Mitochondrial fatty acid oxidation defects—remaining challenges

  • Niels Gregersen
  • Brage S. Andresen
  • Christina B. Pedersen
  • Rikke K. J. Olsen
  • Thomas J. Corydon
  • Peter Bross
Komrower Lecture


Mitochondrial fatty acid oxidation defects have been recognized since the early 1970s. The discovery rate has been rather constant, with 3–4 ‘new’ disorders identified every decade and with the most recent example, ACAD9 deficiency, reported in 2007. In this presentation we will focus on three of the ‘old’ defects: medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, riboflavin responsive multiple acyl-CoA dehydrogenation (RR-MAD) deficiency, and short-chain acyl-CoA dehydrogenase (SCAD) deficiency. These disorders have been discussed in many publications and at countless conference presentations, and many questions relating to them have been answered. However, continuing clinical and pathophysiological research has raised many further questions, and new ideas and methodologies may be required to answer these. We will discuss these challenges. For MCAD deficiency the key question is why 80% of symptomatic patients are homozygous for the prevalent ACADM gene variation c.985A > G whereas this is found in only ∼50% of newborns with a positive screen. For RR-MAD deficiency, the challenge is to find the connection between variations in the ETFDH gene and the observed deficiency of a number of different mitochondrial dehydrogenases as well as deficiency of FAD and coenzyme Q10. With SCAD deficiency, the challenge is to elucidate whether ACADS gene variations are disease-associated, especially when combined with other genetic/cellular/environmental factors, which may act synergistically.


Carnitine Missense Variation Glutaric Aciduria Type Electron Transfer Flavoprotein Dicarboxylic Aciduria 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Amendt BA, Greene C, Sweetman L, et al (1987) Short-chain acyl-coenzyme A dehydrogenase deficiency: clinical and biochemical studies in two patients. J Clin Invest 79: 1303–1309.PubMedCrossRefGoogle Scholar
  2. Andresen BS, Bross P, Udvari S, et al (1997) The molecular basis of medium-chain acyl-CoA degydrogenase (MCAD) deficiency in compound heterozygous patients: is there correlation between genotype and phenotype? Hum Mol Genet 6: 695–707.PubMedCrossRefGoogle Scholar
  3. Andresen BS, Olpin S, Poorthuis BJ, 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.PubMedCrossRefGoogle Scholar
  4. 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.PubMedCrossRefGoogle Scholar
  5. Bennett MJ, Gray RG, Isherwood DM, Murphy N, Pollitt RJ (1985) The diagnosis and biochemical investigation of a patient with a short chain fatty acid oxidation defect. J Inherit Metab Dis 8(Supplement 2): 135–136.PubMedCrossRefGoogle Scholar
  6. Bertrand C, Largilliere C, Zabot MT, Mathieu M, Vianey-Saban C (1993) Very long chain acyl-CoA dehydrogenase deficiency: identification of a new inborn error of mitochondrial fatty acid oxidation in fibroblasts. Biochim Biophys Acta 1180: 327–329.PubMedGoogle Scholar
  7. Birkebaek NH, Simonsen H, Gregersen N (2002) Hypoglycaemia and elevated urine ethylmalonic acid in a child homozygous for the short-chain acyl-CoA dehydrogenase 625G > A gene variation. Acta Paediatr 91: 480–482.PubMedCrossRefGoogle Scholar
  8. Bougneres PF, Saudubray JM, Marsac C, Bernard O, Odievre M, Girard J (1981) Fasting hypoglycemia resulting from hepatic carnitine palmitoyl transferase deficiency. J Pediatr 98: 742–746.PubMedGoogle Scholar
  9. Bross P, Andresen BS, Winter V, et al (1993) Co-overexpression of bacterial GroESL chaperonins partly overcomes non-productive folding and tetramer assembly of E. coli-expressed human medium-chain acyl-CoA dehydrogenase (MCAD) carrying the prevalent disease-causing K304E mutation. Biochim Biophys Acta 1182: 264–274.PubMedGoogle Scholar
  10. Bross P, Jespersen C, Jensen TG, et al (1995) Effects of two mutations detected in medium chain acyl-CoA dehydrogenase (MCAD)-deficient patients on folding, oligomer assembly, and stability of MCAD enzyme. J Biol Chem 270: 10284–10290.PubMedCrossRefGoogle Scholar
  11. Chang YF, Imam JS, Wilkinson MF (2007) The nonsense-mediated decay RNA surveillance pathway. Annu Rev Biochem 76: 51–74.PubMedCrossRefGoogle Scholar
  12. Christensen E, Kølvraa S, Gregersen N (1984) Glutaric aciduria type II: evidence for a defect related to the electron transfer flavoprotein or its dehydrogenase. Pediatr Res 18: 663–667.PubMedCrossRefGoogle Scholar
  13. Clayton PT, Eaton S, Aynsley-Green A, et al (2001) Hyperinsulinism in short-chain L-3-hydroxyacyl-CoA dehydrogenase deficiency reveals the importance of beta-oxidation in insulin secretion. J Clin Invest 108: 457–465.PubMedGoogle Scholar
  14. Coates PM, Hale DE, Finocchiaro G, Tanaka K, Winter SC (1988) Genetic deficiency of short-chain acyl-coenzyme A dehydrogenase in cultured fibroblasts from a patient with muscle carnitine deficiency and severe skeletal muscle weakness. J Clin Invest 81: 171–175.PubMedCrossRefGoogle Scholar
  15. Corydon MJ, Gregersen N, Lehnert W, et al (1996) Ethylmalonic aciduria is associated with an amino acid variant of short-chain acyl-coenzyme A dehydrogenase. Pediatr Res 39: 1059–1966.PubMedCrossRefGoogle Scholar
  16. Corydon TJ, Bross P, Jensen TG, et al (1998) Rapid degradation of short-chain acyl-CoA dehydrogenase (SCAD) variants with temperature-sensitive folding defects occur after import into mitochondria. J Biol Chem 273: 13065–13071.PubMedCrossRefGoogle Scholar
  17. Corydon MJ, Vockley J, Rinaldo P, et al (2001) Role of common gene variations in the molecular pathogenesis of short-chain acyl-CoA dehydrogenase deficiency. Pediatr Res 49: 18–23.PubMedCrossRefGoogle Scholar
  18. Corydon TJ, Hansen J, Bross P, Jensen TG (2005) Down-regulation of Hsp60 expression by RNAi impairs folding of medium-chain acyl-CoA dehydrogenase wild-type and disease-associated proteins. Mol Genet Metab 85: 260–270.PubMedCrossRefGoogle Scholar
  19. DiMauro S, DiMauro PM (1973) Muscle carnitine palmityltransferase deficiency and myoglobinuria. Science 182: 929–931.PubMedCrossRefGoogle Scholar
  20. Frerman FE, Goodman SI (1985) Deficiency of electron transfer flavoprotein or electron transfer flavoprotein:ubiquinone oxidoreductase in glutaric acidemia type II fibroblasts. Proc Natl Acad Sci U S A 82: 4517–4520.PubMedCrossRefGoogle Scholar
  21. Gempel K, Topaloglu H, Talim B, et al (2007) The myopathic form of coenzyme Q10 deficiency is caused by mutations in the electron-transferring-flavoprotein dehydrogenase (ETFDH) gene. Brain 130: 2037–2044.PubMedCrossRefGoogle Scholar
  22. Giak SK, Carpenter K, Hammond J, Christodoulou J, Wilcken B (2002) Quantitative fibroblast acylcarnitine profiles in mitochondrial fatty acid beta-oxidation defects: phenotype/metabolite correlations. Mol Genet Metab 76: 327–334.CrossRefGoogle Scholar
  23. Gianazza E, Vergani L, Wait R, et al (2006) Coordinated and reversible reduction of enzymes involved in terminal oxidative metabolism in skeletal muscle mitochondria from a riboflavin-responsive, multiple acyl-CoA dehydrogenase deficiency patient. Electrophoresis 27: 1182–1198.PubMedCrossRefGoogle Scholar
  24. Gregersen N (1985) Riboflavin-responsive defects of beta-oxidation. J Inher Metab Dis 8(Supplement 1): 65–69.PubMedCrossRefGoogle Scholar
  25. Gregersen N (2006) Protein misfolding disorders: pathogenesis and intervention. J Inherit Metab Dis 29: 456–470.PubMedCrossRefGoogle Scholar
  26. Gregersen N, Lauritzen R, Rasmussen K (1976) Suberylglycine excretion in the urine from a patient with dicarboxylic aciduria. Clin Chim Acta 70: 417–425.PubMedCrossRefGoogle Scholar
  27. Gregersen N, Wintzensen H, Christensen SK, Christensen MF, Brandt NJ, Rasmussen K (1982) C6-C10-dicarboxylic aciduria: investigations of a patient with riboflavin responsive multiple acyl-CoA dehydrogenation defects. Pediatr Res 16: 861–868.PubMedCrossRefGoogle Scholar
  28. Gregersen N, Winter VS, Corydon MJ, et al (1998) Identification of four new mutations in the short-chain acyl-CoA dehydrogenase (SCAD) gene in two patients: one of the variant alleles, 511C→T, is present at an unexpectedly high frequency in the general population, as was the case for 625G→A, together conferring susceptibility to ethylmalonic aciduria. Hum Mol Genet 7: 619–627.PubMedCrossRefGoogle Scholar
  29. Gregersen N, Bross P, Andresen BS (2004) Genetic defects in fatty acid beta-oxidation and acyl-CoA dehydrogenases. Eur J Biochem 271: 470–482.PubMedCrossRefGoogle Scholar
  30. Gregersen N, Bross P, Jørgensen MM (2005) Chapter 13.1: protein folding and misfolding: the role of cellular protein quality control systems in inherited disorders. In: Scriver CR, Beaudet AL, Valle D, Sly WS, Vogelstein B, Childs B, Kinzler KW (eds) MMBID-Online ( New York: McGraw-Hill.Google Scholar
  31. Gregersen N, Bross P, Vang S, Christensen JH (2006) Protein misfolding and human disease. Annu Rev Genomics Hum Genet 7: 103–124.PubMedCrossRefGoogle Scholar
  32. Gregory J, Lowe S (2000) National Diet and Nutrition Survey of Young People age 4–18 Years. London: The Stationery Office.Google Scholar
  33. He M, Rutledge SL, Kelly DR, et al (2007) A new genetic disorder in mitochondrial fatty acid beta-oxidation: ACAD9 deficiency. Am J Hum Genet 81: 87–103.PubMedCrossRefGoogle Scholar
  34. Horwich AL, Fenton WA, Chapman E, Farr GW (2007) Two families of chaperonin: physiology and mechanism. Annu Rev Cell Dev Biol 23: 115–145.PubMedCrossRefGoogle Scholar
  35. Howat AJ, Bennett MJ, Variend S, Shaw L (1984) Deficiency of medium chain fatty acylcoenzyme A dehydrogenase presenting as the sudden infant death syndrome. Br Med J (Clin Res Ed) 288: 976.Google Scholar
  36. Iafolla AK, Thompson RJ, Roe CR (1994) Medium-chain acyl-coenzyme A dehydrogenase deficiency - Clinical course in 120 affected children. J Pediatr 124: 409–415.PubMedCrossRefGoogle Scholar
  37. Ijlst L, Wanders RJA, Ushikubo S, Kamijo T, Hashimoto T (1994) Molecular basis of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: identification of the major disease-causing mutation in the alpha-subunit of the mitochondrial trifunctional protein. Bba-Lipid Lipid Metab 1215: 347–350.CrossRefGoogle Scholar
  38. Jackson S, Kler RS, Bartlett K, et al (1992) Combined enzyme defect of mitochondrial fatty acid oxidation. J Clin Invest 90: 1219–1225.PubMedCrossRefGoogle Scholar
  39. Kamijo T, Indo Y, Souri M, et al (1997) Medium chain 3-ketoacyl-coenzyme A thiolase deficiency: a new disorder of mitochondrial fatty acid beta-oxidation. Pediatr Res 42: 569–576.PubMedCrossRefGoogle Scholar
  40. Karpati G, Carpenter S, Engel AG, et al (1975) The syndrome of systemic carnitine deficiency. Clinical, morphologic, biochemical, and pathophysiologic features. Neurology 25: 16–24.PubMedGoogle Scholar
  41. Kieweg V, Krautle FG, Nandy A, et al (1997) Biochemical characterization of purified, human recombinant Lys304→Glu medium-chain acyl-CoA dehydrogenase containing the common disease- causing mutation and comparison with the normal enzyme. Eur J Biochem 246: 548–556.PubMedCrossRefGoogle Scholar
  42. Koeberl DD, Young SP, Gregersen N, et al (2003) Rare disorders of metabolism with elevated butyryl- and isobutyryl-carnitine detected by tandem mass spectrometry newborn screening. Pediatr Res 54: 219–223.PubMedCrossRefGoogle Scholar
  43. Kølvraa S, Gregersen N, Christensen E, Hobolth N (1982) In vitro fibroblast studies in a patient with C6-C10-dicarboxylic aciduria: evidence for a defect in general acyl-CoA dehydrogenase. Clin Chim Acta 126: 53–67.PubMedCrossRefGoogle Scholar
  44. Kragh PM, Pedersen CB, Schmidt SP, et al (2007) Handling of human short-chain acyl-CoA dehydrogenase (SCAD) variant proteins in transgenic mice. Mol Genet Metab 91: 128–137.PubMedCrossRefGoogle Scholar
  45. Kurian MA, Hartley L, Zolkipli Z, et al (2004) Short-chain acyl-CoA dehydrogenase deficiency associated with early onset severe axonal neuropathy. Neuropediatrics 35: 312–316.PubMedCrossRefGoogle Scholar
  46. Maier EM, Liebl B, Roschinger 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.PubMedCrossRefGoogle Scholar
  47. Moat SJ, Ashfield-Watt PA, Powers HJ, Newcombe RG, McDowell IF (2003) Effect of riboflavin status on the homocysteine-lowering effect of folate in relation to the MTHFR (C677T) genotype. Clin Chem 49: 295–302.PubMedCrossRefGoogle Scholar
  48. Nagan N, Kruckeberg KE, Tauscher AL, Snow BK, Rinaldo P, Matern D (2003) The frequency of short-chain acyl-CoA dehydrogenase gene variants in the US population and correlation with the C(4)-acylcarnitine concentration in newborn blood spots. Mol Genet Metab 78: 239–246.PubMedCrossRefGoogle Scholar
  49. Nagao M, Tanaka K (1992) FAD-dependent regulation of transcription, translation, post-translational processing, and post-processing stability of various mitochondrial acyl-CoA dehydrogenases and of electron transfer flavoprotein and the site of holoenzyme formation. J Biol Chem 267: 17925–17932.PubMedGoogle Scholar
  50. Naito E, Indo Y, Tanaka K (1990) Identification of two variant short chain acyl-coenzyme A dehydrogenase alleles, each containing a different point mutation in a patient with short chain acyl-coenzyme A dehydrogenase deficiency. J Clin Invest 85: 1575–1582.PubMedCrossRefGoogle Scholar
  51. Nielsen KB, Sorensen S, Cartegni L, et al (2007) Seemingly neutral polymorphic variants may confer immunity to splicing-inactivating mutations: a synonymous SNP in exon 5 of MCAD protects from deleterious mutations in a flanking exonic splicing enhancer. Am J Hum Genet 80: 416–432.PubMedCrossRefGoogle Scholar
  52. Odaib AA, Shneider BL, Bennett MJ, et al (1998) A defect in the transport of long-chain fatty acids associated with acute liver failure. N Engl J Med 339: 1752–1757.PubMedCrossRefGoogle Scholar
  53. Okun JG, Kolker S, Schulze A, et al (2002) A method for quantitative acylcarnitine profiling in human skin fibroblasts using unlabelled palmitic acid: diagnosis of fatty acid oxidation disorders and differentiation between biochemical phenotypes of MCAD deficiency. Biochim Biophys Acta 1584: 91–98.PubMedGoogle Scholar
  54. Olsen RK, Andresen BS, Christensen E, Bross P, Skovby F, Gregersen N (2003) Clear relationship between ETF/ETFDH genotype and phenotype in patients with multiple acyl-CoA dehydrogenation deficiency. Hum Mutat 22: 12–23.PubMedCrossRefGoogle Scholar
  55. Olsen RK, Olpin SE, Andresen BS, et al (2007) ETFDH mutations as a major cause of riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency. Brain 130: 2045–2054.PubMedCrossRefGoogle Scholar
  56. 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.PubMedCrossRefGoogle Scholar
  57. Pedersen CB, Bross P, Winter VS, et al (2003) Misfolding, degradation, and aggregation of variant proteins. The molecular pathogenesis of short chain acyl-CoA dehydrogenase (SCAD) deficiency. J Biol Chem 278: 47449–47458.PubMedCrossRefGoogle Scholar
  58. Pedersen CB, Kolvraa S, Kolvraa A, et al (2008) The ACADS gene variation spectrum in 114 patients with short-chain acyl-CoA dehydrogenase (SCAD) deficiency is dominated by missense variations leading to protein misfolding at the cellular level. Hum Genet 124: 43–56.PubMedCrossRefGoogle Scholar
  59. Pettersen JE, Jellum E, Eldjarn L (1972) The occurrence of adipic and suberic acid in urine from ketotic patients. Clin Chim Acta 38: 17–24.PubMedCrossRefGoogle Scholar
  60. Przyrembel H, Wendel U, Becker K, et al (1976) Glutaric aciduria type II: report on a previously undescribed metabolic disorder. Clin Chim Acta 66: 227–239.PubMedCrossRefGoogle Scholar
  61. Rhead WJ (2006) Newborn screening for medium-chain acyl-CoA dehydrogenase deficiency: a global perspective. J Inherit Metab Dis 29: 370–377.PubMedCrossRefGoogle Scholar
  62. Rhead WJ, Amendt BA, Fritchman KS, Felts SJ (1983) Dicarboxylic aciduria: deficient [1-14C]octanoate oxidation and medium-chain acyl-CoA dehydrogenase in fibroblasts. Science 221: 73–75.PubMedCrossRefGoogle Scholar
  63. Rhead W, Roettger V, Marshall T, Amendt B (1993) Multiple acyl-coenzyme A dehydrogenation disorder responsive to riboflavin: substrate oxidation, flavin metabolism, and flavoenzyme activities in fibroblasts. Pediatr Res 33: 129–135.PubMedCrossRefGoogle Scholar
  64. Saijo T, Tanaka K (1995) Isoalloxazine ring of FAD is required for the formation of the core in the Hsp60-assisted folding of medium chain acyl-CoA dehydrogenase subunit into the assembly competent conformation in mitochondria. J Biol Chem 270: 1899–1907.PubMedCrossRefGoogle Scholar
  65. Saijo T, Welch WJ, Tanaka K (1994) Intramitochondrial folding and assembly of medium-chain acyl-CoA dehydrogenase (MCAD)—demonstration of impaired transfer of K304E-variant MCAD from its complex with Hsp60 to the native tetramer. J Biol Chem 269: 4401–4408.PubMedGoogle Scholar
  66. Schiff M, Froissart R, Olsen RK, Acquaviva C, Vianey-Saban C (2006) Electron transfer flavoprotein deficiency: functional and molecular aspects. Mol Genet Metab 88: 153–158.PubMedCrossRefGoogle Scholar
  67. Stanley CA, Hale DE, Berry GT, Deleeuw S, Boxer J, Bonnefont JP (1992) Brief report: a deficiency of carnitine-acylcarnitine translocase in the inner mitochondrial membrane. N Engl J Med 327: 19–23.PubMedGoogle Scholar
  68. Stanley CA, Hale DE, Coates PM, et al (1983) Medium-chain acyl-CoA dehydrogenase deficiency in children with non-ketotic hypoglycemia and low carnitine levels. Pediatr Res 17: 877–884.PubMedGoogle Scholar
  69. Tanaka K, Yokota I, Coates PM, et al (1992) Mutations in the medium chain acyl-CoA dehydrogenase (MCAD) gene. Hum Mutat 1: 271–279.PubMedCrossRefGoogle Scholar
  70. Tein I, Elpeleg O, Ben-Zeev B, et al (2008) Short-chain acyl-CoA dehydrogenase gene mutation (c.319C > T) presents with clinical heterogeneity and is candidate founder mutation in individuals of Ashkenazi Jewish origin. Mol Genet Metab 93: 179–189.PubMedCrossRefGoogle Scholar
  71. Ushikubo S, Aoyama T, Kamijo T, et al (1996) Molecular characterization of mitochondrial trifunctional protein deficiency: formation of the enzyme complex is important for stabilization of both alpha- and beta-subunits. Am J Hum Genet 58: 979–988.PubMedGoogle Scholar
  72. van Maldegem BT, Duran M, Wanders RJ, et al (2006) Clinical, biochemical, and genetic heterogeneity in short-chain acyl-coenzyme A dehydrogenase deficiency. JAMA 296: 943–952.PubMedCrossRefGoogle Scholar
  73. Vergani L, Barile M, Angelini C, et al (1999) Riboflavin therapy. Biochemical heterogeneity in two adult lipid storage myopathies. Brain 122 (Pt 12): 2401–2411.PubMedCrossRefGoogle Scholar
  74. 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.PubMedCrossRefGoogle Scholar
  75. Waisbren SE, Levy HL, Noble M, Matern D, Gregersen N, Marsden D (2008) Short-chain acyl-CoA dehydrogenase (SCAD) deficiency: an examination of the medical and neurodevelopmental characteristics of 14 cases identified through newborn screening or clinical symptoms. Mol Genet Metab (in press).Google Scholar
  76. Wanders RJ, Duran M, Ijlst L, de Jager JP, van Gennip AH, Jakobs C, Dorland L, van Sprang FJ (1989) Sudden infant death and long-chain 3-hydroxyacyl-CoA dehydrogenase [letter]. Lancet 2: 52–53.PubMedCrossRefGoogle Scholar
  77. Wang GS, Cooper TA (2007) Splicing in disease: disruption of the splicing code and the decoding machinery. Nat Rev Genet 8: 749–761.PubMedCrossRefGoogle Scholar
  78. Yotsumoto Y, Hasegawa Y, Fukuda S, et al (2008) Clinical and molecular investigations of Japanese cases of glutaric acidemia type 2. Mol Genet Metab 94: 61–67.PubMedCrossRefGoogle Scholar
  79. Zhang J, Frerman FE, Kim JJ (2006) Structure of electron transfer flavoprotein-ubiquinone oxidoreductase and electron transfer to the mitochondrial ubiquinone pool. Proc Natl Acad Sci U S A 103: 16212–16217.PubMedCrossRefGoogle Scholar
  80. Ziadeh R, Hoffman EP, Finegold DN, et al (1995) Medium chain Acyl-CoA dehydrogenase deficiency in Pennsylvania: neonatal screening shows high incidence and unexpected mutation frequencies. Pediatr Res 37: 675–678.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2008

Authors and Affiliations

  • Niels Gregersen
    • 1
    • 3
  • Brage S. Andresen
    • 1
    • 2
  • Christina B. Pedersen
    • 1
  • Rikke K. J. Olsen
    • 1
  • Thomas J. Corydon
    • 2
  • Peter Bross
    • 1
  1. 1.Research Unit for Molecular Medicine, Institute of Clinical Medicine, The Faculty of Health SciencesAarhus UniversityAarhus NDenmark
  2. 2.Institute of Human Genetics, The Faculty of Health SciencesAarhus UniversityAarhus CDenmark
  3. 3.Research Unit for Molecular Medicine, Institute of Clinical MedicineAarhus University, Aarhus University HospitalAarhus NDenmark

Personalised recommendations