Prospective diagnosis of MT-ATP6-related mitochondrial disease by newborn screening

Mol Genet Metab. 2021 Sep-Oct;134(1-2):37-42. doi: 10.1016/j.ymgme.2021.06.007. Epub 2021 Jun 24.


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.

Keywords: Acylcarnitine; Amino acids; Citrulline; Leigh syndrome; Mitochondrial disease; Newborn screening.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Carnitine / blood
  • Carnitine / chemistry
  • Citrulline / blood
  • DNA, Mitochondrial / genetics
  • Female
  • Genetic Testing / methods*
  • Humans
  • Infant, Newborn
  • Leigh Disease / diagnosis*
  • Leigh Disease / genetics*
  • Male
  • Mitochondrial Diseases / diagnosis*
  • Mitochondrial Diseases / genetics*
  • Mitochondrial Proton-Translocating ATPases / genetics*
  • Neonatal Screening / methods*
  • Prospective Studies


  • DNA, Mitochondrial
  • Citrulline
  • Mitochondrial Proton-Translocating ATPases
  • Carnitine