Infantile-onset myoclonic developmental and epileptic encephalopathy: A new RARS2 phenotype

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• Recessive variants in RARS2, encoding a mitochondrial protein, have been linked to pontocerebellar hypoplasia and early-infantile epileptic encephalopathy.
• Previous studies identified RARS2-related disorders presenting with developmental delay, epilepsy, hypoglycemia, and lactic acidosis.

Observation:

• Two unrelated patients presented with a novel RARS2 phenotype: infantile-onset myoclonic developmental and epileptic encephalopathy.
• These patients exhibited progressive movement disorders, developmental plateau/regression, and drug-resistant epilepsy with various seizure types.
• EEG findings included diffuse slowing and multifocal/generalized spike-wave activity, exacerbated by sleep.

Findings:

• The patients carried compound heterozygous RARS2 variants predicted to impact splicing and transcription.
• Reanalysis of published RARS2 variants revealed that 85% affect splicing or gene expression, leading to protein truncation or nonsense-mediated decay.
• This suggests a high prevalence of splicing-disrupting variants in RARS2-related disorders.

Implications:

• The RARS2 phenotypic spectrum is expanded to include infantile encephalopathy with myoclonic seizures and movement disorders.
• RARS2 should be considered in infantile-onset epileptic encephalopathies, particularly those with movement abnormalities.
• The gene is enriched for pathogenic variants that disrupt RNA splicing, highlighting the importance of evaluating splicing effects in genetic diagnostics.