RARS1‐related developmental and epileptic encephalopathy

Abstract

ObjectiveBiallelic variants of RARS1, a gene that encodes the cytoplasmic tRNA synthetase for arginine (ArgRS), are associated with central nervous system (CNS) manifestations, such as hypomyelinating leukodystrophy‐9 and developmental and epileptic encephalopathy (DEE). This study aimed to better understand the RARS1 biallelic mutations and the associated phenotypes, particularly in patients with DEE.MethodsWe identified two patients with RARS1 biallelic mutations and functionally validated these mutations in vitro. Furthermore, we performed a review of the literature.ResultsTwo patients with hypomyelinating leukodystrophy were found to have RARS1 biallelic variants (Patient 1: c.1535G>A (p.Arg512Gln) and c.1382G>A (p.Arg461His); Patient 2: homozygous variants c.5A>T (p.Asp2Val)). Patient 2 had a severe clinical manifestation of DEE. A review of the literature identified 27 patients from five studies. Among the 29 patients, intellectual disability, developmental delay, and hypomyelination were the common symptoms, while 13 of them exhibited DEE and malformations of cortical development. Of the 25 variants identified, c.5A>G (p.Asp2Gly) was identified in 10 patients. ArgRS protein expression and stability were substantially reduced in the two newly identified patients.SignificancePatients with RARS1 biallelic mutations frequently exhibit DEE, a severe phenotype, along with hypomyelinating leukodystrophy. Besides its effects on the white matter, this mutation also influences cortical development. Moreover, the variants c.5A>T (p.Asp2Val), c.1382G>A (p.Arg461His), and c.1535G>A (p.Arg512Gln) are pathogenic and affect the expression of ArgRS by reducing the protein stability.

RARS1‐related hypomyelinating leukodystrophy‐9 (HLD‐9) in two distinct Iranian families: Case report and literature review

“…We identified that RARS1 homozygous variants can cause a variety of neurological symptoms, which is consistent with earlier findings (Di Bella et al., 2021 ; Ji et al., 2018 ; McSherry et al., 2018 ; Mendes et al., 2020 ; Nafisinia et al., 2017 ; Rezaei et al., 2019 ; Wan et al., 2023 ; Wolf et al., 2014 ). In the prior study, the clinical presentation was divided into three categories: severe, intermediate, and mild.…”

“…Variants in the genes encoding cytoplasmic and mitochondrial tRNA synthetases have been associated with a variety of disorders, ranging from peripheral neuropathy to leukodystrophy (Wolf et al., 2014 ). Biallelic RARS1 variants have been linked to hypomyelination leukodystrophy in 30 cases (Di Bella et al., 2021 ; Ji et al., 2018 ; McSherry et al., 2018 ; Mendes et al., 2020 ; Nafisinia et al., 2017 ; Rezaei et al., 2019 ; Wan et al., 2023 ; Wolf et al., 2014 ). In this study, we used ES on 2 Iranian patients, both had Bakhtiari ethnicity and a history of consanguineous marriage.…”