RARS1-related developmental and epileptic encephalopathy

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• Biallelic variants in RARS1, encoding arginine tRNA-synthetase (ArgRS), are associated with central nervous system (CNS) disorders.
• These disorders include hypomyelinating leukodystrophy-9 and developmental and epileptic encephalopathy (DEE).
• This study investigates RARS1 mutations and their associated phenotypes, particularly in DEE patients.

Approach:

• Identified two patients with RARS1 biallelic mutations.
• Functionally validated these mutations in vitro.
• Conducted a comprehensive literature review of 27 additional patients.

Key Points:

• Two patients presented with hypomyelinating leukodystrophy and RARS1 biallelic variants; one exhibited severe DEE.
• Literature review of 29 patients revealed intellectual disability, developmental delay, and hypomyelination as common symptoms.
• Thirteen patients had DEE and cortical malformations; specific variants (e.g., c.5A>G) were recurrent, and ArgRS protein stability was reduced.

Conclusions:

• RARS1 biallelic mutations frequently cause DEE and hypomyelinating leukodystrophy.
• These mutations impact not only white matter but also cortical development.
• Identified variants are pathogenic, reducing ArgRS expression and protein stability.