Biglari Sajjad, Vahidnezhad Hassan, Tabatabaiefar Mohammad Amin, Khorram Khorshid Hamid Reza, Esmaeilzadeh Emran
Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.
Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Mol Genet Genomic Med. 2024 Apr;12(4):e2435. doi: 10.1002/mgg3.2435.
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.
We identified three patients with RARS1 homozygous pathogenic variants. Furthermore, we performed a comprehensive review of the literature.
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.
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.
低髓鞘形成性脑白质营养不良9型（HLD - 9）由RARS1基因的双等位基因致病性变异引起，该基因编码精氨酸（ArgRS）的细胞质tRNA合成酶。本研究旨在评估RARS1相关疾病患者的临床、神经放射学和遗传学特征，并确定可能的基因型 - 表型关系。
我们鉴定出3例具有RARS1纯合致病性变异的患者。此外，我们对文献进行了全面综述。
在3例HLD - 9患者中鉴定出RARS1的纯合变异（c.2T>C（p.Met1Thr））。所有患者的临床症状均严重。经文献综述，发现来自8项研究的30例HLD - 9病例。这33例患者的主要症状为髓鞘形成不足、语言发育迟缓以及智力残疾或发育迟缓。在已知发病年龄的33例患者组中，HLD9的平均发病年龄为5.8个月（标准差 = 8.1）。发病年龄的四分位间距为0 - 10个月。在鉴定出的25种变异中，11例患者存在c.5A>G（p.Asp2Gly）变异。
RARS1中的致病性变异会降低ArgRS活性，并导致广泛的症状，从伴有脑萎缩的严重早发性癫痫性脑病到髓鞘相对保持的轻度病症。这些症状包括伴有眼球震颤和痉挛的典型低髓鞘形成表现。此外，已证实变异c.2T>C（p.Met1Thr）的致病性。
