A newborn screening approach to diagnose 3-hydroxy-3-methylglutaryl-CoA lyase deficiency

JIMD Reports
Jan VáclavíkTomáš Adam

Abstract

3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency (HMGCLD) is a rare autosomal recessively inherited metabolic disorder. Patients suffer from avoidable neurologically devastating metabolic decompensations and thus would benefit from newborn screening (NBS). The diagnosis is currently made by measuring dry blood spot acylcarnitines (C5OH and C6DC) followed by urinary organic acid profiling for the differential diagnosis from several other disorders. Using untargeted metabolomics (reversed-phase UHPLC coupled to an Orbitrap Elite hybrid mass spectrometer) of plasma samples from 5 HMGCLD patients and 19 age-matched controls, we found 3-methylglutaconic acid and 3-hydroxy-3-methylglutaric acid, together with 3-hydroxyisovalerylcarnitine as the most discriminating metabolites between the groups. In order to evaluate the NBS potential of these metabolites we quantified the most discriminating metabolites from untargeted metabolomics in 23 blood spots from 4 HMGCLD patients and 55 controls by UHPLC tandem mass spectrometry. The results provide a tool for expanded NBS of HMGCLD using tandem mass spectrometry. Selected reaction monitoring transition 262/85 could be used in a first-tier NBS analysis to screen for elevated 3-hydroxyi...Continue Reading

References

Jun 1, 2006·Pediatrics·UNKNOWN American College of Medical Genetics Newborn Screening Expert Group
Aug 19, 2007·Molecular Genetics and Metabolism·Juan PiéNúria Casals
Sep 1, 2007·Metabolomics : Official Journal of the Metabolomic Society·Lloyd W SumnerMark R Viant
Nov 26, 2013·Clinica Chimica Acta; International Journal of Clinical Chemistry·Cristiano RizzoCarlo Dionisi-Vici
Dec 15, 2015·Journal of Inherited Metabolic Disease·Bridget Wilcken
Mar 23, 2017·Amino Acids·María M Adeva-AndanyCristina Sixto-Leal
Jun 7, 2017·Molecular Genetics and Metabolism·Sarah Catharina GrünertJörn Oliver Sass
Nov 16, 2017·Journal of Inherited Metabolic Disease·Jan VáclavíkRon A Wevers
Feb 13, 2018·Journal of Inherited Metabolic Disease·Irene M L W Körver-KeulartsJörgen Bierau

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