Brazilian Network for the dystonia studies: study of variants of GNAL, CIZ1, ANO3 and TUBB4 genes in idiopathic dystonia

Abstract

Dystonia is a syndrome characterized by involuntary and sustained muscle contractions, leading to twisting repetitive movements and/or abnormal postures. It may start at any age, the most aggressive forms begin in infancy, leaving the patient severely handicapped or leading to premature death. The adult-onset forms can be as disabling as the early-onset ones, bringing difficulties in walking, writing, communication, vision, chronic pain and leading the patients to early retirement and social isolation. To date, there is no curative treatment for dystonia. Part of the patients is directed to high cost treatments at the public health system, such as botulinum toxin, which has a partial and temporary effect and is not always able to lead to a complete functional reestablishment. Part of dystonias has a genetic basis. In recent years, several genes related to this syndrome have been identified, and brought in new knowledge to its pathophysiology. In 2011, our group started the project Brazilian Network for Dystonia Studies with funding from FAPESP. We are recruiting patients with dystonia from various research centers, in order to establish their clinical, epidemiological and molecular profile, creating a permanent study group. With this initial two- year funding, we were able to investigate 143 probands and available family members and identified molecular causes in 12% of the cases. Among the investigated genes, THAP1 variants are the most common in our population, whereas a single mutation in TOR1A seems to be the most common cause worldwide. THAP1 variants were found in 9% of the cases with idiopathic isolated dystonia, and are responsible for almost one third of familial cases. However, almost two thirds of the patients with a positive family history remain with no identified genetic cause. In recent years, variants in other genes have been identified as possible causes of dystonia, but not all of them have been confirmed in other populations, including ours.The aim of this study is to verify the contribution of pathological variants in GNAL, CIZ1, ANO3 and TUBB4 genes in patients with idiopathic dystonia, continuing the clinical and molecular characterization of dystonia patients in our population. Patients with idiopathic dystonia already recruited by our group, as well as new patients who remain without a molecular diagnosis after being screened for the most common variants, will be investigated for genetic variants through targeted resequencing (TrueSeq - Illumina). (AU)