Genetic intersection between dystonia and neurodevelopmental disorders: Insights from genomic sequencing. (September 2022)

• Record Type: Journal Article
• Authors: Dzinovic, Ivana; Winkelmann, Juliane; Zech, Michael
• Is Part Of: Parkinsonism & related disorders. Volume 102(2022)
• Page Start: 131
• Page End: 140
• Publication Date: 2022-09
• Subjects: Dystonia -- Neurodevelopmental disorders -- Genetics; Parkinson's disease -- Periodicals; Movement disorders -- Periodicals; Movement Disorders -- Periodicals; Nerve Degeneration -- Periodicals; Nervous System Diseases -- Periodicals; Parkinson Disease -- Periodicals; Tremor -- Periodicals; Parkinson, Maladie de -- Périodiques; Parkinson's disease; 616.833
• DOI: 10.1016/j.parkreldis.2022.08.019
• Languages: English
• ISSNs: 1353-8020

Abstract

Abstract: Animal and human brain-imaging studies have suggested a role for neurodevelopmental abnormalities in the pathophysiology of dystonia. Variants in neurodevelopmental genes have also been sporadically implicated, although no systematic investigation has been undertaken before the more widespread availability of genome-wide sequencing techniques. Here, we review findings from recent whole-exome and whole-genome sequencing approaches in individuals with dystonic conditions, indicating that more than 50% of molecularly diagnosed cases may have variants in neurodevelopmental disorder-associated genes. We describe how genomic sequencing has contributed to phenotypic expansions of several known hereditary forms of dystonia to include classical neurodevelopmental features. Moreover, we demonstrate that many of the newly reported monogenic neurodevelopmental disorders can manifest with prominent dystonic presentations, including isolated generalized dystonia, paroxysmal dystonia, and dopa-responsive dystonia-parkinsonism. Considering the published evidence, we argue that the clinical feature dystonia might be regarded as an expression of developmental brain dysfunction, a status referring to the common etiological basis of many neurodevelopmental disease traits. Finally, we provide a view into clinical implications, including the necessity to integrate the interrogation of neurodevelopmental disorder-associated genes into the molecular analysis process of patients with dystonia. Recognizing the relationship between dystonia and neurodevelopmental disorders is important to improve patient counseling and management and develop novel therapeutic strategies. Highlights: We review literature evidence suggesting a genetic overlap between dystonia and neurodevelopmental disorders. In large dystonia cohorts, more than 50% of molecular diagnoses may be due to variants in neurodevelopmental genes. "Classic" isolated dystonia-related genes (e.g., ANO3 ) can be associated with neurodevelopmental-disease presentations. Variants in many neurodevelopmental disorder-related genes can give rise to dystonia-predominant manifestations. Dystonia may be regarded as a sign of "developmental brain dysfunction", analogously to other neurodevelopmental traits.