The Experts below are selected from a list of 129 Experts worldwide ranked by ideXlab platform
Dietrich Matern - One of the best experts on this subject based on the ideXlab platform.
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newborn screening for disorders of fatty acid oxidation experience and recommendations from an expert meeting
Journal of Inherited Metabolic Disease, 2010Co-Authors: Martin Lindner, Georg F Hoffmann, Dietrich MaternAbstract:Experience with new-born screening (NBS) for disorders of fatty-acid oxidation (FAOD) is now becoming available from an increasing number of programs worldwide. The spectrum of FAOD differs widely between ethnic groups. Incidence calculations from reports from Australia, Germany, and the USA of a total of 5,256,999 newborns give a combined incidence of all FAOD of approximately 1:9,300. However, it appears to be much lower in Asians. Consequently, a significant prevalence and evidence for a clear benefit of NBS is proven for medium-chain Acyl-CoA Dehydrogenase deficiency (MCAD) only in countries with a high percentage of Caucasians, with very-long-chain Acyl-CoA Dehydrogenase deficiency (VLCAD) and long-chain 3-hydroxy Acyl-CoA Dehydrogenase deficiency (LCHAD) being additional candidates. The long-term benefit for many disorders has still to be evaluated and will require international collaboration, especially for the rarest disorders. Short-Chain Acyl-CoA Dehydrogenase deficiency (SCAD) [as well as Systemic carnitine transporter deficiency (CTD) and dienoyl-CoA reductase deficiency (DE-RED)] are conditions of uncertain clinical significance, but most FAOD have a spectrum of clinical presentations (healthy–death). Confirmatory diagnostic procedures should be agreed upon to ensure international comparability of results and evidence-based modifications. The case of Short-Chain Acyl-CoA Dehydrogenase deficiency (SCAD) deficiency shows that even inclusion of conditions without a clearly known natural course may prove useful with respect to gain of knowledge and consecutive exclusion of a biochemical abnormality without clinical significance, although this line of argument implies the existence of structured follow-up programs and bears ethical controversies. As a final conclusion, the accumulated evidence suggests all FAOD should to be included into tandem mass spectrometry (MS/MS)-based NBS programs provided sufficient laboratory performance is guaranteed.
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short chain acyl coa Dehydrogenase scad deficiency an examination of the medical and neurodevelopmental characteristics of 14 cases identified through newborn screening or clinical symptoms
Molecular Genetics and Metabolism, 2008Co-Authors: Susan E Waisbren, Niels Gregersen, Dietrich Matern, Harvey L Levy, M Noble, K Pasley, Deborah MarsdenAbstract:The medical and neurodevelopmental characteristics of 14 children with Short-Chain Acyl-CoA Dehydrogenase deficiency (SCADD) are described. Eight were detected as neonates by newborn screening. Three children diagnosed on the basis of clinical symptoms had normal newborn screening results while three were born in states that did not screen for SCADD. Treatment included frequent feedings and a low fat diet. All children identified by newborn screening demonstrated medical and neuropsychological development within the normative range on follow-up, although one child had a relative weakness in the motor area and another child exhibited mild speech delay. Of the three clinically identified children with newborn screening results below the cut-off value, two were healthy and performed within the normal range on cognitive and motor tests at follow-up. Four clinically identified children with SCADD experienced persistent symptoms and/or developmental delay. However, in each of these cases, there were supplementary or alternative explanations for medical and neuropsychological deficits. Results indicated no genotype-phenotype correlations. These findings suggest that SCADD might be benign and the clinical symptoms ascribed to SCADD reflective of ascertainment bias or that early identification and treatment prevented complications that may have occurred due to interaction between genetic susceptibility and other genetic factors or environmental stressors.
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synergistic heterozygosity in mice with inherited enzyme deficiencies of mitochondrial fatty acid β oxidation
Molecular Genetics and Metabolism, 2005Co-Authors: Michele A Schuler, Jerry Vockley, Piero Rinaldo, Philip A. Wood, Barbara A Gower, Dietrich MaternAbstract:Abstract We have used mice with inborn errors of mitochondrial fatty acid β-oxidation to test the concept of synergistic heterozygosity. We postulated that clinical disease can result from heterozygous mutations in more than one gene in single or related metabolic pathways. Mice with combinations of mutations in mitochondrial fatty acid β-oxidation genes were cold challenged to test their ability to maintain normal body temperature, a sensitive indicator of overall β-oxidation function. This included mice of the following genotypes: triple heterozygosity for mutations in very-long-chain acyl CoA Dehydrogenase, long-chain acyl CoA Dehydrogenase, and Short-Chain acyl CoA Dehydrogenase genes (VLCAD+/−//LCAD+/−//SCAD+/−); double heterozygosity for mutations in VLCAD and LCAD genes (VLCAD+/−//LCAD+/−); double heterozygosity for mutations in LCAD and SCAD genes (LCAD+/−//SCAD+/−); single heterozygous mice (VLCAD+/−, LCAD+/−, SCAD+/−) and wild-type. We found that approximately 33% of mice with any of the combined mutant genotypes tested became hypothermic during a cold challenge. All wild-type and single heterozygous mice maintained normal body temperature throughout a cold challenge. Despite development of hypothermia in some double heterozygous mice, blood glucose concentrations remained normal. Biochemical screening by acylcarnitine and fatty acid analyses demonstrated results that varied by genotype. Thus, physiologic reduction of the β-oxidation pathway, characterized as cold intolerance, occurred in mice with double or triple heterozygosity; however, the derangement was milder than in mice homozygous for any of these mutations. These results substantiate the concept of synergistic heterozygosity and illustrate the potential complexity involved in diagnosis and characterization of inborn errors of fatty acid metabolism in humans.
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the frequency of short chain acyl coa Dehydrogenase gene variants in the us population and correlation with the c4 acylcarnitine concentration in newborn blood spots
Molecular Genetics and Metabolism, 2003Co-Authors: Narasimhan Nagan, Piero Rinaldo, Kent E Kruckeberg, Angela L Tauscher, Karen Snow Bailey, Dietrich MaternAbstract:Abstract Short-Chain Acyl-CoA Dehydrogenase (SCAD) deficiency is a clinically heterogeneous disorder. The clinical phenotype varies from fatal metabolic decompensation in early life to subtle adult onset, some patients remain asymptomatic. Two mutations (511C > T; 625G > A) have been described in exons 5 and 6 of the SCAD gene. Although they alter the structural and catalytic properties of the SCAD protein, these variants are not true disease-causing mutations but confer disease susceptibility. Previous studies found these gene variants to be common in Europeans. We aimed to establish the frequency of these variants in the US population and to determine whether the presence of these variants correlates with elevated butyrylcarnitine (C4-acylcarnitine) concentrations in newborn blood spots. Based on the analysis of 694 samples, we found that the allele frequency of the 625G > A variant was significantly higher (22%) than that of the 511C > T variant (3%). These gene variants were detected in either homozygous or compound heterozygous form in 7% of the study population. Additionally, the frequency of the 625G > A allele in the Hispanic population (30%) was significantly higher than that of the African-American (9%) and Asian (13%) subpopulations. A previously unreported variant, IVS 5 (−10) C > T, was identified in three African-American newborns (0.3%). The C4-acylcarnitine concentration in blood spots was significantly higher in subjects homozygous for the 625A variant when compared to those homozygous for the wild type (p
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the frequency of short chain acyl coa Dehydrogenase gene variants in the us population and correlation with the c4 acylcarnitine concentration in newborn blood spots
Molecular Genetics and Metabolism, 2003Co-Authors: Narasimhan Nagan, Piero Rinaldo, Kent E Kruckeberg, Angela L Tauscher, Karen Snow Bailey, Dietrich MaternAbstract:Abstract Short-Chain Acyl-CoA Dehydrogenase (SCAD) deficiency is a clinically heterogeneous disorder. The clinical phenotype varies from fatal metabolic decompensation in early life to subtle adult onset, some patients remain asymptomatic. Two mutations (511C > T; 625G > A) have been described in exons 5 and 6 of the SCAD gene. Although they alter the structural and catalytic properties of the SCAD protein, these variants are not true disease-causing mutations but confer disease susceptibility. Previous studies found these gene variants to be common in Europeans. We aimed to establish the frequency of these variants in the US population and to determine whether the presence of these variants correlates with elevated butyrylcarnitine (C 4 -acylcarnitine) concentrations in newborn blood spots. Based on the analysis of 694 samples, we found that the allele frequency of the 625G > A variant was significantly higher (22%) than that of the 511C > T variant (3%). These gene variants were detected in either homozygous or compound heterozygous form in 7% of the study population. Additionally, the frequency of the 625G > A allele in the Hispanic population (30%) was significantly higher than that of the African-American (9%) and Asian (13%) subpopulations. A previously unreported variant, IVS 5 (−10) C > T, was identified in three African-American newborns (0.3%). The C 4 -acylcarnitine concentration in blood spots was significantly higher in subjects homozygous for the 625A variant when compared to those homozygous for the wild type ( p 4 -acylcarnitine that would be consistent with a biochemical diagnosis of SCAD deficiency.
Piero Rinaldo - One of the best experts on this subject based on the ideXlab platform.
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synergistic heterozygosity in mice with inherited enzyme deficiencies of mitochondrial fatty acid β oxidation
Molecular Genetics and Metabolism, 2005Co-Authors: Michele A Schuler, Jerry Vockley, Piero Rinaldo, Philip A. Wood, Barbara A Gower, Dietrich MaternAbstract:Abstract We have used mice with inborn errors of mitochondrial fatty acid β-oxidation to test the concept of synergistic heterozygosity. We postulated that clinical disease can result from heterozygous mutations in more than one gene in single or related metabolic pathways. Mice with combinations of mutations in mitochondrial fatty acid β-oxidation genes were cold challenged to test their ability to maintain normal body temperature, a sensitive indicator of overall β-oxidation function. This included mice of the following genotypes: triple heterozygosity for mutations in very-long-chain acyl CoA Dehydrogenase, long-chain acyl CoA Dehydrogenase, and Short-Chain acyl CoA Dehydrogenase genes (VLCAD+/−//LCAD+/−//SCAD+/−); double heterozygosity for mutations in VLCAD and LCAD genes (VLCAD+/−//LCAD+/−); double heterozygosity for mutations in LCAD and SCAD genes (LCAD+/−//SCAD+/−); single heterozygous mice (VLCAD+/−, LCAD+/−, SCAD+/−) and wild-type. We found that approximately 33% of mice with any of the combined mutant genotypes tested became hypothermic during a cold challenge. All wild-type and single heterozygous mice maintained normal body temperature throughout a cold challenge. Despite development of hypothermia in some double heterozygous mice, blood glucose concentrations remained normal. Biochemical screening by acylcarnitine and fatty acid analyses demonstrated results that varied by genotype. Thus, physiologic reduction of the β-oxidation pathway, characterized as cold intolerance, occurred in mice with double or triple heterozygosity; however, the derangement was milder than in mice homozygous for any of these mutations. These results substantiate the concept of synergistic heterozygosity and illustrate the potential complexity involved in diagnosis and characterization of inborn errors of fatty acid metabolism in humans.
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the frequency of short chain acyl coa Dehydrogenase gene variants in the us population and correlation with the c4 acylcarnitine concentration in newborn blood spots
Molecular Genetics and Metabolism, 2003Co-Authors: Narasimhan Nagan, Piero Rinaldo, Kent E Kruckeberg, Angela L Tauscher, Karen Snow Bailey, Dietrich MaternAbstract:Abstract Short-Chain Acyl-CoA Dehydrogenase (SCAD) deficiency is a clinically heterogeneous disorder. The clinical phenotype varies from fatal metabolic decompensation in early life to subtle adult onset, some patients remain asymptomatic. Two mutations (511C > T; 625G > A) have been described in exons 5 and 6 of the SCAD gene. Although they alter the structural and catalytic properties of the SCAD protein, these variants are not true disease-causing mutations but confer disease susceptibility. Previous studies found these gene variants to be common in Europeans. We aimed to establish the frequency of these variants in the US population and to determine whether the presence of these variants correlates with elevated butyrylcarnitine (C4-acylcarnitine) concentrations in newborn blood spots. Based on the analysis of 694 samples, we found that the allele frequency of the 625G > A variant was significantly higher (22%) than that of the 511C > T variant (3%). These gene variants were detected in either homozygous or compound heterozygous form in 7% of the study population. Additionally, the frequency of the 625G > A allele in the Hispanic population (30%) was significantly higher than that of the African-American (9%) and Asian (13%) subpopulations. A previously unreported variant, IVS 5 (−10) C > T, was identified in three African-American newborns (0.3%). The C4-acylcarnitine concentration in blood spots was significantly higher in subjects homozygous for the 625A variant when compared to those homozygous for the wild type (p
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the frequency of short chain acyl coa Dehydrogenase gene variants in the us population and correlation with the c4 acylcarnitine concentration in newborn blood spots
Molecular Genetics and Metabolism, 2003Co-Authors: Narasimhan Nagan, Piero Rinaldo, Kent E Kruckeberg, Angela L Tauscher, Karen Snow Bailey, Dietrich MaternAbstract:Abstract Short-Chain Acyl-CoA Dehydrogenase (SCAD) deficiency is a clinically heterogeneous disorder. The clinical phenotype varies from fatal metabolic decompensation in early life to subtle adult onset, some patients remain asymptomatic. Two mutations (511C > T; 625G > A) have been described in exons 5 and 6 of the SCAD gene. Although they alter the structural and catalytic properties of the SCAD protein, these variants are not true disease-causing mutations but confer disease susceptibility. Previous studies found these gene variants to be common in Europeans. We aimed to establish the frequency of these variants in the US population and to determine whether the presence of these variants correlates with elevated butyrylcarnitine (C 4 -acylcarnitine) concentrations in newborn blood spots. Based on the analysis of 694 samples, we found that the allele frequency of the 625G > A variant was significantly higher (22%) than that of the 511C > T variant (3%). These gene variants were detected in either homozygous or compound heterozygous form in 7% of the study population. Additionally, the frequency of the 625G > A allele in the Hispanic population (30%) was significantly higher than that of the African-American (9%) and Asian (13%) subpopulations. A previously unreported variant, IVS 5 (−10) C > T, was identified in three African-American newborns (0.3%). The C 4 -acylcarnitine concentration in blood spots was significantly higher in subjects homozygous for the 625A variant when compared to those homozygous for the wild type ( p 4 -acylcarnitine that would be consistent with a biochemical diagnosis of SCAD deficiency.
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mitochondrial fatty acid oxidation disorders and cyclic vomiting syndrome
Digestive Diseases and Sciences, 1999Co-Authors: Piero RinaldoAbstract:Inherited fatty acid oxidation (FAO) disorders represent a relatively new group of inborn errors of metabolism. Although our understanding of the biochemical and molecular bases of these disorders has improved dramatically in recent years, many patients remain undetected or are given other diagnoses, cyclic vomiting syndrome (CVS) being one of them in a few known cases. Medium chain Acyl-CoA Dehydrogenase deficiency and the late-onset form of glutaric acidemia type II have been anecdotally misdiagnosed as CVS. In addition, short chain Acyl-CoA Dehydrogenase deficiency (either true defects or polymorphism-related phenotypes) and particularly Short-Chain 3-hydroxy Acyl-CoA Dehydrogenase deficiency may present with clinical and biochemical features that closely resemble CVS. However, the collective role played by FAO and probably other metabolic disorders among the causes of CVS in unknown. Guidelines for a diagnostic approach to FAO disorders at the biochemical level are being presented and discussed. Hopefully, a better understanding and an awareness of FAO disorders could improve the diagnostic evaluation of patients with CVS.
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identification of four new mutations in the short chain acyl coa Dehydrogenase scad gene in two patients one of the variant alleles 511c t is present at an unexpectedly high frequency in the general population as was the case for 625g a together conf
Human Molecular Genetics, 1998Co-Authors: Niels Gregersen, Vibeke Winter, Morten J Corydon, Thomas J Corydon, Antonia Ribes, G Martinez, Christine Vianeysaban, Michael J. Bennett, Piero Rinaldo, Ajay BhalaAbstract:We have shown previously that a variant allele of the Short-Chain Acyl-CoA Dehydrogenase (SCAD) gene, 625G
Niels Gregersen - One of the best experts on this subject based on the ideXlab platform.
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mitochondrial fatty acid oxidation defects remaining challenges
Journal of Inherited Metabolic Disease, 2008Co-Authors: Niels Gregersen, Brage S. Andresen, Thomas J Corydon, Christina Bak Pedersen, Rikke K J Olsen, Peter BrossAbstract:Mitochondrial fatty acid oxidation defects have been recognized since the early 1970s. The discovery rate has been rather constant, with 3–4 ‘new’ disorders identified every decade and with the most recent example, ACAD9 deficiency, reported in 2007. In this presentation we will focus on three of the ‘old’ defects: medium-chain Acyl-CoA Dehydrogenase (MCAD) deficiency, riboflavin responsive multiple Acyl-CoA dehydrogenation (RR-MAD) deficiency, and Short-Chain Acyl-CoA Dehydrogenase (SCAD) deficiency. These disorders have been discussed in many publications and at countless conference presentations, and many questions relating to them have been answered. However, continuing clinical and pathophysiological research has raised many further questions, and new ideas and methodologies may be required to answer these. We will discuss these challenges. For MCAD deficiency the key question is why 80% of symptomatic patients are homozygous for the prevalent ACADM gene variation c.985A > G whereas this is found in only ∼50% of newborns with a positive screen. For RR-MAD deficiency, the challenge is to find the connection between variations in the ETFDH gene and the observed deficiency of a number of different mitochondrial Dehydrogenases as well as deficiency of FAD and coenzyme Q10. With SCAD deficiency, the challenge is to elucidate whether ACADS gene variations are disease-associated, especially when combined with other genetic/cellular/environmental factors, which may act synergistically.
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short chain acyl coa Dehydrogenase scad deficiency an examination of the medical and neurodevelopmental characteristics of 14 cases identified through newborn screening or clinical symptoms
Molecular Genetics and Metabolism, 2008Co-Authors: Susan E Waisbren, Niels Gregersen, Dietrich Matern, Harvey L Levy, M Noble, K Pasley, Deborah MarsdenAbstract:The medical and neurodevelopmental characteristics of 14 children with Short-Chain Acyl-CoA Dehydrogenase deficiency (SCADD) are described. Eight were detected as neonates by newborn screening. Three children diagnosed on the basis of clinical symptoms had normal newborn screening results while three were born in states that did not screen for SCADD. Treatment included frequent feedings and a low fat diet. All children identified by newborn screening demonstrated medical and neuropsychological development within the normative range on follow-up, although one child had a relative weakness in the motor area and another child exhibited mild speech delay. Of the three clinically identified children with newborn screening results below the cut-off value, two were healthy and performed within the normal range on cognitive and motor tests at follow-up. Four clinically identified children with SCADD experienced persistent symptoms and/or developmental delay. However, in each of these cases, there were supplementary or alternative explanations for medical and neuropsychological deficits. Results indicated no genotype-phenotype correlations. These findings suggest that SCADD might be benign and the clinical symptoms ascribed to SCADD reflective of ascertainment bias or that early identification and treatment prevented complications that may have occurred due to interaction between genetic susceptibility and other genetic factors or environmental stressors.
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mutation analysis in mitochondrial fatty acid oxidation defects exemplified by acyl coa Dehydrogenase deficiencies with special focus on genotype phenotype relationship
Human Mutation, 2001Co-Authors: Niels Gregersen, Lars Bolund, Brage S. Andresen, Morten J Corydon, Thomas J Corydon, Rikke K J Olsen, Peter BrossAbstract:Mutation analysis of metabolic disorders, such as the fatty acid oxidation defects, offers an additional, and often superior, tool for specific diagnosis compared to traditional enzymatic assays. With the advancement of the structural part of the Human Genome Project and the creation of mutation databases, procedures for convenient and reliable genetic analyses are being developed. The most straightforward application of mutation analysis is to specific diagnoses in suspected patients, particularly in the context of family studies and for prenatal/preimplantation analysis. In addition, from these practical uses emerges the possibility to study genotype–phenotype relationships and investigate the molecular pathogenesis resulting from specific mutations or groups of mutations. In the present review we summarize current knowledge regarding genotype–phenotype relationships in three disorders of mitochondrial fatty acid oxidation: very-long chain Acyl-CoA Dehydrogenase (VLCAD, also ACADVL), medium-chain Acyl-CoA Dehydrogenase (MCAD, also ACADM), and Short-Chain Acyl-CoA Dehydrogenase (SCAD, also ACADS) deficiencies. On the basis of this knowledge we discuss current understanding of the structural implications of mutation type, as well as the modulating effect of the mitochondrial protein quality control systems, composed of molecular chaperones and intracellular proteases. We propose that the unraveling of the genetic and cellular determinants of the modulating effects of protein quality control systems may help to assess the balance between genetic and environmental factors in the clinical expression of a given mutation. The realization that the effect of the monogene, such as disease-causing mutations in the VLCAD, MCAD, and SCAD genes, may be modified by variations in other genes presages the need for profile analyses of additional genetic variations. The rapid development of mutation detection systems, such as the chip technologies, makes such profile analyses feasible. However, it remains to be seen to what extent mutation analysis will be used for diagnosis of fatty acid oxidation defects and other metabolic disorders. Hum Mutat 18:169–189, 2001. © 2001 Wiley-Liss, Inc.
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identification of four new mutations in the short chain acyl coa Dehydrogenase scad gene in two patients one of the variant alleles 511c t is present at an unexpectedly high frequency in the general population as was the case for 625g a together conf
Human Molecular Genetics, 1998Co-Authors: Niels Gregersen, Vibeke Winter, Morten J Corydon, Thomas J Corydon, Antonia Ribes, G Martinez, Christine Vianeysaban, Michael J. Bennett, Piero Rinaldo, Ajay BhalaAbstract:We have shown previously that a variant allele of the Short-Chain Acyl-CoA Dehydrogenase (SCAD) gene, 625G
George F Grady - One of the best experts on this subject based on the ideXlab platform.
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tandem mass spectrometric analysis for amino organic and fatty acid disorders in newborn dried blood spots a two year summary from the new england newborn screening program
Clinical Chemistry, 2001Co-Authors: Thomas H Zytkovicz, Eileen F Fitzgerald, Deborah Marsden, Cecilia Larson, Vivian E Shih, Donna M Johnson, Arnold W Strauss, Anne Marie Comeau, Roger B Eaton, George F GradyAbstract:BACKGROUND: Tandem mass spectrometry (MS/MS) is rapidly being adopted by newborn screening programs to screen dried blood spots for >20 markers of disease in a single assay. Limited information is available for setting the marker cutoffs and for the resulting positive predictive values. METHODS: We screened >160 000 newborns by MS/MS. The markers were extracted from blood spots into a methanol solution with deuterium-labeled internal standards and then were derivatized before analysis by MS/MS. Multiple reaction monitoring of each sample for the markers of interest was accomplished in approximately 1.9 min. Cutoffs for each marker were set at 6-13 SD above the population mean. RESULTS: We identified 22 babies with amino acid disorders (7 phenylketonuria, 11 hyperphenylalaninemia, 1 maple syrup urine disease, 1 hypermethioninemia, 1 arginosuccinate lyase deficiency, and 1 argininemia) and 20 infants with fatty and organic acid disorders (10 medium-chain Acyl-CoA Dehydrogenase deficiencies, 5 presumptive Short-Chain Acyl-CoA Dehydrogenase deficiencies, 2 propionic acidemias, 1 carnitine palmitoyltransferase II deficiency, 1 methylcrotonyl-CoA carboxylase deficiency, and 1 presumptive very-long chain Acyl-CoA Dehydrogenase deficiency). Approximately 0.3% of all newborns screened were flagged for either amino acid or acylcarnitine markers; approximately one-half of all the flagged infants were from the 5% of newborns who required neonatal intensive care or had birth weights <1500 g. CONCLUSIONS: In screening for 23 metabolic disorders by MS/MS, an mean positive predictive value of 8% can be achieved when using cutoffs for individual markers determined empirically on newborns.
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tandem mass spectrometric analysis for amino organic and fatty acid disorders in newborn dried blood spots a two year summary from the new england newborn screening program
Clinical Chemistry, 2001Co-Authors: Thomas H Zytkovicz, Eileen F Fitzgerald, Vivian E Shih, Arnold W Strauss, Anne Marie Comeau, Deborah Marsde, Cecilia Larso, Donna M Johnso, Roge Eato, George F GradyAbstract:Background: Tandem mass spectrometry (MS/MS) is rapidly being adopted by newborn screening programs to screen dried blood spots for >20 markers of disease in a single assay. Limited information is available for setting the marker cutoffs and for the resulting positive predictive values. Methods: We screened >160 000 newborns by MS/MS. The markers were extracted from blood spots into a methanol solution with deuterium-labeled internal standards and then were derivatized before analysis by MS/MS. Multiple reaction monitoring of each sample for the markers of interest was accomplished in ∼1.9 min. Cutoffs for each marker were set at 6–13 SD above the population mean. Results: We identified 22 babies with amino acid disorders (7 phenylketonuria, 11 hyperphenylalaninemia, 1 maple syrup urine disease, 1 hypermethioninemia, 1 arginosuccinate lyase deficiency, and 1 argininemia) and 20 infants with fatty and organic acid disorders (10 medium-chain Acyl-CoA Dehydrogenase deficiencies, 5 presumptive Short-Chain Acyl-CoA Dehydrogenase deficiencies, 2 propionic acidemias, 1 carnitine palmitoyltransferase II deficiency, 1 methylcrotonyl-CoA carboxylase deficiency, and 1 presumptive very-long chain Acyl-CoA Dehydrogenase deficiency). Approximately 0.3% of all newborns screened were flagged for either amino acid or acylcarnitine markers; approximately one-half of all the flagged infants were from the 5% of newborns who required neonatal intensive care or had birth weights <1500 g. Conclusions: In screening for 23 metabolic disorders by MS/MS, an mean positive predictive value of 8% can be achieved when using cutoffs for individual markers determined empirically on newborns.
Philip A. Wood - One of the best experts on this subject based on the ideXlab platform.
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synergistic heterozygosity in mice with inherited enzyme deficiencies of mitochondrial fatty acid β oxidation
Molecular Genetics and Metabolism, 2005Co-Authors: Michele A Schuler, Jerry Vockley, Piero Rinaldo, Philip A. Wood, Barbara A Gower, Dietrich MaternAbstract:Abstract We have used mice with inborn errors of mitochondrial fatty acid β-oxidation to test the concept of synergistic heterozygosity. We postulated that clinical disease can result from heterozygous mutations in more than one gene in single or related metabolic pathways. Mice with combinations of mutations in mitochondrial fatty acid β-oxidation genes were cold challenged to test their ability to maintain normal body temperature, a sensitive indicator of overall β-oxidation function. This included mice of the following genotypes: triple heterozygosity for mutations in very-long-chain acyl CoA Dehydrogenase, long-chain acyl CoA Dehydrogenase, and Short-Chain acyl CoA Dehydrogenase genes (VLCAD+/−//LCAD+/−//SCAD+/−); double heterozygosity for mutations in VLCAD and LCAD genes (VLCAD+/−//LCAD+/−); double heterozygosity for mutations in LCAD and SCAD genes (LCAD+/−//SCAD+/−); single heterozygous mice (VLCAD+/−, LCAD+/−, SCAD+/−) and wild-type. We found that approximately 33% of mice with any of the combined mutant genotypes tested became hypothermic during a cold challenge. All wild-type and single heterozygous mice maintained normal body temperature throughout a cold challenge. Despite development of hypothermia in some double heterozygous mice, blood glucose concentrations remained normal. Biochemical screening by acylcarnitine and fatty acid analyses demonstrated results that varied by genotype. Thus, physiologic reduction of the β-oxidation pathway, characterized as cold intolerance, occurred in mice with double or triple heterozygosity; however, the derangement was milder than in mice homozygous for any of these mutations. These results substantiate the concept of synergistic heterozygosity and illustrate the potential complexity involved in diagnosis and characterization of inborn errors of fatty acid metabolism in humans.
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Functional Correction of Short-Chain Acyl-CoA Dehydrogenase Deficiency in Transgenic Mice: Implications for Gene Therapy of Human Mitochondrial Enzyme Deficiencies
Human molecular genetics, 1997Co-Authors: C.lisa Kelly, William J. Rhead, William Kutschke, Amy E. Brix, Doug A. Hamm, Carl A. Pinkert, J. Russell Lindsey, Philip A. WoodAbstract:We report the therapeutic effects of liver-specific expression of a Short-Chain Acyl-CoA Dehydrogenase (SCAD) transgene in the SCAD-deficient mouse model. Transgenic mice were produced with a rat albumin promoter/enhancer driving a mouse SCAD minigene (ALB-SCAD) on both the SCAD normal genetic background and a SCAD-deficient background. In three transgenic lines produced on the SCAD-deficient background, recombinant SCAD activity and antigen in liver mitochondria were found up to 7-fold of normal control values. All three lines showed a markedly reduced organic aciduria and fatty liver, which are sensitive indicators of the metabolic abnormality seen in this disease found in children. We found no detrimental effects of high liver SCAD expression in transgenic mice on either background. These studies provide important basic and practical therapeutic information for the potential gene therapy of nuclear-encoded mitochondrial enzyme deficiencies, as well as insights into the mechanisms of the disease.
