Coordinating investigator: Jens Volkmann
Coordination: Christine Klein
The dystonias comprise a heterogeneous group of idiopathic and incurable movement disorders with variable age of onset, body distribution, and genetic background sharing the core clinical features of twisting, repetitive movements or abnormal postures.
There is a pressing clinical need for better therapies in dystonias, which cause lifelong disability, often in children and young adults.
Although dystonias are known to be caused by abnormalities of central motor circuits, the current mainstay treatment is peripheral by selective denervation of affected muscles through repeated botulinum toxin injections.
Deep Brain Stimulation of the internal globus pallidus is an effective surgical alternative, which is thought to correct abnormal central activity, but the mechanisms are enigmatic.
This will be the first large-scale, multidisciplinary coordinated research effort worldwide for uncovering common disease mechanisms in dystonia.
We will combine human clinical and experimental animal research including cutting edge technologies such as iPS cell characterization from human patients to describe the entire disease path of dystonia from a molecular level to brain network abnormalities.
This coherent view is expected to boost our understanding of these model circuitry disorders of the brain and to open up new avenues for better treatment of persons with dystonia. Patients will immediately benefit from this consortium through standardizing the diagnosis and treatment approach to dystonia and establishing a reference database for all groups involved in dystonia care.
Our objectives are:
- 1) To explore phenotypic variability and frequency of mutations in known dystonia genes in a large national cohort of dystonia patients
- 2) To define endophenotypes using neuroimaging or electrophysiology, which may alllow categorizing divergent clinical phenotypes into pathogenetically homogenous groups
- 3) To identify novel disease genes
- 4) To elucidate disease mechanisms and to identify read-out parameters for possible biomarkers and drug targets in iPSCderived neurons from patients with monogenic and non-genetic dystonia and in mouse models
- 5) To better understand environmental factors, which lead to manifestation of dystonia in genetically predisposed individuals
- 6) To better understand mechanisms of compensation in nonmanifesting mutation carriers
- 7) To identify common final pathophysiological pathways of dystonic motor symptoms, which may serve as broad therapeutic targets for many dystonia syndromes
- 8) To compare the efficacy of peripheral selective denervation (by botulinum toxin injection) and central network modulation (by deep brain stimulation) in controlling dystonia-related disability
The Dystract part projects
The overall aim of the consortium is to improve the clinical management of persons with the rare disorder dystonia (middle panel) based on sound scientific evidence and eventually pave the path to a curative treatment as a future perspective.
To improve the clinical management, a clinical study (SP1) will be performed comparing DBS to botulinum toxin injection and a German Dystonia Registry (SP2) will be established. These two core projects will exchange data and patients and are connected and supported by the IT platform (SP3).
These core projects (middle panel) will be fed and interact with four groups of subprojects.
First (right panel; SP5), there is the genetic project that aims at elucidation of novel genetic causes of dystonia. SP5 will use samples from SP2 and feed back the respective genetic information.
Novel mutation carriers will not only be included in SP2 but also in the iPS platform (top panel, SP4) and the clinical projects (lower panel; SP8, SP9, SP10).
The clinical projects will closely collaborate, focus on different genetic and non-genetic forms of dystonia, and use a large spectrum of multimodal investigations. They aim at the definition of endophenotypes by neurophysiological and structural neuroimaging (SP6), at the elucidation of network activity in dystonia (SP7), and the classification of endogenous (genetic) and exogenous (environmental) triggers on patients with musician´s dystonia as an example (SP10).
In addition, there will be two different model systems used to better understand the pathophysiology of dystonia, i.e. cellular (SP4, upper panel) and animal models (SP6, SP7, right panel). In SP7, we will partly address the same research questions as in SP8-10 but use dystonic rats and mice for investigations. SP6 will serve as a resource for transgenic mice and rats and aims at the characterization of the synaptic architecture in these animals. The results from the studies in animals may impact on the clinical study (SP1) and vice versa.
Finally, fibroblasts, iPS cells and iPS cell-derived neurons (SP4) will be used as cellular models to better understand the molecular changes leading to dystonia. In future, these cells might serve as a test platform for the evaluation of novel, preferably curative therapeutics.