IRF2BPL Causes Mild Intellectual Disability Followed by Late-Onset Ataxia

Abstract

Background and objectives: Neurodevelopmental and neurodegenerative disorders have long been considered as different clinical and molecular entities, and only a few genes are known to be involved in both processes. The IRF2BPL (interferon regulatory factor 2 binding protein like) gene was implicated in a severe pediatric phenotype characterized by developmental and epileptic encephalopathy and early regression. In parallel, inherited IRF2BPL variants have been reported in cohorts of patients with late-onset progressive dystonic and ataxic syndrome with few information about the neurodevelopment of these patients. This study aimed to describe both neurodevelopmental and neurodegenerative aspects of the phenotype in adults with IRF2BPL pathogenic variant.

Methods: We report here the clinical and molecular data of 18 individuals carrying truncating IRF2BPL variants (identified by either exome or genome sequencing), including a large pedigree of 16 patients presenting with a neurodevelopmental disorder (NDD) associated with late-onset cerebellar ataxia and atrophy.

Results: Genome sequencing identified the p.(Gln117*) variant in a large family first assessed for familial ataxia, with multiple individuals presenting with NDD. The p.(Ser313*) variant was identified by exome sequencing in a second family with a young adult patient with NDD without ataxia which was inherited from her asymptomatic mother, suggesting incomplete penetrance of IRF2BPL-linked disorders.

Discussion: This study illustrates the importance of neurologic evaluation of adult patients initially diagnosed with NDD to detect a late-onset neurodegenerative condition. Two different disorders may be clinically diagnosed in the same family, when not considering that NDD and late cerebellar changes may be part of the same molecular spectrum such as for IRF2BPL.

Figure 1. Family Structure of SAL-394

Bold symbols indicate that individuals had cerebellar and pyramidal signs; small squares indicate intellectual disability only. Genotypes are indicated; heterozygous carriers are +/−. The arrow indicates the index case. Deceased individuals are crossed out.

Figure 2. Cerebral MRI From SAL-394-048 After 10 Years of Ataxia Duration

T1-weighted MPRAGE sagittal (A) and axial (B) views. Mild but visible cerebellar (vermian), mesencephalic and lower brainstem atrophy, as well as general cortical thinning.