Advertisement

Journal of Inherited Metabolic Disease

, Volume 38, Issue 5, pp 873–879 | Cite as

Genetic basis of alpha-aminoadipic and alpha-ketoadipic aciduria

  • Jacob Hagen
  • Heleen te Brinke
  • Ronald J. A. Wanders
  • Alida C. Knegt
  • Esmee Oussoren
  • A. Jeannette M. Hoogeboom
  • George J. G. Ruijter
  • Daniel Becker
  • Karl Otfried Schwab
  • Ingo Franke
  • Marinus Duran
  • Hans R. Waterham
  • Jörn Oliver Sass
  • Sander M. Houten
Original Article

Abstract

Alpha-aminoadipic and alpha-ketoadipic aciduria is an autosomal recessive inborn error of lysine, hydroxylysine, and tryptophan degradation. To date, DHTKD1 mutations have been reported in two alpha-aminoadipic and alpha-ketoadipic aciduria patients. We have now sequenced DHTKD1 in nine patients diagnosed with alpha-aminoadipic and alpha-ketoadipic aciduria as well as one patient with isolated alpha-aminoadipic aciduria, and identified causal mutations in eight. We report nine novel mutations, including three missense mutations, two nonsense mutations, two splice donor mutations, one duplication, and one deletion and insertion. Two missense mutations, one of which was reported before, were observed in the majority of cases. The clinical presentation of this group of patients was inhomogeneous. Our results confirm that alpha-aminoadipic and alpha-ketoadipic aciduria is caused by mutations in DHTKD1, and further establish that DHTKD1 encodes the E1 subunit of the alpha-ketoadipic acid dehydrogenase complex.

Keywords

Splice Donor Site Severe Intellectual Disability Biochemical Phenotype Biotinidase Deficiency Delay Motor Development 
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.

Notes

Acknowledgments

The authors thank Prof. Udo Wendel (Düsseldorf, Germany) for enabling the investigations on patient 8, and Janet Haasjes (Amsterdam, the Netherlands) for DNA sequencing. Financial support by the Jürgen Manchot Stiftung (Düsseldorf, Germany) and by the Müller-Fahnenberg-Stiftung (Freiburg, Germany) is gratefully acknowledged.

Conflict of interest

None.

Supplementary material

10545_2015_9841_MOESM1_ESM.docx (24 kb)
ESM 1 (DOCX 24 kb)

References

  1. Bunik VI, Degtyarev D (2008) Structure-function relationships in the 2-oxo acid dehydrogenase family: substrate-specific signatures and functional predictions for the 2-oxoglutarate dehydrogenase-like proteins. Proteins 71:874–890CrossRefPubMedGoogle Scholar
  2. Casey RE, Zaleski WA, Philp M, Mendelson IS, MacKenzie SL (1978) Biochemical and clinical studies of a new case of alpha-aminoadipic aciduria. J Inherit Metab Dis 1:129–135CrossRefPubMedGoogle Scholar
  3. Danhauser K, Sauer SW, Haack TB et al (2012) DHTKD1 mutations cause 2-aminoadipic and 2-oxoadipic aciduria. Am J Hum Genet 91:1082–1087PubMedCentralCrossRefPubMedGoogle Scholar
  4. de Ligt J, Willemsen MH, van Bon BW et al (2012) Diagnostic exome sequencing in persons with severe intellectual disability. N Engl J Med 367:1921–1929CrossRefPubMedGoogle Scholar
  5. Duran M, Beemer FA, Wadman SK, Wendel U, Janssen B (1984) A patient with alpha-ketoadipic and alpha-aminoadipic aciduria. J Inherit Metab Dis 7:61CrossRefPubMedGoogle Scholar
  6. Duran M, Dorland L, Wadman SK, Berger R (1994) Group tests for selective screening of inborn errors of metabolism. Eur J Pediatr 153:S27–S32CrossRefPubMedGoogle Scholar
  7. Fiermonte G, Dolce V, Palmieri L et al (2001) Identification of the human mitochondrial oxodicarboxylate carrier. Bacterial expression, reconstitution, functional characterization, tissue distribution, and chromosomal location. J Biol Chem 276:8225–8230CrossRefPubMedGoogle Scholar
  8. Fischer MH, Brown RR (1980) Tryptophan and lysine metabolism in alpha-aminoadipic aciduria. Am J Med Genet 5:35–41CrossRefPubMedGoogle Scholar
  9. Fischer MH, Gerritsen T, Opitz JM (1974) Alpha-aminoadipic aciduria, a non-deleterious inborn metabolic defect. Humangenetik 24:265–270PubMedGoogle Scholar
  10. Gilissen C, Hehir-Kwa JY, Thung DT et al (2014) Genome sequencing identifies major causes of severe intellectual disability. Nature 511:344–347CrossRefPubMedGoogle Scholar
  11. Goodman SI, Duran M (2014) Biochemical phenotypes of questionable clinical significance. In Blau N, Duran M, Gibson KM, Dionisi-Vici C eds. Physician’s guide to the diagnosis, treatment, and follow-up of inherited metabolic diseases. Heidelberg: Springer, pp 691–705Google Scholar
  12. Gray RGF, O’Neill EM, Pollitt RJ (1979) α-aminoadipic aciduria: chemical and enzymatic studies. J Inherit Metab Dis 2:89–92CrossRefGoogle Scholar
  13. Guescini M, Sisti D, Rocchi MB, Stocchi L, Stocchi V (2008) A new real-time PCR method to overcome significant quantitative inaccuracy due to slight amplification inhibition. BMC Bioinformatics 9:326PubMedCentralCrossRefPubMedGoogle Scholar
  14. Houten SM, te Brinke H, Denis S et al (2013) Genetic basis of hyperlysinemia. Orphanet J Rare Dis 8:57PubMedCentralCrossRefPubMedGoogle Scholar
  15. Lehnert W (1994) Long-term results of selective screening for inborn errors of metabolism. Eur J Pediatr 153:S9–S13CrossRefPubMedGoogle Scholar
  16. Lormans S, Lowenthal A (1974) Alpha-amino adipic aciduria in an oligophrenic child. Clin Chim Acta 57:97–101CrossRefPubMedGoogle Scholar
  17. Manders AJ, von Oostrom CG, Trijbels JM, Rutten FJ, Kleijer WJ (1981) alpha-Aminoadipic aciduria and persistence of fetal haemoglobin in an oligophrenic child. Eur J Pediatr 136:51–55CrossRefPubMedGoogle Scholar
  18. Peng H, Shinka T, Inoue Y et al (1999) Asymptomatic alpha-ketoadipic aciduria detected during a pilot study of neonatal urine screening. Acta Paediatr 88:911–914CrossRefPubMedGoogle Scholar
  19. Przyrembel H, Bachmann D, Lombeck I et al (1975) Alpha-ketoadipic aciduria, a new inborn error of lysine metabolism; biochemical studies. Clin Chim Acta 58:257–269CrossRefPubMedGoogle Scholar
  20. Sewell AC, Herwig J, Bohles H, Abeling NG, van Gennip AH (1999) Normal kynurenine metabolism in 2-oxoadipic aciduria. J Inherit Metab Dis 22:949–950CrossRefPubMedGoogle Scholar
  21. Takechi T, Okada T, Wakiguchi H et al (1993) Identification of N-acetyl-alpha-aminoadipic acid in the urine of a patient with alpha-aminoadipic and alpha-ketoadipic aciduria. J Inherit Metab Dis 16:119–126CrossRefPubMedGoogle Scholar
  22. Vianey-Liaud C, Divry P, Cotte J, Teyssier G (1985) alpha-Aminoadipic and alpha-ketoadipic aciduria: detection of a new case by a screening program using two-dimensional thin layer chromatography of amino acids. J Inherit Metab Dis 8(Suppl 2):133–134CrossRefPubMedGoogle Scholar
  23. Wendel U, Rudiger HW, Przyrembel H, Bremer HJ (1975) Alpha-ketoadipic aciduria: degradation studies with fibroblasts. Clin Chim Acta 58:271–276CrossRefPubMedGoogle Scholar
  24. Wilcken B, Smith A, Brown DA (1980) Urine screening for aminoacidopathies: is it beneficial? Results of a long-term follow-up of cases detected by screening one millon babies. J Pediatr 97:492–497CrossRefPubMedGoogle Scholar
  25. Wilson RW, Wilson CM, Gates SC, Higgins JV (1975) Alpha-ketoadipic aciduria: a description of a new metabolic error in lysine-tryptophan degradation. Pediatr Res 9:522–526CrossRefPubMedGoogle Scholar
  26. Wu Y, Williams EG, Dubuis S et al (2014) Multilayered genetic and omics dissection of mitochondrial activity in a mouse reference population. Cell 158:1415–1430CrossRefPubMedGoogle Scholar
  27. Xu WY, Gu MM, Sun LH et al (2012) A nonsense mutation in DHTKD1 causes Charcot-Marie-Tooth disease type 2 in a large Chinese pedigree. Am J Hum Genet 91:1088–1094PubMedCentralCrossRefPubMedGoogle Scholar
  28. Xu W, Zhu H, Gu M et al (2013) DHTKD1 is essential for mitochondrial biogenesis and function maintenance. FEBS Lett 587:3587–3592CrossRefPubMedGoogle Scholar
  29. Yang Y, Muzny DM, Reid JG et al (2013) Clinical whole-exome sequencing for the diagnosis of mendelian disorders. N Engl J Med 369:1502–1511PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© SSIEM 2015

Authors and Affiliations

  • Jacob Hagen
    • 1
    • 2
  • Heleen te Brinke
    • 3
  • Ronald J. A. Wanders
    • 3
    • 4
  • Alida C. Knegt
    • 5
  • Esmee Oussoren
    • 6
  • A. Jeannette M. Hoogeboom
    • 7
  • George J. G. Ruijter
    • 7
  • Daniel Becker
    • 8
  • Karl Otfried Schwab
    • 9
  • Ingo Franke
    • 10
  • Marinus Duran
    • 3
    • 4
  • Hans R. Waterham
    • 3
    • 4
  • Jörn Oliver Sass
    • 8
    • 11
  • Sander M. Houten
    • 1
    • 2
    • 3
    • 4
  1. 1.Department of Genetics and Genomic SciencesIcahn School of Medicine at Mount SinaiNew YorkUSA
  2. 2.Icahn Institute for Genomics and Multiscale BiologyIcahn School of Medicine at Mount SinaiNew YorkUSA
  3. 3.Department of Clinical Chemistry, Laboratory Genetic Metabolic DiseasesUniversity of AmsterdamAmsterdamThe Netherlands
  4. 4.Department of Pediatrics, Emma Children’s HospitalUniversity of AmsterdamAmsterdamThe Netherlands
  5. 5.Department of Clinical Genetics, Academic Medical CenterUniversity of AmsterdamAmsterdamThe Netherlands
  6. 6.Department of PediatricsErasmus MC, University Medical CenterRotterdamThe Netherlands
  7. 7.Department of Clinical Genetics, Center for Lysosomal and Metabolic Diseases, Erasmus MCUniversity Medical CenterRotterdamThe Netherlands
  8. 8.Laboratory of Clinical Biochemistry and MetabolismUniversity Children’s Hospital FreiburgFreiburgGermany
  9. 9.University Children’s Hospital FreiburgFreiburgGermany
  10. 10.University Children’s Hospital BonnBonnGermany
  11. 11.Department of Natural SciencesBonn-Rhein-Sieg University of Applied SciencesRheinbachGermany

Personalised recommendations