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

Abstract

BackgroundFatty 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.Methods and resultsWhole 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.ConclusionsWe propose that genetic alterations in FAAH2 activity contribute to neurologic and psychiatric disorders in humans.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-015-0248-3) contains supplementary material, which is available to authorized users.

Cannabinoids in the Pathophysiology of Skin Inflammation

“…All cannabinoid classes interfere with the skin cannabinoid receptors and signaling, affecting the homeostasis of skin appendages and cutaneous cells' metabolisms [65]. FAAH and MAGL have been identified in sebocytes, mast cells, melanocytes, fibroblasts, and other dermal cells, suggesting that the skin is more than an effector of the ECS, acting as a regulatory center of cannabinoids metabolism [50,[66][67][68]. The cutaneous ECS is involved in skin differentiation, proliferation, and survival through the actions of AEA and 2-AG that are produced in various skin structures and modulate multiple functions of the skin and its appendages, including hair growth, maintaining the skin barrier integrity, immune response, and the processing of sensory input such as pruritus and pain [69][70][71][72].…”

Multiomics tools for the diagnosis and treatment of rare neurological disease

“…Several studies, including ours, have used a “multiomics” approach using NGS in patients with undiagnosed neurological disease and untargeted or targeted metabolomic profiling to examine the effects of mutations on the metabolome (Abela et al 2016 ; 2017 ; Sirrs et al 2015 ; Tarailo-Graovac et al 2016 ). This multidisciplinary and often multicentric approach has enabled elucidation of etiology in several cases of undiagnosed rare neurological disease and led to identification of novel potential biomarkers or metabolic profiles with potential diagnostic utility.…”

“…In one patient in the same study with autistic features before the age of 2 years, a rare missense mutation was detected by WES in FAAH2 encoding fatty-acid amide hydrolase 2 (FAAH2), which has a role in lipid metabolism and mediates degradation of endocannabinoids but had not been linked to neurological disorders. An abnormal whole-blood acylcarnitine profile was seen, with ten-fold elevations in medium-chain species, and targeted quantitative lipidomics showed perturbations in multiple lipid species in patient serum compared with ten controls, including elevations in many long-chain species (Tarailo-Graovac et al 2016 ; Sirrs et al 2015 ). Studies using fibroblasts from the patient demonstrated reduced FAAH2 activity and altered levels of endocannabinoid metabolites.…”

“…Recent collaborative multicenter studies have demonstrated the benefits of an “omics” approach in rare neurological diseases, incorporating the expertise of clinicians and experts in genomic and metabolomic analysis (Abela et al 2016 ; 2017 ; Sirrs et al 2015 ; Tarailo-Graovac et al 2016 ). Analysis and interpretation of the large amounts of data obtained in such studies presents a challenge.…”

The endocannabinoid gene faah2a modulates stress-associated behavior in zebrafish

“…Nonetheless, the translational potential of these compounds are obscured to a certain extent because rodent models only have one gene encoding a fatty acid amide hydrolase while many non-rodent vertebrates, including humans, also have a FAAH2 gene [ 16 ]. A recent case study has suggested that FAAH2 may modulate anxiety in humans, and warranted the use of new model organisms to study the functions of fatty acid amide hydrolase homologues [ 17 ].…”