What is the Dystonia Coalition?
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Dystonia Coalition is an international collaboration between clinical experts, researchers, and patient advocacy groups to advance dystonia research for finding better treatments. The coalition was established in 2009 with the support of the Office of Rare Diseases Research in the National Center for Advancing Translational Sciences and The National Institute of Neurological Disorders and Stroke at the NIH. In the last decade, over 50 sites that provide care to dystonia patients and are interested in advancing research have become members of this coalition. These sites are spread across North America, Europe, Asia, and Australia. In addition to the clinical providers and researchers, there are at least 17 patient advocacy groups committed to the coalition's core activities. The patient advocacy groups play an integral role in identifying the critical needs for the dystonia community from a clinical and scientific perspective. Patient advocates recognize the needs of the community through focused workshops. They work with researchers to design appropriate studies and facilitate patient recruitment to accomplish successful and timely completion. They play an active role in organizing meetings to discuss the annual progress, identify challenges for research, and brainstorm ideas for further advancement of research. Some of the patient advocacy groups are also involved in actively finding and funding dystonia researchers, especially the young and new to the dystonia field.

​The Dystonia Coalition aims to understand the disease better, develop appropriate tools to monitor patients in clinical trials, and identify biomarkers valuable for clinical research. It has brought hundreds of dystonia providers and thousands of patients to a common platform to facilitate large-scale collaborations to address these critical knowledge gaps. The main ongoing projects for the Coalition include the natural history project, development of diagnostic and rating tools for cervical dystonia, development of similar tools for blepharospasm and laryngeal dystonia, the establishment of objective measures for assessment of symptoms, monitoring outcomes with a patient-centered approach, and building a large biobank through the collection of DNA samples. Their ultimate goal is to accomplish "clinical trial readiness." The current projects are essential for developing effective candidate treatments and ensuring their high likelihood of success.

What has the Dystonia Coalition accomplished so far?

The efforts of the Dystonia Coalition have led to many significant clinical and scientific achievements. Before the coalition existed, the definition of dystonia had certain missing elements, and the approach for categorizing various forms of dystonia varied among clinicians and researchers. Differences in diagnosis and classification approach invariably led to confusion in the interpretation of many studies. We now have a revised definition for dystonia and a new scheme to classify patients consensually agreed upon by an international team of experts and patient advocates.  Then over the last decade, many multicenter projects have been completed successfully. These projects have contributed to understanding the evolution patterns for specific forms of dystonia, the determination of clinically employable measurement scales, and the development of objective tools which could be more sensitive for monitoring clinical symptoms. Due to a broad collaboration network, clinical data, video recordings, and DNA samples for over 3000 patients are available for sharing with researchers worldwide. We can characterize the symptoms better, assess the risk of clinical spread of motor symptoms, recognize the importance of co-occurring nonmotor symptoms commonly, understand the treatment patterns, and identify factors that drive a positive response to the available medical and surgical treatments. Many new young investigators have now joined the dystonia field. These efforts are indeed impressive and commendable.

How does the Tyler’s Hope Foundation and the Dystonia Coalition connect?

The Tyler’s Hope Foundation and the Dystonia Coalition have common goals. They both engage in keeping the health care providers and the researchers well informed on the needs of the dystonia community. They both are interested and involved in finding financial and non-financial resources for the dystonia researchers. They both aim to promote awareness and education for dystonia through meetings and webinars. The Tyler’s Hope Foundation focuses on genetic dystonia, mainly DYT-Tor1A dystonia. To bring together patients with this genetic diagnosis and guide clinical studies for these patients, Tyler’s Hope maintains a registry of DYT-Tor1A dystonia patients, Dystonia International Patient Registry. On the other hand, the Dystonia Coalition that focuses on all forms of dystonia, is involved with the Global Dystonia Registry to support future clinical trials. As a patient advocacy group, the Tyler’s Hope Foundation is closely supporting the Dystonia Coalition efforts. Together these organizations plan to advance the pace of clinical and translational research to find better treatments and ultimately a cure for dystonia.

The Dystonia Coalition: A Multicenter Network for Clinical and Translational Studies

Gamze Kilic-Berkmen, Laura J. Wright, Joel S. Perlmutter, Cynthia Comella, Mark Hallett, Jan Teller, Sarah Pirio Richardson, David A. Peterson, Carlos Cruchaga, Codrin Lungu and H. A. Jinnah. Front. Neurol., 08 April 2021
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https://doi.org/10.3389/fneur.2021.660909

Dystonia is the third most common type of movement disorder. Dystonia occurs due to abnormal firing of brain signals that cause excessive and involuntary or out-of-control muscle contractions. As a result, patients develop abnormal twisting postures, involuntary movements, and lose motor control. Dystonia can affect muscles in either a single or multiple body regions. Examples of such regions include eyelids, face, jaws, neck, vocal cords, torso, limbs, hands, feet, or the entire body. For example, in some individuals with a genetic mutation in a gene called ‘DYT-TOR1A,’ the whole body is commonly affected, and such dystonia is referred to as generalized dystonia.
 
 
How is dystonia managed?
 
Focal symptoms in a single body region are usually controlled with oral medications and/or botulinum toxin injection treatments. However, when dystonia is generalized, a significant majority of patients require additional surgical treatments. Many times, dystonia is accompanied by other motor symptoms such as tremor, parkinsonism, and myoclonus. Recently, dystonia has been found to affect patients’ mood, sleep, cognition, and balance, referred to as nonmotor symptoms. Therefore, many patients require multidisciplinary care to treat the numerous aspects of dystonia symptomatology successfully.
 
 
What oral medications are available for treating dystonia?
 
Oral medications for dystonia control the abnormal firing of brain signals. These medications modulate the functions of brain chemicals such as acetylcholine, gamma-aminobutyric acid, or GABA, glutamate, and dopamine that are usually involved in the signaling process.
 
Animal models have shown acetylcholine signaling involving muscarinic receptors in the basal ganglia neurons is abnormal in dystonia. These neurons are located at the base of the brain. In a knock-in mouse model, drugs blocking these receptors (anticholinergic) were observed to reduce dystonia. Medications blocking acetylcholine effects at the muscarinic receptors have been among the oldest treatments available in clinical practice. Trihexyphenidyl (Artane) and benztropine (Cogentin) are commonly prescribed anticholinergic medications and have been observed to effectively treat dystonia symptoms. However, these two drugs non-selectively block all types of muscarinic receptors in the brain (M1, M2, M3, M4, and M5). Thus, side effects related to off-target stimulation such as confusional behavior and constipation are major limiting factors. Scientists have found that selectively blocking M4 receptors, which are highly concentrated in the basal ganglia neurons, will likely result in better clinical outcomes. These selective drugs, with potentially greater benefits and fewer side effects, are currently in the development phase. They will need to be tested and proven to be beneficial in clinical trials before they can be prescribed in clinical practice

Drugs targeting GABAergic receptors, including benzodiazepines (clonazepam, diazepam, and lorazepam) and baclofen, are other commonly used agents for treating dystonia. GABA is an inhibitory neurotransmitter. An increase in GABA signaling leads to the alleviation of excessive muscle contractions. A recent survey involving more than 2000 dystonia patients found benzodiazepines were the most common oral drugs prescribed for individuals with generalized dystonia, whereas botulinum toxin injections (another powerful muscle relaxant) were most frequently employed for treating focal dystonia. Zolpidem is a medication that also modulates GABA receptors in a slightly different way. It was used in a small study of 34 patients with focal dystonia. The study found significant improvements, but further research is needed on whether the clinical benefits can be extended to generalized dystonia, such as the DYT-TOR1A dystonia. Dopamine and dystonia have a complex relationship as medications that increase dopamine or decrease dopamine can improve clinical symptoms in certain forms of dystonia. Drugs such as levodopa-carbidopa, pramipexole, and ropinirole increase dopamine signaling, and drugs like tetrabenazine and deutetrabenazine decrease dopamine signaling through dopamine depletion. 
 
 Drug development can be an extremely lengthy and costly process. Thus, many clinical trials repurpose drugs to leverage their pharmacological properties for benefiting a broader range of clinical applications. One example is escitalopram (Lexapro), a selective serotonin reuptake inhibitor, a drug frequently used to treat pain and depression and generally well tolerated was recently found to improve cervical dystonia symptoms. The benefits were observed to be independent of their influence on mood circuitry. Another example is Perampanel, a drug antagonizing the action of glutamate neurotransmitter and approved for the treatment of epilepsy. Perampanel was recently tested in focal dystonia as the target receptors are widely distributed in the basal ganglia neurons. The target receptors are also seen in other neurons like the cerebellar neurons important for dystonia. While the drug was safe and tolerated by most patients, further studies are needed to confirm clinical efficacy.​
 

​What are the general principles for using oral medications?
 
Oral medications should be initiated at low doses and titrated up slowly to avoid off-target side effects, especially in older patients. Sometimes for certain medications like anticholinergic drugs, peak benefits are observed only weeks after maintaining constant doses. If the peak benefits are not adequate or are short-lasting, a further buildup of doses is recommended. If dose-limiting side effects develop with further escalation, an additional line of therapy is needed to achieve the best possible symptom control. 
  
 
​Are treatments available if a specific cause or etiology is identified?
 
In some individuals with dystonia, a specific cause can be identified. For example, when dystonia occurs due to a deficiency of enzymes needed to synthesize dopamine, the replacement of dopamine is found to alleviate symptoms (dopa-responsive dystonia). Sometimes dystonia is related to abnormalities in protein or lipid metabolism or deposition of heavy metals in the brain (e.g., copper, iron). In these circumstances, once the diagnosis is confirmed, appropriate specific therapies can be initiated.
 
 
References
Update on current and emerging therapies for dystonia; Karlo J Lizarraga, Duha Al-Shorafat & Susan Fox. Neurodegener. Dis.Manag. (2019) 9(3), 135–147
 
 
Anticholinergic drugs rescue synaptic plasticity in DYT1 dystonia: role of M1 muscarinic receptors. Maltese M, Martella G, Madeo G et al Mov. Disord. 29(13), 1655–1665 (2014
 
Dystonia treatment: patterns of medication use in an international cohort. Pirio Richardson S, Wegele AR, Skipper B, Deligtisch A, Jinnah HA. Neurology 88(6), 543–550 (2017).
 
 
Discovery of the first selective M4 muscarinic acetylcholine receptor antagonists with in vivo anti-parkinsonian and anti-dystonic efficacy. Mark S. Moehle, Aaron M. Bender, Jonathan W. Dickerson, et al. doi: https://doi.org/10.1101/2020.10.12.324152

​There are so many exciting projects going on in dystonia research that it has become hard to keep up with all of the advances. We sat down with one of the worlds top dystonia and Parkinson imaging researchers (Dr. David Vaillancourt) to talk about the “top 5” updates in therapies and in dystonia imaging research.