Article type: Narrative Review
Article title: Neurobiology of Dystonia: Review of Genetics, Animal Models, and Neuroimaging
Journal: Brain Sciences
Year: 2025
Authors: Jamir Pitton Rissardo, Andrew McGarry, Yiwen Shi, Ana Leticia Fornari Caprara, and Ian M. Walker
E-mail: jamirrissardo@gmail.com
ABSTRACT
Over the past decade, substantial progress has been made in understanding the pathophysiology of dystonia. The number of identified genes has surged—exceeding 400 by 2024—with approximately 76.6% linked to neurodevelopmental disorders. Despite this, the genetic diagnostic yield remains modest (12–36%), and many newly discovered genes have yet to reveal novel mechanistic insights. The limited number of studies exploring dystonia-related pathways in animal models restricts the generalizability of findings to human disease, raising concerns about their external validity. Developing experimental models remains a challenge, particularly given the importance of critical developmental windows—periods during central nervous system maturation when disruptions can have lasting effects. Some models also exhibit delayed symptom onset, prompting a shift toward faster-developing organisms such as Drosophila. There is a pressing need for standardized, scalable protocols that enable precise evaluation of specific neural tissues. Advances in neuroimaging have improved our understanding of dystonia-related brain networks at both regional and whole-brain levels. The emerging concept of “network kernels” has provided new perspectives on brain connectivity. However, future imaging studies should incorporate effective connectivity analyses to distinguish between hemodynamic and neuronal contributions and to clarify neurobiological pathways. This review synthesizes current knowledge from genetics, animal models, and neuroimaging to present an integrated view of dystonia’s neurobiological underpinnings.
Keywords: pathophysiology; neurobiology; mechanism; torsion; muscle contraction; dystonia.
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DOI
Citation
Rissardo JP, McGarry A, Shi Y, Caprara ALF, Walker IM. Neurobiology of Dystonia: Review of Genetics, Animal Models, and Neuroimaging. Brain Sciences 2025; 15:767. https://doi.org/10.3390/brainsci15070767
Figure 1. Proposed molecular mechanism of dystonia involving impaired autophagy (via EIF2AK2 and EIF4A2) and dysregulation of the integrated stress response pathway (via PRKRA). TOR1A is implicated in the maturation and modulation of the neuronal nuclear pore complex, particularly through its interaction with NUP54. Additional genes, such as THAP1, are involved in transcriptional reprogramming, further contributing to the pathophysiological cascade.
Figure 2. Proposed molecular mechanism of dystonia involving disruptions in autophagy and lysosomal pathways. Key genes implicated in this pathway—such as HEXA, IRF2BPL, NPC1, PINK1, PRKN, SPG11, TECPR2, VPS16, and WDR45—are associated with impaired degradation and recycling of cellular components. These dysfunctions may contribute to neurodegenerative processes in which dystonia appears as part of a broader clinical phenotype.
Table S1. Timeline of Gene Discovery in Dystonia.
Table S2. Phenotype–Gene Relationships of Dystonia in OMIM.
Table S3. Overview of the genetic classification of dystonia according to MDSGene.
Table S4. Genetic intersection between dystonia and neurodevelopmental disorders.
Table S5. Converging Genes And Causative Pathways.