TY - JOUR
T1 - Prospective diagnosis of MT-ATP6-related mitochondrial disease by newborn screening
AU - Peretz, Ryan H.
AU - Ah Mew, Nicholas
AU - Vernon, Hilary J.
AU - Ganetzky, Rebecca D.
N1 - Funding Information:
This research was supported, in part, by the Intramural Research Program of the National Human Genome Research Institute , National Institutes of Health. Funding for the collection of patient samples, genetic sequencing, and salary support for Rebecca D. Ganetzky was provided through grant R03-DK125662 from the National Institute of Diabetes and Digestive and Kidney Diseases .
Publisher Copyright:
© 2021 Elsevier Inc.
PY - 2021/9/1
Y1 - 2021/9/1
N2 - 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.
AB - 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.
KW - Acylcarnitine
KW - Amino acids
KW - Citrulline
KW - Leigh syndrome
KW - Mitochondrial disease
KW - Newborn screening
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U2 - 10.1016/j.ymgme.2021.06.007
DO - 10.1016/j.ymgme.2021.06.007
M3 - Article
C2 - 34176718
AN - SCOPUS:85108817171
SN - 1096-7192
VL - 134
SP - 37
EP - 42
JO - Molecular genetics and metabolism
JF - Molecular genetics and metabolism
IS - 1-2
ER -