Genetics and Pathogenesis of Dystonia

Abstract

Dystonia is a clinically and genetically highly heterogeneous neurological disorder characterized by abnormal movements and postures caused by involuntary sustained or intermittent muscle contractions. A number of groundbreaking genetic and molecular insights have recently been gained. While they enable genetic testing and counseling, their translation into new therapies is still limited. However, we are beginning to understand shared pathophysiological pathways and molecular mechanisms. It has become clear that dystonia results from a dysfunctional network involving the basal ganglia, cerebellum, thalamus, and cortex. On the molecular level, more than a handful of, often intertwined, pathways have been linked to pathogenic variants in dystonia genes, including gene transcription during neurodevelopment (e.g., KMT2B, THAP1), calcium homeostasis (e.g., ANO3, HPCA), striatal dopamine signaling (e.g., GNAL), endoplasmic reticulum stress response (e.g., EIF2AK2, PRKRA, TOR1A), autophagy (e.g., VPS16), and others. Thus, different forms of dystonia can be molecularly grouped, which may facilitate treatment development in the future. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 19 is January 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Clinical Response of Levodopa in CTNNB1-Related Dystonia

“…Moreover, recently, the increasingly widespread use of WES analysis has led to the identification of this gene as one of the causes of dystonia in pediatric patients. 8,9 A review compiled a list of genes associated with neurodevelopmental delay, 10 including CTNNB1, which may be linked to dystonia. This supports the view of dystonia as a neurodevelopmental circuit disorder.…”

Genetic Update and Treatment for Dystonia

“…Furthermore, the genetics of dystonia are characterized by low penetrance, possibly leading to an underestimation of hereditary causes [37]. Pathogenic variants in dystonia genes have been linked to a variety of pathways, including gene transcription during neurodevelopment, endoplasmic reticulum stress response, calcium homeostasis, striatal dopamine signaling, and autophagy [38]. Currently, genes THAP1, GNAL, TOR1A, and ANO3 are linked to isolated dystonia and have undergone extensive validation.…”

Focal Dystonia – an Update of Genetic Background and Novel Treatment

“…Furthermore, the genetics of dystonia are characterized by low penetrance, possibly leading to an underestimate of hereditary causes [33]. Pathogenic variants in dystonia genes have been linked to a variety of pathways, including gene transcription during neurodevelopment, endoplasmic reticulum stress response, calcium homeostasis, striatal dopamine signaling, and autophagy [34].…”