title: The Newborn Screening Paradox: Sensitivity vs. Overdiagnosis in VLCAD Deficiency.
abstract: OBJECTIVE
  To improve the efficacy of newborn screening (NBS) for very long chain acyl-CoA dehydrogenase deficiency (VLCADD).
  
  
  METHODS
  Data on all dried blood spots collected by the Dutch NBS from October 2007 to 2010 (742.728) were included. Based solely on the C14:1 levels (cutoff ≥0.8 μmol/L), six newborns with VLCADD had been identified through NBS during this period. The ratio of C14:1 over C2 was calculated. DNA of all blood spots with a C14:1/C2 ratio of ≥0.020 was isolated and sequenced. Children homozygous or compound heterozygous for mutations in the ACADVL gene were traced back and invited for detailed clinical, biochemical, and genetic evaluation.
  
  
  RESULTS
  Retrospective analysis based on the C14:1/C2 ratio with a cutoff of ≥0.020 identified an additional five children with known ACADVL mutations and low enzymatic activity. All were still asymptomatic at the time of diagnosis (age 2-5 years). Increasing the cutoff to ≥0.023 resulted in a sensitivity of 93% and a positive predictive value of 37%. The sensitivity of the previously used screening approach (C14:1 ≥0.8) was 50%.
  
  
  CONCLUSIONS
  This study shows that the ratio C14:1/C2 is a more sensitive marker than C14:1 for identifying VLCADD patients in NBS. However, as these patients were all asymptomatic at the time of diagnosis, this suggests that a more sensitive screening approach may also identify individuals who may never develop clinical disease. Long-term follow-up studies are needed to establish the risk of these VLCADD-deficient individuals for developing clinical signs and symptoms.
authors.affiliation: Department of Clinical Chemistry and Pediatrics, Laboratory Genetic Metabolic Diseases, Emma Children's Hospital, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.|Department of Paediatric Gastroenterology and Metabolic Diseases, Wilhelmina Children's Hospital UMC Utrecht, Utrecht, The Netherlands.
authors.forename: Eugene
authors.initials: E
authors.lastname: Diekman
authors.affiliation: Department of Medical Genetics, Wilhelmina Children's Hospital UMC Utrecht, Utrecht, The Netherlands.
authors.forename: Monique
authors.initials: M
authors.lastname: de Sain-van der Velden
authors.affiliation: Department of Clinical Chemistry and Pediatrics, Laboratory Genetic Metabolic Diseases, Emma Children's Hospital, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: Waterham
authors.affiliation: Department of Laboratory Medicine, Translational Metabolic Laboratory, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Leo
authors.initials: L
authors.lastname: Kluijtmans
authors.affiliation: National Institute for Public Health and the Environment (RIVM), Reference Laboratory for Pre- and Neonatal Screening, Bilthoven, The Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: Schielen
authors.affiliation: National Institute for Public Health and the Environment (RIVM), Reference Laboratory for Pre- and Neonatal Screening, Bilthoven, The Netherlands.
authors.forename: Evert Ben
authors.initials: EB
authors.lastname: van Veen
authors.affiliation: Department of Clinical Chemistry and Pediatrics, Laboratory Genetic Metabolic Diseases, Emma Children's Hospital, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Sacha
authors.initials: S
authors.lastname: Ferdinandusse
authors.affiliation: Department of Clinical Chemistry and Pediatrics, Laboratory Genetic Metabolic Diseases, Emma Children's Hospital, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Frits
authors.initials: F
authors.lastname: Wijburg
authors.affiliation: Department of Paediatric Gastroenterology and Metabolic Diseases, Wilhelmina Children's Hospital UMC Utrecht, Utrecht, The Netherlands. gvisser4@umcutrecht.nl.
authors.forename: Gepke
authors.initials: G
authors.lastname: Visser
keywords: Biomarker; C14:1; C2; Newborn screening; VLCADD