Abstract：
The MT-TL2 m.12315G>A pathogenic variant has previously been reported in five individuals with mild clinical phenotypes. Herein we report the case of a 5-year-old child with heteroplasmy for this variant who developed neurological regression and stroke-like episodes similar to those observed in mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). Biochemical evaluation revealed depletion of arginine on plasma amino acid analysis and low z-scores for citrulline on untargeted plasma metabolomics analysis. These findings suggested that decreased availability of nitric oxide may have contributed to the stroke-like episodes. The use of intravenous arginine during stroke-like episodes and daily enteral L-citrulline supplementation normalized her biochemical values of arginine and citrulline. Untargeted plasma metabolomics showed the absence of nicotinamide and 1-methylnicotinamide, and plasma total glutathione levels were low; thus, nicotinamide riboside and N-acetylcysteine therapies were initiated. This report expands the phenotype associated with the rare mitochondrial variant MT-TL2 m.12315G>A to include neurological regression and a MELAS-like phenotype. Individuals with this variant should undergo in-depth biochemical analysis to include untargeted plasma metabolomics, plasma amino acids, and glutathione levels to help guide a targeted approach to treatment.
摘要：
先前已经在具有轻度临床表型的五个个体中报道了MT-TL2m.12315G>A致病变体。在这里，我们报告了一个5岁的孩子，该孩子患有这种变异，他发生了类似于线粒体脑病的神经系统消退和中风样发作。乳酸性酸中毒,和中风样发作（MELAS）。生化评估显示血浆氨基酸分析中精氨酸的消耗和非靶向血浆代谢组学分析中瓜氨酸的低z评分。这些发现表明，一氧化氮的可用性降低可能是中风样发作的原因。在中风样发作期间使用静脉注射精氨酸和每日肠内补充L-瓜氨酸使精氨酸和瓜氨酸的生化值正常化。非靶向血浆代谢组学显示不存在烟酰胺和1-甲基烟酰胺，血浆总谷胱甘肽水平较低；因此，开始烟酰胺核苷和N-乙酰半胱氨酸治疗。该报告扩展了与罕见的线粒体变体MT-TL2m.12315G>A相关的表型，以包括神经系统消退和MELAS样表型。具有这种变异的个体应进行深入的生化分析，包括非靶向血浆代谢组学，血浆氨基酸，和谷胱甘肽水平，以帮助指导有针对性的治疗方法。
