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

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Early Onset Ataxia with Comorbid Dystonia : Clinical, Anatomical and Biological Pathway Analysis Expose Shared Pathophysiology. / Sival, Deborah A; Garofalo, Martinica; Brandsma, Rick; Bokkers, Tom A; van den Berg, Marloes; de Koning, Tom J; Tijssen, Marina A J; Verbeek, Dineke S.

In: Diagnostics, Vol. 10, No. 12, 24.11.2020.

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Sival, D. A., Garofalo, M., Brandsma, R., Bokkers, T. A., van den Berg, M., de Koning, T. J., Tijssen, M. A. J., & Verbeek, D. S. (2020). Early Onset Ataxia with Comorbid Dystonia: Clinical, Anatomical and Biological Pathway Analysis Expose Shared Pathophysiology. Diagnostics, 10(12). https://doi.org/10.3390/diagnostics10120997

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Sival, Deborah A ; Garofalo, Martinica ; Brandsma, Rick ; Bokkers, Tom A ; van den Berg, Marloes ; de Koning, Tom J ; Tijssen, Marina A J ; Verbeek, Dineke S. / Early Onset Ataxia with Comorbid Dystonia : Clinical, Anatomical and Biological Pathway Analysis Expose Shared Pathophysiology. In: Diagnostics. 2020 ; Vol. 10, No. 12.

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TY - JOUR

T1 - Early Onset Ataxia with Comorbid Dystonia

T2 - Clinical, Anatomical and Biological Pathway Analysis Expose Shared Pathophysiology

AU - Sival, Deborah A

AU - Garofalo, Martinica

AU - Brandsma, Rick

AU - Bokkers, Tom A

AU - van den Berg, Marloes

AU - de Koning, Tom J

AU - Tijssen, Marina A J

AU - Verbeek, Dineke S

PY - 2020/11/24

Y1 - 2020/11/24

N2 - 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.

AB - 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.

U2 - 10.3390/diagnostics10120997

DO - 10.3390/diagnostics10120997

M3 - Article

C2 - 33255407

VL - 10

JO - Diagnostics

JF - Diagnostics

SN - 2075-4418

IS - 12

ER -