title: Newborn screening for isovaleric acidemia using tandem mass spectrometry: data from 1.6 million newborns.
abstract: BACKGROUND
  Electrospray ionization-tandem mass spectrometry (ESI-MS/MS) has been used in the Bavarian newborn screening (NBS) program since 1999. The use of ESI-MS/MS has led to the inclusion of isovaleric acidemia (IVA) into NBS. We retrospectively evaluated data on more than 1.6 million newborns screened during 9.5 years.
  
  
  METHODS
  Acylcarnitines from whole blood spotted on filter paper were converted to their corresponding butyl esters, and the samples were analyzed by use of ESI-MS/MS with stable isotope labeled internal standards.
  
  
  RESULTS
  A total of 24 individuals with IVA were detected by use of a multiparametric threshold criteria panel including isovalerylcarnitine (C5) and the ratios of C5 to octanoyl-, butyryl-, and propionylcarnitine. A cutoff set at the 99.99th percentile for isolated C5 or at the 99th percentile for C5 plus at least 2 ratios resulted in a positive predictive value for IVA screening of 7.0% and an overall recall rate of 0.024%. Adjusted reference ranges for age and birth weight were applied, and the incidence of IVA in the study population was calculated to be 1 in 67,000. Missed cases were not brought to our attention. IVA was also detectable in cord blood and early postnatal blood samples.
  
  
  CONCLUSIONS
  IVA can be reliably detected in NBS through acylcarnitine analysis in dried blood spots by using multiparametric threshold criteria. Further improvement (positive predictive value 13.0%, recall rate 0.01%) can be achieved by using more stringent recall criteria. In view of the potentially life-threatening natural course of IVA in early life, presymptomatic diagnosis may thus prevent mortality and morbidity.
authors.affiliation: Dr. von Hauner Children's Hospital, Children's Research Centre, Ludwig-Maximilians-Universität, Munich, Germany.
authors.forename: Regina
authors.initials: R
authors.lastname: Ensenauer
authors.forename: Ralph
authors.initials: R
authors.lastname: Fingerhut
authors.forename: Esther M
authors.initials: EM
authors.lastname: Maier
authors.forename: Roman
authors.initials: R
authors.lastname: Polanetz
authors.forename: Bernhard
authors.initials: B
authors.lastname: Olgemöller
authors.forename: Wulf
authors.initials: W
authors.lastname: Röschinger
authors.forename: Ania C
authors.initials: AC
authors.lastname: Muntau
mesh_terms: D045782:Hemiterpenes; D006801:Humans; D007231:Infant, Newborn; D015997:Neonatal Screening; D010421:Pentanoic Acids / Q000097:blood*; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods*; D053719:Tandem Mass Spectrometry / Q000379:methods*
chemical_list: D045782:Hemiterpenes; D010421:Pentanoic Acids; C008216:isovaleric acid