Objective: We examined whether distinct phenotypes in genetic ataxias have any implications for disease pathophysiology.

Background: Inherited ataxias affect at least 150,000 people in the United States. They share a common ataxia phenotype characterized by poor hand eye coordination, dysarthria, gait imbalance, and is most often associated with cerebellar degeneration. However, inherited ataxias can also have many distinct phenotypes beyond pure ataxia including seizures, cognitive impairment, dystonia, and neuropathy.

Method: We used an unbiased systematic approach to create a comprehensive list of disorders associated with autosomal dominant ataxias. We used the OMIM API to automatically associate each disorder with the causative gene, mode of inheritance, and clinical phenotypes. By doing so, we were able to obtain a list of genes for different ataxia plus phenotypes. We performed gene ontology analysis to dissect unique pathways for different ataxia plus phenotypes. We then used these lists of genes as input for further transcriptomic analyses from published single cell RNA sequencing and spatial transcriptomic databases. We analyzed the cell type expression of different ataxia genes based on phenotype in mouse cerebellum (Kozareva 2021). We also used a whole brain spatial transcriptomic dataset to examine RNA expression across brain regions (Langlieb 2023). We asked whether there were distinct spatial expression patterns for ataxia genes based on clinical phenotypes.

Results: Different ataxia plus phenotypes have distinct GO terms. Ataxia + Dystonia was associated with monoamine transport. Ataxia + Neuropathy was associated with axonal transport and axon cytoplasm. Ataxia + Seizure was associated with synapses, cell junctions, and neural development. There was no spatial brain region specific expression patterns for ataxia plus phenotypes. Majority of genes had lower expression in cerebellum relative to other regions. Minority of genes (Ttr, Sox10, Zfhx3, Kcnc2, Slc1a3, Slc2a1, Tmem163, Tuba1a) were found to have predominantly glial expression in mouse cerebellum, suggesting non-Purkinje cell centric mechanism of disease.

Conclusion: Autosomal dominant inherited ataxias have a diverse range of phenotypes and heterogenous mechanisms of disease. Although the cerebellum is the most well known brain region implicated in ataxia, our results suggest that dysfunction of other brain regions can also result in disease.

References: Shen, Fred; Opal, Puneet. “Spatial and cell type specific expression patterns of autosomal dominant ataxias based on distinct clinical phenotypes.” Poster presentation at ICAR, November 2024.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/autosomal-dominant-ataxias-expression-profiles-based-on-distinct-clinical-phenotypes/