Human biochemical genetics: an insight into inborn errors of metabolism

Human biochemical genetics: an insight into inborn errors of metabolism 1 first-author †E-mail:cyu@genetics.emory.edu; crscott@u.washington.edu †E-mail:cyu@genetics.emory.edu; crscott@u.washington.edu cyu@genetics.emory.edu 2 †E-mail:cyu@genetics.emory.edu; crscott@u.washington.edu †E-mail:cyu@genetics.emory.edu; crscott@u.washington.edu cyu@genetics.emory.edu Laboratory of Biochemical Genetics, Emory University, Decatur, GA 30033, USA Laboratory of Biochemical Genetics, Emory University, Decatur, GA 30033, USA Center on Human Development and Disability, University of Washington, Seattle, WA 98195, USA Center on Human Development and Disability, University of Washington, Seattle, WA 98195, USA Inborn errors of metabolism (IEM) include a broad spectrum of defects of various gene products that affect intermediary metabolism in the body. Studying the molecular and biochemical mechanisms of those inherited disorder, systematically summarizing the disease phenotype and natural history, providing diagnostic rationale and methodology and treatment strategy comprise the context of human biochemical genetics. This session focused on: (1) manifestations of representative metabolic disorders; (2) the emergent technology and application of newborn screening of metabolic disorders using tandem mass spectrometry; (3) principles of managing IEM; (4) the concept of carrier testing aiming prevention. Early detection of patients with IEM allows early intervention and more options for treatment. Inborn errors of metabolism (IEM) Newborn screening (NBS) Disease phenotype and therapy Advances in human genome project and related research have been the driving force for detecting and understanding genetic disorders. This is especially true in the area of inborn errors of metabolism. From Garrod’s understanding of alkaptonuria to today’s ability to detect single nucleotide changes, we have had a century of technology-driven discoveries. In the last 30 years, we have seen the utilization of bacterial mutants for the early detection of pehnylketonuria (PKU) (Guthrie, 1969 1969 ) and the development of amino acid analyzers, gas chromotography/mass spectrometers (Hoffmann and Sweetman, 1987 1987 ), and tandem mass spectrometers (Chace and Kalas, 2005 2005 ) for the detection of analytes related to disorders of amino acids, organic acids, and fatty acids. The utilization of these technologies has led to the early detection of metabolic diseases. This early detection has allowed for the development of normal therapies that have included simple dietary alterations, enzyme inhibitors, enzyme replacement therapy, or bone marrow transplantation. Examples of the technology used for detection or confirmation of phenylketonuria, medium chain acyl-CoA dehydrogenase deficiency, and tyrosinemia-1 will be presented. Clinical and biochemical phenotypes of representative disorders from amino acids, organic acids, fatty acids and carbohydrate metabolism will be illustrated. Each disorder represents unique clinical approaches and insights to metabolic disorders. Concept of carrier testing will also be introduced as example for disease prevention. In all cases, the early identification of persons affected with genetic disorders by new technology has led to unexpected discoveries related to the natural history of the disorder or options for therapy. References DH Chace , TA Kalas . A biochemical perspective on the use of tandem mass spectrometry for newborn screening and clinical testing . Clin Biochem , 2005 . 38 ( 4 ): 296 - 309 . DOI: 10.1016/j.clinbiochem.2005.01.017 http://doi.org/10.1016/j.clinbiochem.2005.01.017 . A biochemical perspective on the use of tandem mass spectrometry for newborn screening and clinical testing R Guthrie . Screening for phenylketonuria . Triangle , 1969 . 9 104 - 109 . . Screening for phenylketonuria G Hoffmann , L Sweetman . O-(2,3,4,5,6-pentafluorobenzyl)oxime-trimethylsilyl ester derivatives for quantitative gas chromatographic and gas chromatographic-mass spectrometric studies of aldehydes, ketones and oxoacids . J Chromatogr , 1987 . 421 336 - 343 . . O-(2,3,4,5,6-pentafluorobenzyl)oxime-trimethylsilyl ester derivatives for quantitative gas chromatographic and gas chromatographic-mass spectrometric studies of aldehydes, ketones and oxoacids 10.1631/jzus.2006.B0165 2005-11-22 2005-12-22 2006-01-19 2022-01-05 Copyright © 2006, Journal of Zhejiang University Science 2006 Journal of Zhejiang University-SCIENCE B (Biomedicine and Biotechnology) 02 07