SCREENING OF GENETIC VARIANTS IN BRAZILIAN PATIENTS WITH IDIOPATHIC DYSTONIA.

Abstract

Dystonia is a movement disorder of neurological order, characterized by involuntary contractions that lead to abnormal movements and / or postures that can occur in an isolated part or in the whole body. Dystonia is a complex syndrome from the etiological and clinical point of view with a lack of efficient symptomatic treatment for the majority of the cases. Besides hindering the execution of simple daily tasks, the "dystonic movements" can be uncomfortable, painful and tend to worsen overtime increasing the chances of developing psychiatric disorders such as depression, phobia and isolation. Recently, studies in dystonia have advanced due to improvement of sequencing technologies. Discovery of novel genes and pathogenic allelic variants observed in hereditary cases allowed the identification of several proteins involved in the pathophysiology of the dystonia implicated in several metabolic pathways when dysfunctional. Although there are no specific treatments for the different molecular changes, the knowledge of the genetic profile of our patients is of fundamental importance, once this type of treatment becomes available. Moreover, the identification of the genetic basis of dystonia is an element used to define prognosis and to make decisions for treatment with deep brain stimulation surgery. This project aims to standardize the molecular analysis of variants in dystonia related genes in Brazilian patients with idiopathic dystonia, to characterizing them according their pathogenic potential and to establish genotype - phenotype correlations. For this purpose,approximately160 patients with isolated or combined idiopathic dystonia, recruited through the project Brazilian Network for the Study of Dystonia, will be investigated for allelic variants in TOR1A, TUBB4, THAP1, CIZ1, ANO3, GNAL, GCH1, TH, ATP1A3, PRKRA, SGCE and KCTD17 genes by a custom amplicon-based assay for targeted resequencing (TruSeq® Custom Amplicon) in the MiSeq system (illumina). The obtained sequences will be aligned to human genome reference and allelic variants potentially related to the clinical diagnosis will characterized by in silico analysis according its pathogenic potential. The results of this research will allow the identification of genetic cases of dystonia in Brazilian patients and contribute to a better understanding of the pathophysiological mechanisms involved in dystonia with its several clinical presentations.