The Experts below are selected from a list of 120 Experts worldwide ranked by ideXlab platform
Stefan Kolker - One of the best experts on this subject based on the ideXlab platform.
-
newborn screening by tandem mass spectrometry for glutaric aciduria type 1 a cost effectiveness analysis
Orphanet Journal of Rare Diseases, 2013Co-Authors: Johannes Pfeil, Stefan Kolker, Georg F Hoffmann, Stefan Listl, Martin Lindner, Peter BurgardAbstract:Background Glutaric aciduria type I (GA-I) is a rare metabolic disorder caused by inherited deficiency of Glutaryl-CoA Dehydrogenase. Despite high prognostic relevance of early diagnosis and start of metabolic treatment as well as an additional cost saving potential later in life, only a limited number of countries recommend newborn screening for GA-I. So far only limited data is available enabling health care decision makers to evaluate whether investing into GA-I screening represents value for money. The aim of our study was therefore to assess the cost-effectiveness of newborn screening for GA-I by tandem mass spectrometry (MS/MS) compared to a scenario where GA-I is not included in the MS/MS screening panel.
-
diagnosis and management of glutaric aciduria type i revised recommendations
Journal of Inherited Metabolic Disease, 2011Co-Authors: Stefan Kolker, M Dixon, Avihu Boneh, Alberto Burlina, Cheryl R Greenberg, M Duran, J V Leonard, E Christensen, Angels Garcia CazorlaAbstract:Glutaric aciduria type I (synonym, glutaric acidemia type I) is a rare organic aciduria. Untreated patients characteristically develop dystonia during infancy resulting in a high morbidity and mortality. The neuropathological correlate is striatal injury which results from encephalopathic crises precipitated by infectious diseases, immunizations and surgery during a finite period of brain development, or develops insidiously without clinically apparent crises. Glutaric aciduria type I is caused by inherited deficiency of Glutaryl-CoA Dehydrogenase which is involved in the catabolic pathways of L-lysine, L-hydroxylysine and L-tryptophan. This defect gives rise to elevated glutaric acid, 3-hydroxyglutaric acid, glutaconic acid, and glutarylcarnitine which can be detected by gas chromatography/mass spectrometry (organic acids) or tandem mass spectrometry (acylcarnitines). Glutaric aciduria type I is included in the panel of diseases that are identified by expanded newborn screening in some countries. It has been shown that in the majority of neonatally diagnosed patients striatal injury can be prevented by combined metabolic treatment. Metabolic treatment that includes a low lysine diet, carnitine supplementation and intensified emergency treatment during acute episodes of intercurrent illness should be introduced and monitored by an experienced interdisciplinary team. However, initiation of treatment after the onset of symptoms is generally not effective in preventing permanent damage. Secondary dystonia is often difficult to treat, and the efficacy of available drugs cannot be predicted precisely in individual patients. The major aim of this revision is to re-evaluate the previous diagnostic and therapeutic recommendations for patients with this disease and incorporate new research findings into the guideline.
-
therapeutic modulation of cerebral l lysine metabolism in a mouse model for glutaric aciduria type i
Brain, 2011Co-Authors: Sven W Sauer, David M. Koeller, Georg F Hoffmann, Jurgen G Okun, Stefan KolkerAbstract:Glutaric aciduria type I, an inherited deficiency of glutaryl-coenzyme A Dehydrogenase localized in the final common catabolic pathway of l-lysine, l-hydroxylysine and l-tryptophan, leads to accumulation of neurotoxic glutaric and 3-hydroxyglutaric acid, as well as non-toxic glutarylcarnitine. Most untreated patients develop irreversible brain damage during infancy that can be prevented in the majority of cases if metabolic treatment with a low l-lysine diet and l-carnitine supplementation is started in the newborn period. The biochemical effect of this treatment remains uncertain, since cerebral concentrations of neurotoxic metabolites can only be determined by invasive techniques. Therefore, we studied the biochemical effect and mechanism of metabolic treatment in glutaryl-coenzyme A Dehydrogenase-deficient mice, an animal model with complete loss of glutaryl–coenzyme A Dehydrogenase activity, focusing on the tissue-specific changes of neurotoxic metabolites and key enzymes of l-lysine metabolism. Here, we demonstrate that low l-lysine diet, but not l-carnitine supplementation, lowered the concentration of glutaric acid in brain, liver, kidney and serum. l-carnitine supplementation restored the free l-carnitine pool and enhanced the formation of glutarylcarnitine. The effect of low l-lysine diet was amplified by add-on therapy with l-arginine, which we propose to result from competition with l-lysine at system y+ of the blood–brain barrier and the mitochondrial l-ornithine carriers. l-Lysine can be catabolized in the mitochondrial saccharopine or the peroxisomal pipecolate pathway. We detected high activity of mitochondrial 2-aminoadipate semialdehyde synthase, the rate-limiting enzyme of the saccharopine pathway, in the liver, whereas it was absent in the brain. Since we found activity of the subsequent enzymes of l-lysine oxidation, 2-aminoadipate semialdehyde Dehydrogenase, 2-aminoadipate aminotransferase and 2-oxoglutarate Dehydrogenase complex as well as peroxisomal pipecolic acid oxidase in brain tissue, we postulate that the pipecolate pathway is the major route of l-lysine degradation in the brain and the saccharopine pathway is the major route in the liver. Interestingly, treatment with clofibrate decreased cerebral and hepatic concentrations of glutaric acid in glutaryl-coenzyme A Dehydrogenase-deficient mice. This finding opens new therapeutic perspectives such as pharmacological stimulation of alternative l-lysine oxidation in peroxisomes. In conclusion, this study gives insight into the discrepancies between cerebral and hepatic l-lysine metabolism, provides for the first time a biochemical proof of principle for metabolic treatment in glutaric aciduria type I and suggests that further optimization of treatment could be achieved by exploitation of competition between l-lysine and l-arginine at physiological barriers and enhancement of peroxisomal l-lysine oxidation and glutaric acid breakdown. * Abbreviations : AADAT : aminoadipate aminotransferase AASDH : aminoadipate semialdehyde Dehydrogenase AASS : 2-aminoadipate semialdehyde synthase GCDH : Glutaryl-CoA Dehydrogenase LOR : lysine 2-oxoglutarate reductase OGDHc : 2-oxoglutarate Dehydrogenase complex
-
glutaric aciduria type i and methylmalonic aciduria simulation of cerebral import and export of accumulating neurotoxic dicarboxylic acids in in vitro models of the blood brain barrier and the choroid plexus
Biochimica et Biophysica Acta, 2010Co-Authors: Sven W Sauer, Anne Mahringer, M Kaminski, Christian Thiel, Jurgen G Okun, Gert Fricker, M A Morath, Stefan KolkerAbstract:article i nfo Intracerebral accumulation of neurotoxic dicarboxylic acids (DCAs) plays an important pathophysiological role in glutaric aciduria type I and methylmalonic aciduria. Therefore, we investigated the transport characteristics of accumulating DCAs - glutaric (GA), 3-hydroxyglutaric (3-OH-GA) and methylmalonic acid (MMA) - across porcine brain capillary endothelial cells (pBCEC) and human choroid plexus epithelial cells (hCPEC) representing in vitro models of the blood-brain barrier (BBB) and the choroid plexus respectively. We identified expression of organic acid transporters 1 (OAT1) and 3 (OAT3) in pBCEC on mRNA and protein level. For DCAs tested, transport from the basolateral to the apical site (i.e. efflux) was higher than influx. Efflux transport of GA, 3-OH-GA, and MMA across pBCEC was Na + -dependent, ATP-independent, and was inhibited by the OAT substrates para-aminohippuric acid (PAH), estrone sulfate, and taurocholate, and the OAT inhibitor probenecid. Members of the ATP-binding cassette transporter family or the organic anion transporting polypeptide family, namely MRP2, P-gp, BCRP, and OATP1B3, did not mediate transport of GA, 3-OH-GA or MMA confirming the specificity of efflux transport via OATs. In hCPEC, cellular import of GA was dependent on Na + -gradient, inhibited by NaCN, and unaffected by probenecid suggesting a Na + -dependent DCA transporter. Specific transport of GA across hCPEC, however, was not found. In conclusion, our results indicate a low but specifi ce fflux transport for GA, 3-OH-GA, and MMA across pBCEC, an in vitro model of the BBB, via OAT1 and OAT3 but not across hCPEC, an in vitro model of the choroid plexus. C-glutaric acid; CNS, central nervous system; CoA, coenzyme A; CPM, counts per minute; CSF, cerebrospinal fluid; d4-GA, d4-glutaric acid; d5-3-OH-GA, d5-3-hydroxyglutaric acid; d3-MMA, d3-methylmalonic acid; DCAs, dicarboxylic acids; GA, glutaric acid; GA-I, glutaric aciduria type I; GCDH, Glutaryl-CoA Dehydrogenase; hCPEC, human choroid plexus epithelial cells; 3-OH-GA, 3-hydroxyglutaric acid; KRB, Krebs-Ringer buffer; MCM, methylmalonyl-CoA mutase; MMA, methylmalonic acid; MMAuria, methylmalonic aciduria; MCT1, monocarboxylic acid/proton co-transporter; MRP2, multidrug resistance protein 2; MTT, tetrazolium salt 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide; NaDC, Na + -dependent dicarboxylic acid transporter; NMG,n-methylglucamine; OAT, organic acid transporter; OATP, organic anion transporting polypeptide; Papp, apparent permeability coefficient; PAH, para-aminohippuric acid; pBCEC, porcine brain capillary endothelial cells; P-gp, P-glycoprotein; TBST, tris-buffered saline Tween-20; Vac, volume of the acceptor compartment
-
neuroradiological findings in glutaric aciduria type i glutaryl coa Dehydrogenase deficiency
Journal of Inherited Metabolic Disease, 2004Co-Authors: Eva Neumaierprobst, Inga Harting, A Seitz, C Ding, Stefan KolkerAbstract:Summary: This article summarizes the magnetic resonance imaging features of glutaric aciduria type I (GA I) based on the cases presented at the 3rd International Workshop on Glutaryl-CoA Dehydrogenase Deficiency together with a review of previously reported neuroimaging characteristics of GA I. Previous reports have focused on characteristic findings, such as basal ganglia injury and frontotemporal atrophy or hypoplasia, subdural effusions and white-matter disease. Most of these findings have been demonstrated in symptomatic children, i.e. after manifestation of acute encephalopathic crises. In contrast, prospective investigations in presymptomatically diagnosed children are rare. Since more recent investigations have highlighted CNS changes in patients without encephalopathic crises, systematic prospective investigations of neuroradiological findings in this disease are indispensable for a better understanding of this disease. Based on these findings a suggestion for a MRI protocol is presented, supporting a standardized evaluation of patients with GA I.
Georg F Hoffmann - One of the best experts on this subject based on the ideXlab platform.
-
proposed recommendations for diagnosing and managing individuals with glutaric aciduria type i second revision
Journal of Inherited Metabolic Disease, 2017Co-Authors: Chris Muhlhausen, M Dixon, Cheryl R Greenberg, Inga Harting, Peter Burgard, Esther M Maier, Jana Heringer, Birgit Assmann, Sandra Fleissner, Georg F HoffmannAbstract:Glutaric aciduria type I (GA-I; synonym, glutaric acidemia type I) is a rare inherited metabolic disease caused by deficiency of Glutaryl-CoA Dehydrogenase located in the catabolic pathways of L-lysine, L-hydroxylysine, and L-tryptophan. The enzymatic defect results in elevated concentrations of glutaric acid, 3-hydroxyglutaric acid, glutaconic acid, and glutaryl carnitine in body tissues, which can be reliably detected by gas chromatography/mass spectrometry (organic acids) and tandem mass spectrometry (acylcarnitines). Most untreated individuals with GA-I experience acute encephalopathic crises during the first 6 years of life that are triggered by infectious diseases, febrile reaction to vaccinations, and surgery. These crises result in striatal injury and consequent dystonic movement disorder; thus, significant mortality and morbidity results. In some patients, neurologic disease may also develop without clinically apparent crises at any age. Neonatal screening for GA-I us being used in a growing number of countries worldwide and is cost effective. Metabolic treatment, consisting of low lysine diet, carnitine supplementation, and intensified emergency treatment during catabolism, is effective treatment and improves neurologic outcome in those individuals diagnosed early; treatment after symptom onset, however, is less effective. Dietary treatment is relaxed after age 6 years and should be supervised by specialized metabolic centers. The major aim of this second revision of proposed recommendations is to re-evaluate the previous recommendations (Kolker et al. J Inherit Metab Dis 30:5-22, 2007b; J Inherit Metab Dis 34:677-694, 2011) and add new research findings, relevant clinical aspects, and the perspective of affected individuals.
-
newborn screening by tandem mass spectrometry for glutaric aciduria type 1 a cost effectiveness analysis
Orphanet Journal of Rare Diseases, 2013Co-Authors: Johannes Pfeil, Stefan Kolker, Georg F Hoffmann, Stefan Listl, Martin Lindner, Peter BurgardAbstract:Background Glutaric aciduria type I (GA-I) is a rare metabolic disorder caused by inherited deficiency of Glutaryl-CoA Dehydrogenase. Despite high prognostic relevance of early diagnosis and start of metabolic treatment as well as an additional cost saving potential later in life, only a limited number of countries recommend newborn screening for GA-I. So far only limited data is available enabling health care decision makers to evaluate whether investing into GA-I screening represents value for money. The aim of our study was therefore to assess the cost-effectiveness of newborn screening for GA-I by tandem mass spectrometry (MS/MS) compared to a scenario where GA-I is not included in the MS/MS screening panel.
-
therapeutic modulation of cerebral l lysine metabolism in a mouse model for glutaric aciduria type i
Brain, 2011Co-Authors: Sven W Sauer, David M. Koeller, Georg F Hoffmann, Jurgen G Okun, Stefan KolkerAbstract:Glutaric aciduria type I, an inherited deficiency of glutaryl-coenzyme A Dehydrogenase localized in the final common catabolic pathway of l-lysine, l-hydroxylysine and l-tryptophan, leads to accumulation of neurotoxic glutaric and 3-hydroxyglutaric acid, as well as non-toxic glutarylcarnitine. Most untreated patients develop irreversible brain damage during infancy that can be prevented in the majority of cases if metabolic treatment with a low l-lysine diet and l-carnitine supplementation is started in the newborn period. The biochemical effect of this treatment remains uncertain, since cerebral concentrations of neurotoxic metabolites can only be determined by invasive techniques. Therefore, we studied the biochemical effect and mechanism of metabolic treatment in glutaryl-coenzyme A Dehydrogenase-deficient mice, an animal model with complete loss of glutaryl–coenzyme A Dehydrogenase activity, focusing on the tissue-specific changes of neurotoxic metabolites and key enzymes of l-lysine metabolism. Here, we demonstrate that low l-lysine diet, but not l-carnitine supplementation, lowered the concentration of glutaric acid in brain, liver, kidney and serum. l-carnitine supplementation restored the free l-carnitine pool and enhanced the formation of glutarylcarnitine. The effect of low l-lysine diet was amplified by add-on therapy with l-arginine, which we propose to result from competition with l-lysine at system y+ of the blood–brain barrier and the mitochondrial l-ornithine carriers. l-Lysine can be catabolized in the mitochondrial saccharopine or the peroxisomal pipecolate pathway. We detected high activity of mitochondrial 2-aminoadipate semialdehyde synthase, the rate-limiting enzyme of the saccharopine pathway, in the liver, whereas it was absent in the brain. Since we found activity of the subsequent enzymes of l-lysine oxidation, 2-aminoadipate semialdehyde Dehydrogenase, 2-aminoadipate aminotransferase and 2-oxoglutarate Dehydrogenase complex as well as peroxisomal pipecolic acid oxidase in brain tissue, we postulate that the pipecolate pathway is the major route of l-lysine degradation in the brain and the saccharopine pathway is the major route in the liver. Interestingly, treatment with clofibrate decreased cerebral and hepatic concentrations of glutaric acid in glutaryl-coenzyme A Dehydrogenase-deficient mice. This finding opens new therapeutic perspectives such as pharmacological stimulation of alternative l-lysine oxidation in peroxisomes. In conclusion, this study gives insight into the discrepancies between cerebral and hepatic l-lysine metabolism, provides for the first time a biochemical proof of principle for metabolic treatment in glutaric aciduria type I and suggests that further optimization of treatment could be achieved by exploitation of competition between l-lysine and l-arginine at physiological barriers and enhancement of peroxisomal l-lysine oxidation and glutaric acid breakdown. * Abbreviations : AADAT : aminoadipate aminotransferase AASDH : aminoadipate semialdehyde Dehydrogenase AASS : 2-aminoadipate semialdehyde synthase GCDH : Glutaryl-CoA Dehydrogenase LOR : lysine 2-oxoglutarate reductase OGDHc : 2-oxoglutarate Dehydrogenase complex
-
biochemistry of glutaric aciduria type i activities of in vitro expressed wild type and mutant cdna encoding human glutaryl coa Dehydrogenase
Journal of Inherited Metabolic Disease, 1999Co-Authors: Michael Liesert, Johannes Zschocke, Georg F Hoffmann, N Muhlhauser, Wolfgang BuckelAbstract:Glutaric aciduria type I (GA I; McKusick 231670) is caused by deficiency of Glutaryl-CoA Dehydrogenase activity (EC 1.3.99.7), a key enzyme in the catabolism of the amino acids lysine, hydroxylysine and tryptophan (Besrat et al 1969; Goodman et al 1975). The failure to metabolize Glutaryl-CoA may give rise to elevated levels of glutarate, 3-hydroxyglutarate and glutaconate in the body fluids of the patient. Recent studies showed the leading role of 3-hydroxyglutarate in the pathogenesis of GA I (Baric et al, unpublished). Yet the source of this dicarboxylic acid is not well understood. Glutaryl-CoA Dehydrogenase catalyses the reaction in two steps: dehydrogenation of Glutaryl-CoA to glutaconyl-CoA and decarboxylation of glutaconyl-CoA to crotonyl-CoA, which can be measured separately (Hartel et al 1993). Whereas the hydration of glutaconyl-CoA to 3-hydroxyglutarylCoA is catalysed by methylglutaconase (EC 4.2.1.18; Liesert and Buckel, unpublished), the formation of glutaconyl-CoA is less clear. It could arise from Glutaryl-CoA Dehydrogenase mutants in which the decarboxylase activity is more affected than the Dehydrogenase activity. Another possibility would be a nonspecific oxidation of Glutaryl-CoA by medium-chain acyl-CoA Dehydrogenase (MCAD, EC 1.3.99.3) or similar enzymes. In order to address this question, mechanistically and clinically interesting mutants were introduced into a modified human Glutaryl-CoA Dehydrogenase cDNA that can be expressed in Escherichia coli.
-
die glutarazidamie glutarazidurie i als differentialdiagnose der chorea minor
Klinische Padiatrie, 1993Co-Authors: Renate Voll, Georg F Hoffmann, C. G. Lipinski, F. K. Trefz, J. WeisserAbstract:Glutaracidemia/glutaraciduria type I is an acute or subacute neuropathic disorder of infancy or early childhood. The following symptoms characterize the clinical course: macrocephalus present at birth, cerebral atrophy revealed by CT or MRI scans, most striking in the frontal and temporal lobes, choreoathetosis and dystonia as neurological handicaps. The deficiency of Glutaryl-CoA-Dehydrogenase leads to glutaracidemia and glutaraciduria. It is reported on a three year old girl. The glutaraciduria is an important differential diagnosis to chorea minor.
Peter Burgard - One of the best experts on this subject based on the ideXlab platform.
-
proposed recommendations for diagnosing and managing individuals with glutaric aciduria type i second revision
Journal of Inherited Metabolic Disease, 2017Co-Authors: Chris Muhlhausen, M Dixon, Cheryl R Greenberg, Inga Harting, Peter Burgard, Esther M Maier, Jana Heringer, Birgit Assmann, Sandra Fleissner, Georg F HoffmannAbstract:Glutaric aciduria type I (GA-I; synonym, glutaric acidemia type I) is a rare inherited metabolic disease caused by deficiency of Glutaryl-CoA Dehydrogenase located in the catabolic pathways of L-lysine, L-hydroxylysine, and L-tryptophan. The enzymatic defect results in elevated concentrations of glutaric acid, 3-hydroxyglutaric acid, glutaconic acid, and glutaryl carnitine in body tissues, which can be reliably detected by gas chromatography/mass spectrometry (organic acids) and tandem mass spectrometry (acylcarnitines). Most untreated individuals with GA-I experience acute encephalopathic crises during the first 6 years of life that are triggered by infectious diseases, febrile reaction to vaccinations, and surgery. These crises result in striatal injury and consequent dystonic movement disorder; thus, significant mortality and morbidity results. In some patients, neurologic disease may also develop without clinically apparent crises at any age. Neonatal screening for GA-I us being used in a growing number of countries worldwide and is cost effective. Metabolic treatment, consisting of low lysine diet, carnitine supplementation, and intensified emergency treatment during catabolism, is effective treatment and improves neurologic outcome in those individuals diagnosed early; treatment after symptom onset, however, is less effective. Dietary treatment is relaxed after age 6 years and should be supervised by specialized metabolic centers. The major aim of this second revision of proposed recommendations is to re-evaluate the previous recommendations (Kolker et al. J Inherit Metab Dis 30:5-22, 2007b; J Inherit Metab Dis 34:677-694, 2011) and add new research findings, relevant clinical aspects, and the perspective of affected individuals.
-
newborn screening by tandem mass spectrometry for glutaric aciduria type 1 a cost effectiveness analysis
Orphanet Journal of Rare Diseases, 2013Co-Authors: Johannes Pfeil, Stefan Kolker, Georg F Hoffmann, Stefan Listl, Martin Lindner, Peter BurgardAbstract:Background Glutaric aciduria type I (GA-I) is a rare metabolic disorder caused by inherited deficiency of Glutaryl-CoA Dehydrogenase. Despite high prognostic relevance of early diagnosis and start of metabolic treatment as well as an additional cost saving potential later in life, only a limited number of countries recommend newborn screening for GA-I. So far only limited data is available enabling health care decision makers to evaluate whether investing into GA-I screening represents value for money. The aim of our study was therefore to assess the cost-effectiveness of newborn screening for GA-I by tandem mass spectrometry (MS/MS) compared to a scenario where GA-I is not included in the MS/MS screening panel.
Stephen I. Goodman - One of the best experts on this subject based on the ideXlab platform.
-
impairment of gabaergic system contributes to epileptogenesis in glutaric acidemia type i
Epilepsia, 2017Co-Authors: Mayara Vendramin Pasquetti, Stephen I. Goodman, David M. Koeller, Leticia Meier, Samanta Oliveira Loureiro, Marcelo Ganzella, Bernardo Junges, Leticia Barbieri Caus, Alexandre Umpierrez Amaral, Michael WoontnerAbstract:SummaryObjectives Glutaric acidemia type I (GA-I) is an inherited neurometabolic disorder caused by deficiency of Glutaryl-CoA Dehydrogenase (GCDH) and characterized by increased levels of glutaric, 3-OH-glutaric, and glutaconic acids in the brain parenchyma. The increment of these organic acids inhibits glutamate decarboxylase (GAD) and consequently lowers the γ-aminobutyric acid (GABA) synthesis. Untreated patients exhibit severe neurologic deficits during development, including epilepsy, especially following an acute encephalopathy outbreak. In this work, we evaluated the role of the GABAergic system on epileptogenesis in GA-I using the Gcdh−/− mice exposed to a high lysine diet (Gcdh−/−-Lys). Methods Spontaneous recurrent seizures (SRS), seizure susceptibility, and changes in brain oscillations were evaluated by video–electroencephalography (EEG). Cortical GABAergic synaptic transmission was evaluated using electrophysiologic and neurochemical approaches. Results SRS were observed in 72% of Gcdh−/−-Lys mice, whereas no seizures were detected in age-matched controls (Gcdh+/+ or Gcdh−/− receiving normal diet). The severity and number of PTZ-induced seizures were higher in Gcdh−/−-Lys mice. EEG spectral analysis showed a significant decrease in theta and gamma oscillations and predominant delta waves in Gcdh−/−-Lys mice, associated with increased EEG left index. Analysis of cortical synaptosomes revealed a significantly increased percentage of glutamate release and decreased GABA release in Gcdh−/−-Lys mice that were associated with a decrease in cortical GAD immunocontent and activity and confirmed by reduced frequency of inhibitory events in cortical pyramidal cells. Significance Using an experimental model with a phenotype similar to that of GA-I in humans—the Gcdh−/− mice under high lysine diet (Gcdh−/−-Lys)—we provide evidence that a reduction in cortical inhibition of Gcdh−/−-Lys mice, probably induced by GAD dysfunction, leads to hyperexcitability and increased slow oscillations associated with neurologic abnormalities in GA-I. Our findings offer a new perspective on the pathophysiology of brain damage in GA-I.
-
a diet induced mouse model for glutaric aciduria type i
Brain, 2006Co-Authors: William J Zinnanti, Stephen I. Goodman, Michael Woontner, Jelena Lazovic, Ellen B Wolpert, David A Antonetti, Michael B Smith, James R Connor, Keith C ChengAbstract:In the autosomal recessive human disease, glutaric aciduria type I (GA-1), Glutaryl-CoA Dehydrogenase (GCDH) deficiency disrupts the mitochondrial catabolism of lysine and tryptophan. Affected individuals accumulate glutaric acid (GA) and 3-hydroxyglutaric acid (3-OHGA) in the serum and often suffer acute striatal injury in childhood. Prior attempts to produce selective striatal vulnerability in an animal model have been unsuccessful. We hypothesized that acute striatal injury may be induced in GCDH-deficient ( Gcdh−/− ) mice by elevated dietary protein and lysine. Here, we show that high protein diets are lethal to 4-week-old and 8-week-old Gcdh −/− mice within 2–3 days and 7–8 days, respectively. High lysine alone resulted in vasogenic oedema and blood–brain barrier breakdown within the striatum, associated with serum and tissue GA accumulation, neuronal loss, haemorrhage, paralysis, seizures and death in 75% of 4-week-old Gcdh −/− mice after 3–12 days. In contrast, most 8-week-old Gcdh −/− mice survived on high lysine, but developed white matter lesions, reactive astrocytes and neuronal loss after 6 weeks. Thus, the Gcdh −/− mouse exposed to high protein or lysine may be a useful model of human GA-1 including developmentally dependent striatal vulnerability.
-
proton abstraction reaction steady state kinetics and oxidation reduction potential of human glutaryl coa Dehydrogenase
Biochemistry, 2000Co-Authors: Timothy M Dwyer, Stephen I. Goodman, K S Rao, Frank E FrermanAbstract:Glutaryl-CoA Dehydrogenase catalyzes the oxidation of Glutaryl-CoA to crotonyl-CoA and CO(2) in the mitochondrial degradation of lysine, hydroxylysine, and tryptophan. We have characterized the human enzyme that was expressed in Escherichia coli. Anaerobic reduction of the enzyme with sodium dithionite or substrate yields no detectable semiquinone; however, like other acyl-CoA Dehydrogenases, the human enzyme stabilizes an anionic semiquinone upon reduction of the complex between the enzyme and 2,3-enoyl-CoA product. The flavin potential of the free enzyme determined by the xanthine-xanthine oxidase method is -0.132 V at pH 7.0, slightly more negative than that of related flavoprotein Dehydrogenases. A single equivalent of substrate reduces 26% of the Dehydrogenase flavin, suggesting that the redox equilibrium on the enzyme between substrate and product and oxidized and reduced flavin is not as favorable as that observed with other acyl-CoA Dehydrogenases. This equilibrium is, however, similar to that observed in isovaleryl-CoA Dehydrogenase. Comparison of steady-state kinetic constants of Glutaryl-CoA Dehydrogenase with Glutaryl-CoA and the alternative substrates, pentanoyl-CoA and hexanoyl-CoA, suggests that the gamma-carboxyl group of Glutaryl-CoA stabilizes the enzyme-substrate complex by at least 5.7 kJ/mol, perhaps by interaction with Arg94 or Ser98. Glu370 is positioned to function as the catalytic base, and previous studies indicate that the conjugate acid of Glu370 also protonates the transient crotonyl-CoA anion following decarboxylation [Gomes, B., Fendrich, G. , and Abeles, R. H. (1981) Biochemistry 20, 3154-3160]. Glu370Asp and Glu370Gln mutants of Glutaryl-CoA Dehydrogenase exhibit 7% and 0. 04% residual activity, respectively, with human electron-transfer flavoprotein; these mutations do not grossly affect the flavin redox potentials of the mutant enzymes. The reduced catalytic activities of these mutants can be attributed to reduced extent and rate of substrate deprotonation based on experiments with the nonoxidizable substrate analogue, 3-thiaGlutaryl-CoA, and kinetic experiments. Determination of these fundamental properties of the human enzyme will serve as the basis for future studies of the decarboxylation reaction which is unique among the acyl-CoA Dehydrogenases.
-
atypical riboflavin responsive glutaric aciduria and deficient peroxisomal glutaryl coa oxidase activity a new peroxisomal disorder
Journal of Inherited Metabolic Disease, 1991Co-Authors: M J Bennett, Stephen I. Goodman, R J Pollitt, Daniel E Hale, Joseph VamecqAbstract:Investigation of cultured skin fibroblasts in a patient with atypical riboflavin-responsive glutaric acidura revealed a marked deficiency of peroxisomal Glutaryl-CoA oxidase. This is the first patient to be reported with glutaric aciduria caused by a peroxisomal rather than a mitochondrial dysfunction. This enzyme appears to be specific for Glutaryl-CoA, as lauryl-CoA and dodecanedioyl-CoA oxidase activities in the fibroblasts were both normal. The urinary excretion of glutaric acid (0.5 mmol mmol creatinine−1) suggests that the flux through this pathway is considerably less than the mitochondrial flux through Glutaryl-CoA Dehydrogenase. The elevated glutaric acid excretion (to 0.8 mmol mmol creatinine−1) in response to lysine loading suggests that lysine is a precursor.
Kevin A. Strauss - One of the best experts on this subject based on the ideXlab platform.
-
Safety, efficacy and physiological actions of a lysine-free, arginine-rich formula to treat Glutaryl-CoA Dehydrogenase deficiency: focus on cerebral amino acid influx.
Molecular Genetics and Metabolism, 2011Co-Authors: Kevin A. Strauss, Joan Brumbaugh, Alana Duffy, Bridget Wardley, Donna L. Robinson, Christine Hendrickson, Silvia Tortorelli, Ann B. Moser, Erik G. Puffenberger, Nicholas L. RiderAbstract:Striatal degeneration from Glutaryl-CoA Dehydrogenase deficiency (glutaric aciduria type 1, GA1) is associated with cerebral formation and entrapment of Glutaryl-CoA and its derivatives that depend on cerebral lysine influx. In 2006 we designed a lysine-free study formula enriched with arginine to selectively block lysine transport across cerebral endothelia and thereby limit Glutaryl-CoA production by brain. Between 2006 and present, we treated twelve consecutive children with study formula (LYSx group) while holding all other treatment practices constant. Clinical and biochemical outcomes were compared to 25 GA1 patients (PROx group) treated between 1995 and 2005 with natural protein restriction (dietary lysine/arginine ratio of 1.7±0.3 mg:mg). We used published kinetic parameters of the y+and LAT1 blood-brain barrier transporters to model the influx of amino acids into the brain. Arginine fortification to achieve a mean dietary lysine/arginine ratio of 0.7±0.2 mg:mg was neuroprotective. All 12 LYSx patients are physically and neurologically healthy after 28 aggregate patient-years of follow up (current ages 28±21 months) and there were no adverse events related to formula use. This represents a 36% reduction of neurological risk (95% confidence interval 14-52%, p=0.018) that we can directly attribute to altered amino acid intake. During the first year of life, 20% lower lysine intake and two-fold higher arginine intake by LYSx patients were associated with 50% lower plasma lysine, 3-fold lower plasma lysine/arginine concentration ratio, 42% lower mean calculated cerebral lysine influx, 54% higher calculated cerebral arginine influx, 15-26% higher calculated cerebral influx of several anaplerotic precursors (isoleucine, threonine, methionine, and leucine), 50% less 3-hydroxyglutarate excretion, and a 3-fold lower hospitalization rate (0.8 versus 2.3 hospitalizations per patient per year). The relationship between arginine fortification and plasma lysine indicates that transport competition exists at both cerebrovascular and gastrointestinal barriers, suggesting their co-administration is key to efficacy. Monitoring the ratio between lysine and arginine in diet and plasma may prove a useful strategy for treating children with GA1.
-
type i glutaric aciduria part 1 natural history of 77 patients
American Journal of Medical Genetics Part C-seminars in Medical Genetics, 2003Co-Authors: Kevin A. Strauss, Donna L. Robinson, Erik G. Puffenberger, Holmes D MortonAbstract:Time is that wherein there is opportunity, and opportunity is that wherein there is no great time. … Healing is a matter of time, but it is also a matter of opportunity. —Hippocrates, Epidemics Type I glutaric aciduria (GA1) results from mitochondrial matrix flavoprotein Glutaryl-CoA Dehydrogenase deficiency and is a cause of acute striatal necrosis in infancy. We present detailed clinical, neuroradiologic, molecular, biochemical, and functional data on 77 patients with GA1 representative of a 14-year clinical experience. Micrencephalic macrocephaly at birth is the earliest sign of GA1 and is associated with stretched bridging veins that can be a cause of subdural hematoma and acute retinal hemorrhage. Acute striatal necrosis during infancy is the principal cause of morbidity and mortality and leads to chronic oromotor, gastroesophageal, skeletal, and respiratory complications of dystonia. Injury to the putamen is heralded by abrupt-onset behavioral arrest. Tissue degeneration is stroke-like in pace, radiologic appearance, and irreversibilty. It is uniformly symmetric, regionally selective, confined to children under 18 months of age, and occurs almost always during an infectious illness. Our knowledge of disease mechanisms, though incomplete, is sufficient to allow a rational approach to management of encephalopathic crises. Screening of asymptomatic newborns with GA1 followed by thoughtful prospective care reduces the incidence of radiologically and clinically evident basal ganglia injury from approximately 90% to 35%. Uninjured children have good developmental outcomes and thrive within Amish and non-Amish communities. © 2003 Wiley-Liss, Inc.