Canna~Fangled Abstracts

Defects in fatty acid amide hydrolase 2 in a male with neurologic and psychiatric symptoms.

By March 28, 2015 No Comments
2015 Mar 28;10(1):38. [Epub ahead of print]
Sirrs S1, van Karnebeek CD2,3,4,5, Peng X6, Shyr C7,8,9, Tarailo-Graovac M10,11,12, Mandal R13, Testa D14, Dubin D15, Carbonetti G16, Glynn SE17, Sayson B18,19, Robinson WP20, Han B21, Wishart D22, Ross CJ23,24,25, Wasserman WW26,27,28, Hurwitz TA29, Sinclair G30,31, Kaczocha M32,33.



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.


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.


We propose that genetic alterations in FAAH2 activity contribute to neurologic and psychiatric disorders in humans.





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