Elevated citrulline and C5-OH levels are reported as part of the newborn screening of core and secondary disorders on the Recommended Uniform Screening Panel (RUSP). Additionally, some state laboratory newborn screening programs report low citrulline levels, which may be observed in proximal urea cycle disorders. We report six patients who were found on newborn screening to have low citrulline and/or elevated C5-OH levels in whom confirmatory testing showed the combination of these two abnormal analytes. Mitochondrial sequencing revealed known pathogenic variants in MT-ATP6 at high heteroplasmy levels in all cases. MT-ATP6 at these heteroplasmy levels is associated with Leigh syndrome, a progressive neurodegenerative disease. Patients were treated with supplemental citrulline and, in some cases, mitochondrial cofactor therapy. These six patients have not experienced metabolic crises or developmental regression, and early diagnosis and management may help prevent the neurological sequelae of Leigh syndrome. The affected mothers and siblings are asymptomatic or paucisymptomatic (e.g. intellectual disability, depression, migraines, obsessive-compulsive disorder, and poor balance) despite high heteroplasmy or apparent homoplasmy of the familial variant, thus expanding the clinical spectrum seen in pathogenic variants of MT-ATP6. Confirmatory plasma amino acid analysis and acylcarnitine profiling should be ordered in a patient with either low citrulline and/or elevated C5-OH, as this combination appears specific for pathogenic variants in MT-ATP6.

瓜氨酸和 C5-OH 水平升高是推荐的统一筛查小组 (RUSP) 新生儿核心和继发性疾病筛查的一部分。此外，一些州实验室新生儿筛查计划报告瓜氨酸水平低，这可能在近端尿素循环障碍中观察到。我们报告了 6 名在新生儿筛查中发现瓜氨酸水平低和/或 C5-OH 水平升高的患者，在这些患者中，确认测试显示这两种异常分析物的组合。线粒体测序揭示了所有病例中MT-ATP6中已知的高异质性致病变异。MT-ATP6在这些异质性水平上与 Leigh 综合征有关，这是一种进行性神经退行性疾病。患者接受了补充瓜氨酸治疗，在某些情况下，还接受了线粒体辅助因子治疗。这六名患者没有经历过代谢危机或发育退化，早期诊断和管理可能有助于预防 Leigh 综合征的神经系统后遗症。受累的母亲和兄弟姐妹无症状或无症状（例如智力障碍、抑郁、偏头痛、强迫症和平衡差），尽管家族变异的异质性或明显同质性很高，因此扩大了MT-致病性变异的临床谱。 ATP6. 对于瓜氨酸含量低和/或 C5-OH 升高的患者，应进行确认性血浆氨基酸分析和酰基肉碱分析，因为这种组合似乎对MT-ATP6中的致病变异具有特异性。