Extended Mutation Detection of Dystonia Gene in Familial and Early Onset Dystonias and Exploration of Electrophysiological Mechanisms and Imaging Biomarkers in Genetic Dystonia

Background Dystonias (or dystonia syndromes) are a heterogeneous group of hyperkinetic movement disorders characterized by involuntary sustained muscle contractions that lead to abnormal postures and repetitive movements. Dystonia is among the common movement disorders like Parkinson's disease (PD) and essential tremor. The most fascinating feature is that dystonia is often combined with parkinsonism or other involuntary movements. The etiology and pathogenesis of dystonia remain unknown, despite genetic causes had been identified since a decade ago, those were responsible for a minor part of dystonia only. It is hypothesized that understanding of the pathogenesis of those genetic dystonia might shed some clues for those in idiopathic dystonia. To date, there are about 24 DYT locus and 14 genes identified worldwide. The discovery of DYT genes have not only provided biomarkers for diagnosis but also guided the treatment strategy. In our previous genetic studies, we have found TOR1A, GCH1, SGCE, THAP1 and PRKN and in 23% our Taiwanese cohort (104 patients from 87 families) of familial dystonia (FD) and early onset (onset ＜=26 years) dystonia (EOD). In this project, we will continue to identify the possible mutations in the newly collected patients with FD and EOD. Due to DYT5 are presenting with both dystonia and parkinsonism, it is most interesting to understand the underlying pathophysiological mechanisms which remain unknown. Therefore, we will target those genetic dystonia, focus on DYT5 patients with GCH1 mutation and plan to further explore its electrophysiological mechanisms and possible biomarker of kurtosis imaging. We hypothesize that the underlying pathogenesis of DYT5 might be different from those with PRKN mutation in which lower limbs dystonias are common feature. And those above biomarkers might help us to reach an early diagnosis and therapeutic guidance. Specific Aims Aim 1: Further detection of the genetic mutations of primary dystonias. To extend our previous study of mutation detection by using candidate gene approach. As mentioned before, we have identified TOR1A, GCH1, SGCE, THAP1 and PRKN mutations in about 23% of patients from FD and EOD cohort. The mutation detection study of the 17 genes related to dystonia will be continued in FD and EOD patients. Aim 2: Explore electrophysiological mechanisms in genetic dystonias . To explore the underlying pathophysiology of genetic dystonia (focus on DYT5) by using rTMS (particularly TBS). Aim 3: Investigate the imaging biomakers in genetic dystonias . To study the connectivity of white matter of genetic dystonia (focus on DYT5) by using diffuse kurtosis imaging. Research Designs Subject: 100 newly collected patients with FD and EOD(onset＜=26 years) (not including previous104 dystonia patients) and 100 controls including age-match controls and unaffected members dystonia will be enrolled for genetics analysis. Methods: (1) Clinical assessment of all 100 newly collected patients: the biobank of these patients include clinical data, dystonia scores, and essential laboratory data. (2) Genetic analysis of 100 newly collected patients with dystonia: The genomic DNA obtained from each participant was undergoing mutational analysis for genetic causes such as TOR1A, GCH1, THAP1, SGCE, PRKRA, PNKD/MR-1, SLC2A1, PRRT2, CIZ1, GNAL, ATP1A3, ATP7B, PANK2, PRKN, PINK1, PLA2G6 and FBXO7. (3) The electrophysiological and imaging assessments of 40 patients with genetic dystonia: rTMS and DKI will be conducted mainly in those patients with GCH1carrier, non-manifesting gene-carrier and 20 controls without DYT gene-carrier. Expected Achievements This project will: (1) provide more clinical and genetic data from a large cohort of FD and EOD in Taiwan, and the explorations of the above data might be unique and different from those in the Caucasian and Japanese populations; (2) have great potential to discover the novel genetic mutation in the large cohort of FD and EOD; (3) dissect the pathophysiology of genetic dystonia. We expect this project could lead a better understanding the pathogenesis and guide the development of treatment strategy in dystonia; (4) find the imaging biomarker of genetic dystonia which might be helpful for early diagnosis and prognosis prediction.

Project ID:PC10308-1025
External Project ID:MOST103-2314-B182-024-MY3