Rars1-Related Hypomyelinating Leukodystrophy-9 (Hld-9) in Two Distinct Iranian Families: Case Report and Literature Review Publisher Pubmed



Biglari S¹ ; Vahidnezhad H^{2, 3, 4} ; Tabatabaiefar MA¹ ; Khorramkhorshid HR⁵ ; Esmaeilzadeh E⁶ Show Affiliations
Source: Molecular Genetics and Genomic Medicine Published:2024

Abstract

Background: Hypomyelinating leukodystrophy-9 (HLD-9) is caused by biallelic pathogenic variants in RARS1, which codes for the cytoplasmic tRNA synthetase for arginine (ArgRS). This study aims to evaluate the clinical, neuroradiological, and genetic characteristics of patients with RARS1-related disease and determine probable genotype–phenotype relationships. Methods: We identified three patients with RARS1 homozygous pathogenic variants. Furthermore, we performed a comprehensive review of the literature. Results: Homozygous variants of RARS1 (c.2T>C (p.Met1Thr)) were identified in three patients with HLD-9. Clinical symptoms were severe in all patients. Following the literature review, thirty HLD-9 cases from eight studies were found. The 33 patients' main symptoms were hypomyelination, language delay, and intellectual disability or developmental delay. The mean age of onset for HLD9 in the group of 33 patients with a known age of onset was 5.8 months (SD = 8.1). The interquartile range of age of onset was 0–10 months. Of the 25 variants identified, c.5A>G (p.Asp2Gly) was identified in 11 patients. Conclusion: Pathogenic variants in RARS1 decrease ArgRS activity and cause a wide range of symptoms, from severe, early onset epileptic encephalopathy with brain atrophy to a mild condition with relatively maintained myelination. These symptoms include the classic hypomyelination presentation with nystagmus and spasticity. Furthermore, the pathogenicity of the variation c.2T>C (p.Met1Thr) has been shown. © 2024 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.