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

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 patie...

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Autores principales: Sirrs, Sandra, van Karnebeek, Clara DM, Peng, Xiaoxue, Shyr, Casper, Tarailo-Graovac, Maja, Mandal, Rupasri, Testa, Daniel, Dubin, Devin, Carbonetti, Gregory, Glynn, Steven E, Sayson, Bryan, Robinson, Wendy P, Han, Beomsoo, Wishart, David, Ross, Colin J, Wasserman, Wyeth W, Hurwitz, Trevor A, Sinclair, Graham, Kaczocha, Martin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4423390/
https://www.ncbi.nlm.nih.gov/pubmed/25885783
http://dx.doi.org/10.1186/s13023-015-0248-3
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author Sirrs, Sandra
van Karnebeek, Clara DM
Peng, Xiaoxue
Shyr, Casper
Tarailo-Graovac, Maja
Mandal, Rupasri
Testa, Daniel
Dubin, Devin
Carbonetti, Gregory
Glynn, Steven E
Sayson, Bryan
Robinson, Wendy P
Han, Beomsoo
Wishart, David
Ross, Colin J
Wasserman, Wyeth W
Hurwitz, Trevor A
Sinclair, Graham
Kaczocha, Martin
author_facet Sirrs, Sandra
van Karnebeek, Clara DM
Peng, Xiaoxue
Shyr, Casper
Tarailo-Graovac, Maja
Mandal, Rupasri
Testa, Daniel
Dubin, Devin
Carbonetti, Gregory
Glynn, Steven E
Sayson, Bryan
Robinson, Wendy P
Han, Beomsoo
Wishart, David
Ross, Colin J
Wasserman, Wyeth W
Hurwitz, Trevor A
Sinclair, Graham
Kaczocha, Martin
author_sort Sirrs, Sandra
collection PubMed
description 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. METHODS AND 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13023-015-0248-3) contains supplementary material, which is available to authorized users.
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spelling pubmed-44233902015-05-08 Defects in fatty acid amide hydrolase 2 in a male with neurologic and psychiatric symptoms Sirrs, Sandra van Karnebeek, Clara DM Peng, Xiaoxue Shyr, Casper Tarailo-Graovac, Maja Mandal, Rupasri Testa, Daniel Dubin, Devin Carbonetti, Gregory Glynn, Steven E Sayson, Bryan Robinson, Wendy P Han, Beomsoo Wishart, David Ross, Colin J Wasserman, Wyeth W Hurwitz, Trevor A Sinclair, Graham Kaczocha, Martin Orphanet J Rare Dis Research 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. METHODS AND 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13023-015-0248-3) contains supplementary material, which is available to authorized users. BioMed Central 2015-03-28 /pmc/articles/PMC4423390/ /pubmed/25885783 http://dx.doi.org/10.1186/s13023-015-0248-3 Text en © Sirrs et al.; licensee BioMed Central. 2015 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Sirrs, Sandra
van Karnebeek, Clara DM
Peng, Xiaoxue
Shyr, Casper
Tarailo-Graovac, Maja
Mandal, Rupasri
Testa, Daniel
Dubin, Devin
Carbonetti, Gregory
Glynn, Steven E
Sayson, Bryan
Robinson, Wendy P
Han, Beomsoo
Wishart, David
Ross, Colin J
Wasserman, Wyeth W
Hurwitz, Trevor A
Sinclair, Graham
Kaczocha, Martin
Defects in fatty acid amide hydrolase 2 in a male with neurologic and psychiatric symptoms
title Defects in fatty acid amide hydrolase 2 in a male with neurologic and psychiatric symptoms
title_full Defects in fatty acid amide hydrolase 2 in a male with neurologic and psychiatric symptoms
title_fullStr Defects in fatty acid amide hydrolase 2 in a male with neurologic and psychiatric symptoms
title_full_unstemmed Defects in fatty acid amide hydrolase 2 in a male with neurologic and psychiatric symptoms
title_short Defects in fatty acid amide hydrolase 2 in a male with neurologic and psychiatric symptoms
title_sort defects in fatty acid amide hydrolase 2 in a male with neurologic and psychiatric symptoms
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4423390/
https://www.ncbi.nlm.nih.gov/pubmed/25885783
http://dx.doi.org/10.1186/s13023-015-0248-3
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