Early Onset Ataxia with Comorbid Dystonia: Clinical, Anatomical and Biological Pathway Analysis Expose Shared Pathophysiology
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<sup>+</sup>), are still unclear. In 80 EOA-patients, we determined the EOAD<...
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MDPI AG
2020-11-01
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| Series: | Diagnostics |
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| Online Access: | https://www.mdpi.com/2075-4418/10/12/997 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Deborah A. Sival |
| collection | DOAJ |
| description | 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<sup>+</sup>), are still unclear. In 80 EOA-patients, we determined the EOAD<sup>+</sup>-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<sup>+</sup>-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<sup>+</sup>-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<sup>+</sup>-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<sup>+</sup>-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<sup>+</sup>-phenotype-genotype relationships supports the rationale for testing with complete, up-to-date movement disorder gene lists, instead of single EOA gene-panels. |
| first_indexed | 2024-03-10T14:36:05Z |
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| id | doaj.art-9787db4af53e4bb49a4833aa56946569 |
| institution | Directory Open Access Journal |
| issn | 2075-4418 |
| language | English |
| last_indexed | 2024-03-10T14:36:05Z |
| publishDate | 2020-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Diagnostics |
| spelling | doaj.art-9787db4af53e4bb49a4833aa569465692023-11-20T22:10:21ZengMDPI AGDiagnostics2075-44182020-11-01101299710.3390/diagnostics10120997Early Onset Ataxia with Comorbid Dystonia: Clinical, Anatomical and Biological Pathway Analysis Expose Shared PathophysiologyDeborah A. Sival0Martinica Garofalo1Rick Brandsma2Tom A. Bokkers3Marloes van den Berg4Tom J. de Koning5Marina A. J. Tijssen6Dineke S. Verbeek7Department of Paediatric Neurology, Beatrix Children’s Hospital, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The NetherlandsDepartment of Paediatric Neurology, Beatrix Children’s Hospital, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The NetherlandsDepartment of Paediatric Neurology, Beatrix Children’s Hospital, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The NetherlandsDepartment of Paediatric Neurology, Beatrix Children’s Hospital, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The NetherlandsDepartment of Paediatric Neurology, Beatrix Children’s Hospital, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The NetherlandsDepartment of Neurology, Beatrix Children’s Hospital, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The NetherlandsDepartment of Neurology, Beatrix Children’s Hospital, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The NetherlandsDepartment of Genetics, Beatrix Children’s Hospital, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The NetherlandsIn 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<sup>+</sup>), are still unclear. In 80 EOA-patients, we determined the EOAD<sup>+</sup>-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<sup>+</sup>-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<sup>+</sup>-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<sup>+</sup>-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<sup>+</sup>-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<sup>+</sup>-phenotype-genotype relationships supports the rationale for testing with complete, up-to-date movement disorder gene lists, instead of single EOA gene-panels.https://www.mdpi.com/2075-4418/10/12/997clinical geneticsearly onset ataxiadystonianeurodevelopmentnetwork analysisbioinformatics |
| spellingShingle | 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 Early Onset Ataxia with Comorbid Dystonia: Clinical, Anatomical and Biological Pathway Analysis Expose Shared Pathophysiology Diagnostics clinical genetics early onset ataxia dystonia neurodevelopment network analysis bioinformatics |
| title | Early Onset Ataxia with Comorbid Dystonia: Clinical, Anatomical and Biological Pathway Analysis Expose Shared Pathophysiology |
| title_full | Early Onset Ataxia with Comorbid Dystonia: Clinical, Anatomical and Biological Pathway Analysis Expose Shared Pathophysiology |
| title_fullStr | Early Onset Ataxia with Comorbid Dystonia: Clinical, Anatomical and Biological Pathway Analysis Expose Shared Pathophysiology |
| title_full_unstemmed | Early Onset Ataxia with Comorbid Dystonia: Clinical, Anatomical and Biological Pathway Analysis Expose Shared Pathophysiology |
| title_short | Early Onset Ataxia with Comorbid Dystonia: Clinical, Anatomical and Biological Pathway Analysis Expose Shared Pathophysiology |
| title_sort | early onset ataxia with comorbid dystonia clinical anatomical and biological pathway analysis expose shared pathophysiology |
| topic | clinical genetics early onset ataxia dystonia neurodevelopment network analysis bioinformatics |
| url | https://www.mdpi.com/2075-4418/10/12/997 |
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