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

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.

[1]  Ji-Hoon Na,et al.  Genotype‐phenotype analysis of MT‐ATP6‐associated Leigh syndrome , 2021, Acta neurologica Scandinavica.

[2]  R. Ganetzky,et al.  Prospective diagnosis of MT-ATP6-related mitochondrial disease by newborn screening. , 2021, Molecular genetics and metabolism.

[3]  A. Fiumara,et al.  New ratio as a useful marker for early diagnosis of proximal urea cycle disorders. , 2021, Clinica chimica acta; international journal of clinical chemistry.

[4]  P. Rinaldo,et al.  A Novel Approach to Improve Newborn Screening for Congenital Hypothyroidism by Integrating Covariate-Adjusted Results of Different Tests into CLIR Customized Interpretive Tools , 2021, International journal of neonatal screening.

[5]  J. Merritt,et al.  Considering Proximal Urea Cycle Disorders in Expanded Newborn Screening , 2020, International journal of neonatal screening.

[6]  Marni J. Falk,et al.  Delineating MT-ATP6-associated disease , 2020, Neurology. Genetics.

[7]  Marni J. Falk,et al.  MT‐ATP6 mitochondrial disease variants: Phenotypic and biochemical features analysis in 218 published cases and cohort of 14 new cases , 2019, Human mutation.

[8]  P. Rinaldo,et al.  Precision newborn screening for lysosomal disorders , 2018, Genetics in Medicine.

[9]  P. Rinaldo,et al.  Moonlighting newborn screening markers: the incidental discovery of a second-tier test for Pompe disease , 2018, Genetics in Medicine.

[10]  R. Rodenburg,et al.  Leigh-Like Syndrome Due to Homoplasmic m.8993T>G Variant with Hypocitrullinemia and Unusual Biochemical Features Suggestive of Multiple Carboxylase Deficiency (MCD). , 2016, JIMD reports.

[11]  J. Rahman,et al.  Mitochondrial DNA-Associated Leigh Syndrome and NARP , 2014 .

[12]  Vagelis Papakonstantinou,et al.  Enhanced interpretation of newborn screening results without analyte cutoff values , 2012, Genetics in Medicine.

[13]  G. Enns,et al.  Inherited disorders affecting mitochondrial function are associated with glutathione deficiency and hypocitrullinemia , 2009, Proceedings of the National Academy of Sciences.

[14]  N. Hauser,et al.  Biochemical signatures mimicking multiple carboxylase deficiency in children with mutations in MT-ATP6. , 2019, Mitochondrion.

[15]  N. Stollery.  Inherited disorders. , 2016, The Practitioner.

[16]  D. Bartholomew,et al.  m.8993T>G-Associated Leigh Syndrome with Hypocitrullinemia on Newborn Screening. , 2014, JIMD reports.