Mutations in antiquitin in individuals with pyridoxine-dependent seizures

Philippa B Mills¹, Eduard Struys², Cornelis Jakobs², Barbara Plecko³, Peter Baxter⁴, Matthias Baumgartner⁵, Michèl A A P Willemsen⁶, Heymut Omran⁷, Uta Tacke⁷, Birgit Uhlenberg⁸, Bernhard Weschke⁸ & Peter T Clayton¹

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

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

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

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

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

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

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

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

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 ¹-piperideine-6-carboxylate (P6C)–-aminoadipic semialdehyde (-AASA) dehydrogenase. The accumulating P6C inactivates pyridoxal 5'-phosphate (PLP) by forming a Knoevenagel condensation product. Measurement of urinary -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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