- Email: [email protected]
The importance of challenging phenylalanine (Phe) tolerance in patients with phenylketonuria (PKU)
Abstracts
liver cells from a cadaveric donor with immune modulating agents to promote engraftment. Results: Between October 2012 and December 2013, 6 subjects were recruited from within Canada. Four subjects underwent the procedure: subject 1 (female, citrullinemia, 3 months of age), subject 2 (ornithine transcarbamoylase deficiency; OTC, male, 2.5 years of age), subject 3 (OTC, male, 3 months of age) and subject 4 (OTC, male, 3 months of age). Two subjects had exclusion criteria. All 4/4 subjects that initiated study procedures completed all infusion sessions and achieved normal ammonia levels (b50 μmol/L) within 30 days. Post-LCT, the period of time during which subjects had sustained normal ammonia levels were: 14 months (subject 1), 10 months (subject 2), 2 months (subject 3), and 2 months (subject 4). Subject 3 developed severe hyperammonemia at 3 months postLCT, had vascular access problems, developed severe brain injury which precluded his acceptance for solid organ transplant, was transitioned to palliative care and died of his underlying disease. Subject 4 was successfully bridged to solid organ liver transplant. Subjects 1 and 2 are currently stable. Conclusion: All 4 subjects achieved a period of sustained normalization of ammonia levels after LCT but the duration of control was variable. LCT does appear to temporarily provide a degree of ammonia control when used in addition to standard therapy. doi:10.1016/j.clinbiochem.2014.07.078
Towards a clinical trial of lentivirus-mediated gene therapy for Fabry disease: In vitro patient cell mobilization and transduction outcomes Tony Rupar a, Aneal Khan b, Brian C. Au c, Chet Tailor c, Michael Rothe d, Daniela Bischof e, Sandra Sirrs f, Christiane Auray-Blais g, Nicole Prokopishyn b, Pam O'Hoski h, Ju Huang c, Gabi Paul d, Rym Benabid c, Sowmya Viswanathan c, Chantal Morel c, Julian Raiman i, Axel Schambach d, Michael West j, Armand Keating c, Ken Cornetta e, Ronan Foley h, Jeffrey A. Medin c a Western University, London, ON, Canada b University of Calgary, Calgary, AB, Canada c University Health Network, Toronto, ON, Canada d Medizinische Hochscule Hannover, Hannover, Germany e Indiana University, Indianapolis, USA f University of British Columbia, Vancouver, BC, Canada g Université de Sherbrooke, Sherbrooke, QC, Canada h McMaster University, Hamilton, ON, Canada i Hospital for Sick Children, Toronto, ON, Canada j Dalhousie University, Halifax, NS, Canada Objectives: Fabry disease is caused by a deficiency of alphagalactosidase A (alpha gal A) activity. Enzyme replacement therapy for Fabry disease is an intrusive and expensive therapy that has unfavorable pharmacokinetics and does not address the core genetic defect nor does it prevent the occurrence of adverse clinical outcomes. Gene therapy is compelling in Fabry disease and many other lysosomal storage disorders due to metabolic cooperativity. Cells transduced with a gene therapy vector are both enzymatically corrected and secrete alpha gal A that is taken up by distal naive secondary cell populations. Methods: A lentiviral gene therapy vector, LV/FAB, that expresses alpha gal A in tandem with a cell-fate control fusion protein (CD19delTmpkF105Y) for tracking and safety has been developed. CD34+ cells have been enriched from apheresis products collected from clinically-stable volunteer adult male Fabry patient donors mobilized with G-CSF. Cells were then pre-stimulated and transduced with near-GMP LV/FAB virus produced by the Indiana University Vector Production Facility (IUVPF).
151
Results: CD34+ cell yields were in the expected range and no untoward issues occurred with the procedure. A single transduction event at a functionally-determined MOI of 10 led to N70% of input CD34+ cells positive for transgene expression. An in vitro immortalization assay demonstrated a strongly reduced risk of immortalization of murine hematopoietic stem cells with no corresponding cytotoxicity following transduction with the IUVPF-made LV/FAB compared to controls. Conclusions: These results will support a clinical trial application to Health Canada for a gene therapy trial to treat Fabry disease. doi:10.1016/j.clinbiochem.2014.07.079
Outcomes in 48 individuals with guanidinoacetatemethyltransferase (GAMT) deficiency and establishment of a Canadian longitudinal database Sylvia Stockler-Ipsiroglua, The Canadian GAMT Consortium (Clara van Karnebeek, Catherine Brunel Guitton, Michael T. Geraghty, Alina Levtova, Jennifer MacKenzie, Bruno Maranda, Alicia Chan, Saadet Mercimek-Mahmutoglu, Aizeddin A. Mhanni, Grant Mitchell, Andreas Schulze), CIMDRN (Pranesh Chakraborty, Monica Hernandez, Sarah Khanghura, Beth Potter) a Division of Biochemical Diseases, British Columbia Children's Hospital, University of British Columbia, Vancouver, B.C., Canada Guanidinoacetatemethyltransferase (GAMT) deficiency is an autosomal recessive inborn error of creatine synthesis, causing global developmental delay/intellectual disability (DD/ID). Since its description in 1994, b100 patients have been diagnosed. An international consortium of 32 physicians collected data on 48 patients from 38 families with GAMT deficiency (MolGenetMetab2014; 111:16–25). DD/ID with speech/language delay and behavioral problems was present in 44 participants, with additional epilepsy present in 35 and movement disorder in 13. Treatment regimens included various combinations/dosages of creatine-monohydrate, l-ornithine, sodium benzoate and protein/arginine-restricted diets. The median age at treatment initiation was 25.5 and 39 months in patients with mild/ moderate DD/ID, and 11 years in patients with severe DD/ID. Increase of cerebral creatine and decrease of plasma/CSF guanidinoacetate was achieved by supplementation with creatine-monohydrate combined with high dosages of l-ornithine and/or an arginine-restricted diet (250 mg/kg/d l-arginine). Therapy was associated with improvement or stabilization of symptoms in all symptomatic cases. The 4 patients treated b9 months had normal or almost normal developmental outcomes. One with inconsistent compliance had a borderline IQ at age 8.6 years. Currently there are 7 patients with GAMT deficiency in Canada. Our consortium together with the Canadian Inherited Disease Research Network (CIMDRN) aims to establish an observational GAMT database, to create better evidence for the various treatment strategies and to systematically assess long-term outcomes. This database will also serve long term follow-up of children diagnosed via newborn screening, which is currently piloted in British Columbia. doi:10.1016/j.clinbiochem.2014.07.080
The importance of challenging phenylalanine (Phe) tolerance in patients with phenylketonuria (PKU) Erica L. Langley a, Julie A. Nedvidek b, Jennifer J. MacKenzie c, d, Michael T. Geraghty a, e a Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada b Hotel Dieu Hospital, Kingston, Ontario, Canada
152
Abstracts
c
Kingston General Hospital, Kingston, Ontario, Canada Queen's University, Kingston, Ontario, Canada e University of Ottawa, Ottawa, Ontario, Canada d
Introduction: Standard treatment for PKU is a diet restricted in phe (intact protein) and for some, the use of the cofactor sapropterin. The aim of treatment is to maintain blood phe levels within treatment goal range while maximizing phe intake to ensure optimal nutrition, growth and improved quality of life. Case descriptions: We present 4 patients whose phe intake was challenged as part of clinic protocol. All had good blood phe control but their intact protein intake had not been challenged for some time. All proved to tolerate more phe from diet. Blood phe levels remained within treatment goal range for all 4 patients during the challenges which were stopped when blood phe levels rose outside the treatment range. The first patient, a 10 y.o. female increased her phe intake from 250 to 300 mg/day to 1700 mg/day. Her 15 y.o. brother increased his phe intake from 300 to 350 mg/day to 3200 mg/day. The third patient, an 8 y.o. male increased his phe intake from 480 mg/day to 1515 mg/day. The final patient, a 13 y.o. male increased his reported phe intake from 300 mg/day to 1030 mg/day. Conclusion: These patients highlight the need for ongoing evaluation of phe tolerance, especially in well controlled patients. Secondly, maximum phe tolerance should be established prior to trialing sapropterin to ensure any response (especially when defined by an increase in phe/intact protein tolerance) is related to the medication and not the result of an over-restriction of phenylalanine. doi:10.1016/j.clinbiochem.2014.07.081
Metabolic clinic atlas: Organization of care for pediatric metabolic patients in Canada Jonathan B. Kronick a, Monica Hernandez b, Kylie Tingley c, Beth K. Potter c, Alicia K.J. Chan d, Doug Coyle c, Linda Dodds e, Sarah Dyack e, Annette Feigenbaum a, Michael T. Geraghty b, c, Jane Gillis e, Cheryl Rockman-Greenberg f, Aneal Khan g, Julian Little c, Jennifer MacKenzie h, Bruno Maranda i, Aizeddin Mhanni f, John J. Mitchell j, Grant Mitchell k, Anne-Marie Laberge k, Murray Potter l, Chitra Prasad m, Komudi Siriwardena a, Kathy N. Speechley m, Sylvia Stockler n, Yannis Trakadis j, Lesley Turner o, Clara Van Karnebeek n, Kumanan Wilson c, Pranesh Chakraborty b, con behalf of the Canadian Inherited Metabolic Diseases Research Network (CIMDRN) a Hospital for Sick Children/University of Toronto, Toronto, Ontario, Canada b Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada c University of Ottawa, Ottawa, Ontario, Canada d University of Alberta, Edmonton, Alberta, Canada e Dalhousie University/IWK Health Centre, Halifax, Nova Scotia, Canada f University of Manitoba/HSC Winnipeg, Winnipeg, Manitoba, Canada g University of Calgary/Alberta Children's Hospital, Calgary, Alberta, Canada h Queen's University/Kingston General Hospital, Kingston, Ontario, Canada i University of Sherbrooke/CHU Sherbrooke, Sherbrooke, Québec, Canada j McGill University/Montréal Children's Hospital, Montréal, Québec, Canada k CHU Ste-Justine, Montréal, Québec, Canada l McMaster University, Hamilton, Ontario, Canada m Western University/LHSC London, London, Ontario, Canada n University of British Columbia/BC Children's Hospital, Vancouver, British Columbia, Canada o Memorial University/Janeway Children's Health Centre, Canada Objectives: In Canada, nearly all children diagnosed with an inherited metabolic disease (IMD) are treated at one of the country's Hereditary Metabolic Disease Treatment Centres. Given existing evidence of variation in IMD patient management within and across countries, the purpose of this study was to better understand the system of care for pediatric IMD patients in Canada.
Methods: A metabolic physician at each Treatment Centre participating in a national network was invited to complete a webbased survey. The survey addressed the population served and scope of practice, available human resources and clinic services, and research capacity at each Centre. Results: 13 of the 14 Treatment Centres invited to participate completed the survey. All Centres reported pediatric IMD patients as their main population. Every Centre reported having at least one physician and one dietician on staff; additional staff was variable. The most common ancillary services available included telehealth (92%) and biochemical genetic laboratory testing (83%), with a high variability of specific on-site laboratory tests. 80% of the Centres indicated access to off-site services, including social work. Barriers to some services, including nutritional and psychological care, were reported. Larger Centres had more human resources and more onsite clinic and laboratory services. All but one Centre indicated previous experience with research. Conclusion: We found variation in the organization and delivery of care for pediatric IMD patients across Canada. Further research is needed to better understand these differences and determine whether they are associated with clinically meaningful differences in patient outcomes. doi:10.1016/j.clinbiochem.2014.07.082
Psychosis: Clinical evaluation for inborn errors of metabolism Yannis Trakadis a, Christiane Auray-Blais b, Karim Tabbane c, Paula Waters b, Ridha Joober c, John Mitchell a a McGill Health University Health Centre, Montréal, QC, Canada b Biochemical Genetics Laboratory, Centre Hospitalier Universitaire de Sherbrooke, QC, Canada c Douglas Hospital, Montréal, QC, Canada Objectives: • To identify inborn errors of metabolism (IEM) with evidence for an association with psychosis and develop a systematic approach for their clinical evaluation • To explore the diagnostic yield of this approach using a real cohort of patients with psychosis and identify criteria for appropriate referrals to metabolic genetics Methods: A literature search was performed for IEM associated with psychosis. Based on the IEM with published evidence supporting a link, checklists were created for targeted past medical history and physical exam evaluation. Next, 300 patients with psychosis, ascertained through the Douglas Hospital, are being recruited. Information for all patients will be collected using the above checklists and reviewed. 100 patients with evidence suggestive of a metabolic disease and/or refractory to antipsychotic treatment will have the full metabolic work-up targeting the IEM associated with psychosis. Results: Certain IEM may be misdiagnosed as schizophrenia since psychosis can be the only presenting sign for many years. Storage diseases involving multiple small organelles (lysosomes, peroxisomes, mitochondria), iron or copper accumulation, as well as defects in other pathways (e.g. defects leading to hyperammonemia or homocystinemia and cobalamin deficiency) can all present as psychosis. Preliminary data from the real cohort of patients will be presented. Conclusions: The prevalence of IEM in a real cohort of patients with psychosis is not known. Many of these IEM are treatable conditions. The checklists summarizing important features to explore history and physical examination can help psychiatrists to
liver cells from a cadaveric donor with immune modulating agents to promote engraftment. Results: Between October 2012 and December 2013, 6 subjects were recruited from within Canada. Four subjects underwent the procedure: subject 1 (female, citrullinemia, 3 months of age), subject 2 (ornithine transcarbamoylase deficiency; OTC, male, 2.5 years of age), subject 3 (OTC, male, 3 months of age) and subject 4 (OTC, male, 3 months of age). Two subjects had exclusion criteria. All 4/4 subjects that initiated study procedures completed all infusion sessions and achieved normal ammonia levels (b50 μmol/L) within 30 days. Post-LCT, the period of time during which subjects had sustained normal ammonia levels were: 14 months (subject 1), 10 months (subject 2), 2 months (subject 3), and 2 months (subject 4). Subject 3 developed severe hyperammonemia at 3 months postLCT, had vascular access problems, developed severe brain injury which precluded his acceptance for solid organ transplant, was transitioned to palliative care and died of his underlying disease. Subject 4 was successfully bridged to solid organ liver transplant. Subjects 1 and 2 are currently stable. Conclusion: All 4 subjects achieved a period of sustained normalization of ammonia levels after LCT but the duration of control was variable. LCT does appear to temporarily provide a degree of ammonia control when used in addition to standard therapy. doi:10.1016/j.clinbiochem.2014.07.078
Towards a clinical trial of lentivirus-mediated gene therapy for Fabry disease: In vitro patient cell mobilization and transduction outcomes Tony Rupar a, Aneal Khan b, Brian C. Au c, Chet Tailor c, Michael Rothe d, Daniela Bischof e, Sandra Sirrs f, Christiane Auray-Blais g, Nicole Prokopishyn b, Pam O'Hoski h, Ju Huang c, Gabi Paul d, Rym Benabid c, Sowmya Viswanathan c, Chantal Morel c, Julian Raiman i, Axel Schambach d, Michael West j, Armand Keating c, Ken Cornetta e, Ronan Foley h, Jeffrey A. Medin c a Western University, London, ON, Canada b University of Calgary, Calgary, AB, Canada c University Health Network, Toronto, ON, Canada d Medizinische Hochscule Hannover, Hannover, Germany e Indiana University, Indianapolis, USA f University of British Columbia, Vancouver, BC, Canada g Université de Sherbrooke, Sherbrooke, QC, Canada h McMaster University, Hamilton, ON, Canada i Hospital for Sick Children, Toronto, ON, Canada j Dalhousie University, Halifax, NS, Canada Objectives: Fabry disease is caused by a deficiency of alphagalactosidase A (alpha gal A) activity. Enzyme replacement therapy for Fabry disease is an intrusive and expensive therapy that has unfavorable pharmacokinetics and does not address the core genetic defect nor does it prevent the occurrence of adverse clinical outcomes. Gene therapy is compelling in Fabry disease and many other lysosomal storage disorders due to metabolic cooperativity. Cells transduced with a gene therapy vector are both enzymatically corrected and secrete alpha gal A that is taken up by distal naive secondary cell populations. Methods: A lentiviral gene therapy vector, LV/FAB, that expresses alpha gal A in tandem with a cell-fate control fusion protein (CD19delTmpkF105Y) for tracking and safety has been developed. CD34+ cells have been enriched from apheresis products collected from clinically-stable volunteer adult male Fabry patient donors mobilized with G-CSF. Cells were then pre-stimulated and transduced with near-GMP LV/FAB virus produced by the Indiana University Vector Production Facility (IUVPF).
151
Results: CD34+ cell yields were in the expected range and no untoward issues occurred with the procedure. A single transduction event at a functionally-determined MOI of 10 led to N70% of input CD34+ cells positive for transgene expression. An in vitro immortalization assay demonstrated a strongly reduced risk of immortalization of murine hematopoietic stem cells with no corresponding cytotoxicity following transduction with the IUVPF-made LV/FAB compared to controls. Conclusions: These results will support a clinical trial application to Health Canada for a gene therapy trial to treat Fabry disease. doi:10.1016/j.clinbiochem.2014.07.079
Outcomes in 48 individuals with guanidinoacetatemethyltransferase (GAMT) deficiency and establishment of a Canadian longitudinal database Sylvia Stockler-Ipsiroglua, The Canadian GAMT Consortium (Clara van Karnebeek, Catherine Brunel Guitton, Michael T. Geraghty, Alina Levtova, Jennifer MacKenzie, Bruno Maranda, Alicia Chan, Saadet Mercimek-Mahmutoglu, Aizeddin A. Mhanni, Grant Mitchell, Andreas Schulze), CIMDRN (Pranesh Chakraborty, Monica Hernandez, Sarah Khanghura, Beth Potter) a Division of Biochemical Diseases, British Columbia Children's Hospital, University of British Columbia, Vancouver, B.C., Canada Guanidinoacetatemethyltransferase (GAMT) deficiency is an autosomal recessive inborn error of creatine synthesis, causing global developmental delay/intellectual disability (DD/ID). Since its description in 1994, b100 patients have been diagnosed. An international consortium of 32 physicians collected data on 48 patients from 38 families with GAMT deficiency (MolGenetMetab2014; 111:16–25). DD/ID with speech/language delay and behavioral problems was present in 44 participants, with additional epilepsy present in 35 and movement disorder in 13. Treatment regimens included various combinations/dosages of creatine-monohydrate, l-ornithine, sodium benzoate and protein/arginine-restricted diets. The median age at treatment initiation was 25.5 and 39 months in patients with mild/ moderate DD/ID, and 11 years in patients with severe DD/ID. Increase of cerebral creatine and decrease of plasma/CSF guanidinoacetate was achieved by supplementation with creatine-monohydrate combined with high dosages of l-ornithine and/or an arginine-restricted diet (250 mg/kg/d l-arginine). Therapy was associated with improvement or stabilization of symptoms in all symptomatic cases. The 4 patients treated b9 months had normal or almost normal developmental outcomes. One with inconsistent compliance had a borderline IQ at age 8.6 years. Currently there are 7 patients with GAMT deficiency in Canada. Our consortium together with the Canadian Inherited Disease Research Network (CIMDRN) aims to establish an observational GAMT database, to create better evidence for the various treatment strategies and to systematically assess long-term outcomes. This database will also serve long term follow-up of children diagnosed via newborn screening, which is currently piloted in British Columbia. doi:10.1016/j.clinbiochem.2014.07.080
The importance of challenging phenylalanine (Phe) tolerance in patients with phenylketonuria (PKU) Erica L. Langley a, Julie A. Nedvidek b, Jennifer J. MacKenzie c, d, Michael T. Geraghty a, e a Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada b Hotel Dieu Hospital, Kingston, Ontario, Canada
152
Abstracts
c
Kingston General Hospital, Kingston, Ontario, Canada Queen's University, Kingston, Ontario, Canada e University of Ottawa, Ottawa, Ontario, Canada d
Introduction: Standard treatment for PKU is a diet restricted in phe (intact protein) and for some, the use of the cofactor sapropterin. The aim of treatment is to maintain blood phe levels within treatment goal range while maximizing phe intake to ensure optimal nutrition, growth and improved quality of life. Case descriptions: We present 4 patients whose phe intake was challenged as part of clinic protocol. All had good blood phe control but their intact protein intake had not been challenged for some time. All proved to tolerate more phe from diet. Blood phe levels remained within treatment goal range for all 4 patients during the challenges which were stopped when blood phe levels rose outside the treatment range. The first patient, a 10 y.o. female increased her phe intake from 250 to 300 mg/day to 1700 mg/day. Her 15 y.o. brother increased his phe intake from 300 to 350 mg/day to 3200 mg/day. The third patient, an 8 y.o. male increased his phe intake from 480 mg/day to 1515 mg/day. The final patient, a 13 y.o. male increased his reported phe intake from 300 mg/day to 1030 mg/day. Conclusion: These patients highlight the need for ongoing evaluation of phe tolerance, especially in well controlled patients. Secondly, maximum phe tolerance should be established prior to trialing sapropterin to ensure any response (especially when defined by an increase in phe/intact protein tolerance) is related to the medication and not the result of an over-restriction of phenylalanine. doi:10.1016/j.clinbiochem.2014.07.081
Metabolic clinic atlas: Organization of care for pediatric metabolic patients in Canada Jonathan B. Kronick a, Monica Hernandez b, Kylie Tingley c, Beth K. Potter c, Alicia K.J. Chan d, Doug Coyle c, Linda Dodds e, Sarah Dyack e, Annette Feigenbaum a, Michael T. Geraghty b, c, Jane Gillis e, Cheryl Rockman-Greenberg f, Aneal Khan g, Julian Little c, Jennifer MacKenzie h, Bruno Maranda i, Aizeddin Mhanni f, John J. Mitchell j, Grant Mitchell k, Anne-Marie Laberge k, Murray Potter l, Chitra Prasad m, Komudi Siriwardena a, Kathy N. Speechley m, Sylvia Stockler n, Yannis Trakadis j, Lesley Turner o, Clara Van Karnebeek n, Kumanan Wilson c, Pranesh Chakraborty b, con behalf of the Canadian Inherited Metabolic Diseases Research Network (CIMDRN) a Hospital for Sick Children/University of Toronto, Toronto, Ontario, Canada b Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada c University of Ottawa, Ottawa, Ontario, Canada d University of Alberta, Edmonton, Alberta, Canada e Dalhousie University/IWK Health Centre, Halifax, Nova Scotia, Canada f University of Manitoba/HSC Winnipeg, Winnipeg, Manitoba, Canada g University of Calgary/Alberta Children's Hospital, Calgary, Alberta, Canada h Queen's University/Kingston General Hospital, Kingston, Ontario, Canada i University of Sherbrooke/CHU Sherbrooke, Sherbrooke, Québec, Canada j McGill University/Montréal Children's Hospital, Montréal, Québec, Canada k CHU Ste-Justine, Montréal, Québec, Canada l McMaster University, Hamilton, Ontario, Canada m Western University/LHSC London, London, Ontario, Canada n University of British Columbia/BC Children's Hospital, Vancouver, British Columbia, Canada o Memorial University/Janeway Children's Health Centre, Canada Objectives: In Canada, nearly all children diagnosed with an inherited metabolic disease (IMD) are treated at one of the country's Hereditary Metabolic Disease Treatment Centres. Given existing evidence of variation in IMD patient management within and across countries, the purpose of this study was to better understand the system of care for pediatric IMD patients in Canada.
Methods: A metabolic physician at each Treatment Centre participating in a national network was invited to complete a webbased survey. The survey addressed the population served and scope of practice, available human resources and clinic services, and research capacity at each Centre. Results: 13 of the 14 Treatment Centres invited to participate completed the survey. All Centres reported pediatric IMD patients as their main population. Every Centre reported having at least one physician and one dietician on staff; additional staff was variable. The most common ancillary services available included telehealth (92%) and biochemical genetic laboratory testing (83%), with a high variability of specific on-site laboratory tests. 80% of the Centres indicated access to off-site services, including social work. Barriers to some services, including nutritional and psychological care, were reported. Larger Centres had more human resources and more onsite clinic and laboratory services. All but one Centre indicated previous experience with research. Conclusion: We found variation in the organization and delivery of care for pediatric IMD patients across Canada. Further research is needed to better understand these differences and determine whether they are associated with clinically meaningful differences in patient outcomes. doi:10.1016/j.clinbiochem.2014.07.082
Psychosis: Clinical evaluation for inborn errors of metabolism Yannis Trakadis a, Christiane Auray-Blais b, Karim Tabbane c, Paula Waters b, Ridha Joober c, John Mitchell a a McGill Health University Health Centre, Montréal, QC, Canada b Biochemical Genetics Laboratory, Centre Hospitalier Universitaire de Sherbrooke, QC, Canada c Douglas Hospital, Montréal, QC, Canada Objectives: • To identify inborn errors of metabolism (IEM) with evidence for an association with psychosis and develop a systematic approach for their clinical evaluation • To explore the diagnostic yield of this approach using a real cohort of patients with psychosis and identify criteria for appropriate referrals to metabolic genetics Methods: A literature search was performed for IEM associated with psychosis. Based on the IEM with published evidence supporting a link, checklists were created for targeted past medical history and physical exam evaluation. Next, 300 patients with psychosis, ascertained through the Douglas Hospital, are being recruited. Information for all patients will be collected using the above checklists and reviewed. 100 patients with evidence suggestive of a metabolic disease and/or refractory to antipsychotic treatment will have the full metabolic work-up targeting the IEM associated with psychosis. Results: Certain IEM may be misdiagnosed as schizophrenia since psychosis can be the only presenting sign for many years. Storage diseases involving multiple small organelles (lysosomes, peroxisomes, mitochondria), iron or copper accumulation, as well as defects in other pathways (e.g. defects leading to hyperammonemia or homocystinemia and cobalamin deficiency) can all present as psychosis. Preliminary data from the real cohort of patients will be presented. Conclusions: The prevalence of IEM in a real cohort of patients with psychosis is not known. Many of these IEM are treatable conditions. The checklists summarizing important features to explore history and physical examination can help psychiatrists to