Risk Factor Genes in Patients with Dystonia: A Comprehensive Review

Abstract

Background: Dystonia is a movement disorder with high heterogeneity regarding phenotypic appearance and etiology that occurs in both sporadic and familial forms. The etiology of the disease remains unknown. However, there is increasing evidence suggesting that a small number of gene alterations may lead to dystonia. Although pathogenic variants to the familial type of dystonia have been extensively reviewed and discussed, relatively little is known about the contribution of singlenucleotide polymorphisms (SNPs) to dystonia. This review focuses on the potential role of SNPs and other variants in dystonia susceptibility. Methods: We searched the PubMed database for peer-reviewed articles published in English, from its inception through January 2018, that concerned human studies of dystonia and genetic variants. The following search terms were included: ''dystonia'' in combination with the following terms: 1) ''polymorphisms'' and 2) ''SNPs'' as free words.

Whole genome sequencing for the genetic diagnosis of heterogenous dystonia phenotypes

“…Gender, phenotype, family history, and MRI findings were compared using a Fisher's exact test (Bonferroni correction applied). We also tested 10 previously identified genetic risk variants for dystonia [16] (rs11655081, rs61999318, rs6265, rs3759664, rs10483639, rs12147422, rs71521601, rs1182, rs1801968 and rs35153737), using a Fisher exact test (p value less than 0.005, Bonferroni correction applied). We analysed the entire dystonia sample as a homogenous group and compared to the Medical Genome Reference Bank (MGRB) database of healthy elderly individuals with a predominant European background (97% non-Finnish European) [17].…”

Secondary Worsening Following DYT1 Dystonia Deep Brain Stimulation: A Multi-country Cohort

“…Although the genetics of DYT1 dystonia appear simple because virtually all cases have the same pathogenic deletion variant (c.907_909delGAG), the reduced penetrance and variable clinical phenomenology suggest that other genetic or environmental modifying factors influence phenotypic expression and that these factors may factor into responses to DBS or other treatments (Charlesworth et al, 2013 ; Weisheit et al, 2018 ). Dystonia patients carrying different variants in the TOR1A gene have been reported, but the consensus has yet to be reached regarding their pathogenicity (Martino et al, 2013 ; Siokas et al, 2019 ). A polymorphism in exon 4 of the DYT1 gene (rs1801968, D216H) was reported to affect the clinical penetrance of DYT1 (Risch et al, 2007 ).…”

“…Additionally, the multi-country cohort was not tested for other dystonia-causing genes such as DYT- THAP1 and DYT- GNAL , which are known to have a higher incidence of cranial involvement. Furthermore, some variants in brain-derived neurotrophic factor (BDNF) and apolipoprotein E (APOE) have also been reported to lead to an increased incidence of dystonia, possibly via altered neural plasticity (Siokas et al, 2019 ). These findings lead us to speculate on the intriguing possibility that variants within the TOR1A gene or other genes may affect the phenotypic manifestation of dystonia and the consequent DBS responses.…”

Dystonia updates: definition, nomenclature, clinical classification, and etiology

“…isolated dystonia, several studies, almost exclusively candidate-based, have been performed but no compelling association has been identified (Ohlei et al 2018). Furthermore, variants in several molecular pathways have been detected, however, with the necessity to confirm a robust association in larger cohorts (Siokas et al 2018).…”