title: Lysine restricted diet for pyridoxine-dependent epilepsy: first evidence and future trials.
abstract: OBJECTIVE
  To evaluate the efficacy and safety of dietary lysine restriction as an adjunct to pyridoxine therapy on biochemical parameters, seizure control, and developmental/cognitive outcomes in children with pyridoxine-dependent epilepsy (PDE) caused by antiquitin (ATQ) deficiency.
  
  
  METHODS
  In this observational study, seven children with confirmed ATQ deficiency were started on dietary lysine restriction with regular nutritional monitoring. Biochemical outcomes were evaluated using pipecolic acid and α-aminoadipic semialdehyde (AASA) levels in body fluids; developmental/cognitive outcomes were evaluated using age-appropriate tests and parental observations.
  
  
  RESULTS
  Lysine restriction was well tolerated with good compliance; no adverse events were reported. Reduction in biomarker levels (measurement of the last value before and first value after initiation of dietary lysine restriction) ranged from 20 to 67% for plasma pipecolic acid, 13 to 72% for urinary AASA, 45% for plasma AASA and 42% for plasma P6C. For the 1 patient in whom data were available and who showed clinical deterioration upon interruption of diet, cerebrospinal fluid levels decreased by 87.2% for pipecolic acid and 81.7% for AASA. Improvement in age-appropriate skills was observed in 4 out of 5 patients showing pre-diet delays, and seizure control was maintained or improved in 6 out 7 children.
  
  
  CONCLUSIONS
  This observational study provides Level 4 evidence that lysine restriction is well tolerated with significant decrease of potentially neurotoxic biomarkers in different body compartments, and with the potential to improve developmental outcomes in children with PDE caused by ATQ deficiency. To generate a strong level of evidence before this potentially burdensome dietary therapy becomes the mainstay treatment, we have established: an international PDE consortium to conduct future studies with an all-inclusive integrated study design; a website containing up-to-date information on PDE; a methodological toolbox; and an online registry to facilitate the participation of interested physicians, scientists, and families in PDE research.
authors.affiliation: Division of Biochemical Diseases, Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, Canada.
authors.forename: Clara D M
authors.initials: CD
authors.lastname: van Karnebeek
authors.forename: Hans
authors.initials: H
authors.lastname: Hartmann
authors.forename: Sravan
authors.initials: S
authors.lastname: Jaggumantri
authors.forename: Levinus A
authors.initials: LA
authors.lastname: Bok
authors.forename: Barb
authors.initials: B
authors.lastname: Cheng
authors.forename: Mary
authors.initials: M
authors.lastname: Connolly
authors.forename: Curtis R
authors.initials: CR
authors.lastname: Coughlin
authors.forename: Anibh M
authors.initials: AM
authors.lastname: Das
authors.forename: Sidney M
authors.initials: SM
authors.lastname: Gospe
authors.forename: Cornelis
authors.initials: C
authors.lastname: Jakobs
authors.forename: Johanna H
authors.initials: JH
authors.lastname: van der Lee
authors.forename: Saadet
authors.initials: S
authors.lastname: Mercimek-Mahmutoglu
authors.forename: Uta
authors.initials: U
authors.lastname: Meyer
authors.forename: Eduard
authors.initials: E
authors.lastname: Struys
authors.forename: Graham
authors.initials: G
authors.lastname: Sinclair
authors.forename: Johan
authors.initials: J
authors.lastname: Van Hove
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Collet
authors.forename: Barbara R
authors.initials: BR
authors.lastname: Plecko
authors.forename: Sylvia
authors.initials: S
authors.lastname: Stockler
mesh_terms: D015074:2-Aminoadipic Acid / Q000031:analogs & derivatives / Q000097:blood / Q000134:cerebrospinal fluid / Q000652:urine; D000444:Aldehyde Dehydrogenase / Q000172:deficiency / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D003071:Cognition; D004032:Diet; D004827:Epilepsy / Q000178:diet therapy* / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D005260:Female; D006801:Humans; D007223:Infant; D008137:Longitudinal Studies; D008239:Lysine / Q000008:administration & dosage*; D008297:Male; D010875:Pipecolic Acids / Q000097:blood / Q000134:cerebrospinal fluid / Q000652:urine; D011736:Pyridoxine / Q000627:therapeutic use
chemical_list: D010875:Pipecolic Acids; D015074:2-Aminoadipic Acid; C000061:allysine; C089507:ALDH7A1 protein, human; D000444:Aldehyde Dehydrogenase; C031345:pipecolic acid; D008239:Lysine; D011736:Pyridoxine