias to find better treatments and a cure. The objectives are to develop a fuller understanding of the many different features of dystonia and how they change over the years, to develop validated diagnostic strategies and rating tools for diagnosis and monitoring patients in clinical trials, to establish a biorepository where samples of blood and other materials can be stored and distributed for research, to catalyze clinical trials for promising new treatments, and to promote education and awareness.

 

The Dystonia Coalition uses an open-door policy in which new investigators and institutions may join the effort at any time. Each of these centers may participate in ongoing research projects, submit proposals for new projects, or nominate candidates for career development awards.

 

Emory University serves as the Central Coordinating Center for the Dystonia Coalition’s activities. Three main research projects are directed through three Project Centers. Joel Perlmutter at Washington University in St. Louis is directing the Natural History with Linked Biorepository project encompassing all of the focal dystonias. Cynthia Comella at Rush University in Chicago is directing the project involving Development of Comprehensive Rating Tools for Cervical Dystonia. Christy Ludlow at James Madison University in Harrisonburg, VA is directing the development of a project involving Diagnostic and Rating Tools for Spasmodic Dysphonia. In addition to the four centers outlined above, the Dystonia Coalition has more than 40 Participating Clinical Centers distributed throughout North America and Europe. The Dystonia Coalition uses an open-door policy in which new investigators and institutions may join the effort at any time. Each of these centers may participate in ongoing research projects, submit proposals for new projects, or nominate candidates for career development awards.

Integral to the mission are the patient advocacy groups. Each of the patient advocacy groups is encouraged to be involved in the yearly meeting of the Dystonia Coalition, participant in the Pilot Projects Program or Career Development Program, and refer patients to our centers for participation in studies or expert treatment, and help keep patients and providers well informed.  The Dystonia Medical Research Foundation also serves as an administrative center.

The primary goal of the Dystonia Coalition is to conduct research relating to dystonia. The academic centers in the Dystonia Coalition all have a special interest in dystonia research as well as expertise in its diagnosis and treatment of all forms of dystonia.  Patients come to these centers for both research opportunities and expert clinical care. The Dystonia Coalition welcomes patients to come for either or both.

Bios:

  • portrait_2020-150x150Philippe Coubes, MD, PhD, completed his Neurosurgery residency at the University Medical School of Montpellier (France) in 1989. He then received a PhD in Biomedical Sciences in 1995 at the University of Montpellier after being a trainee at the Cleveland Clinic (USA) in the departments of Neurological Surgery and Nuclear Medicine. Coubes is currently a Professor of the departments of Functional and Stereotactic Neurosurgery and Pediatric Neurosurgery at the Gui de Chauliac University Hospital in Montpellier, France. He is also the director of a Research Lab working on Movement Disorders (URMA) at the IGF institute, INSERM U661, CNRS UMR 5203, Montpellier. Coubes was one of the first neurosurgeons to adapt DBS for the treatment of dystonia. His work is focused on the mechanisms of action and long-term effects of DBS. Coubes receives public funding for patient care and his research is mostly supported by French patient foundations.
  • Dauer-2-150x150William Dauer, MD is an Elinor Levine Associate Professor of Neurology & Cell and Developmental Biology at the University of Michigan. He serves on a number of advisory boards including the Dystonia Medical Research Foundation (DMRF) Medical & Scientific Advisory Council. Dauer is a recipient of the DMRF’s most prestigious grant, the Stanley Fahn Award. The central goal of William Dauer’s studies is to unravel the molecular and cellular mechanisms of diseases that disrupt the motor system. The primary focus is on Parkinson’s disease and DYT1 dystonia. For each of these projects, special focus is directed toward disease genes that cause these disorders, employing a range of molecular, cellular, and whole animal studies to dissect the normal role of disease proteins, and how pathogenic mutations lead to disease. http://www.dauerlab.org/
  • Jinnah-photo-150x150H. A. Jinnah, MD, PhD received his BS from Duke University in 1985 and combined MD/PhD degrees in Neurosciences via the NIH-sponsored Medical Scientist Training Program at the University of California in San Diego in 1993. He completed a Neurology Residency and Fellowship in Movement Disorders at Johns Hopkins University in 1997. He is currently a Professor in the Departments of Neurology, Human Genetics & Pediatrics at Emory University, Atlanta. Jinnah’s research interests are in the biological basis for neurological and behavioral disorders with a special interest in the biological basis of dystonia. The research strategy involves two complementary approaches. One approach entails studies of biological mechanisms responsible for dystonia in Lesch-Nyhan disease, a rare neurogenetic disorder for which the genetic mutations and biochemical defects are known. The other approach involves the investigation of biological mechanisms shared by different forms of dystonia, with the goal of identifying final common molecular and neural pathways. His laboratory takes a multidisciplinary approach that encompasses molecular genetics, biochemistry, cell biology, anatomy and histopathology, neuropharmacology, and animal models. The laboratory programs are linked with a clinical research program that addresses the same problems in humans and their treatments. Jinnah has received both private and NIH funding for his research programs since 1997.  He has served on a number of advisory boards including the Dystonia Medical Research Foundation.

 

ADDITIONAL LINKS

Dystonia Medical Research Foundation

http://www.dystonia-foundation.org

 

Faces of Dystonia

http://www.dystonia-foundation.org/faces_of_dystonia

 

Dystonia Coalition

http://rarediseasesnetwork.epi.usf.edu/dystonia

 

We wish to thank the members of the Dystonia Medical Research Foundation (DMRF) for helping put this content together, as well as the video participants.

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