Validation of MCADD newborn screening
- 1 August 2009
- journal article
- research article
- Published by Wiley in Clinical Genetics
- Vol. 76 (2), 179-187
- https://doi.org/10.1111/j.1399-0004.2009.01217.x
Abstract
Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) represents a potentially fatal fatty acid beta-oxidation disorder. Newborn screening (NBS) by tandem mass spectrometry (MS/MS) has been implemented worldwide, but is associated with unresolved questions regarding population heterogeneity, burden on healthy carriers, cut-off policies, false-positive and negative rates. In a retrospective case-control study, 333 NBS samples showing borderline acylcarnitine patterns but not reaching recall criteria were genotyped for the two most common mutations (c.985A>G/c.199C>T) and compared with genotypes and acylcarnitines of 333 controls, 68 false-positives, and 34 patients. c.985A>G was more frequently identified in the study group and false-positives compared to controls (1:4.3/1:2.3 vs. 1:42), whereas c.199C>T was found more frequently only within the false-positives (1:23). Biochemical criteria were devised to differentiate homozygous (c.985A>G), compound heterozygous (c.985A>G/c.199C>T), and heterozygous individuals. Four false-negatives were identified because our initial algorithm required an elevation of octanoylcarnitine (C(8)) and three secondary markers in the initial and follow-up sample. The new approach allowed a reduction of false-positives (by defining high cut-offs: 1.4 micromol/l for C(8); 7 for C(8)/C(12)) and false-negatives (by sequencing the ACADM gene of few suspicious samples). Our validation strategy is able to differentiate healthy carriers from patients doubling the positive predictive value (42-->88%) and to target NBS to MCADD-subsets with potentially higher risk of adverse outcome. It remains controversial, if NBS programs should aim at identifying all subsets of all diseases included. Because the natural course of milder variants cannot be assessed by observational studies, our strategy could serve as a general model for evaluation of MS/MS-based NBSKeywords
This publication has 30 references indexed in Scilit:
- Novel mutations causing medium chain acyl-CoA dehydrogenase deficiency: Under-representation of the common c.985 A > G mutation in the New York state populationAmerican Journal of Medical Genetics Part A, 2008
- Neonatal screening for medium‐chain acyl‐CoA dehydrogenase (MCAD) deficiency in The Netherlands: The importance of enzyme analysis to ascertain true MCAD deficiencyJournal of Inherited Metabolic Disease, 2008
- Newborn screening for medium‐chain acyl‐CoA dehydrogenase deficiency: A global perspectiveJournal of Inherited Metabolic Disease, 2005
- Reduced incidence of severe metabolic crisis or death in children with medium chain acyl-CoA dehydrogenase deficiency homozygous for c.985A>G identified by neonatal screeningMolecular Genetics and Metabolism, 2005
- The Y42H mutation in medium‐chain acyl‐CoA dehydrogenase, which is prevalent in babies identified by MS/MS‐based newborn screening, is temperature sensitiveJBIC Journal of Biological Inorganic Chemistry, 2004
- Advances in analytical mass spectrometry to improve screening for inherited metabolic diseasesEuropean Journal of Pediatrics, 2003
- Newborn screening for medium chain acyl-CoA dehydrogenase deficiency: evaluating the effects on outcomeEuropean Journal of Pediatrics, 2003
- Penetrance and expressivity in the molecular ageGenetics in Medicine, 2003
- Newborns with C8‐acylcarnitine level over the 90th centile have an increased frequency of the common MCAD 985A>G mutationJournal of Inherited Metabolic Disease, 2002
- Expanded Newborn Screening in Bavaria: Tracking to Achieve Requested Repeat TestingPreventive Medicine, 2002