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JIMD Rep. 2016;27:101-6. doi: 10.1007/8904_2015_476. Epub 2015 Oct 10.

The Newborn Screening Paradox: Sensitivity vs. Overdiagnosis in VLCAD Deficiency.

Author information

1
Department of Clinical Chemistry and Pediatrics, Laboratory Genetic Metabolic Diseases, Emma Children's Hospital, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
2
Department of Paediatric Gastroenterology and Metabolic Diseases, Wilhelmina Children's Hospital UMC Utrecht, Utrecht, The Netherlands.
3
Department of Medical Genetics, Wilhelmina Children's Hospital UMC Utrecht, Utrecht, The Netherlands.
4
Department of Laboratory Medicine, Translational Metabolic Laboratory, Radboud University Medical Center, Nijmegen, The Netherlands.
5
National Institute for Public Health and the Environment (RIVM), Reference Laboratory for Pre- and Neonatal Screening, Bilthoven, The Netherlands.
6
Department of Paediatric Gastroenterology and Metabolic Diseases, Wilhelmina Children's Hospital UMC Utrecht, Utrecht, The Netherlands. gvisser4@umcutrecht.nl.

Abstract

OBJECTIVE:

To improve the efficacy of newborn screening (NBS) for very long chain acyl-CoA dehydrogenase deficiency (VLCADD).

PATIENTS AND 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%.

CONCLUSION:

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.

KEYWORDS:

Biomarker; C14:1; C2; Newborn screening; VLCADD

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