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Examining the genotype–phenotype relationship for patients with very-long-chain acyl CoA dehydrogenase deficiency
Abstracts
X-linked inheritance, presentation in females can be highly variable, some remain asymptomatic throughout life, whereas others present with recurrent hyperammonemia. We present two families with a contiguous gene deletion involving the OTC gene along with RPGR and TSPAN7. Family 1 has a 8.05 Mb deletion involving Xp11.4–Xp21.2 which includes 20 refseq genes, 8 of which are known disease causing (Glycerol kinase (CK), Duchenne muscular dystrophy (DMD), McLeod syndrome (XK), Chronic granulomatous disease (CYBB), X-linked retinitis pigmentosa (RPGR), OTC (OTC), X-linked mental retardation (TSPAN7)). Within this family, 3 out of 4 cytogenetically confirmed carriers have manifested symptoms of OTC. There have been no affected males born. Family 2 carries a 0.742 Mb deletion involving Xp11.4 which includes 5 refseq genes, 3 of which are known disease causing (X-linked retinitis pigmentosa (RPGR), OTC (OTC), X-linked mental retardation (TSPAN7)). Within this family, 1 out of 2 molecularly confirmed females and one male have manifested symptoms of OTC. These cases highlight: (1) The susceptible nature of this genomic region to chromosomal re-arrangements; (2) the need for molecular and cytogenetic analysis when an OTC deletion is found so that the full phenotype can be understood; (3) variable phenotype in manifesting female carriers of contiguous gene deletions and; (4) the complexity of OTC management and potential for liver transplant when multiple other genetic factors play a role.
doi:10.1016/j.clinbiochem.2014.07.037
Examining the genotype–phenotype relationship for patients with very-long-chain acyl CoA dehydrogenase deficiency Kylie Tingley a, Beth K. Potter a, Michael T. Geraghty b, Julian Little a, Lindsey Sikora a in collaboration with the Canadian Inherited Metabolic Diseases Research Network (CIMDRN) a University of Ottawa, Ottawa, Ontario, Canada b Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada Objectives: The expansion of newborn screening (NBS) panels to include very-long-chain acyl CoA dehydrogenase deficiency (VLCADD) has led to an increase in the observed prevalence of this disease and a broadening of the clinical spectrum to include a greater proportion of cases with less severe clinical manifestations. Predicting disease severity and the risk of metabolic decompensation in VLCADD is challenging, particularly for asymptomatic newborns diagnosed through NBS. An inability to precisely predict prognosis may lead to some overtreatment of affected infants who are at lower risk. The objective of this study is to systematically review existing evidence characterizing the genotype– phenotype correlation in VLCADD, emphasizing the implications for diagnosis and treatment. Methods: We used an environmental scan of the literature to inform the development of a detailed review protocol. A combination of MeSH headings and keywords in electronic databases was used to identify relevant studies. Human studies of VLCADD that contained information about each patient's genotype (i.e. mutational analysis) and phenotype (biochemical profile, clinical presentation, and/or measure of enzymatic function) met eligibility criteria. Two independent reviewers screened potentially relevant articles using a twostage process. A single reviewer abstracted data, validated by a second reviewer. Results: Preliminary results indicate that over 85 mutations have been described, with no clear dominant, pathogenic mutation. The results suggest a weak correlation between genotype and phenotype. Conclusions: Our final results contribute to improved risk assessment for NBS-identified VLCADD patients in order to better inform
137
disease management. We will also identify priorities for further research.
doi:10.1016/j.clinbiochem.2014.07.038
Building a pan-Canadian practice-based research network for inherited metabolic diseases: The first two years of the Canadian Inherited Metabolic Diseases Research Network (CIMDRN) Beth K. Potter a, Pranesh Chakraborty a, b, Doug Coyle a, Jonathan B. Kronick c, d, Kumanan Wilson a, e, Marni Brownell f, Alicia Chan g, Linda Dodd s, h, Sarah Dyack h, Annette Feigenbaum c, d, Deshayne Fell i, Michael T. Geraghty a, b, Jane Gillis h, Cheryl Rockman-Greenberg j, Astrid Guttmann c, d, Monica Hernandez b, Maria Karaceper a, Aneal Khan k, Sara D. Khangura a, Anne-Marie Laberge l, Julian Little a, Jennifer MacKenzie m, Bruno Maranda n, Aizeddin Mhanni j, Fiona A. Miller d, John J. Mitchell o, Grant Mitchell l, Meranda Nakhla o, Murray Potter p, Chitra Prasad q, Komudi Siriwardena c, d, Rebecca Sparkes k, Kathy N. Speechley q, Sylvia Stockler r, Kylie Tingley a, Yannis Trakadis o, Lesley Turner s, Hilary Vallance r, Clara van Karnebeek r, Brenda J. Wilson a, Nataliya Yuskiv r on behalf of the Canadian Inherited Metabolic Diseases Research Network a University of Ottawa, Ottawa, Ontario, Canada b Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada c Hospital for Sick Children, Canada d University of Toronto, Toronto, Ontario, Canada e Ottawa Hospital Research Institute, Ottawa, Ontario, Canada f Manitoba Centre for Health Policy/University of Manitoba, Winnipeg, Manitoba, Canada g University of Alberta, Edmonton, Alberta, Canada h Dalhousie University/IWK Health Centre, Halifax, Nova Scotia, Canada i BORN Ontario, Ottawa, Ontario, Canada j University of Manitoba/HSC Winnipeg, Winnipeg, Manitoba, Canada k University of Calgary/Alberta Children's Hospital, Calgary, Alberta, Canada l CHU Ste-Justine, Montréal, Québec, Canada m Queen's University/Kingston General Hospital, Kingston, Ontario, Canada n University of Sherbrooke/CHU Sherbrooke, Québec, Canada o McGill University/Montréal Children's Hospital, Montréal, Québec, Canada p McMaster University, Hamilton, Ontario, Canada q Western University/LHSC London, Ontario, Canada r University of British Columbia/BC Children's Hospital, Vancouver, British Columbia, Canada s Memorial University/Janeway Children's Health Centre, Canada Objectives: We established The Canadian Inherited Metabolic Diseases Research Network (CIMDRN) in 2012, supported by an Emerging Team Grant from the Canadian Institutes of Health Research. Our goal is to develop an evidence-informed approach to health care for pediatric inherited metabolic diseases (IMD) that: Integrates policy-level and clinical decisions and considers patient characteristics and other factors that may influence outcomes; Addresses high priority research questions that can provide generalizable insights; and Focuses on outcomes that capture patient experiences with care as well as clinical and health system impacts. Methods: CIMDRN has grown to include 35 investigators based at 14 clinical sites and additional academic settings. We have built a platform with three main research streams: (i) clinical interventions and outcomes, (ii) patient/family-reported outcomes, and (iii) health service organization and impact.
X-linked inheritance, presentation in females can be highly variable, some remain asymptomatic throughout life, whereas others present with recurrent hyperammonemia. We present two families with a contiguous gene deletion involving the OTC gene along with RPGR and TSPAN7. Family 1 has a 8.05 Mb deletion involving Xp11.4–Xp21.2 which includes 20 refseq genes, 8 of which are known disease causing (Glycerol kinase (CK), Duchenne muscular dystrophy (DMD), McLeod syndrome (XK), Chronic granulomatous disease (CYBB), X-linked retinitis pigmentosa (RPGR), OTC (OTC), X-linked mental retardation (TSPAN7)). Within this family, 3 out of 4 cytogenetically confirmed carriers have manifested symptoms of OTC. There have been no affected males born. Family 2 carries a 0.742 Mb deletion involving Xp11.4 which includes 5 refseq genes, 3 of which are known disease causing (X-linked retinitis pigmentosa (RPGR), OTC (OTC), X-linked mental retardation (TSPAN7)). Within this family, 1 out of 2 molecularly confirmed females and one male have manifested symptoms of OTC. These cases highlight: (1) The susceptible nature of this genomic region to chromosomal re-arrangements; (2) the need for molecular and cytogenetic analysis when an OTC deletion is found so that the full phenotype can be understood; (3) variable phenotype in manifesting female carriers of contiguous gene deletions and; (4) the complexity of OTC management and potential for liver transplant when multiple other genetic factors play a role.
doi:10.1016/j.clinbiochem.2014.07.037
Examining the genotype–phenotype relationship for patients with very-long-chain acyl CoA dehydrogenase deficiency Kylie Tingley a, Beth K. Potter a, Michael T. Geraghty b, Julian Little a, Lindsey Sikora a in collaboration with the Canadian Inherited Metabolic Diseases Research Network (CIMDRN) a University of Ottawa, Ottawa, Ontario, Canada b Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada Objectives: The expansion of newborn screening (NBS) panels to include very-long-chain acyl CoA dehydrogenase deficiency (VLCADD) has led to an increase in the observed prevalence of this disease and a broadening of the clinical spectrum to include a greater proportion of cases with less severe clinical manifestations. Predicting disease severity and the risk of metabolic decompensation in VLCADD is challenging, particularly for asymptomatic newborns diagnosed through NBS. An inability to precisely predict prognosis may lead to some overtreatment of affected infants who are at lower risk. The objective of this study is to systematically review existing evidence characterizing the genotype– phenotype correlation in VLCADD, emphasizing the implications for diagnosis and treatment. Methods: We used an environmental scan of the literature to inform the development of a detailed review protocol. A combination of MeSH headings and keywords in electronic databases was used to identify relevant studies. Human studies of VLCADD that contained information about each patient's genotype (i.e. mutational analysis) and phenotype (biochemical profile, clinical presentation, and/or measure of enzymatic function) met eligibility criteria. Two independent reviewers screened potentially relevant articles using a twostage process. A single reviewer abstracted data, validated by a second reviewer. Results: Preliminary results indicate that over 85 mutations have been described, with no clear dominant, pathogenic mutation. The results suggest a weak correlation between genotype and phenotype. Conclusions: Our final results contribute to improved risk assessment for NBS-identified VLCADD patients in order to better inform
137
disease management. We will also identify priorities for further research.
doi:10.1016/j.clinbiochem.2014.07.038
Building a pan-Canadian practice-based research network for inherited metabolic diseases: The first two years of the Canadian Inherited Metabolic Diseases Research Network (CIMDRN) Beth K. Potter a, Pranesh Chakraborty a, b, Doug Coyle a, Jonathan B. Kronick c, d, Kumanan Wilson a, e, Marni Brownell f, Alicia Chan g, Linda Dodd s, h, Sarah Dyack h, Annette Feigenbaum c, d, Deshayne Fell i, Michael T. Geraghty a, b, Jane Gillis h, Cheryl Rockman-Greenberg j, Astrid Guttmann c, d, Monica Hernandez b, Maria Karaceper a, Aneal Khan k, Sara D. Khangura a, Anne-Marie Laberge l, Julian Little a, Jennifer MacKenzie m, Bruno Maranda n, Aizeddin Mhanni j, Fiona A. Miller d, John J. Mitchell o, Grant Mitchell l, Meranda Nakhla o, Murray Potter p, Chitra Prasad q, Komudi Siriwardena c, d, Rebecca Sparkes k, Kathy N. Speechley q, Sylvia Stockler r, Kylie Tingley a, Yannis Trakadis o, Lesley Turner s, Hilary Vallance r, Clara van Karnebeek r, Brenda J. Wilson a, Nataliya Yuskiv r on behalf of the Canadian Inherited Metabolic Diseases Research Network a University of Ottawa, Ottawa, Ontario, Canada b Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada c Hospital for Sick Children, Canada d University of Toronto, Toronto, Ontario, Canada e Ottawa Hospital Research Institute, Ottawa, Ontario, Canada f Manitoba Centre for Health Policy/University of Manitoba, Winnipeg, Manitoba, Canada g University of Alberta, Edmonton, Alberta, Canada h Dalhousie University/IWK Health Centre, Halifax, Nova Scotia, Canada i BORN Ontario, Ottawa, Ontario, Canada j University of Manitoba/HSC Winnipeg, Winnipeg, Manitoba, Canada k University of Calgary/Alberta Children's Hospital, Calgary, Alberta, Canada l CHU Ste-Justine, Montréal, Québec, Canada m Queen's University/Kingston General Hospital, Kingston, Ontario, Canada n University of Sherbrooke/CHU Sherbrooke, Québec, Canada o McGill University/Montréal Children's Hospital, Montréal, Québec, Canada p McMaster University, Hamilton, Ontario, Canada q Western University/LHSC London, Ontario, Canada r University of British Columbia/BC Children's Hospital, Vancouver, British Columbia, Canada s Memorial University/Janeway Children's Health Centre, Canada Objectives: We established The Canadian Inherited Metabolic Diseases Research Network (CIMDRN) in 2012, supported by an Emerging Team Grant from the Canadian Institutes of Health Research. Our goal is to develop an evidence-informed approach to health care for pediatric inherited metabolic diseases (IMD) that: Integrates policy-level and clinical decisions and considers patient characteristics and other factors that may influence outcomes; Addresses high priority research questions that can provide generalizable insights; and Focuses on outcomes that capture patient experiences with care as well as clinical and health system impacts. Methods: CIMDRN has grown to include 35 investigators based at 14 clinical sites and additional academic settings. We have built a platform with three main research streams: (i) clinical interventions and outcomes, (ii) patient/family-reported outcomes, and (iii) health service organization and impact.