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Genotypic and phenotypic spectrum of pyridoxine-dependent epilepsy (ALDH7A1 deficiency)

Mills, Philippa B. ; Footitt, Emma J. ; Mills, Kevin A. ; Tuschl, Karin ; Aylett, Sarah ; Varadkar, Sophia ; Hemingway, Cheryl ; Marlow, Neil ; Rennie, Janet ; Baxter, Peter ; Dulac, Olivier ; Nabbout, Rima ; Craigen, William J. ; Schmitt, Bernhard ; Feillet, François ; Christensen, Ernst ; De Lonlay, Pascale ; Pike, Mike G. ; Hughes, M. Imelda ; Struys, Eduard A. ; Jakobs, Cornelis ; Zuberi, Sameer M. ; Clayton, Peter T.

In: Brain, 2010, vol. 133, no. 7, p. 2148-2159

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    Titel
    • Genotypic and phenotypic spectrum of pyridoxine-dependent epilepsy (ALDH7A1 deficiency)
    Autor
    • Mills, Philippa B.. 1 Institute of Child Health, University College London with Great Ormond Street Hospital for Children, National Health Service Trust, London, UK
    • Footitt, Emma J.. 1 Institute of Child Health, University College London with Great Ormond Street Hospital for Children, National Health Service Trust, London, UK
    • Mills, Kevin A.. 1 Institute of Child Health, University College London with Great Ormond Street Hospital for Children, National Health Service Trust, London, UK
    • Tuschl, Karin. 1 Institute of Child Health, University College London with Great Ormond Street Hospital for Children, National Health Service Trust, London, UK
    • Aylett, Sarah. 1 Institute of Child Health, University College London with Great Ormond Street Hospital for Children, National Health Service Trust, London, UK
    • Varadkar, Sophia. 1 Institute of Child Health, University College London with Great Ormond Street Hospital for Children, National Health Service Trust, London, UK
    • Hemingway, Cheryl. 1 Institute of Child Health, University College London with Great Ormond Street Hospital for Children, National Health Service Trust, London, UK
    • Marlow, Neil. 2 Division of Neonatal Medicine, EGA UCL Institute for Women's Health, University College Hospital, London WC1N 1EH, UK
    • Rennie, Janet. 2 Division of Neonatal Medicine, EGA UCL Institute for Women's Health, University College Hospital, London WC1N 1EH, UK
    • Baxter, Peter. 3 Department of Paediatric Neurology, Sheffield Children's National Health Service Foundation Trust, Sheffield S10 5DD, UK
    • Dulac, Olivier. 4 Department of Neuropaediatrics APHP, Centre de Référence Épilepsies Rares, Necker-Enfants Malades Hospital, 75743 Paris, Cedex 15, France
    • Nabbout, Rima. 4 Department of Neuropaediatrics APHP, Centre de Référence Épilepsies Rares, Necker-Enfants Malades Hospital, 75743 Paris, Cedex 15, France
    • Craigen, William J.. 5 Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza MS BCM225 Houston, TX, 77030, USA
    • Schmitt, Bernhard. 6 Department of Neurology, University Children's Hospital, Steinwiesstrasse 75, CH-8032 Zurich, Switzerland
    • Feillet, François. 7 Centre de Référence des Maladies Héréditaires du Métabolisme et INSERM U954, CHU Brabois Enfants, et Faculté de Médecine de Nancy, Allée du Morvan, 54500 Vandoeuvre les Nancy, France
    • Christensen, Ernst. 8 Department of Clinical Genetics, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark
    • De Lonlay, Pascale. 9 Centre Reference of Metabolic Diseases, APHP, University René Descartes, Necker-Enfants Malades Hospital, 149 rue de Sèvres, 75743 Paris, Cedex 15, France
    • Pike, Mike G.. 10 Children's Hospital, Headley Way, Headington, Oxford, OX3 9DU, UK
    • Hughes, M. Imelda. 11 Department of Paediatric Neurology, Royal Manchester Children's Hospital, Hospital Road, Pendlebury, Swinton, Manchester, Lancashire M27 4HA, UK
    • Struys, Eduard A.. 12 Metabolic Unit, Department of Clinical Chemistry, VU University Medical Center Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands
    • Jakobs, Cornelis. 12 Metabolic Unit, Department of Clinical Chemistry, VU University Medical Center Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands
    • Zuberi, Sameer M.. 13 Fraser of Allander Neurosciences Unit, Royal Hospital for Sick Children, Dalnair Street, Yorkhill, Glasgow, G3 8SJ, UK
    • Clayton, Peter T.. 1 Institute of Child Health, University College London with Great Ormond Street Hospital for Children, National Health Service Trust, London, UK
    Dokumententyp
    • Postprint
    Sprache
    • Englisch
    Veröffentlicht in
    • Brain, 2010, vol. 133, no. 7, p. 2148-2159. Oxford University Press
    Andere elektronische Ausgabe
    OAI-PMH-ID
    • oai:doc.rero.ch:304544
    Summary
    Pyridoxine-dependent epilepsy was recently shown to be due to mutations in the ALDH7A1 gene, which encodes antiquitin, an enzyme that catalyses the nicotinamide adenine dinucleotide-dependent dehydrogenation of l-α-aminoadipic semialdehyde/l-Δ1-piperideine 6-carboxylate. However, whilst this is a highly treatable disorder, there is general uncertainty about when to consider this diagnosis and how to test for it. This study aimed to evaluate the use of measurement of urine l-α-aminoadipic semialdehyde/creatinine ratio and mutation analysis of ALDH7A1 (antiquitin) in investigation of patients with suspected or clinically proven pyridoxine-dependent epilepsy and to characterize further the phenotypic spectrum of antiquitin deficiency. Urinary l-α-aminoadipic semialdehyde concentration was determined by liquid chromatography tandem mass spectrometry. When this was above the normal range, DNA sequencing of the ALDH7A1 gene was performed. Clinicians were asked to complete questionnaires on clinical, biochemical, magnetic resonance imaging and electroencephalography features of patients. The clinical spectrum of antiquitin deficiency extended from ventriculomegaly detected on foetal ultrasound, through abnormal foetal movements and a multisystem neonatal disorder, to the onset of seizures and autistic features after the first year of life. Our relatively large series suggested that clinical diagnosis of pyridoxine dependent epilepsy can be challenging because: (i) there may be some response to antiepileptic drugs; (ii) in infants with multisystem pathology, the response to pyridoxine may not be instant and obvious; and (iii) structural brain abnormalities may co-exist and be considered sufficient cause of epilepsy, whereas the fits may be a consequence of antiquitin deficiency and are then responsive to pyridoxine. These findings support the use of biochemical and DNA tests for antiquitin deficiency and a clinical trial of pyridoxine in infants and children with epilepsy across a broad range of clinical scenarios