BackgroundHypomyelinating 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.MethodsWe identified three patients with RARS1 homozygous pathogenic variants. Furthermore, we performed a comprehensive review of the literature.ResultsHomozygous 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.ConclusionPathogenic 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.

中文翻译：

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两个不同伊朗家族中的 RARS1 相关低髓鞘性脑白质营养不良 9 (HLD-9)：病例报告和文献综述

背景低髓鞘性脑白质营养不良‐9 (HLD‐9) 是由双等位基因致病变异引起的RARS1，编码精氨酸细胞质 tRNA 合成酶 (ArgRS)。本研究旨在评估 RARS1 相关疾病患者的临床、神经放射学和遗传特征，并确定可能的基因型-表型关系。方法我们确定了三名患有 RARS1 相关疾病的患者RARS1纯合致病变异。此外，我们对文献进行了全面的回顾。结果纯合变异RARS1在三名 HLD-9 患者中发现了 (c.2T>C (p.Met1Thr))。所有患者的临床症状都很严重。文献综述后，发现了来自 8 项研究的 30 例 HLD-9 病例。 33例患者的主要症状为髓鞘形成不足、语言发育迟缓、智力障碍或发育迟缓。在 33 名已知发病年龄的患者中，HLD9 的平均发病年龄为 5.8 个月（SD = 8.1）。发病年龄的四分位数范围为0-10个月。在鉴定的 25 个变异中，在 11 名患者中鉴定出 c.5A>G (p.Asp2Gly)。 结论RARS1降低 ArgRS 活性并引起多种症状，从严重的、早发性癫痫性脑病伴脑萎缩到髓鞘形成相对维持的轻度病症。这些症状包括典型的髓鞘形成不足，伴有眼球震颤和痉挛。此外，变异 c.2T>C (p.Met1Thr) 的致病性已被证明。