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Mutations in antiquitin in individuals with pyridoxine-dependent seizures

Nature Medicine volume 12, pages 307–309 (2006)Cite this article

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Abstract

We show here that children with pyridoxine-dependent seizures (PDS) have mutations in the ALDH7A1 gene, which encodes antiquitin; these mutations abolish the activity of antiquitin as a Δ1-piperideine-6-carboxylate (P6C)–α-aminoadipic semialdehyde (α-AASA) dehydrogenase. The accumulating P6C inactivates pyridoxal 5′-phosphate (PLP) by forming a Knoevenagel condensation product. Measurement of urinary α-AASA provides a simple way of confirming the diagnosis of PDS and ALDH7A1 gene analysis provides a means for prenatal diagnosis.

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Figure 1: Catabolism of (a) proline and (b) L-pipecolic acid showing the structures of Δ1-pyrroline-5-carboxylate (P5C) and Δ1-piperideine-6-carboxylate (P6C).
Figure 2: Mutations in ALDH7A1 and formation of complexes between PLP and P6C.

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Change history

  • 24 February 2006

    1) References in text and at the end of the document were incorrect, and changes had to be made. 2) In the main text, a symbol (representing a mutation) was written incorrectly. 3) The files for Supplementary Methods, Supplementary Table 1 and Supplementary Figure 2 converted incorrectly to PDF format from Word, and must be replaced.

Notes

  1. Note: In the version of this article initially published online, some references were cited incorrectly, and the reference list was numbered incorrectly. One mutation was also written incorrectly (“Y308X” should have been “Y380X”), and symbols were missing from the supplementary information. The errors have been corrected for all versions of the article.

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Acknowledgements

This work was funded in part by the Horst Bickel Prize (sponsored by SHS Gesellschaft für klinische Ernähhrung mbH, Heilbronn, Germany). Research at the University College London Institute of Child Health and Great Ormond Street Hospital for Children National Health Service (NHS) Trust benefits from research and development funding received from the NHS Executive. We are grateful to K. Pearce and L. Bland for their skillful operation of the MegaBACE sequencer within the London IDEAS Genetics Knowledge Park, to K. Tuschl and C. Beesley for their technical assistance and to H. ten Brink for his assistance in the preparation of the P6C–α-aminoadipic semialdehyde.

Author information

Authors and Affiliations

  1. Institute of Child Health, University College London with Great Ormond Street Hospital for Children National Health Service Trust, 30 Guilford Street, London, UK

    Philippa B Mills & Peter T Clayton

  2. Department of Clinical Chemistry, Metabolic Unit, VU University Medical Center, De Boelelaan 1117, Amsterdam, 1081 HV, The Netherlands

    Eduard Struys & Cornelis Jakobs

  3. Department of Pediatrics, University Hospital Graz, Auenbruggerplatz 30, Graz, A-8036, Austria

    Barbara Plecko

  4. Sheffield Children's Hospital, Western Bank, Sheffield, SI0 2TH, UK

    Peter Baxter

  5. Division of Metabolism and Molecular Pediatrics, University Children's Hospital, Steinwiesstr. 75, Zürich, CH-8032, Switzerland

    Matthias Baumgartner

  6. Department of Pediatric Neurology, University Medical Center, Nijmegen, 9101, Nijmegen, 6500 HB, The Netherlands

    Michèl A A P Willemsen

  7. Department of Neuropediatrics, Albert-Ludwigs University of Freiburg, Freiburg im Breisgau, 79106, Germany

    Heymut Omran & Uta Tacke

  8. Department of Neuropediatrics, Charité Medical School, Augustenburger Platzl, Berlin, D-13353, Germany

    Birgit Uhlenberg & Bernhard Weschke

Authors
  1. Philippa B Mills
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  2. Eduard Struys
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  4. Barbara Plecko
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  6. Matthias Baumgartner
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  7. Michèl A A P Willemsen
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  8. Heymut Omran
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  9. Uta Tacke
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  10. Birgit Uhlenberg
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  11. Bernhard Weschke
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  12. Peter T Clayton
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Corresponding author

Correspondence to Peter T Clayton.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Mutations found in the human ALDH7A1 gene. (PDF 36 kb)

Supplementary Fig. 2

Schematic representation of human ALDH7A1 showing positions of mutations. (PDF 20 kb)

Supplementary Table 1

Subject details. (PDF 132 kb)

Supplementary Table 2

Primers and PCR conditions required for the amplification of the human ALDH7A1 gene. (PDF 15 kb)

Supplementary Table 3

Summary of mutations found in antiquitin. (PDF 20 kb)

Supplementary Table 4

Prediction of the effect of splice site mutations detected in PDS patients using the human splice site prediction using neural networks program. (PDF 15 kb)

Supplementary Methods (PDF 101 kb)

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Mills, P., Struys, E., Jakobs, C. et al. Mutations in antiquitin in individuals with pyridoxine-dependent seizures. Nat Med 12, 307–309 (2006). https://doi.org/10.1038/nm1366

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