The apparent paradox of phenotypic diversity and shared mechanisms across dystonia syndromes

• Type of Material: Article
• Authors: Alessio Di Fonzo, Dino Ferrari Center; Alberto Albanese, IRCCS Humanitas Research Hospital; Hyder Jinnah, Emory University
• Language: English
• Date: 2022-08-01
• Publisher: LIPPINCOTT WILLIAMS & WILKINS
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2022, Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1097/WCO.0000000000001076
• Title of Journal or Parent Work: CURRENT OPINION IN NEUROLOGY
• Volume: 35
• Issue: 4
• Start Page: 502
• End Page: 509
• Grant/Funding Information: HAJ is supported by grants to The Dystonia Coalition (NS065701, TR001456, NS116025) which is part of the National Institutes of Health (NIH) Rare Disease Clinical Research Network (RDCRN), supported by the Office of Rare Diseases Research (ORDR) at the National Center for Advancing Translational Science (NCATS), and the National Institute of Neurological Diseases and Stroke (NINDS). He is also supported by NIH R01 grants (NS109242, NS119758, NS119831).
• Keywords: CLASSIFICATION; dystonia; environment; Life Sciences & Biomedicine; GENE; molecular mechanisms; VARIANTS; NR4A2; NEUROLOGICAL DISORDERS; IDENTIFICATION; Neurosciences & Neurology; Science & Technology; TORSINA; Clinical Neurology; MOUSE MODEL; MUTATIONS; HAPLOINSUFFICIENCY; genetics; movement disorders; Neurosciences
• Research Categories: Biology, Genetics; Biology, Neuroscience

Abstract

Purpose of reviewWe describe here how such mechanisms shared by different genetic forms can give rise to motor performance dysfunctions with a clinical aspect of dystonia.Recent findingsThe continuing discoveries of genetic causes for dystonia syndromes are transforming our view of these disorders. They share unexpectedly common underlying mechanisms, including dysregulation in neurotransmitter signaling, gene transcription, and quality control machinery. The field has further expanded to include forms recently associated with endolysosomal dysfunction.SummaryThe discovery of biological pathways shared between different monogenic dystonias is an important conceptual advance in the understanding of the underlying mechanisms, with a significant impact on the pathophysiological understanding of clinical phenomenology. The functional relationship between dystonia genes could revolutionize current dystonia classification systems, classifying patients with different monogenic forms based on common pathways. The most promising effect of these advances is on future mechanism-based therapeutic approaches.