title: Genotypic and phenotypic spectrum of pyridoxine-dependent epilepsy (ALDH7A1 deficiency).
abstract: 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-alpha-aminoadipic semialdehyde/L-Delta1-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-alpha-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-alpha-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.
authors.affiliation: Institute of Child Health, University College London with Great Ormond Street Hospital for Children, National Health Service Trust, London, UK.
authors.forename: Philippa B
authors.initials: PB
authors.lastname: Mills
authors.forename: Emma J
authors.initials: EJ
authors.lastname: Footitt
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Mills
authors.forename: Karin
authors.initials: K
authors.lastname: Tuschl
authors.forename: Sarah
authors.initials: S
authors.lastname: Aylett
authors.forename: Sophia
authors.initials: S
authors.lastname: Varadkar
authors.forename: Cheryl
authors.initials: C
authors.lastname: Hemingway
authors.forename: Neil
authors.initials: N
authors.lastname: Marlow
authors.forename: Janet
authors.initials: J
authors.lastname: Rennie
authors.forename: Peter
authors.initials: P
authors.lastname: Baxter
authors.forename: Olivier
authors.initials: O
authors.lastname: Dulac
authors.forename: Rima
authors.initials: R
authors.lastname: Nabbout
authors.forename: William J
authors.initials: WJ
authors.lastname: Craigen
authors.forename: Bernhard
authors.initials: B
authors.lastname: Schmitt
authors.forename: François
authors.initials: F
authors.lastname: Feillet
authors.forename: Ernst
authors.initials: E
authors.lastname: Christensen
authors.forename: Pascale
authors.initials: P
authors.lastname: De Lonlay
authors.forename: Mike G
authors.initials: MG
authors.lastname: Pike
authors.forename: M Imelda
authors.initials: MI
authors.lastname: Hughes
authors.forename: Eduard A
authors.initials: EA
authors.lastname: Struys
authors.forename: Cornelis
authors.initials: C
authors.lastname: Jakobs
authors.forename: Sameer M
authors.initials: SM
authors.lastname: Zuberi
authors.forename: Peter T
authors.initials: PT
authors.lastname: Clayton
mesh_terms: D015074:2-Aminoadipic Acid / Q000031:analogs & derivatives / Q000652:urine; D000444:Aldehyde Dehydrogenase / Q000172:deficiency* / Q000235:genetics* / Q000652:urine; D015415:Biomarkers / Q000652:urine; D004827:Epilepsy / Q000188:drug therapy / Q000235:genetics* / Q000652:urine; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D020125:Mutation, Missense; D010641:Phenotype; D011736:Pyridoxine / Q000627:therapeutic use*
chemical_list: D015415:Biomarkers; D015074:2-Aminoadipic Acid; C000061:allysine; C089507:ALDH7A1 protein, human; D000444:Aldehyde Dehydrogenase; D011736:Pyridoxine