Novel NARS2 variants in a patient with early-onset status epilepticus: case study and literature review

Abstract

Background NARS2 as a member of aminoacyl-tRNA synthetases was necessary to covalently join a specific tRNA to its cognate amino acid. Biallelic variants in NARS2 were reported with disorders such as Leigh syndrome, deafness, epilepsy, and severe myopathy. Case presentation Detailed clinical phenotypes were collected and the NARS2 variants were discovered by whole exome sequencing and verified by Sanger sequencing. Additionally, 3D protein structure visualization was performed by UCSF Chimera. The proband in our study had early-onset status epilepticus with abnormal EEG and MRI results. She also performed global developmental delay (GDD) and myocardial dysfunction. Next-generation sequencing (NGS) and Sanger sequencing revealed compound heterozygous missense variants [NM_024678.6:exon14: c.1352G > A(p.Arg451His); c.707T > C(p.Phe236Ser)] of the NARS2 gene. The proband develops refractory epilepsy with GDD and hyperlactatemia. Unfortunately, she finally died for status seizures two months later. Conclusion We discovered two novel missense variants of NARS2 in a patient with early-onset status epilepticus and myocardial dysfunction. The NGS enables the patient to be clearly diagnosed as combined oxidative phosphorylation deficiency 24 (COXPD24, OMIM:616,239), and our findings expands the spectrum of gene variants in COXPD24.

tRNA Modifications and Dysregulation: Implications for Brain Diseases

“…The patient's clinical profile included early-life seizures, developmental delays, and cardiac dysfunction, which evolved into intractable epilepsy, further developmental challenges, and hyperlactatemia. These findings underscore the crucial role of NARS2 in neurological and cardiac health, indicating that mutations in aminoacyl-tRNA synthetases like NARS2 can disrupt normal brain and heart development, leading to severe epilepsy and systemic conditions [231]. Furthermore, mutations in the WARS2 gene, responsible for encoding tryptophanyl-tRNA synthetase 2, have been correlated with a variety of neurological manifestations, such as epilepsy and motor deficits.…”