Multiple Directions to Explore the Pathophysiology of Dystonia-Parkinsonism Syndrome: Molecular Genetics, Functional Brain Imaging, and Electrophysiological Studies

Background Parkinson’s disease (PD) is principally caused by the degeneration of the dopamine neurons presenting characteristically resting tremor rigidity and bradykinesia, a pure Parkinsonism. Idiopathic dystonia is caused by the dysfunction of basal ganglia characterized by sustained muscle contractions with twisting limbs and body in nature, a pure dystonia. On reviewing the genetic causes of PD and dystonia, however, both Parkinsonism and dystonia might be manifesting in familial PD patients with autosomal recessive inheritance, like Park2, Park6 and Park7 and in familial dystonia with autosomal domiant inheritance, like DYT3 and DYT5. These patients were often with an early onset, such as early onset Parkinson’s disease (EOPD) and dystonia. In broad sense, these genetically mediated diseases are belonging to the big family of dystonia-parkinsonism syndrome (DPS). Recently, there is a group of disorders been paying attention with overlapping features of Parkinsonism and dystonia, so called DPS. The causes of these DPS can be complex. The differential diagnoses have been projected as PANK2, PLA2G6, ATP13A2, FBXO7, TAF1 and PRKRA. The other causes were possibly Parkin, PINK1, DJ1 and GCH1 mentioned previously. Some of these genetic etiologies have been discovered in our previous studies on EOPD and recently on DPS in Taiwanese population. However, a systemic work-up of clinical features, genetic interventions, imaging examinations, electrophysiological analyses in DPS have not been investigated in a large scale of patients populations. On the other hand, the underlying pathophysiology of DPS has rarely been elucidated in the Caucasian populations either. We intend to investigate DPS as the subject in the present proposal. The primary genes to be screened are including PRNK, PINK1, GCH1, ATP13A2, PRKRA, PLA2G6 and FBXO7. In this three-year project, our research teams are going to consecutively explore these important clinical, genetic, imaging and electrophysiological data as well as the correlations between them in a large DPS population. We hypothesize that the explorations of the above insights might be unique and different from those in the Caucasian and Japanese populations and provide an important source data for Taiwanese DPS population with ethnic Chinese. Subject: 1. 60 patients with DPS. 2. 300 patients with EOPD (onset＜45 years). 3. 300 unaffected members of EOPD. 4. 500 age-match controls. Methods: 1. The biobank of these patients included specific parkinsonian and dystonia data and the MRI and TRODAT imaging of the brain and oxidative stress 2. The genomic DNA obtained from each participant was undergoing serial genetic tests on mutations of GCH1, PRKRA, PRKN, PINK1, ATP13A2, PLA2G6, and FBXO7 genes. 3. The electrophysiological assessments will be performed in those patients with mutation carriers and non-carriers. Goals 1. To identify the possible mutations in the causing genes of DPS including PRKRA, PRKN, PINK1, ATP13A2, PLA2G6, FBXO7 and GCH1genes and its correlations with other data. 2. To define the phenotype and genotype of each genetic DPS 3. To understand the DAT activity and brain MRI in each genetic DPS 4. To reveal the underlying pathophysiology of DPS of various genetic causes of DPS 5. To seek the abnormality oxidative stress in DPS with and without genetic causes

Project ID:PC10001-1140
External Project ID:NSC99-2314-B182-027-MY3