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Genetic basis of alpha-aminoadipic and alpha-ketoadipic aciduria

  • Original Article
  • Published:
Journal of Inherited Metabolic Disease

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.

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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.

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Authors and Affiliations

  1. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, Box 1498, New York, NY, 10029, USA

    Jacob Hagen & Sander M. Houten

  2. Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, Box 1498, New York, NY, 10029, USA

    Jacob Hagen & Sander M. Houten

  3. Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands

    Heleen te Brinke, Ronald J. A. Wanders, Marinus Duran, Hans R. Waterham & Sander M. Houten

  4. Department of Pediatrics, Emma Children’s Hospital, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands

    Ronald J. A. Wanders, Marinus Duran, Hans R. Waterham & Sander M. Houten

  5. Department of Clinical Genetics, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands

    Alida C. Knegt

  6. Department of Pediatrics, Erasmus MC, University Medical Center, Rotterdam, The Netherlands

    Esmee Oussoren

  7. Department of Clinical Genetics, Center for Lysosomal and Metabolic Diseases, Erasmus MC, University Medical Center, Rotterdam, The Netherlands

    A. Jeannette M. Hoogeboom & George J. G. Ruijter

  8. Laboratory of Clinical Biochemistry and Metabolism, University Children’s Hospital Freiburg, Freiburg, Germany

    Daniel Becker & Jörn Oliver Sass

  9. University Children’s Hospital Freiburg, Freiburg, Germany

    Karl Otfried Schwab

  10. University Children’s Hospital Bonn, Bonn, Germany

    Ingo Franke

  11. Department of Natural Sciences, Bonn-Rhein-Sieg University of Applied Sciences, Rheinbach, Germany

    Jörn Oliver Sass

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  1. Jacob Hagen
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  2. Heleen te Brinke
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  3. Ronald J. A. Wanders
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  8. Daniel Becker
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  14. Sander M. Houten
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Corresponding author

Correspondence to Sander M. Houten.

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Communicated by: Carla E. Hollak

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Hagen, J., te Brinke, H., Wanders, R.J.A. et al. Genetic basis of alpha-aminoadipic and alpha-ketoadipic aciduria. J Inherit Metab Dis 38, 873–879 (2015). https://doi.org/10.1007/s10545-015-9841-9

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  • DOI: https://doi.org/10.1007/s10545-015-9841-9

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