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

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title = "Early Onset Ataxia with Comorbid Dystonia: Clinical, Anatomical and Biological Pathway Analysis Expose Shared Pathophysiology",
abstract = "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 (p = 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.",
author = "Sival, {Deborah A} and Martinica Garofalo and Rick Brandsma and Bokkers, {Tom A} and {van den Berg}, Marloes and {de Koning}, {Tom J} and Tijssen, {Marina A J} and Verbeek, {Dineke S}",
year = "2020",
month = nov,
day = "24",
doi = "10.3390/diagnostics10120997",
language = "English",
volume = "10",
journal = "Diagnostics",
issn = "2075-4418",
publisher = "MDPI AG",
number = "12",