Second NINDS-DMRF Workshop on Dystonia
Recent Advances and Future Directions
June 6-7, 2006
Bethesda, MD
Meeting Organizers:
The Second NINDS-DMRF Workshop on Dystonia, Recent Advances and Future Directions, was held on June 6-7, 2006, in Bethesda, MD. The meeting brought together leading researchers, clinicians, industry scientists, and representatives from patient advocacy groups. Current research approaches to dystonia were reflected in the themes of the workshop sessions.
Session I: Genetics and Epidemiology
The majority of dystonia patients do not inherit the disease. However, studying the genes that cause a variety of inheritable dystonias provides invaluable knowledge about the mechanism. Identification of genes that cause dystonia is essential for understanding the disease process, discovering molecular drug targets, and enabling early and precise diagnosis. Genetic animal models should facilitate the understanding of the pathophysiology of dystonia and provide tools for drug testing. Discovery of new genes causing other forms of dystonia should shed light on the basic mechanisms of this disease. Finally, understanding the complex interactions between genes and environment should provide answers related to fundamental questions concerning the etiology and progression of dystonia.
Out of fifteen genes linked to dystonia, six have been isolated. They code for structural proteins, enzymes, transcription factors, and proteins of unknown primary function. Genetic and symptomatic heterogeneity is considered a complicating factor in the study of dystonia. More studies on dystonia prevalence and incidence are needed since dystonia remains under-diagnosed or misdiagnosed. Research into the causes of dystonia should first concentrate on new and already identified genes and their products. In addition, studies on environmental and occupational risk factors are also warranted.
Immediate next steps should involve:
Session II: Pathophysiology of the Dystonias
The basal ganglia is considered to be the primary site of the physiological and biochemical abnormalities observed in dystonia. What are the principles governing the coordination of movement? Is plasticity an underlying principle in the etiology of dystonia? If so, what role does plasticity play? Is dystonia the reaction of the motor systems to a variety of insults? What is the involvement of the cerebellum in human pathophysiology? To answer these fundamental questions, physiological studies of dystonia should be focused on mechanisms leading to the loss of inhibition, increased plasticity, and abnormal sensory function. More research is needed on therapies derived from the understanding of pathophysiology of the dystonias, which are based on motor and sensory retraining, increased inhibition, and normalized plasticity. If disease causing mutations are known, research should be aimed at the identification of physiological substrates directly linked to such mutations - mechanism-based therapies should then be developed. Studies on motor learning and motor adaptation may provide the interpretational framework for dystonia etiology. Studies on corrective strategies for acquired or developmentally disrupted models of sensorimotor patterns in the brain may provide viable treatment options. The use of afferent electric nerve and transcranial magnetic stimulation in the motor cortex, known as paired associative stimulation (PAS), should provide more information on how cortical afferent inhibition is modulated. By using PAS and other techniques one could attempt to reveal the role of the basal ganglia in cortical plasticity.
The physiological and pathophysiological aspects of dystonia that need to be studied include:
Session III: Neuroimaging the Dystonias
Neuroimaging technologies provide noninvasive visualization of brain structures and functional changes. Rapidly developing neuroimaging techniques have found wide application in dystonia research ranging from clinical diagnosis and determination of pathogenesis to biomarker development. Measurement of the dynamics of different transmitter/receptor systems, measurement of endogenous neurotransmitters metabolism, assessment of effects of drugs on endogenous dopamine are just a few examples. Since novel technologies are being constantly added there is great hope that they can provide a necessary means to integrate our knowledge about dystonia. Imaging may provide the optimal and most accessible readout for therapies and research efforts attempting to correlate genotype with phenotype. Imaging might be the best source of universal biomarkers.
Current areas of interest are as follows:
Session IV: Brain Pathology, Brain Banking, and Biomarkers
Very little is known about dystonia brain pathology; we know more about dystonia mouse models pathology than human pathology. Although no overt neurodegeneration has been detected, there might be undiscovered pathological changes. More post-mortem brain specimens are needed to expand and intensify neuropathological studies. Patients, support groups, and brain banks should all be involved. More neuropathological studies are needed on genetically-linked dystonia with the inclusion of non-manifesting carrier and controls. In addition, the neuropathology of focal dystonia cases should be included due to its relatively high prevalence,
The issues to be addressed immediately are:
Session V: Rehabilitation
Rehabilitation remains the most direct and often very effective treatment for all forms of dystonia. Quality of life is improved by reducing general disability, increasing range of motion, recovering normal gait or voice, reduction of tremors and rigidity, and fighting depression. Yet, current dystonia rehabilitation strategies should be more comprehensive and include active exercise, motor, sensory, and cognitive retraining, often combined with other therapeutic interventions. Since assessment of success in rehabilitation therapies is often subjective, more efforts should be devoted to studying design issues: control group selection, study duration, etc.
The immediate needs in this field are:
Session VI: TorsinA - Function and Interactions
Since the discovery of the DYT1 gene, the field of torsinA research has matured considerably. The most promising leads to elucidate torsinA function should be pursued: the role of torsinA at the nuclear envelope, the role of the nucleotide binding site, the putative enzymatic activity, and the chaperone function. Several recently identified torsinA binding proteins offer clues as to the protein's function and localization in the cell. Continuous studies on the nuclear envelope structure and function provide the necessary background in this area. One of the primary questions is why and how the torsinA pathogenic mutant protein accumulates in the nuclear envelope. TorsinA has a 'substrate' in the nuclear envelope, thus more efforts should be directed at the identification and understanding of this process. LAP1 and LULL1, two protein binding partners of torsinA, may be crucial to understanding the torsinA function, especially at the nuclear envelope. The idea that the ∆E-torsinA functionally represents a loss of function allele establishes a conceptual framework for research. Studies on torsinA should take into account that torsinA-related nuclear envelope abnormalities are neuronal specific and developmentally depended. What cellular function is regulated by the torsinA pathway? What is the role of the nucleo-skeletal connections and secretory pathways? What is the role of membrane dynamics in this process? More efforts should be directed toward fully understanding the protein-protein interactions in which torsinA and its binding partners participate. At the biochemical/molecular level, the major challenge is to determine the three-dimensional structure of torsinA. One of the fundamental prerequisites for structural studies - high level of torsinA expression - has not been achieved. More insight into the ATP/ADP binding mechanism and kinetics is needed. The role of the redox state dependency of the nucleotide binding could be relevant in vivo. What cellular conditions, from a biochemical perspective, contribute to altered functionality of the torsinA mutant? Are these conditions unique in neurons?
The fundamental questions to be answered are:
Session VII: Animal Models
A comprehensive approach to animal modeling of the dystonias is essential. Both etiologic and phenotypic models are indispensable. Animal models implicate two major brain regions involved in dystonia: basal ganglia and cerebellum. Basal ganglia models include animals with drug-induced pathologies as well as episodic dystonia, apparently caused by unknown autosomal recessive mutation(s). Does abnormal cerebellar signaling induce dystonia? Yes, since cerebellar injection of kainate causes dystonia. Recent studies confirm communication between the cerebellum and the basal ganglia. Discoveries of new dystonia-causing genes prompted numerous studies using transgenic, knock-in, knock-down, knock-out, and conditional knock-out animals. DYT1 delta GAG knock-in mice display aggregates in the brainstem; similar aggregates have been seen in DYT1 transgenics. Valid genetic models of dystonia typically demonstrate slip deficits in beam walking tests and hyperactivity in open field tests, abnormal dopaminergic function, brainstem cellular aggregates, and EMG-detectable abnormal co-contraction of agonist and antagonist muscles. The knock-in mice show deficits in motor coordination and balance, in dopaminergic metabolism, and in brainstem neuropathology. However, the mice do not show "dystonia". Animal genetic models appear not to display dystonic phenotype - are these phenotypes masked by unknown factors? Are selected drugs necessary to induce dystonia even in genetic models?
Among the issues that need further study are:
Session VIII: Surgical Approaches
Deep brain stimulation (DBS) is an effective treatment for torsion dystonia. Why does DBS work? How does it work? How long does it work? Why doesn't it benefit everyone equally? How do lesions compare to DBS? What are the differences in targeting thalamic vs. pallidal sites? Are there any other target sites? We need to consider genetic status, phenotype, lead location, programming parameters, and other factors. Understanding the pathophysiology of the disease will elucidate the mechanism of action of the therapy. These efforts are critical for developing new surgical therapies since parameter selection is currently done by 'clinical intuition' and one can describe DBS as 'one-size-fits-all' technology. Patient-specific DBS can be achieved through complex computer modeling.
The goals of such modeling are to merge neural stimulation modeling techniques with MR/CT imaging data and electrophysiological recording data:
These modeling efforts should also involve:
Beyond modeling, research on DBS should consider the following:
Session IX: Experimental Therapeutics
Genetics continues to provide diverse molecular targets, although pathophysiology of the dystonias is not fully understood. Selected brain regions provide the basis for anatomical, physiological, and molecular inquiry. Therapeutics development is further complicated by tremendous heterogeneity of the patient population and lack of uniform outcome measures.
RNA interference (RNAi) offers a new avenue for innovative drug development. Dystonia is a primarily a dominantly inherited disorder with likely dominant negative effect. There is an apparent window of susceptibility and, since there is no neuronal loss, there is potential for reversibility. Sparing wild-type torsinA levels might be important. Therefore the siRNA-based therapy should be allele-specific. Before such therapy can be moved to the clinic, several fundamental questions need to be answered: What to deliver? How, when, and where? Allele-specific silencing of torsinA (delatGAG) is feasible in cells - it leads to rescuing dominant negative effects of torsinA (delatGAG) over the wild type allele. Suppression of endogenous torsinA has been achieved in mammalian neurons. As the feasibility of siRNA-based therapy is now being established in animals, a major challenge will be to develop successful brain delivery methods and safe viral or non-viral methods of targeting selected brain structures. Searches for more conventional drugs use several assays based on torsinA properties. Several such assays have been established in research laboratories: fibroblast adhesion assay, neurite outgrowth assay, membrane abnormalities assessment, and nuclear envelope mislocalization assay.
In another model system, using C. elegans, it has been shown that torsinA has the capacity to function as a molecular chaperone. Wild type torsinA can suppress the aggregation and toxic protein misfolding in vivo. In contrast, mutant torsinA (∆E) or a combination of wild type and mutant torsinA show diminished chaperone function. This system has been used to evaluate the potential of small molecule drugs to affect the chaperone activity of torsinA in suppressing polyglutamine (polyQ)-induced protein aggregation associated with α- synuclein overexpression in dopaminergic neurons of C. elegans. Out of 240 structurally diverse, mostly off-patent FDA-approved drugs, five were identified that exhibit aggregation-suppressing activity by exerting their effects through modulating the function of torsinA. The identified compounds fall into four different therapeutic categories and will be evaluated in other cellular assays and transgenic animals. Medicinal chemistry efforts may potentially expand this family of drugs.
Issues to consider in developing dystonia experimental therapeutics are:
Epidemiological Studies
Genetic Studies
Pathophysiology
Neuroimaging
Neuropathology
Functional Rehabilitation and Quality of Life
Modeling
Neurosurgery and Brain Stimulation
Experimental Therapeutics
Ron Alterman, M.D.
Director of Functional & Restorative Neurosurgery
Mount Sinai School of Medicine
Ioanna Armata, M.S.
Graduate Student
Mount Sinai School of Medicine
Craig Blackstone, M.D., Ph.D.
Chief, Cellular Neurology Unit
National Institute of Neurological Disorders and Stroke
National Institutes of Health
Anne Blood, Ph.D.
Athinoula Martinos Center for Biomedical Imaging
Massachusetts General Hospital
Department of Neurology
Xandra Breakefield, Ph.D. Professor & Genecist
Massachusetts General Hospital & Harvard Medical School
Susan Bressman, M.D.
Chairman and Professor
Beth Israel Medical Center
Kim Caldwell, Ph.D.
Assistant Professor
The University of Alabama
Guy Caldwell, Ph.D.
Associate Professor of Biological Sciences
The University of Alabama
Department of Biological Sciences
Claire Centrella
President
Dystonia Medical Research Foundation
A. Ray Chaudhuri, Ph.D., M.B.A.
Program Analyst
National Institute of Neurological Disorders and Stroke
National Institutes of Health
Daofen Chen, Ph.D.
Program Director
National Institute of Neurological Disorders and Stroke
National Institutes of Health
Cynthia Comella, M.D.
Professor
Rush University Medical Center
Mark Corrigan, M.D.
Executive Vice President of Research & Development
Sepracor Inc.
Jan Craig
Vice President of Science
Dystonia Medical Research Foundation
William Dauer, M.D.
Assistant Professor of Neurology & Pharmacology
Columbia University
Mahlon DeLong, M.D.
Professor and Director of Neuroscience
Emory University School of Medicine
Department of Neurology
Dennis Dickson, M.D.
Professor
Mayo Clinic College of Medicine
David Eidelberg, M.D.
Director
The Feinstein Institute for Medical Research
Center for Neurosciences
Glen Estrin, B.M.
President
Dystonia Medical Research Foundation
Craig Evinger, Ph.D.
Professor
SUNY Stony Brook
Stanley Fahn, M.D.
Professor of Neurology
Columbia University College of Physicians and Surgeons
Steven Frucht, M.D.
Assistant Professor of Neurology
Columbia University Medical Center
Wendy Galpern, M.D., Ph.D.
Program Director
National Institute of Neurological Disorders and Stroke
National Institutes of Health
Clinical Trials Division
Pedro Gonzalez-Alegre, M.D.
Assistant Professor
University of Iowa
Steve Groft, M.D.
Director
Office of Rare Diseases
National Institutes of Health
Mark Hallett, M.D.
Chief, Medical Neurology Branch
National Institute of Neurological Disorders and Stroke
National Institutes of Health
Phyllis Hanson, M.D., Ph.D.
Associate Professor
Washington University School of Medicine
Department of Cell Biology
Ellen Hess, Ph.D.
Associate Professor
Johns Hopkins University
Jeff Hewett
Senior Laboratory Manager
Massachusetts General Hospital
Neuroscience Center
Janet Hieshetter
Executive Director
Dystonia Medical Research Foundation
Ross Hoffman, M.D.
Western Slope Cardiology
Neville Hogan, Ph.D.
Professor
Massachusetts Institute of Technology
Hans-Christian Jabusch, M.D.
Assistant Director
University of Music and Drama, Hannover
Teresa Jacobson Kimberley, Ph.D.
Assistant Professor
University of Minnesota
Hyder Jinnah, M.D., Ph.D.
Associate Professor
Johns Hopkins University
Melinda Kelley, Ph.D.
Senior Science Advisor
National Institute of Neurological Disorders and Stroke
National Institutes of Health
Art Kessler
Dystonia Medical Research Foundation
Dennis Kessler
Christine Klein, M.D.
Professor of Clinical and Molecular Neurogenetics
University of Luebeck
Kimberly Kuman
Executive Director
National Spasmodic Dysphonia Association
Story Landis, Ph.D.
Director
National Institute of Neurological Disorders and Stroke
National Institutes of Health
Anthony Lang, M.D., F.R.C.P.C.
Director, Movement Disorders Unit
University of Toronto, Toronto Western Hospital
Mark LeDoux, M.D., Ph.D.
Professor
University of Tennessee Health Science Center
Stephane Lehericy, Ph.D.
Professor
University Pierre and Marie Curie
Rosalie Lewis
Vice President of Public Policy
Dystonia Medical Research Foundation
Yuqing Li, Ph.D.
Member
University of Illinois at Urbana-Champaign
NeuroTech Group, Beckman Institute for Advanced Science and Technology
Steven Lo, M.D.
Clinical Fellow in Movement Disorders
Columbia University Medical Center
David Lovinger, Ph.D.
Chief, Laboratory for Integrative Neuroscience
National Institute on Alcohol Abuse and Alcoholism
National Institutes of Health
Christy Ludlow, Ph.D.
Chief, Laryngeal and Speech Section
National Institute of Neurological Disorders and Stroke
National Institutes of Health
Charles Markham, M.D.
Research Professor
University of California
Cameron McIntyre, Ph.D.
Assistant Professor
Cleveland Clinic Foundation
Sabine Meunier, M.D.
Clinical Fellow
National Institute of Neurological Disorders and Stroke
National Institutes of Health
Helen Miller, M.S.S.W.
Executive Director
Mt. Sinai Medical Center
Bachmann-Strauss Dystonia Parkinson Foundation
Jonathan Mink, M.D., Ph.D.
Associate Professor
University of Rochester
Flavia Nery, Ph.D.
Massachusetts General Hospital
Tan Nguyen, M.D., Ph.D.
Medical Officer
U.S. Food and Drug Administration
Laurie Ozelius, Ph.D.
Associate Professor
Albert Einstein College of Medicine
Henry Paulson, M.D., Ph.D.
Professor
University of Iowa
Audrey Penn, M.D.
Deputy Director
National Institute of Neurological Disorders and Stroke
National Institutes of Health
Joel Perlmutter, M.D.
Professor of Neurology and Radiology
Washington Hospital
Jody Roosevelt
Manager of Science and Technology
Dystonia Medical Research Foundation
John Rothwell, Ph.D.
Professor of Human Neurophysiology
Institute of Neurology
Terence Sanger, M.D., Ph.D.
Assistant Professor
Stanford University
Nutan Sharma, M.D., Ph.D.
Assistant Professor of Neurology
Massachusetts General Hospital
Pullanipally Shashidharan, Ph.D.
Associate Professor of Neurology
Mount Sinai School of Medicine
Lisa Shulman, M.D.
Associate Professor of Neurology
University of Maryland
Mary Smith
Board Secretary and Office Manager
Benign Essential Blepharospasm Research Foundation, Inc.
David Standaert, M.D., Ph.D.
Associate Professor
Massachusetts General Hospital
A. Jon Stoessl, M.D., F.R.C.P.C.
Professor and Director
University of British Columbia
Bonnie Strauss
President
MT Sinai Medical Center
Bachmann-Strauss Dystonia Parkinson Foundation
Danilo Tagle, Ph.D.
Program Director
National Institute of Neurological Disorders and Stroke
National Institutes of Health
Michele Tagliati, M.D.
Associate Professor
Mount Sinai School of Medicine
Caroline Tanner, M.D., Ph.D.
Director
The Parkinson's Institute
Jan Teller, M.A., Ph.D.
Science Officer
Dystonia Medical Research Foundation
Philip Thomas, Ph.D.
Professor
University of Texas Southwestern Medical Center at Dallas
Gonzalo Torres, Ph.D.
Assistant Professor
University of Pittsburgh
Jerrold Vitek, M.D., Ph.D.
Director, Functional Neurosciences
The Cleveland Clinic Foundation
Department of Neurosciences
Ruth Walker, M.D., Ch.B., Ph.D.
Assistant Professor
James J. Peters VAMC/Mount Sinai School of Medicine
Benjamin Walter, M.D.
Movement Disorder Specialist
The Cleveland Clinic Foundation
Howard Worman, M.D.
Associate Director
Columbia University Medical Center
H. Ronald Zielke, Ph.D.
Director, Brain and Tissue Bank
University of Maryland at Baltimore
Onsite Participants:
Ted Dawson, Bachmann-Strauss Dystonia Parkinson Foundation
Joseph Pancrazio, NINDS
Rucha Vyas, Dystonia Medical Research Foundation
Last updated February 07, 2007