title: Defects in fatty acid amide hydrolase 2 in a male with neurologic and psychiatric symptoms.
abstract: BACKGROUND
  Fatty acid amide hydrolase 2 (FAAH2) is a hydrolase that mediates the degradation of endocannabinoids in man. Alterations in the endocannabinoid system are associated with a wide variety of neurologic and psychiatric conditions, but the phenotype and biochemical characterization of patients with genetic defects of FAAH2 activity have not previously been described. We report a male with autistic features with an onset before the age of 2 years who subsequently developed additional features including anxiety, pseudoseizures, ataxia, supranuclear gaze palsy, and isolated learning disabilities but was otherwise cognitively intact as an adult.
  
  
  RESULTS
  Whole exome sequencing identified a rare missense mutation in FAAH2, hg19: g.57475100G > T (c.1372G > T) resulting in an amino acid change (p.Ala458Ser), which was Sanger confirmed as maternally inherited and absent in his healthy brother. Alterations in lipid metabolism with abnormalities of the whole blood acyl carnitine profile were found. Biochemical and molecular modeling studies confirmed that the p.Ala458Ser mutation results in partial inactivation of FAAH2. Studies in patient derived fibroblasts confirmed a defect in FAAH2 activity resulting in altered levels of endocannabinoid metabolites.
  
  
  CONCLUSIONS
  We propose that genetic alterations in FAAH2 activity contribute to neurologic and psychiatric disorders in humans.
authors.affiliation: Departments of Medicine, University of British Columbia, Vancouver, Canada. Sandra.Sirrs@vch.ca.
authors.forename: Sandra
authors.initials: S
authors.lastname: Sirrs
authors.affiliation: Departments of Pediatrics, University of British Columbia, Vancouver, Canada. cvankarnebeek@cw.bc.ca.|Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, Canada. cvankarnebeek@cw.bc.ca.|Treatable Intellectual Disability Endeavour in British Columbia (TIDE-BC), Vancouver, Canada. cvankarnebeek@cw.bc.ca.|Division of Biochemical Diseases, Rm K3-201, Department of Pediatrics, B.C. Children's Hospital, Centre for Molecular Medicine & Therapeutics, University of British Columbia, 4480 Oak Street, Vancouver, B.C. V6H 3V4, Canada. cvankarnebeek@cw.bc.ca.
authors.forename: Clara D M
authors.initials: CD
authors.lastname: van Karnebeek
authors.affiliation: Department of Anesthesiology, Stony Brook University, Stony Brook, NY, 11794-8480, USA. xiaoxue.peng@stonybrook.edu.
authors.forename: Xiaoxue
authors.initials: X
authors.lastname: Peng
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, Canada. casper@cmmt.ubc.ca.|Treatable Intellectual Disability Endeavour in British Columbia (TIDE-BC), Vancouver, Canada. casper@cmmt.ubc.ca.|Department of Medical Genetics, University of British Columbia, Vancouver, Canada. casper@cmmt.ubc.ca.
authors.forename: Casper
authors.initials: C
authors.lastname: Shyr
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, Canada. maja@cmmt.ubc.ca.|Treatable Intellectual Disability Endeavour in British Columbia (TIDE-BC), Vancouver, Canada. maja@cmmt.ubc.ca.|Department of Medical Genetics, University of British Columbia, Vancouver, Canada. maja@cmmt.ubc.ca.
authors.forename: Maja
authors.initials: M
authors.lastname: Tarailo-Graovac
authors.affiliation: Departments of Biological and Computing Sciences, University of Alberta, Edmonton, T6G 2E8, Canada. rmandal@ualberta.ca.
authors.forename: Rupasri
authors.initials: R
authors.lastname: Mandal
authors.affiliation: Half Hollow Hills High School, Dix Hills, NY, 11746, USA. dtesta9@optonline.net.
authors.forename: Daniel
authors.initials: D
authors.lastname: Testa
authors.affiliation: Half Hollow Hills High School, Dix Hills, NY, 11746, USA. devindubin@gmail.com.
authors.forename: Devin
authors.initials: D
authors.lastname: Dubin
authors.affiliation: Graduate Program in Molecular and Cellular Biology, Stony Brook University, Stony Brook, NY, 11794, USA. gregory.carbonetti@stonybrook.edu.
authors.forename: Gregory
authors.initials: G
authors.lastname: Carbonetti
authors.affiliation: Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY, 11794-5215, USA. steven.glynn@stonybrook.edu.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Glynn
authors.affiliation: Departments of Pediatrics, University of British Columbia, Vancouver, Canada. bryan.sayson@cw.bc.ca.|Treatable Intellectual Disability Endeavour in British Columbia (TIDE-BC), Vancouver, Canada. bryan.sayson@cw.bc.ca.
authors.forename: Bryan
authors.initials: B
authors.lastname: Sayson
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, Canada. wrobinson@cfri.ca.
authors.forename: Wendy P
authors.initials: WP
authors.lastname: Robinson
authors.affiliation: Departments of Biological and Computing Sciences, University of Alberta, Edmonton, T6G 2E8, Canada. beomsoo@ualberta.ca.
authors.forename: Beomsoo
authors.initials: B
authors.lastname: Han
authors.affiliation: Departments of Biological and Computing Sciences, University of Alberta, Edmonton, T6G 2E8, Canada. dwishart@ualberta.ca.
authors.forename: David
authors.initials: D
authors.lastname: Wishart
authors.affiliation: Departments of Pediatrics, University of British Columbia, Vancouver, Canada. Colinross1@gmail.com.|Treatable Intellectual Disability Endeavour in British Columbia (TIDE-BC), Vancouver, Canada. Colinross1@gmail.com.|Department of Medical Genetics, University of British Columbia, Vancouver, Canada. Colinross1@gmail.com.
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Ross
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, Canada. wyeth@cmmt.ubc.ca.|Treatable Intellectual Disability Endeavour in British Columbia (TIDE-BC), Vancouver, Canada. wyeth@cmmt.ubc.ca.|Department of Medical Genetics, University of British Columbia, Vancouver, Canada. wyeth@cmmt.ubc.ca.
authors.forename: Wyeth W
authors.initials: WW
authors.lastname: Wasserman
authors.affiliation: Psychiatry, University of British Columbia, Vancouver, Canada. t.hurwitz@ubc.ca.
authors.forename: Trevor A
authors.initials: TA
authors.lastname: Hurwitz
authors.affiliation: Treatable Intellectual Disability Endeavour in British Columbia (TIDE-BC), Vancouver, Canada. gsinclair@cw.bc.ca.|Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada. gsinclair@cw.bc.ca.
authors.forename: Graham
authors.initials: G
authors.lastname: Sinclair
authors.affiliation: Department of Anesthesiology, Stony Brook University, Stony Brook, NY, 11794-8480, USA. martin.kaczocha@stonybrook.edu.|Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY, 11794-5215, USA. martin.kaczocha@stonybrook.edu.
authors.forename: Martin
authors.initials: M
authors.lastname: Kaczocha
mesh_terms: D000328:Adult; D000581:Amidohydrolases / Q000235:genetics / Q000378:metabolism*; D001007:Anxiety / Q000235:genetics / Q000473:pathology*; D002493:Central Nervous System Diseases / Q000235:genetics / Q000473:pathology*; D003001:Cloning, Molecular; D003863:Depression / Q000235:genetics / Q000473:pathology*; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008958:Models, Molecular; D020125:Mutation, Missense; D011487:Protein Conformation; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; C516565:FAAH2 protein, human; D000099252:Fatty Acid Amide Hydrolases