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Making and managing policies about neonatal screening
S32
PATHOLOGY UPDATE 2010 ABSTRACTS
TWO KINDRED WITH X-LINKED RECESSIVE TUBERCULOUS MYCOBACTERIAL DISEASE: TOWARDS A GENETIC THEORY OF INFECTIOUS DISEASES Jean-Laurent Casanova Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, United States The observation that only a small fraction of individuals infected by infectious agents develop clinical disease raises fundamental questions about the actual pathogenesis of infectious diseases. Epidemiological and experimental evidence is accumulating to suggest that human genetics plays a major role in this process. Although many studies have provided proof-of-principle that infectious diseases may result from various types of inborn errors of immunity, the genetic determinism of most infectious diseases in most patients remains unclear. It is commonly thought that rare patients with multiple infections display Mendelian primary immunodeficiencies, whereas common infections in otherwise healthy patients reflect polygenic predisposition. However, patients cannot be ascribed to such discrete binary categories (rare v. common, multi-infected v. otherwise healthy), and we have previously documented various Mendelian traits predisposing to a single type of infection. For human genetics to establish a new paradigm, the genetic architecture of infectious diseases should be deciphered. Our laboratory tests the hypothesis that life-threatening diseases of childhood, typically in the course of primary infection, each result from a collection of highly diverse but immunologically related single-gene variations; whereas the corresponding infections in adults, typically caused by secondary infection or reactivation of latent infection, reflect a more complex predisposition. The genetictheory of infectious diseases has important clinical implications, paving the way to novel treatment, aimed at restoring the patients’ immunity to specific pathogens. The immunological implications are equally important, as studies of experiments of nature define the function of host defence genes in natura, i.e., in the setting of a natural ecosystem governed by natural selection. We will illustrate our endeavors in the field of human genetics of infectious diseases by relating the clinical investigation of patients from two unrelated kindreds with X-linked recessive susceptibility to tuberculous mycobacterial diseases. METABOLOMIC SCREENING IN NEONATES James Pitt VCGS Pathology, Murdoch Childrens Research Institute, Royal Children’s Hospital, Melbourne, Victoria, Australia Surveillance for inborn errorsof metabolism(IEMs) typically relies on three programs: universal neonatal screening, targeted screening of children and adults who present with symptoms, and postmortem screening of sudden unexpected deaths. Tandem mass spectrometry isnow a keytechnology inallthese areas. All neonates in Australasia are screened for approximately 24 IEMs with dried blood spot samples being analysed for a panel of amino acids and acyl carnitines. Some metabolites have relatively poor positive predictive value and second tier tests for more specific metabolites can be used to improve this situation. Earlier diagnosis has resulted in improved treatment and outcomes and some maternal deficiencies are detected via testing of the baby. Some IEMs can cause death before the neonatal screening sample is collected but these disorders can be diagnosed from dried blood spots collected
Pathology (2010), 42(S1)
post-mortem. Many more IEMs can be diagnosed through urine screening of symptomatic patients and a metabolomics platform has been developed to target 4100 biomarkers. New biomarkers are easily added to the panel as new disorders are discovered. This platform has streamlined laboratory procedures and improved the overall performance of Victoria’s urine screening program.
CHALLENGES IN TRANSLATING METABOLOMIC SCREENING INTO CLINICAL PRACTICE Avihu Boneh Genetic Health Services Victoria, Murdoch Childrens Research Institute, Royal Children’s Hospital, Department of Paediatrics University of Melbourne, Victoria, Australia New technologies enable faster and broader screening for inborn metabolic disorders. Information can be obtained nowadays about many metabolites through one test using tandem mass spectrometry (TMS). As well, new therapies for lysosomal storage diseases open the prospects for new screening programs for these disorders. Indeed, the development of screening tests for these disorders is in advanced stages. The decision on what metabolites to include in a screening program that uses one-test-many-results technology and what diseases to screen for when developing specific screening tests rests with screening policy makers. There are disorders for which there is solid evidence that newborn screening is unequivocally beneficial (e.g., congenital hypothyroidism). However, should we wait for evidence for every disorder? Not waiting might impose an enormous cost without proven benefit (e.g., Pompe disease). Waiting may cost in infants’ lives and disability (e.g., glutaric aciduria type I, congenital adrenal hyperplasia). Clinicians should, and do, play a pivotal role in this process, being responsible for communicating results to families and treating the diagnosed infants. The results obtained from TMS screening represent the biochemical phenotype of the infant, the result of his/her genetic makeup, age, diet and possibly other environmental factors. Some infants who manifest the biochemical alterations suggestive of severe metabolic diseases are clinically asymptomatic. Scientists aim to improve accuracy and specificity of detected metabolites. Clinicians aim to improve the specificity of the diagnosis by organising additional tests and tailoring individual therapeutic regimens. The challenge for both disciplines is to combine their experience into a comprehensive view that will enable sensitive, specific and evidence based screening programs. MAKING AND MANAGING POLICIES ABOUT NEONATAL SCREENING Jim McGill1,2,3 Newborn Screening Laboratory, Division of Chemical Pathology, Pathology Queensland, Brisbane, 2Department of Metabolic Medicine, Royal Children’s Hospital, Brisbane, and 3 Chemical Pathology, Mater Laboratory Services, Brisbane, Queensland, Australia 1
Policies relating to Newborn Screening Programs (NBSP) in Australia are State based. A Human Genetics Society of Australia (HGSA) / Royal Australasian College of Physicians (RACP) Joint Committee on Newborn Screening sets laboratory and clinical standards for NBSP. An Australian Health Ministers’ Advisory Council (AHMAC) advisory group failed
PATHOLOGY UPDATE 2010 ABSTRACTS
to achieve consensus between States. The importance of the inclusion of health professionals actively involved in NBSP in any policy making body was highlighted by this exercise. Controlled studies of NBSP are difficult because the disorders are rare, requiring vast numbers of screened infants and lengthy follow up periods to demonstrate benefit. The problems of requiring published data before instituting NBSP are well demonstrated by screening for congenital adrenal hyperplasia, as the technologies used in published studies have become superseded before publication, and by the comparison of NBSPs in Australia and the United Kingdom regarding expanded newborn screening. There have been recent challenges to the Wilson and Jungner guidelines for selection of screened disorders with the value of genetic knowledge for families, even if there are no accepted treatments, being promoted. Conditions such as Duchenne muscular dystrophy, for which treatments have been developed for only certain genotypes, and lysosomal storage disorders, for which treatment is very expensive and very burdensome, will provide challenges for NBSP in the immediate future.
A METABOLOMIC APPROACH TO LIPIDOPATHIES Peter J. Meikle Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia
S33
Metabolomics is the systematic quantification and characterisation of the complement of small molecules involved in primary and intermediary metabolism. The metabolome is the downstream product of gene regulation and expression but is also influenced by other factors including diet, exercise and environment. Thus the metabolome offers a unique insight into the phenotype, providing a measure of both genetic and environmental influences and has the potential to provide detailed information on disease status and progression in a setting of personalised medicine. Dyslipidaemia, reflecting altered lipid metabolism, is characteristic of many chronic diseases including the clinical spectrum from obesity through metabolic syndrome, insulin resistance, diabetes and atherosclerosis. Thus lipidomics, a subdiscipline of metabolomics, offers an attractive option to address the growing need for risk assessment, early diagnosis and monitoring in these increasingly prevalent diseases. However, new approaches will be required to deal with the increasing numbers of analytes that can be measured with metabolomic analyses. Current strategies for development of lipidomic screening programs will be discussed with specific reference to our work in the area of coronary artery disease and the differentiation of stable and unstable atherosclerotic plaque.
PATHOLOGY UPDATE 2010 ABSTRACTS
TWO KINDRED WITH X-LINKED RECESSIVE TUBERCULOUS MYCOBACTERIAL DISEASE: TOWARDS A GENETIC THEORY OF INFECTIOUS DISEASES Jean-Laurent Casanova Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, United States The observation that only a small fraction of individuals infected by infectious agents develop clinical disease raises fundamental questions about the actual pathogenesis of infectious diseases. Epidemiological and experimental evidence is accumulating to suggest that human genetics plays a major role in this process. Although many studies have provided proof-of-principle that infectious diseases may result from various types of inborn errors of immunity, the genetic determinism of most infectious diseases in most patients remains unclear. It is commonly thought that rare patients with multiple infections display Mendelian primary immunodeficiencies, whereas common infections in otherwise healthy patients reflect polygenic predisposition. However, patients cannot be ascribed to such discrete binary categories (rare v. common, multi-infected v. otherwise healthy), and we have previously documented various Mendelian traits predisposing to a single type of infection. For human genetics to establish a new paradigm, the genetic architecture of infectious diseases should be deciphered. Our laboratory tests the hypothesis that life-threatening diseases of childhood, typically in the course of primary infection, each result from a collection of highly diverse but immunologically related single-gene variations; whereas the corresponding infections in adults, typically caused by secondary infection or reactivation of latent infection, reflect a more complex predisposition. The genetictheory of infectious diseases has important clinical implications, paving the way to novel treatment, aimed at restoring the patients’ immunity to specific pathogens. The immunological implications are equally important, as studies of experiments of nature define the function of host defence genes in natura, i.e., in the setting of a natural ecosystem governed by natural selection. We will illustrate our endeavors in the field of human genetics of infectious diseases by relating the clinical investigation of patients from two unrelated kindreds with X-linked recessive susceptibility to tuberculous mycobacterial diseases. METABOLOMIC SCREENING IN NEONATES James Pitt VCGS Pathology, Murdoch Childrens Research Institute, Royal Children’s Hospital, Melbourne, Victoria, Australia Surveillance for inborn errorsof metabolism(IEMs) typically relies on three programs: universal neonatal screening, targeted screening of children and adults who present with symptoms, and postmortem screening of sudden unexpected deaths. Tandem mass spectrometry isnow a keytechnology inallthese areas. All neonates in Australasia are screened for approximately 24 IEMs with dried blood spot samples being analysed for a panel of amino acids and acyl carnitines. Some metabolites have relatively poor positive predictive value and second tier tests for more specific metabolites can be used to improve this situation. Earlier diagnosis has resulted in improved treatment and outcomes and some maternal deficiencies are detected via testing of the baby. Some IEMs can cause death before the neonatal screening sample is collected but these disorders can be diagnosed from dried blood spots collected
Pathology (2010), 42(S1)
post-mortem. Many more IEMs can be diagnosed through urine screening of symptomatic patients and a metabolomics platform has been developed to target 4100 biomarkers. New biomarkers are easily added to the panel as new disorders are discovered. This platform has streamlined laboratory procedures and improved the overall performance of Victoria’s urine screening program.
CHALLENGES IN TRANSLATING METABOLOMIC SCREENING INTO CLINICAL PRACTICE Avihu Boneh Genetic Health Services Victoria, Murdoch Childrens Research Institute, Royal Children’s Hospital, Department of Paediatrics University of Melbourne, Victoria, Australia New technologies enable faster and broader screening for inborn metabolic disorders. Information can be obtained nowadays about many metabolites through one test using tandem mass spectrometry (TMS). As well, new therapies for lysosomal storage diseases open the prospects for new screening programs for these disorders. Indeed, the development of screening tests for these disorders is in advanced stages. The decision on what metabolites to include in a screening program that uses one-test-many-results technology and what diseases to screen for when developing specific screening tests rests with screening policy makers. There are disorders for which there is solid evidence that newborn screening is unequivocally beneficial (e.g., congenital hypothyroidism). However, should we wait for evidence for every disorder? Not waiting might impose an enormous cost without proven benefit (e.g., Pompe disease). Waiting may cost in infants’ lives and disability (e.g., glutaric aciduria type I, congenital adrenal hyperplasia). Clinicians should, and do, play a pivotal role in this process, being responsible for communicating results to families and treating the diagnosed infants. The results obtained from TMS screening represent the biochemical phenotype of the infant, the result of his/her genetic makeup, age, diet and possibly other environmental factors. Some infants who manifest the biochemical alterations suggestive of severe metabolic diseases are clinically asymptomatic. Scientists aim to improve accuracy and specificity of detected metabolites. Clinicians aim to improve the specificity of the diagnosis by organising additional tests and tailoring individual therapeutic regimens. The challenge for both disciplines is to combine their experience into a comprehensive view that will enable sensitive, specific and evidence based screening programs. MAKING AND MANAGING POLICIES ABOUT NEONATAL SCREENING Jim McGill1,2,3 Newborn Screening Laboratory, Division of Chemical Pathology, Pathology Queensland, Brisbane, 2Department of Metabolic Medicine, Royal Children’s Hospital, Brisbane, and 3 Chemical Pathology, Mater Laboratory Services, Brisbane, Queensland, Australia 1
Policies relating to Newborn Screening Programs (NBSP) in Australia are State based. A Human Genetics Society of Australia (HGSA) / Royal Australasian College of Physicians (RACP) Joint Committee on Newborn Screening sets laboratory and clinical standards for NBSP. An Australian Health Ministers’ Advisory Council (AHMAC) advisory group failed
PATHOLOGY UPDATE 2010 ABSTRACTS
to achieve consensus between States. The importance of the inclusion of health professionals actively involved in NBSP in any policy making body was highlighted by this exercise. Controlled studies of NBSP are difficult because the disorders are rare, requiring vast numbers of screened infants and lengthy follow up periods to demonstrate benefit. The problems of requiring published data before instituting NBSP are well demonstrated by screening for congenital adrenal hyperplasia, as the technologies used in published studies have become superseded before publication, and by the comparison of NBSPs in Australia and the United Kingdom regarding expanded newborn screening. There have been recent challenges to the Wilson and Jungner guidelines for selection of screened disorders with the value of genetic knowledge for families, even if there are no accepted treatments, being promoted. Conditions such as Duchenne muscular dystrophy, for which treatments have been developed for only certain genotypes, and lysosomal storage disorders, for which treatment is very expensive and very burdensome, will provide challenges for NBSP in the immediate future.
A METABOLOMIC APPROACH TO LIPIDOPATHIES Peter J. Meikle Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia
S33
Metabolomics is the systematic quantification and characterisation of the complement of small molecules involved in primary and intermediary metabolism. The metabolome is the downstream product of gene regulation and expression but is also influenced by other factors including diet, exercise and environment. Thus the metabolome offers a unique insight into the phenotype, providing a measure of both genetic and environmental influences and has the potential to provide detailed information on disease status and progression in a setting of personalised medicine. Dyslipidaemia, reflecting altered lipid metabolism, is characteristic of many chronic diseases including the clinical spectrum from obesity through metabolic syndrome, insulin resistance, diabetes and atherosclerosis. Thus lipidomics, a subdiscipline of metabolomics, offers an attractive option to address the growing need for risk assessment, early diagnosis and monitoring in these increasingly prevalent diseases. However, new approaches will be required to deal with the increasing numbers of analytes that can be measured with metabolomic analyses. Current strategies for development of lipidomic screening programs will be discussed with specific reference to our work in the area of coronary artery disease and the differentiation of stable and unstable atherosclerotic plaque.