MT‐ATP6 mitochondrial disease identified by newborn screening reveals a distinct biochemical phenotype

Abstract Although decreased citrulline is used as a newborn screening (NBS) marker to identify proximal urea cycle disorders (UCDs), it is also a feature of some mitochondrial diseases, including MT‐ATP6 mitochondrial disease. Here we describe biochemical and clinical features of 11 children born to eight mothers from seven separate families who were identified with low citrulline by NBS (range 3–5 μM; screening cutoff >5) and ultimately diagnosed with MT‐ATP6 mitochondrial disease. Follow‐up testing revealed a pattern of hypocitrullinemia together with elevated propionyl‐(C3) and 3‐hydroxyisovaleryl‐(C5‐OH) acylcarnitines, and a homoplasmic pathogenic variant in MT‐ATP6 in all cases. Single and multivariate analysis of NBS data from the 11 cases using Collaborative Laboratory Integrated Reports (CLIR; https://clir.mayo.edu ) demonstrated citrulline <1st percentile, C3 > 50th percentile, and C5‐OH >90th percentile when compared with reference data, as well as unequivocal separation from proximal UCD cases and false‐positive low citrulline cases using dual scatter plots. Five of the eight mothers were symptomatic at the time of their child(ren)'s diagnosis, and all mothers and maternal grandmothers evaluated molecularly and biochemically had a homoplasmic pathogenic variant in MT‐ATP6, low citrulline, elevated C3, and/or elevated C5‐OH. All molecularly confirmed individuals ( n = 17) with either no symptoms ( n = 12), migraines ( n = 1), or a neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP) phenotype ( n = 3) were found to have an A or U mitochondrial haplogroup, while one child with infantile‐lethal Leigh syndrome had a B haplogroup.