Abstract
Tandem mass spectrometry-based newborn screening correctly identifies individuals with very long-chain acyl-CoA dehydrogenase deficiency (VLCADD). However, a great number of healthy individuals present with identical acylcarnitine profiles during catabolism in the first three days of life. We routinely perform an enzyme activity assay as confirmation analysis in newborns identified by screening. Whereas VLCAD residual activities of less than 10% are clearly diagnostic and indicate patients at risk of clinical disease, the clinical relevance of higher residual activities is unclear. In this study we assess the molecular basis in 34 individuals with residual activities of 10-50%. We identify two pathogenic mutations in patients that result in residual activities as high as 22%, while individuals with residual activities of 25-50% either present with a heterozygous or no mutation in the VLCAD gene. In addition, confirmed heterozygous parents present with residual activities as low as 32%.
In conclusion, we identify individuals with 2 pathogenic mutations and those with only one heterozygous mutation in the residual activity range of 20-30%. Whereas heterozygosity is generally regarded as clinically irrelevant, identification of 2 VLCAD mutations leads to precautions in the management of the children. Based on our data we anticipate that individuals with a residual enzyme activity >20% present with a biochemical phenotype but likely remain asymptomatic throughout life. Studies in greater patient numbers are needed to correlate residual activities >10% with the genotype and the outcome.
Similar content being viewed by others
References
Andresen BS, Bross P, Vianey-Saban C et al. (1996) Cloning and characterization of human very-long-chain Acyl-CoA dehydrogenase cDNA,. chromosomal assignment of the gene and identification in four patients of nine different mutations within the VLCAD gene. Hum Mol Genet 5:461–472
Andresen BS, Olpin S, Poorthuis BJHM et al. (1999) Clear correlation of genotype with disease phenotype in very-long-chain Acyl-CoA dehydrogenase deficiency. Am J Hum Genet 64:479–494
Dipple KM, McCabe ERB (2000a) Modifier genes convert "simple" mendelian disorders to complex traits. Mol Genet Metab 71:43–50
Dipple KM, McCabe ERB (2000b) Phenotypes of patients with "simple" mendelian disorders are complex traits: thresholds, modifiers, and systems dynamics. Am J Hum Genet 66:1729–1735
Dipple KM, Phelan JK, McCabe ERB (2001) Consequences of complexity within biological networks: robustness and health, or vulnerability and disease. Mol Genet Metab 74:45–50
Gregersen N, Andresen BS, Corydon MJ et al. (2001) Mutation analysis in mitochondrial fatty acid oxidation defects: Exemplified by acyl-CoA dehydrogenase deficiencies, with special focus on genotype - phenotype relationship. Hum Mutat 18:169–189
Gregersen N, Andresen B, Pedersen C, Olsen R, Corydon T, Bross P (2008) Mitochondrial fatty acid oxidation defects - remaining challenges. J Inherit Metab Dis 31:643–657
Liebig M, Schymik I, Mueller M et al. (2006) Neonatal screening for very long-chain Acyl-CoA dehydrogenase deficiency: enzymatic and molecular evaluation of neonates with elevated C14:1-carnitine levels. Pediatrics 118:1065–1069
Lindner M, Hoffmann G, Matern D (2010) Newborn screening for disorders of fatty-acid oxidation: experience and recommendations from an expert meeting. J Inherit Metab Dis 33:521–526
Maier EM, SrW G, Kemter KF et al. (2009) Protein misfolding is the molecular mechanism underlying MCADD identified in newborn screening. Hum Mol Genet 18:1612–1623
Mathur A, Sims HF, Gopalakrishnan D et al. (1999) Molecular heterogeneity in very-long-chain Acyl-CoA dehydrogenase deficiency causing pediatric cardiomyopathy and sudden death. Circulation 99:1337–1343
McAndrew RP, Wang Y, Mohsen AW, He M, Vockley J, Kim JJ (2008) Structural basis for substrate fatty acyl chain specificity. J Biol Chem 283:9435–9443
McGoey RR, Marble M (2011) Positive newborn screen in a normal infant of a mother with asymptomatic very long-chain Acyl-CoA dehydrogenase deficiency. J Pediatr 158:1031–1032
Pons R, Cavadini P, Baratta S et al. (2000) Clinical and molecular heterogeneity in very-long-chain acyl-coenzyme a dehydrogenase deficiency. Pediatr Neurol 22:98–105
Roe DS, Vianey-Saban C, Sharma S, Zabot MT, Roe CR (2001) Oxidation of unsaturated fatty acids by human fibroblasts with very-long-chain acyl-CoA dehydrogenase deficiency: aspects of substrate specificity and correlation with clinical phenotype. 312: 55–67
Schymik I, Liebig M, Mueller M et al. (2006) Pitfalls of neonatal screening for very-long-chain acyl-CoA dehydrogenase deficiency using tandem mass spectrometry. J Pediatr 149:128–130
Shekawat PS, Matern D, Strauss AW (2005) Fetal fatty acid oxidation disorders, their effect on maternal health and neonatal outcome: impact of expanded newborn screening on their diagnosis and management. Review 57(5 Pt 2):78R–86R
Smith EH, Thomas C, McHugh D et al. (2010) Allelic diversity in MCAD deficiency: The biochemical classification of 54 variants identified during 5 years of ACADM sequencing. Mol Genet Metab 100:241–250
Souri M, Aoyama T, Yamaguchi S, Hashimoto T (1998) Relationship between structure and substrate-chain-length specificity of mitochondrial very-long-chain acyl-coenzyme A dehydrogenase. Eur J Biochem 257:592–598
Spiekerkoetter U, Sun B, Zytkovicz T, Wanders R, Strauss AW, Wendel U (2003) MS/MS-based newborn and family screening detects asymptomatic patients with very-long-chain acyl-CoA dehydrogenase deficiency. J Pediatr 143:335–342
Spiekerkoetter U, Lindner M, Santer R et al. (2009) Treatment recommendations in long-chain fatty acid oxidation defects: consensus from a workshop. J Inherit Metab Dis 32:498–505
Spiekerkoetter U, Haussmann U, Mueller M et al. (2010) Tandem Mass Spectrometry Screening for Very Long-Chain Acyl-CoA Dehydrogenase Deficiency: The Value of Second-Tier Enzyme Testing. J Pediatr 157:668–673
Veale EL, Rees KA, Mathie A, Trapp S (2010) Dominant negative effects of a non-conducting TREK1 splice variant expressed in brain. J Biol Chem 285:29295–29304
Vianey-Saban C, Divry P, Brivet M et al. (1998) Mitochondrial very-long-chain acyl-coenzyme A dehydrogenase deficiency: clinical characteristics and diagnostic considerations in 30 patients. Clin Chim Acta 269:43–62
Vockley J, Rinaldo P, Bennett MJ, Matern D, Vladutiu GD (2000) Synergistic heterozygosity: disease resulting from multiple partial defects in one or more metabolic pathways. Mol Genet Metab 71:10–18
Wanders R, Vreken P, den Boer M, Wijburg F, Van Gennip A, IJlst L (1999) Disorders of mitochondrial fatty acyl-CoA beta-oxidation. J Inherit Metab Dis 22:442–487
Author information
Authors and Affiliations
Corresponding author
Additional information
Communicated by: Bridget Wilcken
Competing interest: None declared.
Lars Hoffmann and Ulrike Haussmann contributed equally to this work.
Electronic supplementary material
Below is the link to the electronic supplementary material.
ESM 1
(DOC 36 kb)
Rights and permissions
About this article
Cite this article
Hoffmann, L., Haussmann, U., Mueller, M. et al. VLCAD enzyme activity determinations in newborns identified by screening: a valuable tool for risk assessment. J Inherit Metab Dis 35, 269–277 (2012). https://doi.org/10.1007/s10545-011-9391-8
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10545-011-9391-8