PDF(Pubmed)
Abstract：
BACKGROUND: 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).
METHODS: 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 T, a previously unpublished variant that is predicted to affect splicing and is, therefore, likely pathogenic and c.419 T 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.
CONCLUSIONS: 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.
METHODS: 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.
CONCLUSIONS: 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.
摘要：
背景：RARS2相关的线粒体疾病是一种常染色体隐性遗传的线粒体脑病，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变体引起。RARS2在线粒体编码的蛋白质的翻译过程中催化L-精氨酸向其同源tRNA的转移。RARS2相关线粒体疾病的经典表现包括桥脑小脑发育不全（PCH），进行性小头畸形,严重的发育迟缓，喂养困难，和低张力。大多数患者在三个月大时也会发展为严重的癫痫，由局灶性或全身性癫痫发作组成，这些癫痫发作经常具有药物抗性并导致发育性和癫痫性脑病（DEE）。
方法：这里，我们描述了一个发育迟缓的六岁男孩，低张力,发展出符合Lennox-Gastaut综合征（LGS）的早发性DEE，以前在这种疾病中没有观察到。他有畸形特征，包括双侧巨症，覆盖第二脚趾，一个凹陷的鼻梁,回颌,和下倾斜的睑裂，他没有表现出进行性小头畸形。全基因组测序确定了RARS2中的两个变体，c.36+1G>T，一个以前未发表的变体，预测会影响剪接，因此,可能致病，c.419T>G（p.Phe140Cys)，一种已知的致病变种。他表现出显著的，脑MRI上进行性全身性脑萎缩和幕上心室系统真空扩张，未显示PCH。用生酮饮食（KD）治疗可减少癫痫发作频率，并使他能够取得发育进展。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。
结论：我们的工作扩展了RARS2相关线粒体疾病的临床范围，证明患者可以表现出畸形特征和没有进行性小头畸形，这可以帮助指导这种情况的诊断。我们的案例强调了在这种情况下适当的癫痫发作表型的重要性，并表明患者可以发展为LGS，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。
方法：这里，我们描述了一个发育迟缓的六岁男孩，低张力,发展出符合Lennox-Gastaut综合征（LGS）的早发性DEE，以前在这种疾病中没有观察到。他有畸形特征，包括双侧巨症，覆盖第二脚趾，一个凹陷的鼻梁,回颌,和下倾斜的睑裂，他没有表现出进行性小头畸形。全基因组测序确定了RARS2中的两个变体，c.36+1G>T，一个以前未发表的变体，预测会影响剪接，因此,可能致病，c.419T>G（p.Phe140Cys)，一种已知的致病变种。他表现出显著的，脑MRI上进行性全身性脑萎缩和幕上心室系统真空扩张，未显示PCH。用生酮饮食（KD）治疗可减少癫痫发作频率，并使他能够取得发育进展。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。
结论：我们的工作扩展了RARS2相关线粒体疾病的临床范围，证明患者可以表现出畸形特征和没有进行性小头畸形，这可以帮助指导这种情况的诊断。我们的案例强调了在这种情况下适当的癫痫发作表型的重要性，并表明患者可以发展为LGS，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。
