Hypocitrullinemia as an Early Diagnostic Biomarker for MT-ATP6 Mitochondrial Diseases

MT-ATP6 mitochondrial diseases are a group of disorders inherited from the maternal lineage caused by pathogenic variants in the MT-ATP6 gene, which encodes the a subunit of mitochondrial complex V (ATP synthase) in the electron transport chain. In this study, statistical analysis of 69 mitochondrial disease patients with complete blood metabolic screening at our center demonstrated that hypocitrullinemia exhibited 58% sensitivity (7/12) and 100% specificity (57/57) for diagnosing MT-ATP6 mitochondrial diseases. For detecting the m.8993T > G variant, the diagnostic sensitivity reached 78% (7/9) with maintained 100% specificity (60/60). Among the 7 patients with hypocitrullinemia, one had mtDNA large segment deletion syndrome involving MT-ATP6, and the other 6 had MT-ATP6 mitochondrial diseases due to the m.8993T > G variant. Hypocitrullinemia was initially detected in 3 patients during newborn screening and persisted in follow-up evaluations. A literature review identified 42 cases with MT-ATP6 variants exhibiting hypocitrullinemia, of whom 21 were diagnosed with decreased citrulline during newborn screening. We propose that hypocitrullinemia may serve as an early, characteristic serum biomarker for MT-ATP6 mitochondrial diseases, particularly aiding in the early diagnosis of the m.8993T > G variant. It also exhibits high specificity for diagnosing MT-ATP6 mitochondrial diseases and the m.8993T > G variant. Timely interventions, such as proactive diagnosis of pathogenic variants and administration of mitochondrial cofactors and citrulline, can mitigate the risk of decompensation and improve long-term prognosis.