Eugene Diekman1,2, Monique de Sain-van der Velden3, Hans Waterham1, Leo Kluijtmans4, Peter Schielen5, Evert Ben van Veen5, Sacha Ferdinandusse1, Frits Wijburg1, Gepke Visser6. 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.
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.
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