RARS2-related mitochondrial disorder is an autosomal recessive mitochondrial encephalopathy caused by biallelic pathogenic variants in the gene encoding the mitochondrial arginyl-transfer RNA synthetase 2 (RARS2, MIM *611524, NM_020320.5). RARS2 catalyzes the transfer of L-arginine to its cognate tRNA during the translation of mitochondrially-encoded proteins. The classical presentation of RARS2-related mitochondrial disorder includes pontocerebellar hypoplasia (PCH), progressive microcephaly, profound developmental delay, feeding difficulties, and hypotonia. Most patients also develop severe epilepsy by three months of age, which consists of focal or generalized seizures that frequently become pharmacoresistant and lead to developmental and epileptic encephalopathy (DEE). Here, we describe a six-year-old boy with developmental delay, hypotonia, and failure to thrive who developed an early-onset DEE consistent with Lennox-Gastaut Syndrome (LGS), which has not previously been observed in this disorder. He had dysmorphic features including bilateral macrotia, overriding second toes, a depressed nasal bridge, retrognathia, and downslanting palpebral fissures, and he did not demonstrate progressive microcephaly. Whole genome sequencing identified two variants in RARS2, c.36 + 1G > T, a previously unpublished variant that is predicted to affect splicing and is, therefore, likely pathogenic and c.419 T > G (p.Phe140Cys), a known pathogenic variant. He exhibited significant, progressive generalized brain atrophy and ex vacuo dilation of the supratentorial ventricular system on brain MRI and did not demonstrate PCH. Treatment with a ketogenic diet (KD) reduced seizure frequency and enabled him to make developmental progress. Plasma untargeted metabolomics analysis showed increased levels of lysophospholipid and sphingomyelin-related metabolites. Our work expands the clinical spectrum of RARS2-related mitochondrial disorder, demonstrating that patients can present with dysmorphic features and an absence of progressive microcephaly, which can help guide the diagnosis of this condition. Our case highlights the importance of appropriate seizure phenotyping in this condition and indicates that patients can develop LGS, for which a KD may be a viable therapeutic option. Our work further suggests that analytes of phospholipid metabolism may serve as biomarkers of mitochondrial dysfunction.

中文翻译：

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RARS2 相关线粒体疾病的扩展临床表型和非靶向代谢组学分析：病例报告

RARS2 相关线粒体疾病是一种常染色体隐性遗传线粒体脑病，由编码线粒体精氨酰转移 RNA 合成酶 2 (RARS2、MIM *611524、NM_020320.5) 的基因中的双等位基因致病性变异引起。在线粒体编码蛋白的翻译过程中，RARS2 催化 L-精氨酸转移至其同源 tRNA。RARS2 相关线粒体疾病的典型表现包括脑桥小脑发育不全 (PCH)、进行性小头畸形、严重发育迟缓、进食困难和肌张力减退。大多数患者在三个月大时还会出现严重癫痫，包括局灶性或全身性癫痫发作，这些癫痫发作经常产生耐药性并导致发育性癫痫性脑病（DEE）。在这里，我们描述了一名患有发育迟缓、肌张力低下和发育迟缓的六岁男孩，他患有与 Lennox-Gastaut 综合征 (LGS) 一致的早发性 DEE，而这种疾病以前从未在这种疾病中观察到。他具有畸形特征，包括双侧大耳畸形、第二脚趾压倒、鼻梁凹陷、下颌后缩和下斜睑裂，并且没有表现出进行性小头畸形。全基因组测序鉴定出 RARS2 中的两个变体，c.36 + 1G > T（一种先前未发表的变体，预计会影响剪接，因此可能具有致病性）和 c.419 T > G (p.Phe140Cys)，一种已知的致病性变体。在脑部 MRI 上，他表现出显着的、进行性的全身性脑萎缩和幕上脑室系统的真空扩张，但没有表现出 PCH。生酮饮食（KD）治疗减少了癫痫发作频率，并使他能够取得发育进步。血浆非靶向代谢组学分析显示溶血磷脂和鞘磷脂相关代谢物水平升高。我们的工作扩大了 RARS2 相关线粒体疾病的临床范围，证明患者可能表现出畸形特征且不存在进行性小头畸形，这有助于指导这种疾病的诊断。我们的病例强调了在这种情况下进行适当的癫痫表型分析的重要性，并表明患者可能会出现 LGS，而 KD 可能是一种可行的治疗选择。我们的工作进一步表明磷脂代谢分析物可以作为线粒体功能障碍的生物标志物。