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

Suus A M van Noort; Sterre van der Veen; Tom J de Koning; Marina A J de Koning-Tijssen; Dineke S Verbeek; Deborah A Sival

doi:10.1016/j.ejpn.2023.05.009

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

Eur J Paediatr Neurol. 2023 Jul:45:47-54. doi: 10.1016/j.ejpn.2023.05.009. Epub 2023 May 23.

Authors

Suus A M van Noort¹, Sterre van der Veen², Tom J de Koning³, Marina A J de Koning-Tijssen², Dineke S Verbeek⁴, Deborah A Sival⁵

Affiliations

¹ Department of Paediatrics, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; Department of Pediatric Neurology, Beatrix Children's Hospital, University Medical Center Groningen, Groningen, the Netherlands; Department of Neurology, University Medical Center Groningen, Groningen, the Netherlands.
² Department of Paediatrics, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; Department of Neurology, University Medical Center Groningen, Groningen, the Netherlands.
³ Department of Paediatrics, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; Department of Pediatrics, University Medical Center Groningen, Groningen, the Netherlands; Pediatrics, Department of Clinical Sciences, Lund University, Lund, Sweden.
⁴ Department of Paediatrics, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; Department of Genetics, University Medical Center Groningen, Groningen, the Netherlands.
⁵ Department of Paediatrics, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; Department of Pediatric Neurology, Beatrix Children's Hospital, University Medical Center Groningen, Groningen, the Netherlands. Electronic address: d.a.sival@umcg.nl.

PMID: 37301083
DOI: 10.1016/j.ejpn.2023.05.009

Abstract

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.

Keywords: Bioinformatics; Clinical genetics; Early onset ataxia; Epilepsy; Myoclonus; Network; Neurodevelopment; Pediatric; Phenotype.

MeSH terms

Ataxia / complications
Ataxia / epidemiology
Ataxia / genetics
Cerebellar Ataxia*
Comorbidity
Epilepsy* / complications
Epilepsy* / epidemiology
Epilepsy* / genetics
Humans
Myoclonus* / complications
Myoclonus* / epidemiology
Myoclonus* / genetics