About Dystonia:

Dystonia is a neurological movement disorder characterized by involuntary muscle contractions, which force certain parts of the body into abnormal, sometimes painful, movements or postures. Dystonia can affect any part of the body including the arms and legs, trunk, neck, eyelids, face, or vocal cords.



• Dystonia is a neurological movement disorder characterized by involuntary muscle contractions, which force certain parts of the body into abnormal, sometimes painful, movements or postures.

•Dystonia can affect any part of the body including the arms and legs, trunk, neck, eyelids, face, or vocal cords.

• Abilities such as cognition, strength and the senses are normal in Dystonia sufferers, though speech can be impaired as a symptom.

•Dystonia is not fatal, but is a chronic disorder with often unpredictable prognoses.

•Dystonia is the third most common movement disorder after Parkinson’s Disease and Tremor.

•Dystonia does not discriminate: it affects people of every race and ethnic group and one-third of Dystonia patients are children.

•Dystonia affects more people than Muscular Dystrophy, Huntington’s Disease and Lou Gehrig’s Disease combined.


Dystonia News

Duke researchers develop new cell-based drug screening test for dystonia

Published on December 8, 2016

Duke University researchers have identified a common mechanism underlying separate forms of dystonia, a family of brain disorders that cause involuntary, debilitating and often painful movements, including twists and turns of different parts of the body.

Described online Dec. 8 in the journal Neuron, the research has also led to the development of a new cell-based screening test that is being deployed on a large scale to identify new drug candidates to treat dystonia.

"We're excited to have found not only a new potential therapeutic inroad for multiple forms of dystonia, but also a mechanism that we think causes the disease," said Nicole Calakos, M.D., Ph.D., an associate professor of neurology at Duke and a clinician who specializes in the care of patients with dystonia and other movement disorders.

Dystonia is the third most common movement disorder, after Parkinson's disease and tremors. It is believed to affect 300 to 400 people per million population, and is more common in the elderly. The spectrum of dystonia's many distinct forms include rare inherited cases like DYT1 dystonia, which is caused by a specific mutation in a single gene and leads to a severe disorder that arises in childhood. A larger proportion of cases, grouped into non-familial dystonia, have no known cause and tend to occur during adulthood.

In the new study, the team uncovered a mechanism for dystonia that links together rare inherited dystonia with the more common non-familial cases.

The path leading to this discovery started with a clinical observation more than six years ago. In 2009, Calakos became intrigued by a patient she had seen who had non-familial dystonia and harbored a rare variation in the same gene that causes childhood-onset DYT1 dystonia. This variant wasn't exactly the same as the DYT1 mutation, but the research team wanted to figure out whether it could have contributed to the patient's symptoms.

The mutation seemed to cause the DYT1 protein to be stuck near the cell's nucleus, rather than where it should be in the cell's protein-making factory, the endoplasmic reticulum. That's the same misplacement of DYT1 found in childhood-onset dystonia. They published that case in the Journal of Medical Genetics in late 2009.

The coincidence of finding the same protein displacement in the two different kinds of dystonia planted the seed for a new way of thinking about the disorder, Calakos said.

In the new study, Duke neurobiology research analyst Zachary Caffall reasoned that if the DYT1 protein's proper location within the cell meant the difference between health and disease, then it might be possible to search for new treatments using the mutant protein's misplacement as tool for studying the disorder.

The idea was risky but it worked. Caffall was able to engineer a human cell line in which the DYT1 protein is misplaced near the nucleus with the flick of a chemical switch.

Using these cells, the team silenced each of 23,000 genes in the genome one by one to see which genes, when turned off, would correct the DYT1 protein's location to the endoplasmic reticulum. Their tests hit a handful of genes that pointed to a molecular pathway called eIF2-alpha.

In another rare dystonia known as DYT16, the activity of the eIF2-alpha pathway is weaker than usual. And in the new study, Calakos's team found that eIF2alpha activity is also lower in DYT1 patient samples.

Another piece of evidence connected non-familial dystonia with both DYT1 and DYT16 dystonia. Calakos happened to have additional data on her desk from several years earlier: sequences of protein-coding genes from a small group of patients with non-familial dystonia. Her team looked at these data again, spotting rare variations in an eIF2-alpha pathway gene in several patients who had a form of dystonia called torticollis, which causes the neck to twist.

Fortunately, numerous research groups and a National Institutes of Health-sponsored patient repository had already collected DNA from patients with torticollis. Pooling these data allowed Calakos's team to quickly determine that the eIF2alpha pathway gene was much more frequently altered in individuals with dystonia than in the general population.

Calakos's team is now collaborating with NIH scientists to deploy their cell-based assay to identify drug-like chemicals that correct the DYT1 protein's location. So far, the researchers have screened more than 40,000 compounds.

Calakos's lab is also developing better animal models of dystonia to understand how eIF2alpha pathway dysfunction affects the brain to cause dystonia.

Calakos said the screen would not have been possible without seed funding and continued support from a disease foundation started by an affected family that was willing to support "out-of-the-box" ideas.

Tyler's Hope Foundation for a Dystonia Cure was started in 2006 by Rick and Michelle Staab, whose firstborn Tyler (now a 19-year-old college student) was diagnosed with dystonia at age 7. The couple's daughter Samantha, now 15, was diagnosed on her seventh birthday. Their youngest, 11-year-old Luke, does not show symptoms but he has a 50% chance of having the gene. If he does have the gene, he has a 30% chance of having dystonia.

"We want to find a cure for our kids," Rick Staab said. Of the money Tyler's Hope raises, 97% funds high-risk, high-reward research. The Foundation is now supporting Calakos's research in looking for new drugs with the screening assay.

"When we learned what our initial investment in Dr. Calakos's research ultimately led to, we were extremely excited," Staab said.

 Dr. Nicole Calakos Lab at Duke University

Link to the article: 

Link to the Calakos lab: 




  • •Genome-wide RNAi screen of a novel DYT1 dystonia assay identifies the eIF2α pathway
  • •Enhancing eIF2α signaling restores absent corticostriatal LTD in DYT1 knockin mice
  • •DYT1 dystonia patient-derived cells have a deficient eIF2α pathway stress response
  • •Rare loss-of-function variants in ATF4 are enriched in sporadic dystonia patients


Dystonia is a brain disorder causing involuntary, often painful movements. Apart from a role for dopamine deficiency in some forms, the cellular mechanisms underlying most dystonias are currently unknown. Here, we discover a role for deficient eIF2α signaling in DYT1 dystonia, a rare inherited generalized form, through a genome-wide RNAi screen. Subsequent experiments including patient-derived cells and a mouse model support both a pathogenic role and therapeutic potential for eIF2α pathway perturbations. We further find genetic and functional evidence supporting similar pathway impairment in patients with sporadic cervical dystonia, due to rare coding variation in the eIF2α effector ATF4. Considering also that another dystonia, DYT16, involves a gene upstream of the eIF2α pathway, these results mechanistically link multiple forms of dystonia and put forth a new overall cellular mechanism for dystonia pathogenesis, impairment of eIF2α signaling, a pathway known for its roles in cellular stress responses and synaptic plasticity.


 Dr. Rose Goodchild's Lab at the VIB in Belgium

 Are cellular lipids the missing link between a faulty gene and a neurological disorder?

Researchers at VIB-KU Leuven have managed to get a clearer view on the roots of dystonia, a neurological disorder that causes involuntary twisting movements. Led by Rose Goodchild (VIB-KU Leuven) and supported by the Foundation for Dystonia Research, the VIB scientists unraveled the mechanism by which DYT1 dystonia - the disease's most common hereditary form - causes cellular defects. The findings shed new light on this poorly understood condition - and may, ultimately, lead to new medical approaches to overcome it.

 Dystonia looks like a muscle problem, but actually originates in the brain. The patient's brain sends out too many messages that activate too many muscles, causing twisting movements. In some cases, including DYT1/TOR1A dystonia, a genetic mutation is the main culprit. In the VIB Center for the Biology of Disease at KU Leuven, Rose Goodchild and her team are conducting basic research into dystonia, the essential stepping stone for a cure.

Molecular defects unveiled

 In DYT1 dystonia, a genetic error results in a defective protein called torsin. Scientists already knew that this protein disrupts the neural communication that controls the muscles, but the how has remained unclear. Until now: research in the Goodchild lab indicates that torsins regulate the levels of lipids, molecules that form cell membranes and store energy.

 Prof. Rose Goodchild (VIB-KU Leuven): "For the first time, we understand that a dystonia protein is responsible for cellular lipid levels. Although we had expected a more complex picture, with various direct and indirect effects, our data clearly labeled torsin as the regulator for a particular enzyme of lipid metabolism. This now focuses attention on how the lipid substrates and products of this enzyme contribute to neuronal function, and gives us a better view on the exact molecular defects that cause dystonia."

 Multidisciplinary approach

 Crucial to the success of this project was the access to state-of-the-art research instruments, such as VIB's Electron Microscopy facilities, allowing deep-study of how torsin affects cellular membranes composed of lipids. Furthermore, the collaboration with the lab of professor Patrik Verstreken (VIB-KU Leuven) enabled numerous experiments on fruit flies. But although these tiny creatures have much more similarities with humans than meets the eye, research on mammals is crucial as well.

 Prof. Rose Goodchild (VIB-KU Leuven): "We have already started exploring dystonia mutation in mouse neurons. This will help us understand dystonia in humans. However, much more research is still to be carried out. It is our mission to find the exact pathway between a faulty gene and the neuronal defects. And, in time, we aim to develop therapeutic approaches that intervene in this pathway."


UF Center For Movement Disorders and Neurorestoration 

Visit the University of Florida's Movement Disorders Center, home of the Tyler's Hope Center of Excellence.