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IRF2BPL-Related Disorder, Causing Neurodevelopmental Disorder with Regression, Abnormal Movements, Loss of Speech and

Sunita Venkateswaran1,2, Jean Michaud3, Yoko Ito1

  • 1Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Canada.

Movement Disorders : Official Journal of the Movement Disorder Society
|September 3, 2024
PubMed

Insights

This study identifies a novel cause of childhood neurodegeneration, interferon regulatory factor 2 binding protein like (IRF2BPL)-related disorder, characterized by spasticity and ataxia, and provides its first pathological description.

Area of Science:

  • Genetics
  • Neurology
  • Pathology

Background:

  • Childhood neurodegenerative diseases present diagnostic challenges due to genetic heterogeneity and varied symptoms.
  • A case of progressive neurodegeneration with spasticity, dystonia, and ataxia is presented.
  • Postmortem analysis revealed interferon regulatory factor 2 binding protein like (IRF2BPL)-related disorder.

Purpose of the Study:

  • To describe the first detailed pathological findings of IRF2BPL-related disorder.
  • To establish NEDAMSS (neurodevelopmental disorder with regression, abnormal movements, loss of speech and seizures) as a distinct clinical entity.
  • To include IRF2BPL-related disorder in the differential diagnosis of spastic-ataxic neurodegenerative conditions.

Main Methods:

  • Postmortem gross and histological examination.
  • Genetic testing, including exome sequencing reanalysis.
  • Analysis of patient-derived cells to assess molecular abnormalities.

Main Results:

  • Pathological findings were initially suggestive of dentatorubral-pallidoluysian atrophy (DRPLA) with polyglutamine (polyQ) inclusions.
  • Exome sequencing identified a pathogenic de novo IRF2BPL variant (c.562C>T, p.(Arg188Ter)).
  • The identified variant led to decreased brain mRNA levels, protein destabilization, and downstream molecular abnormalities.

Conclusions:

  • This study provides the first detailed pathological description of IRF2BPL-related disorder (NEDAMSS).
  • IRF2BPL-related disorder should be considered in the differential diagnosis of spastic-ataxic neurodegenerative conditions.
  • The role of the polyQ repeat tract in pathological inclusions suggests a novel disease mechanism for polyQ repeats.
Abstract

Keywords:
DRPLAIRF2BPLNEDAMSSdystonianeurodegenerationpolyglutamine repeatsspastic‐ataxia

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