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.
Competing interests: None declared
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Acknowledgments
We are most grateful to Dr. B. Elvers of the National Institute for Public Health and the Environment (RIVM) for providing the selected blood spots for further analyses and to Dr. P. Verkerk of TNO (Applied Scientific Research Institute) and Prof. Dr. E.E.S. Nieuwenhuis of the Wilhelmina’s Children’s Hospital/University Medical Centre Utrecht (WKZ/UMCU) for their biochemical and ethical advice. They were not compensated for their efforts.
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Communicated by: Bridget Wilcken
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Synopsis
We show that the C14:1/C2 (≥0.023) ratio is a better biomarker (sensitivity 93%) to detect patients with VLCADD compared to C14:1 (≥0.8, sensitivity 50%) and identified five additional patients.
Conflict of Interest
Eugene Diekman has no conflict of interest, Monique de Sain-van der Velden has no conflict of interest, Hans Waterham has no conflict of interest, Leo Kluijtmans has no conflict of interest, Peter Schielen has no conflict of interest, Evert Ben van Veen has no conflict of interest, Sacha Ferdinandusse has no conflict of interest, Frits Wijburg has no conflict of interest, and Gepke Visser has no conflict of interest.
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This research was supported by ZonMW (dossier 200320006), Metakids (www.metakids.nl), and the ESN-stimuleringsprijs.
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All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5). Informed consent was obtained from all patients for being included in the study.
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Diekman, E. et al. (2015). The Newborn Screening Paradox: Sensitivity vs. Overdiagnosis in VLCAD Deficiency. In: Morava, E., Baumgartner, M., Patterson, M., Rahman, S., Zschocke, J., Peters, V. (eds) JIMD Reports, Volume 27. JIMD Reports, vol 27. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2015_476
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DOI: https://doi.org/10.1007/8904_2015_476
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