Early Onset Ataxia with Comorbid Dystonia: Clinical, Anatomical and Biological Pathway Analysis Expose Shared Pathophysiology

• Main Authors: Deborah A. Sival, Martinica Garofalo, Rick Brandsma, Tom A. Bokkers, Marloes van den Berg, Tom J. de Koning, Marina A. J. Tijssen, Dineke S. Verbeek
• Format: Article
• Language: English
• Published: MDPI AG 2020-11-01
• Series: Diagnostics
• Subjects: clinical genetics; early onset ataxia; dystonia; neurodevelopment; network analysis; bioinformatics
• Online Access: https://www.mdpi.com/2075-4418/10/12/997

In degenerative adult onset ataxia (AOA), dystonic comorbidity is attributed to one disease continuum. However, in early adult onset ataxia (EOA), the prevalence and pathogenesis of dystonic comorbidity (EOAD⁺), are still unclear. In 80 EOA-patients, we determined the EOAD⁺-prevalence in association with MRI-abnormalities. Subsequently, we explored underlying biological pathways by genetic network and functional enrichment analysis. We checked pathway-outcomes in specific EOAD⁺-genotypes by comparing results with non-specifically (in-silico-determined) shared genes in up-to-date EOA, AOA and dystonia gene panels (that could concurrently cause ataxia and dystonia). In the majority (65%) of EOA-patients, mild EOAD⁺-features concurred with extra-cerebellar MRI abnormalities (at pons and/or basal-ganglia and/or thalamus (<i>p</i> = 0.001)). Genetic network and functional enrichment analysis in EOAD⁺-genotypes indicated an association with organelle- and cellular-component organization (important for energy production and signal transduction). In non-specifically, in-silico-determined shared EOA, AOA and dystonia genes, pathways were enriched for Krebs-cycle and fatty acid/lipid-metabolic processes. In frequently occurring EOAD⁺-phenotypes, clinical, anatomical and biological pathway analyses reveal shared pathophysiology between ataxia and dystonia, associated with cellular energy metabolism and network signal transduction. Insight in the underlying pathophysiology of heterogeneous EOAD⁺-phenotype-genotype relationships supports the rationale for testing with complete, up-to-date movement disorder gene lists, instead of single EOA gene-panels.