A new developmental and epileptic encephalopathy: PUM1-neurodevelopmental disorder with epilepsy with...

Pathogenic variants in the PUM1 gene are linked to late-onset spinocerebellar ataxia and to a neurodevelopmental disorder (PUM1-associated developmental disability, ataxia, and seizures). The latter is very rare and encompasses developmental delay, intellectual disability, ataxia, seizures, and dysmorphic features with structural brain anomalies. This report introduces a novel presentation of a PUM1-related phenotype, characterized by epilepsy with myoclonic-atonic seizures (EMAtS) as the predominant feature, evolving without ataxia.

Through trio-based whole exome sequencing (WES), we identified a novel de novo heterozygous frameshift variant in the PUM1 gene. We reviewed all medical charts of the present patient, assessed his development and reviewed all previously reported cases with pathogenic variant of PUM1.

A 3.5-year-old boy presented with epilepsy with myoclonic-atonic seizures (EMAtS), mild speech delay, mild dysmorphic features and no motor impairments. WES showed a de novo heterozygous frameshift pathogenic variant in PUM1 (NM_001020658:c.1159delC; p.Leu387Cysfs*13) NM_001020658.2(PUM1):c.1159delC (p.Leu387Cysfs*13. Treatment with antiseizure medication and dietary intervention led seizure control within one year, enabling developmental gains despite persisting delays in adaptive functioning and communication. A hallmark of this cases - ataxia - was not observed after epilepsy remission.

This case highlights the variability in PUM1-related phenotypes and underscores the importance of considering PUM1 pathogenic variants in early-onset generalized epilepsy, even in the absence of hallmark systemic features. It expands the phenotypic spectrum of PUM1-associated disorders by describing a unique childhood-onset epilepsy presentation, emphasizing the variability in clinical manifestations and the potential for favorable outcomes with appropriate management.