title: Pyridoxine dependent epilepsy and antiquitin deficiency: clinical and molecular characteristics and recommendations for diagnosis, treatment and follow-up.
abstract: Antiquitin (ATQ) deficiency is the main cause of pyridoxine dependent epilepsy characterized by early onset epileptic encephalopathy responsive to large dosages of pyridoxine. Despite seizure control most patients have intellectual disability. Folinic acid responsive seizures (FARS) are genetically identical to ATQ deficiency. ATQ functions as an aldehyde dehydrogenase (ALDH7A1) in the lysine degradation pathway. Its deficiency results in accumulation of α-aminoadipic semialdehyde (AASA), piperideine-6-carboxylate (P6C) and pipecolic acid, which serve as diagnostic markers in urine, plasma, and CSF. To interrupt seizures a dose of 100 mg of pyridoxine-HCl is given intravenously, or orally/enterally with 30 mg/kg/day. First administration may result in respiratory arrest in responders, and thus treatment should be performed with support of respiratory management. To make sure that late and masked response is not missed, treatment with oral/enteral pyridoxine should be continued until ATQ deficiency is excluded by negative biochemical or genetic testing. Long-term treatment dosages vary between 15 and 30 mg/kg/day in infants or up to 200 mg/day in neonates, and 500 mg/day in adults. Oral or enteral pyridoxal phosphate (PLP), up to 30 mg/kg/day can be given alternatively. Prenatal treatment with maternal pyridoxine supplementation possibly improves outcome. PDE is an organic aciduria caused by a deficiency in the catabolic breakdown of lysine. A lysine restricted diet might address the potential toxicity of accumulating αAASA, P6C and pipecolic acid. A multicenter study on long term outcomes is needed to document potential benefits of this additional treatment. The differential diagnosis of pyridoxine or PLP responsive seizure disorders includes PLP-responsive epileptic encephalopathy due to PNPO deficiency, neonatal/infantile hypophosphatasia (TNSALP deficiency), familial hyperphosphatasia (PIGV deficiency), as well as yet unidentified conditions and nutritional vitamin B6 deficiency. Commencing treatment with PLP will not delay treatment in patients with pyridox(am)ine phosphate oxidase (PNPO) deficiency who are responsive to PLP only.
authors.affiliation: Division of Biochemical Diseases, British Columbia Children's Hospital, University of British Columbia, 4480 Oak Street, Vancouver BC, Canada V6H 3V4. sstockler@cw.bc.ca
authors.forename: Sylvia
authors.initials: S
authors.lastname: Stockler
authors.forename: Barbara
authors.initials: B
authors.lastname: Plecko
authors.forename: Sidney M
authors.initials: SM
authors.lastname: Gospe
authors.forename: Marion
authors.initials: M
authors.lastname: Coulter-Mackie
authors.forename: Mary
authors.initials: M
authors.lastname: Connolly
authors.forename: Clara
authors.initials: C
authors.lastname: van Karnebeek
authors.forename: Saadet
authors.initials: S
authors.lastname: Mercimek-Mahmutoglu
authors.forename: Hans
authors.initials: H
authors.lastname: Hartmann
authors.forename: Gunter
authors.initials: G
authors.lastname: Scharer
authors.forename: Eduard
authors.initials: E
authors.lastname: Struijs
authors.forename: Ingrid
authors.initials: I
authors.lastname: Tein
authors.forename: Cornelis
authors.initials: C
authors.lastname: Jakobs
authors.forename: Peter
authors.initials: P
authors.lastname: Clayton
authors.forename: Johan L K
authors.initials: JL
authors.lastname: Van Hove
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D004827:Epilepsy / Q000175:diagnosis* / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D005500:Follow-Up Studies; D006801:Humans; D017410:Practice Guidelines as Topic; D025101:Vitamin B 6 / Q000627:therapeutic use
chemical_list: D015415:Biomarkers; D025101:Vitamin B 6; C089507:ALDH7A1 protein, human; D000444:Aldehyde Dehydrogenase