Cargando…

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(+)), are still unclear. In 80 EOA-patients, we determined the EOAD(+)-prevalence in associa...

Descripción completa

Detalles Bibliográficos
Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7760948/
https://www.ncbi.nlm.nih.gov/pubmed/33255407
http://dx.doi.org/10.3390/diagnostics10120997
_version_ 1783627453214752768
author 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.
author_facet 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.
author_sort Sival, Deborah A.
collection PubMed
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(+)), 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.
format Online
Article
Text
id pubmed-7760948
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-77609482020-12-26 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. Diagnostics (Basel) Article 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. MDPI 2020-11-24 /pmc/articles/PMC7760948/ /pubmed/33255407 http://dx.doi.org/10.3390/diagnostics10120997 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
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
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 Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7760948/
https://www.ncbi.nlm.nih.gov/pubmed/33255407
http://dx.doi.org/10.3390/diagnostics10120997
work_keys_str_mv AT sivaldeboraha earlyonsetataxiawithcomorbiddystoniaclinicalanatomicalandbiologicalpathwayanalysisexposesharedpathophysiology
AT garofalomartinica earlyonsetataxiawithcomorbiddystoniaclinicalanatomicalandbiologicalpathwayanalysisexposesharedpathophysiology
AT brandsmarick earlyonsetataxiawithcomorbiddystoniaclinicalanatomicalandbiologicalpathwayanalysisexposesharedpathophysiology
AT bokkerstoma earlyonsetataxiawithcomorbiddystoniaclinicalanatomicalandbiologicalpathwayanalysisexposesharedpathophysiology
AT vandenbergmarloes earlyonsetataxiawithcomorbiddystoniaclinicalanatomicalandbiologicalpathwayanalysisexposesharedpathophysiology
AT dekoningtomj earlyonsetataxiawithcomorbiddystoniaclinicalanatomicalandbiologicalpathwayanalysisexposesharedpathophysiology
AT tijssenmarinaaj earlyonsetataxiawithcomorbiddystoniaclinicalanatomicalandbiologicalpathwayanalysisexposesharedpathophysiology
AT verbeekdinekes earlyonsetataxiawithcomorbiddystoniaclinicalanatomicalandbiologicalpathwayanalysisexposesharedpathophysiology