Early onset ataxia with comorbid myoclonus and epilepsy : A disease spectrum with shared molecular pathways and cortico-thalamo-cerebellar network involvement

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van Noort, Suus A MUniversity of Groningen (författare)

Early onset ataxia with comorbid myoclonus and epilepsy : A disease spectrum with shared molecular pathways and cortico-thalamo-cerebellar network involvement

Artikel/kapitelEngelska2023

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2023
28 s.

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LIBRIS-ID:oai:lup.lub.lu.se:14e2b72b-66b5-42d6-8ea8-a67dd6ff0ce2
https://lup.lub.lu.se/record/14e2b72b-66b5-42d6-8ea8-a67dd6ff0ce2URI
https://doi.org/10.1016/j.ejpn.2023.05.009DOI

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Språk:engelska
Sammanfattning på:engelska

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OBJECTIVES: Early onset ataxia (EOA) concerns a heterogeneous disease group, often presenting with other comorbid phenotypes such as myoclonus and epilepsy. Due to genetic and phenotypic heterogeneity, it can be difficult to identify the underlying gene defect from the clinical symptoms. The pathological mechanisms underlying comorbid EOA phenotypes remain largely unknown. The aim of this study is to investigate the key pathological mechanisms in EOA with myoclonus and/or epilepsy.METHODS: For 154 EOA-genes we investigated (1) the associated phenotype (2) reported anatomical neuroimaging abnormalities, and (3) functionally enriched biological pathways through in silico analysis. We assessed the validity of our in silico results by outcome comparison to a clinical EOA-cohort (80 patients, 31 genes).RESULTS: EOA associated gene mutations cause a spectrum of disorders, including myoclonic and epileptic phenotypes. Cerebellar imaging abnormalities were observed in 73-86% (cohort and in silico respectively) of EOA-genes independently of phenotypic comorbidity. EOA phenotypes with comorbid myoclonus and myoclonus/epilepsy were specifically associated with abnormalities in the cerebello-thalamo-cortical network. EOA, myoclonus and epilepsy genes shared enriched pathways involved in neurotransmission and neurodevelopment both in the in silico and clinical genes. EOA gene subgroups with myoclonus and epilepsy showed specific enrichment for lysosomal and lipid processes.CONCLUSIONS: The investigated EOA phenotypes revealed predominantly cerebellar abnormalities, with thalamo-cortical abnormalities in the mixed phenotypes, suggesting anatomical network involvement in EOA pathogenesis. The studied phenotypes exhibit a shared biomolecular pathogenesis, with some specific phenotype-dependent pathways. Mutations in EOA, epilepsy and myoclonus associated genes can all cause heterogeneous ataxia phenotypes, which supports exome sequencing with a movement disorder panel over conventional single gene panel testing in the clinical setting.

Ämnesord och genrebeteckningar

MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin Pediatrik hsv//swe
MEDICAL AND HEALTH SCIENCES Clinical Medicine Pediatrics hsv//eng
MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin Neurologi hsv//swe
MEDICAL AND HEALTH SCIENCES Clinical Medicine Neurology hsv//eng
Early onset ataxia
myoclonus
Epilepsy
Child
Neurodevelopment
Netwoek
Clinical genetics
Phenotype
Bioinformatics

Biuppslag (personer, institutioner, konferenser, titlar ...)

van der Veen, SterreUniversity of Groningen (författare)
de Koning, Tom JLund University,Lunds universitet,Pediatrik, Lund,Sektion V,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Paediatrics (Lund),Section V,Department of Clinical Sciences, Lund,Faculty of Medicine,University of Groningen(Swepub:lu)to2856jd (författare)
de Koning-Tijssen, Marina A JUniversity of Groningen (författare)
Verbeek, Dineke SUniversity of Groningen (författare)
Sival, Deborah AUniversity of Groningen (författare)
University of GroningenPediatrik, Lund (creator_code:org_t)

Sammanhörande titlar

Ingår i:European Journal of Paediatric Neurology45, s. 47-541090-3798

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Av författaren/redakt...: van Noort, Suus ...; van der Veen, St ...; de Koning, Tom J; de Koning-Tijsse ...; Verbeek, Dineke ...; Sival, Deborah A

Om ämnet

MEDICIN OCH HÄLSOVETENSKAP: MEDICIN OCH HÄLS ...; och Klinisk medicin; och Pediatrik

MEDICIN OCH HÄLSOVETENSKAP: MEDICIN OCH HÄLS ...; och Klinisk medicin; och Neurologi

Artiklar i publikationen: European Journal ...

Av lärosätet: Lunds universitet

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