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Orphanet Journal of Rare Diseases
Published in: Orphanet Journal of Rare Diseases 1/2013

Open Access 01-12-2013 | Research

Newborn screening for medium-chain acyl-CoA dehydrogenase deficiency: regional experience and high incidence of carnitine deficiency

Authors: Maria Luz Couce, Paula Sánchez-Pintos, Luisa Diogo, Elisa Leão-Teles, Esmeralda Martins, Helena Santos, Maria Amor Bueno, Carmen Delgado-Pecellín, Daisy E Castiñeiras, José A Cocho, Judit García-Villoria, Antonia Ribes, José M Fraga, Hugo Rocha

Published in: Orphanet Journal of Rare Diseases | Issue 1/2013

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Abstract

Background

Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is the most common inherited defect in the mitochondrial fatty acid oxidation pathway, resulting in significant morbidity and mortality in undiagnosed patients.
Newborn screening (NBS) has considerably improved MCADD outcome, but the risk of complication remains in some patients. The aim of this study was to evaluate the relationship between genotype, biochemical parameters and clinical data at diagnosis and during follow-up, in order to optimize monitoring of these patients.

Methods

We carried out a multicenter study in southwest Europe, of MCADD patients detected by NBS. Evaluated NBS data included free carnitine (C0) and the acylcarnitines C8, C10, C10:1 together with C8/C2 and C8/C10 ratios, clinical presentation parameters and genotype, in 45 patients. Follow-up data included C0 levels, duration of carnitine supplementation and occurrence of metabolic crises.

Results

C8/C2 ratio and C8 were the most accurate biomarkers of MCADD in NBS. We found a high number of patients homozygous for the prevalent c.985A > G mutation (75%). Moreover, in these patients C8, C8/C10 and C8/C2 were higher than in patients with other genotypes, while median value of C0 was significantly lower (23 μmol/L vs 36 μmol/L).
The average follow-up period was 43 months. To keep carnitine levels within the normal range, carnitine supplementation was required in 82% of patients, and for a longer period in patients homozygotes for the c.985A>G mutation than in patients with other genotypes (average 31 vs 18 months). Even with treatment, median C0 levels remained lower in homozygous patients than in those with other genotypes (14 μmol/L vs 22 μmol/L).
Two patients died and another three suffered a metabolic crisis, all of whom were homozygous for the c.985 A>G mutation.

Conclusions

Our data show a direct association between homozygosity for c.985A>G and lower carnitine values at diagnosis, and a higher dose of carnitine supplementation for maintenance within the normal range. This study contributes to a better understanding of the relationship between genotype and phenotype in newborn patients with MCADD detected through screening which could be useful in improving follow-up strategies and clinical outcome.
Appendix
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Literature
1.
Houten SM, Wanders RJA: A general introduction to the biochemistry of mitochondrial fatty acid oxidation. J Inherit Metab Dis. 2010, 33: 469-477. 10.1007/s10545-010-9061-2.PubMedCentralPubMedCrossRef
2.
Rhead WJ: Newborn screening for medium-chain acyl-CoA dehydrogenase deficiency: a global perspective. J Inherit Metab Dis. 2006, 29: 370-377. 10.1007/s10545-006-0292-1.PubMedCrossRef
3.
Maier EM, Liebl B, Röschinger W, Nennstiel-Ratzel U, Fingerhut R, Olgemöller B, Busch U, Krone N, Kries R, Roscher AA: Population spectrum of ACADM genotypes correlated to biochemical phenotypes in newborn screening for medium-chain acyl-CoA dehydrogenase deficiency. Hum Mutat. 2005, 25: 443-452. 10.1002/humu.20163.PubMedCrossRef
4.
Andresen BJ, Lund AM, Hougaard DM, Christensen E, Gahrn B, Christensen M, Bross P, Vested A, Simonsen H, Skogstrand K, Olpin S, Brandt NJ, Skovby F, Nørgaard-Pedersen B, Gregersen N: MCAD deficiency in Denmark. Mol Genet Metab. 2012, 106: 175-188. 10.1016/j.ymgme.2012.03.018.PubMedCrossRef
5.
Leydiker KB, Neidich JA, Lorey F, Barr EM, Puckett RL, Lobo RM, Abdenur JE: Maternal medium-chain acyl-CoA dehydrogenase deficiency identified by newborn screening. Mol Genet Metab. 2011, 103: 92-95. 10.1016/j.ymgme.2011.01.011.PubMedCrossRef
6.
Hoflack M, Caruba C, Pitelet G, Hass H, Mas JC, Paquis V, Berard E: Infant coma in the emergency department: 2 cases of MCAD deficiency. Arch Pediatr. 2010, 17: 1074-1077. 10.1016/j.arcped.2010.03.011.PubMedCrossRef
7.
Yusupov R, Finegold DN, Naylor EW, Sahai I, Wainsbren S, Levy HL: Sudden death in medium chain acyl-coenzyme a dehydrogenase deficiency (MCADD) despite newborn screening. Mol Genet Metab. 2010, 101: 33-39. 10.1016/j.ymgme.2010.05.007.PubMedCrossRef
8.
Wilcken B, Haas M, Joy P, Wiley V, Chaplin M, Black C, Fletcher J, McGill J, Boneh A: Outcome of neonatal screening for medium-chain acyl-CoA dehydrogenase deficiency in Australia: a cohort study. Lancet. 2007, 369: 37-42. 10.1016/S0140-6736(07)60029-4.PubMedCrossRef
9.
Schatz UA, Ensenauer R: The clinical manifestation of MCAD deficiency: challenges towards adulthood in the screened population. J Inherit Metab Dis. 2010, 33: 513-520. 10.1007/s10545-010-9115-5.PubMedCrossRef
10.
Maclean K, Rasiah VS, Kirk EPE, Carpenter K, Cooper S, Lui K, Oei J: Pulmonary haemorrhage and cardiac dysfunction in a neonate with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency. Acta Paediatr. 2005, 94: 114-6. 10.1080/08035250410018300.PubMedCrossRef
11.
Rice G, Brazelton T, Maginot K, Srinivasan S, Hollman G, Wolff JA: Medium chain acyl-coenzyme A dehydrogenase deficiency in a neonate. N Engl J Med. 2007, 357: 1781-10.1056/NEJMc071277.PubMedCrossRef
12.
Yusuf K, Jirapradittha J, Amin HJ, Yu W, Hasan SU: Neonatal ventricular tachyarrhythmias in medium chain acyl-CoA dehydrogenase deficiency. Neonatology. 2010, 98: 260-264. 10.1159/000295713.PubMedCrossRef
13.
Meng X, Mao W, Sun W, Li L, Zhan S, Wu X, Huang Z, Zhang X, Ma Y, Wang Y: Sleep induces abnormal motor behaviors caused by medium-chain acyl-CoA dehydrogenase deficiency: a case report. Sleep Med. 2012, 13: 115-117.PubMedCrossRef
14.
Grosse SD, Khoury MJ, Greene CL, Crider KS, Pollit RJ: The epidemiology of medium chain acyl-CoA dehydrogenase deficiency: an update. Genet Med. 2006, 8: 205-212. 10.1097/01.gim.0000204472.25153.8d.PubMedCrossRef
15.
Derks TG, Rejngoud DJ, Waterham HR, Gerver WJ, van den Berg M, Sauer PJ, Smit GP: The natural history of medium-chain acyl CoA dehydrogenase deficiency in The Netherlands: clinical presentation and outcome. J Pediatr. 2006, 148: 665-70. 10.1016/j.jpeds.2005.12.028.PubMedCrossRef
16.
Wilcken B: Fatty acid oxidation disorders: outcome and long-term prognosis. J Inherit Metab Dis. 2010, 33: 501-506. 10.1007/s10545-009-9001-1.PubMedCrossRef
17.
Lindner M, Hoffman GF, Matern D: Newborn screening for disorders of fatty-acid oxidation: experience and recommendations from an expert meeting. J Inherit Metab Dis. 2010, 33: 521-526. 10.1007/s10545-010-9076-8.PubMedCrossRef
18.
Nennstiel-Ratzel U, Arenz S, Maier EM, Knerr I, Baumkötter J, Röschinger W, Liebl B, Hadorn HB, Roscher AA, von Kries R: 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. 2005, 85: 157-59. 10.1016/j.ymgme.2004.12.010.PubMedCrossRef
19.
Cyriac J, Venkatesh V, Gupta C: A fatal neonatal presentation of medium-chain acyl coenzyme A dehydrogenase deficiency. J Int Med Res. 2008, 36: 609-610. 10.1177/147323000803600330.PubMedCrossRef
20.
Oerton J, Khalid JM, Besley G, Dalton RN, Downing M, Green A, Henderson M, Krywawych S, Leonard J, Andresen BS, Dezateux C: Newborn screening for medium chain acyl-CoA dehydrogenase deficiency in England: prevalence, predictive value and test validity based on 1.5million screened babies. J Med Screen. 2011, 18: 173-181. 10.1258/jms.2011.011086.PubMedCentralPubMedCrossRef
21.
Frazier D, Millington D, McCandless S, Koebert D, Weavil S, Chaing S, Boney A, Moore E, Frazier DM: The tandem mass spectrometry newborn screening experience in North Carolina: 1997-2005. J Inherit Metab Dis. 2006, 29: 76-85. 10.1007/s10545-006-0228-9.PubMedCrossRef
22.
Touw CM, Smit GP, de Vries M, de Klerk JB, Bosch AM, Visser G, Mulder MF, Rubio-Gozalbo ME, Elvers B, Niezen-Koning KE, Wanders RJ, Waterham HR, Reijngoud DJ, Derks TG: Risk stratification by residual enzyme activity after newborn screening for medium-chain acyl-CoA dehydrogenase deficiency: data from a cohort study. Orphanet J Rare Dis. 2012, 7: 30-10.1186/1750-1172-7-30.PubMedCentralPubMedCrossRef
23.
Blois B, Riddell C, Dooley K, Dyack S: Newborns with C8 acylcarnitine level over the 90th centile have an increased frequency of the common MCAD 985A > G mutation. J Inherit Metab Dis. 2005, 28: 551-556. 10.1007/s10545-005-0551-6.PubMedCrossRef
24.
Couce ML, Castiñeiras DE, Moure JD, Cocho JA, Sánchez-Pintos P, García-Villoria J, Quelhas D, Gregersen N, Andresen BS, Ribes A, Fraga JM: Relevance of expanded neonatal screening of medium-chain acyl Co-A dehydrogenase deficiency: outcome of a decade in Galicia (Spain). JIMD Reports. 2011, 28: 131-136.CrossRef
25.
Arnold GL, Saavedra- Matiz CA, Galvin-Parton PA, Erbe R, DeVicentis E, Kronn D, Mofidi S, Wasserstein M, Pellegrino JE, Levy PA, Adams DJ, Nichols M, Caggana M: Lack of genotype-phenotype correlations and outcome in MCAD deficiency diagnosed by newborn screening in New York State. Mol Genet Metab. 2010, 99: 263-268. 10.1016/j.ymgme.2009.10.188.PubMedCrossRef
26.
McHugh DM, Cameron CA, Abdenur JE, Abdulrahman M, Adair O, Al Nuaimi SA, Ahlman H, Allen JJ, Antonozzi I, Archer S, Grady GF, et al.: Clinical validation of cutoff target ranges in newborn screening of metabolic disorders by tandem mass spectrometry: a worldwide collaborative project. Genet Med. 2011, 13: 230-254. 10.1097/GIM.0b013e31820d5e67.PubMedCrossRef
27.
Zytkovicz TH, Fitzgerald EF, Marsden D, Larson CA, Shih VE, Johnson DM, Strauss AW, Comeau AM, Eaton RB, Grady GF: Tandem mass spectrometric analysis for amino, organic, and fatty acid disorders in newborn dried bloodspots: a two-year summary from the New England Newborn Screening Program. Clin Chem. 2001, 47: 1945-1955.PubMed
28.
Gregersen N, Andresen BS, Pedersen CB, Olsen RKJ, Corydon TJ, Bross P: Mitochondrial fatty acid oxidation defects-remaining challenges. J Inherit Metab Dis. 2008, 31: 643-657. 10.1007/s10545-008-0990-y.PubMedCrossRef
29.
Gregersen N, Winter V, Curtis D, Deufel T, Mack M, Hendrickx J, Willems PJ, Ponzone A, Parrella T, Ponzone R, et al.: Medium-chain acyl-CoA dehydrogenase deficiency: the prevalent mutation G985 is subject to a strong founder effect from northwestern Europe. Hum Heredity. 1993, 43: 342-50. 10.1159/000154157.PubMedCrossRef
30.
Yokota I, Coates P, Hale DE, Rinaldo P, Tanaka K: Molecular survey of a prevalent mutation, 985 A-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. 1991, 49: 1280-1291.PubMedCentralPubMed
31.
Derks TG, Boer TS, van Assen A, Bos T, Ruiter J, Waterham HR, Niezen-Koning KE, Wanders RJ, Rondeel JM, Loeber JG, Ten Kate LP, Smit GP, Reijngoud DJ: Neonatal screening for medium-chain acyl-CoA dehydrogenase (MCAD) deficiency in The Netherlands: the importance of enzyme analysis to ascertain true MCAD deficiency. J Inherit Metab Dis. 2008, 31: 88-96. 10.1007/s10545-007-0492-3.PubMedCrossRef
32.
Andresen BS, Dobrowolski SF, O’Reilly L, Muenzer J, McCandless SE, Frazier DM, Udvari S, Bross P, Knudsen I, Banas R, Chace DH, Engel P, Naylor EW, Gregersen N: 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. 2001, 68: 108-118.CrossRef
33.
Carpenter K, Wiley V, Sim K, Heath D, Wilcken B: Evaluation of newborn screening for medium chain acyl-CoA dehydrogenase deficiency in 275000 babies. Arch Dis Child Fetal Neonatal Ed. 2001, 85: F105-F109. 10.1136/fn.85.2.F105.PubMedCentralPubMedCrossRef
34.
Kennedy S, Potter BK, Wilson K, Fisher L, Geraghty M, Milburn J, Chakraborty P: The first three years of screening for medium chain acyl-CoA dehydrogenase deficiency (MCADD) by newborn screening Ontario. BMC Pediatr. 2010, 10: 82-10.1186/1471-2431-10-82.PubMedCentralPubMedCrossRef
35.
Nichols MJ, Saavedra-Matiz CA, Kenneth AP, Caggana M: Novel mutations causing medium chain acyl-CoA dehydrogenase deficiency: under representation of the common c.985 A > G mutation in the New York State population. Am J Med Genet A. 2008, 146A: 610-619. 10.1002/ajmg.a.32192.PubMedCrossRef
36.
Zschocke J, Schulze A, Lindner M, Fiesel S, Olgemöller K, Hoffman GF, Penzien J, Ruiter JP, Wanders RJ, Mayatepek E: Molecular and functional characterization of mild MCAD deficiency. Hum Genet. 2001, 108: 404-8. 10.1007/s004390100501.PubMedCrossRef
37.
Hsu H-W, Zytkovicz TH, Comeau AM, Strauss AW, Marsden D, Shih VE, Grady GF, Eaton RB: Spectrum of medium-chain acyl-CoA dehydrogenase deficiency detected by newborn screening. Pediatrics. 2008, 121: 108-114.CrossRef
38.
Waddell L, Wiley V, Carpenter K, Bennetts B, Angel L, Andresen BS, Wilcken B: Medium-chain acyl-CoA dehydrogenase deficiency: genotype-biochemical phenotype correlations. Mol Genet Metab. 2006, 87: 32-39. 10.1016/j.ymgme.2005.09.020.PubMedCrossRef
39.
Duran M, Hofkamp M, Rhead WJ, Saudubray JM, Wadman SK: Sudden child death and “healthy · affected family members with medium-chain acyl-CoA dehydrogenase deficiency. Pediatrics. 1986, 78: 1052-1057.PubMedCrossRef
40.
Wieland OH: Methods of Enzymatic analysis. Volume 8. 3rd edition. Edited by: Bergmeyer HU. Florida: VCH Verlagsgesellschaft, Weinhiem Deerfield Beach; 1965:481-488.
41.
McKinney JT, Longo N, Hahn SH, Matern D, Rinaldo P, Strauss AW, Dobrowolski SF: Rapid, comprehensive screening of the human medium chain acyl-CoA dehydrogenase gene. Mol Genet Metab. 2004, 82: 112-120. 10.1016/j.ymgme.2004.04.004.PubMedCrossRef
42.
Hsu HW, Zytkovicz TH, Comeau AM, Strauss AW, Marsden D, Shih VE, Grady GF, Eaton RB: Spectrum of medium-chain acyl-CoA dehydrogenase deficiency detected by newborn screening. Pediatrics. 2008, 121: e1108-14. 10.1542/peds.2007-1993.PubMedCrossRef
43.
Martinez G, Garcia-Lozano JR, Ribes A, Maldonado MD, Baldellou A, de Pablo R, Nuñez-Roldan A: High risk of medium chain acyl-coenzyme A dehydrogenase deficiency among gypsies. Pediatr Res. 1998, 44: 83-84. 10.1203/00006450-199807000-00013.PubMedCrossRef
44.
Smith EH, Tomas C, McHugh D, Gavrilov D, Raymond K, Rinaldo P, Tortorelli S, Matern D, Highsmith WE, Oglesbee D: Allelic diversity in MCAD deficiency: the biochemical classification of 54 variants identified during 5 years of ACADM sequencing. Mol Genet Metab. 2010, 100: 241-250. 10.1016/j.ymgme.2010.04.001.PubMedCrossRef
45.
Feillet F, Ogier H, Cheillan D, Aquaviva C, Labarthe F, Baruteau J, Chabrol B, de Lonlay P, Valayanopoulos V, Garnotel R, Dobbelaere D, Briand G, Jeannesson E, Vassault A, Vianey-Saban C: SFEIM: Medium-chain acyl-CoA-dehydrogenase (MCAD) deficiency: French consensus for neonatal screening, diagnosis, and management. Arch Pediatr. 2012, 19: 184-193. 10.1016/j.arcped.2011.10.025.PubMedCrossRef
46.
Walter JH: L-carnitine in inborn errors of metabolism: what is the evidence?. J Inherit Metab Dis. 2003, 26: 181-188. 10.1023/A:1024485117095.PubMedCrossRef
47.
Bzduch V, Behulova D, Salingova A, Ponec J, Fabriciova K, Kozak L: Serum free carnitine in medium chain acyl-CoA dehydrogenase deficiency. Bratisl Lek Listy. 2003, 104: 405-407.PubMed
48.
Maier EM, Pongratz J, Muntau AC, Liebl B, Nennstiel-Ratzel U, Busch U, Fingerhut R, Olgemöller B, Roscher AA, Röschinger W: Dissection of biochemical borderline phenotypes in carriers and genetic variants of medium-chain acyl-CoA dehyrogenase deficiency: implications for newborn screening [corrected]. Clin Genet. 2010, 77: 304.CrossRef
49.
Purevsuren J, Kobayashi H, Hasegawa Y, Mushimoto Y, Li H, Fukuda S, Shigematsu Y, Fukao T, Yamaguchi S: A novel molecular aspect of Japanese patients with medium-chain acyl-CoA dehydrogenase deficiency (MCADD): c.449-452delCTGA is a common mutation in Japanese patients with MCADD. Mol Genet Metab. 2009, 96: 77-79. 10.1016/j.ymgme.2008.10.012.PubMedCrossRef
50.
Thodi G, Georgiou V, Molou E, Loukas YL, Dotsikas Y, Biti S, Papadopoulos K, Doulgerakis E: Characterization of the molecular spectrum of Medium-Chain Acyl-CoA Dehydrogenase Deficiency in a Greek newborns cohort: Identification of a novel variant. Clin Biochem. 2012, 45: 116-1172.CrossRef
Metadata
Title
Newborn screening for medium-chain acyl-CoA dehydrogenase deficiency: regional experience and high incidence of carnitine deficiency
Authors
Maria Luz Couce
Paula Sánchez-Pintos
Luisa Diogo
Elisa Leão-Teles
Esmeralda Martins
Helena Santos
Maria Amor Bueno
Carmen Delgado-Pecellín
Daisy E Castiñeiras
José A Cocho
Judit García-Villoria
Antonia Ribes
José M Fraga
Hugo Rocha
Publication date
01-12-2013
Publisher
BioMed Central
Published in
Orphanet Journal of Rare Diseases / Issue 1/2013
Electronic ISSN: 1750-1172
DOI
https://doi.org/10.1186/1750-1172-8-102

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