Affiliation:
1. Children's Hospital of Eastern Ontario Research Institute University of Ottawa Ottawa Canada
2. Children's Hospital, London Health Sciences Centre Western University London Canada
3. Department of Pathology and Laboratory Medicine University of Ottawa Ottawa Canada
4. Newborn Screening Ontario Ottawa Canada
5. University of Toronto Toronto Canada
6. Division of Pathology CHU Ste‐Justine, University of Montréal Montréal Canada
Abstract
AbstractBackgroundChildhood neurodegenerative diseases often pose a challenge to clinicians to diagnose because of the degree of genetic heterogeneity and variable presentations. Here, we present a child with progressive neurodegeneration consisting of spasticity, dystonia, and ataxia in which postmortem pathological analysis led to the diagnosis of interferon regulatory factor 2 binding protein like (IRF2BPL)‐related disorder.MethodsDetailed postmortem gross and histological examination was conducted, and findings consistent with dentatorubral‐pallidoluysian atrophy (DRPLA) and included polyglutamine (polyQ) inclusions. Follow up testing for the CAG repeat expansion at ATN1 was non‐diagnostic.ResultsSubsequent exome sequencing reanalysis of the research exome identified a pathogenic de novo IRF2BPL variant. The IRF2BPL c.562C>T, p.(Arg188Ter) variant, distal to the polyQ repeat tract, results in variable mRNA levels depending on the cell type examined with decreased mRNA in the brain, as well as destabilization of the protein product and corresponding downstream molecular abnormalities in patient derived cells.ConclusionWe provide the first detailed pathological description for IRF2BPL‐related disorder, termed NEDAMSS (neurodevelopmental disorder with regression, abnormal movements, loss of speech and seizures; Mendelian Inheritance in Man, 618088) and evidence for the inclusion of this condition in the differential diagnosis of spastic‐ataxic neurodegenerative conditions, reminiscent of DRPLA. Although the individuals with NEDAMSS do not carry an expansion, the polyQ repeat tract may play a role in the pathological inclusions that would represent a novel disease mechanism for polyQ repeats. © 2024 International Parkinson and Movement Disorder Society.