Abstract
Neonatal screening of medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is of major importance due to the significant morbidity and mortality in undiagnosed patients. MCADD screening has been performed routinely in Galicia since July 2000, and until now 199,943 newborns have been screened. We identified 11 cases of MCADD, which gives an incidence of 1/18,134. During this period, no false negative screens have been detected. At diagnosis, all identified newborns were asymptomatic. Our data showed that octanoylcarnitine (C8) and C8/C10 ratio are the best markers for screening of MCADD. C8 was increased in all patients and C8/C10 was increased in all but one patient.
The common mutation, c.985A > G, was found in homozygosity in seven newborns and in compound heterozygosity in three, while one patient did not carry the common mutation at all. In addition, two novel mutations c.245G > C (p.W82S) and c.542A > G (p.D181G) were identified. Ten of the 11 identified newborns did not experience any episodes of decompensation. The patient with the highest level of medium chain acylcarnitines at diagnosis, who was homozygous for the c.985A > G mutation, died at the age of 2 years due to a severe infection.
This is the first report of the results from neonatal screening for MCADD in Spain. Our data provide further evidence of the benefits of MCADD screening and contribute to better understanding of this disease.
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References
Al-Hassnan ZN, Imtiaz F, Al-Amoudi M (2010) Medium-chain acyl-CoA dehydrogenase deficiency in Saudi Arabia: incidence, genotype, and preventive implications. J Inherit Metab Dis. doi:10.1007/s10545-010-9143-1
Andresen BS, Bross P, Jensen TG et al (1993) A rare disease-associated mutation in the gene for medium chain Acyl-CoA dehydrogenase (MCAD) changes a conserved arginine residue previously shown to be functionally essential in short-chain Acyl-CoA dehydrogenase (SCAD). Am J Hum Genet 53:730–739
Andresen BS, Bross P, Udvari S et al (1997) The molecular basis of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency in compound heterozygous patients: is there correlation between genotype and phenotype? Hum Mol Genet 6:695–707
Andresen BS, Dobrowolski SF, O’Reilly L et al (2001) Medium-chain acyl-CoA dehydrogenase (MCAD) mutations identified by MS/MS-based prospective screening of newborns differ from those observed in patients with clinical symptoms: identification and characterization of a new, prevalent mutation that results in mild MCAD deficiency. Am J Hum Genet 68:1408–1418
Arnold GL, Saavedra-Matiz CA, Galvin-Parton PA et al (2010) Lack of genotype-phenotype correlations and outcome in MCAD deficiency diagnosed by newborn screening in New York State. Mol Genet Metab 99:263–268
Blois B, Riddell C, Dooley K, Dyack S (2005) Newborns with C8 acylcarnitine level over the 90th centile have an increased frequency of the common MCAD 985A > G mutation. J Inherit Metab Dis 28:551–556
Bonafé L, Troxler H, Kuster T et al (2000) Evaluation of urinary acylglicines by electrospray tandem mass spectrometry in mitochondrial energy metabolism defects and organic acidurias. Mol Genet Metab 69:302–311
Chace DH, DiPerna JC, Mitchell BL, Sgroi B, Hofman LF, Naylor EW (2001) Electrospray tandem mass spectrometry for analysis of acylcarnitines in dried postmortem blood specimens collected at autopsy from infants with unexplained cause of death. Clin Chem 47:1166–1182
Giroux S, Dubé-Linteau A, Cardinal G et al (2007) Assessment of the prevalence of the 985A > G MCAD mutation in the french-canadian population using allele-specific PCR. Clin Genet 71:569–575
Gregersen N, Blakemore A, Winter V et al (1991) Specific diagnosis of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency in dried blood spots by a polymerase chain reaction (PCR) assay detecting a point-mutation (G985) in the MCAD gene. Clin Chim Acta 203:23–34
Gregersen N, Andresen BS, Pedersen CB, Olsen RK, Corydon TJ, Bross P (2008) Mitochondrial fatty acid oxidation defects-remaining challenges. J Inherit Metab Dis 31:643–657
Grosse SD, Khoury MJ, Greene CL, Crider KS, Pollitt RJ (2006) The epidemiology of medium chain acyl-CoA dehydrogenase deficiency: an update. Genet Med 8:205–212
Hsu HW, Zytkovic TH, Comeau AM et al (2008) Spectrum of medium-chain acyl-CoA dehydrogenase deficiency detected by newborn screening. Pediatrics 121:108–114
Kobayashi H, Hasegawa Y, Endo M, Purevsuren J, Yamaguchi S (2007) ESI-MS/MS study of acylcarnitine profiles in urine from patients with organic acidemias and fatty acid oxidation disorders. J Chromatogr B Analyt Technol Biomed Life Sci 855:80–87
Lehotay DC, LePage J, Thompson JR, Rockman-Greenberg C (2004) Blood acylcarnitine levels in normal newborns and heterocygotes for medium-chan acyl-CoA dehydrogenase deficiency: a relationship between genotype and biochemical phenotype? J Inherit Metab Dis 27:81–88
Maier EM, Liebl B, Röschinger W et al (2005) Population spectrum of ACADM genotypes correlated to biochemical phenotypes in newborn screening for medium-chain acyl-CoA dehydrogenase deficiency. Hum Mutat 25:443–452
Martínez G, Jiménez-Sánchez G, Divry P et al (1997) Plasma free fatty acids in mitochondrial fatty acid oxidation defects. Clin Chim Acta 267:143–154
Millington DS, Kodo N, Norwood DL, Roe CR (1990) Tandem mass spectrometry: a new method for acylcarnitine profiling with potential for neonatal screening for inborn errors of metabolism. J Inherit Metab Dis 13:321–324
Nennstiel-Ratzel U, Arenz S, Maier EM et al (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 screening. Mol Genet Metab 85:157–159
Nichols MJ, Saavedra-Matiz CA, Pass KA, Caggana M (2008) Novel mutations causing medium chain acyl-CoA dehydrogenase deficiency: under-representation of the common c.985A > G mutation in the New York state population. Am J Med Genet A 146:610–619
Onkenhout W, Venizelos V, van der Poet PFH, van den Heuvel MP, Poorthuis BJ (1995) Identification and quantification of intermediates of unsaturated fatty acid metabolism in plasma of patients with fatty acid oxidation disorders. Clin Chem 41:1467–1474
O’Reilly L, Bross P, Corydon TJ et al (2004) The Y42H mutation in medium-chain acyl-CoA dehydrogenase, which is prevalent in babies identified by MS/MS-based newborn screening, is temperature sensitive. Eur J Biochem 271:4053–4063
Pollitt RJ, Leonard JV (1998) Prospective surveillance study of medium chain acyl-CoA dehydrogenase deficiency in the UK. Arch Dis Child 79:116–119
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(3):241–250, Epub 2010 Apr 8.PMID: 20434380 [PubMed – in process]
Tanaka K, West-Dull A, Hine DG, Lynn TB, Lowe T (1980) Gas-chromatographic method of analysis for urinary organic acids. II. Description of the procedure, and its application to diagnosis of patients with organic acidurias. Clin Chem 26:1847–1853
Tran K, Banerjee S, Li H, Noorani HZ, Mensinkai S, Dooley K (2007) Clinical efficacy and cost-effectiveness of newborn screening for medium chain acyl-CoA dehydrogenase deficiency using tandem mass spectrometry. Clin Biochem 40:235–241
Waddell L, Wiley V, Carpenter K et al (2006) Medium-chain acyl-CoA dehydrogenase deficiency: genotype–biochemical phenotype correlations. Mol Genet Metab 87:32–39
Wilcken B, Haas M, Joy P et al (2007) Outcome of neonatal screening for medium-chain acyl-CoA dehydrogenase deficiency in Australia: a cohort study. Lancet 369:37–42
Wilson CJ, Champion MP, Collins JE, Clayton PT, Leonard JV (1999) Outcome of medium chain acyl-CoA dehydrogenase deficiency after diagnosis. Arch Dis Child 80:459–462
Yokota I, Coates PM, Hale DE, Rinaldo P, Tanaka K (1991) Molecular survey of a prevalent mutation, 985A-to-G transition, and identification of five infrequent mutations in the medium- chain acyl-CoA dehydrogenase (MCAD) gene in 55 patients with MCAD deficiency. Am J Hum Genet 49:1280–1291
Zschocke J, Schulze A, Lindner M et al (2001) Molecular and functional characterisation of mild MCAD deficiency. Hum Genet 108(5):404–408
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This study presents the first published data about neonatal screening for MCADD and evolution of the diagnosed patients in Spain (region of Galicia) describing the prevalence of mutations, two novel mutations and the correlation phenotype–genotype.
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– All the authors have contributed equally to the planning and execution of this work.
– M.L. Couce serves as guarantor for the article, accepts full responsibility for the work and the conduct of the study, had full access to the data, and controlled the decision to publish.
– Competing interest statement: All authors declare that they have no competing interests.
– The authors confirm independence from the sponsors; the content of this article has not been influenced by the sponsors.
– The patients’ parents were fully informed about this study and gave informed voluntary consent to participation.
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Couce, M.L. et al. (2011). Relevance of Expanded Neonatal Screening of Medium-Chain Acyl Co-A Dehydrogenase Deficiency: Outcome of a Decade in Galicia (Spain). In: JIMD Reports - Case and Research Reports, 2011/1. JIMD Reports, vol 1. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2011_28
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DOI: https://doi.org/10.1007/8904_2011_28
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