Yet another form of dystonia is called the myoclonus-dystonia (MD). In a separate program, supported by the Brown Family Foundation, several projects are underway or close to completion.
Marina A.J.de Koning-Tijssen (Groningen, The Netherlands) studies the motor and non-motor symptoms in MD also exploring a potential role of serotonin, one of the major neurotransmitters. MD is a rare movement disorder can be described as a combination of involuntary myoclonic jerks and dystonia. The disease usually starts in childhood but the natural course of the disease has never been investigated. The first aim of this study is to compare the present symptoms of MD patients to the symptoms they had 10 years before in order to see how the symptoms evolve over time. Moreover, since MD patients frequently experience non-motor symptoms including psychological problems, sleep disturbances, and fatigue, it is believed that such symptoms are part of the disease and not secondary to a movement disorder. These non-motor symptoms may result from an altered metabolism of a specific brain neurotransmitter called serotonin that is involved in various psychiatric disorders such as depression and anxiety and also in sleep disturbances. Because patients with MD frequently have those non-motor symptoms, serotonin may play a role in the disease. This is tested in this study by analyzing the serotonin levels in the blood of MD patients, healthy controls and cervical dystonia patients to assess the MD specificity of the changes. In addition, a genetic study of the serotonin-related genes will be performed using DNA collected from all three groups. We hope that this study will provide: a thorough description of the natural course and prevalence of non-motor symptoms in MD; characterization of the serotonergic metabolism in MD patients compared to healthy controls and cervical dystonia patients revealing the association between the serotonergic metabolism and non-motor symptoms in MD.
In a separate study, Yulia Worbe (Salpetriere Hospital) characterized neuronal mechanisms of agency in MD. Studies in patients with different types of dystonia suggested that dystonic symptoms might result from dysfunction of brain circuits that are involved with organization and action control, which constitute cognitive control of movement. The sense of agency, which refers to the experience of initiating and controlling one’s own actions, is an integral part of cognitive control of movement. In dystonia, the sense of agency has received very little attention from the research community. In a preliminary study, the group in Paris showed alterations of sense of agency in patients with dystonia of the neck muscles. In this study, they aim to show that alteration of the sense of agency is a common mechanism across the different types of dystonia by investigating MD patients in whom dystonia is complicated by persistent involuntary myoclonic jerks. They evaluate MD patients and compare them to healthy controls matched by age, gender, hand-dominance and education level. To study in-depth different aspects of the sense of agency, they use a battery of computerized tests. The results of the tests will be integrated with brain imaging, which allows us to identify brain pathways implicated in the sense of agency. The findings of this study provide a new perspective on the fundamental mechanism of MD and direct involvement of cognitive processes in dystonia.
Very recently, Dr. Yulia Worbe received another grant to decipher the origins of myoclonus in patients with SGCE mutations. In MD, two brain circuits have been related to myoclonic jerks: one linking the cerebellum to the upper part of the brain cortex; the other linking cortex to the basal ganglia. Recent studies showed that cerebellum and basal ganglia are interconnected and through these connections, they can influence how the different movements would be performed. Magnetoencephalography (MEG) is a non-invasive technique for investigating human brain activity. It is based on the recording of magnetic fields produced by electrical currents in the brain. It allows the measurement of ongoing brain activity on a millisecond-by-millisecond basis, and it shows where in the brain this activity is produced. In the current project. Dr. Worbe uses a new MEG system that can be worn like a helmet, allowing free and natural movement during scanning. This system opens up new possibilities as myoclonic jerks will no longer interfere with the study of brain activity. The goal is to identify the neuronal origins of the jerks in M-D. Understanding of the temporal sequence of brain alterations leading to myoclonus could eventually provide a direct non-invasive brain stimulation as a treatment option.
The same genetic form of MD is studied by Karen Grütz from the University of Lübeck. In about 25% of MD patients, the disease is caused by mutations in the SGCE gene. Typically, only individuals who inherited the mutation from their fathers are affected by the disease because a special mechanism called maternal imprinting silences the information handed down from the mother leading to incomplete penetrance of the clinical symptoms. The protein product of the SGCE gene is called ε-sarcoglycan and has been identified as a component of a membrane-bound complex within the brain. To investigate the molecular causes of M-D, it is imperative to work directly on patient-derived biospecimens, preferably of the nervous system. Since brain tissue from living patients is impossible to retrieve, the approach of the so-called induced pluripotent stem cells (iPSCs) Starting with patient skin cells one can convert them back to stem cells, i.e. iPSCs, and then transform into neurons. Two of these M-D patient-derived iPSCs have already been generated and successfully used in experiments. In the present study, Dr. Grütz aims to identify a specific pattern of SGCE gene modification that can explain the varying severity among M-D patients and whether this pattern also affects other genes and pathways. Such new methods and approaches will help to identify the so-called phenotypic fingerprint of patients that can then help in understating M-D and also contribute to the generation of personalized treatments.
Another major, long-term MD project is led by Kathryn Peall, Cardiff University (UK). In this international study, the goal is to investigate the non-motor and psychological impact of MD. The objective is the recruitment of a large, global group of individuals with SCGE-mutation-positive MD. The study will assess a broad spectrum of non-motor symptoms and quality of life with the use of a systematic and standardized questionnaire. Specifically, issues of psychiatric symptoms, cognitive difficulties, particularly executive functioning, emotional recognition, sleep disturbances, and pain will be focused on in the survey. Under consideration is the recruitment of participants with MD either known to be negative for all known disease-causing genes or found to have a mutation in one of the other MD.
In parallel, Mark LeDoux at the University of Memphis is setting up a collection of MD biological materials. The goal here is to bank such materials, primarily DNA collected from MD patients, to identify individuals with particular phenotypes (myoclonus AND dystonia) and, if available, specific genotypes, particularly variants in SGCE. These materials will be acquired from clinical centers around the world as well as commercial laboratories involved in genetic testing and available for research purposes to qualified investigators.
A small, retrospective study is led by Marie Vidailhet at Salpetriere Hospital to compare the efficacy and impact of DBS in myoclonus-dystonia patients operated at different centers in Europe and North America. The project systematically assesses the impact of DBS on patients’ lives and should provide novel insight into DBS targets, programing, and protocols directly benefiting MD patients.