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KM Gibson - One of the best experts on this subject based on the ideXlab platform.
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Therapeutic relevance of mTOR inhibition in murine Succinate Semialdehyde Dehydrogenase deficiency (SSADHD), a disorder of GABA metabolism.
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2017Co-Authors: Kara R. Vogel, Gajja S. Salomons, Erwin E.w. Jansen, Garrett R. Ainslie, KM GibsonAbstract:Aldehyde Dehydrogenase 5a1-deficient (aldh5a1−/−) mice, the murine orthologue of human succinic Semialdehyde Dehydrogenase deficiency (SSADHD), manifest increased GABA (4-aminobutyric acid) that disrupts autophagy, increases mitochondria number, and induces oxidative stress, all mitigated with the mTOR (mechanistic target of rapamycin) inhibitor rapamycin [1]. Because GABA regulates mTOR, we tested the hypothesis that aldh5a1−/− mice would show altered levels of mRNA for genes associated with mTOR signaling and oxidative stress that could be mitigated by inhibiting mTOR. We observed that multiple metabolites associated with GABA metabolism (γ-hydroxybutyrate, succinic Semialdehyde, D-2-hydroxyglutarate, 4,5-dihydrohexanoate) and oxidative stress were significantly increased in multiple tissues derived from aldh5a1−/− mice. These metabolic perturbations were associated with decreased levels of reduced glutathione (GSH) in brain and liver of aldh5a1−/− mice, as well as increased levels of adducts of the lipid peroxidation by-product, 4-hydroxy-2-nonenal (4-HNE). Decreased liver mRNA levels for multiple genes associated with mTOR signaling and oxidative stress parameters were detected in aldh5a1−/− mice, and several were significantly improved with the administration of mTOR inhibitors (Torin 1/Torin 2). Western blot analysis of selected proteins corresponding to oxidative stress transcripts (glutathione transferase, superoxide dismutase, peroxiredoxin 1) confirmed gene expression findings. Our data provide additional preclinical evidence for the potential therapeutic efficacy of mTOR inhibitors in SSADHD.
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Visual evoked potentials in Succinate Semialdehyde Dehydrogenase (SSADH) deficiency.
Journal of Inherited Metabolic Disease, 2009Co-Authors: G. Di Rosa, Patrizia Malaspina, Paola Blasi, Carlo Dionisi-vici, Cristiano Rizzo, Gaetano Tortorella, S. R. Crutchfield, KM GibsonAbstract:In mammals, increased GABA in the central nervous system has been associated with abnormalities of visual evoked potentials (VEPs), predominantly manifested as increased latency of the major positive component P100. Accordingly, we hypothesized that patients with a defect in GABA metabolism, Succinate Semialdehyde Dehydrogenase (SSADH) deficiency (in whom supraphysiological levels of GABA accumulate), would manifest VEP anomalies. We evaluated VEPs on two patients with confirmed SSADH deficiency. Whereas the P100 latencies and amplitudes for binocular VEP analyses were within normal ranges for both patients, the P100 latencies were markedly delayed for left eye (OS) (and right eye (OD), patient 1) and monocular OS (patient 2): 134–147 ms; normal
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visual evoked potentials in Succinate Semialdehyde Dehydrogenase ssadh deficiency
Journal of Inherited Metabolic Disease, 2009Co-Authors: G. Di Rosa, KM Gibson, Patrizia Malaspina, Paola Blasi, Cristiano Rizzo, Gaetano Tortorella, S. R. Crutchfield, Carlo DionisiviciAbstract:In mammals, increased GABA in the central nervous system has been associated with abnormalities of visual evoked potentials (VEPs), predominantly manifested as increased latency of the major positive component P100. Accordingly, we hypothesized that patients with a defect in GABA metabolism, Succinate Semialdehyde Dehydrogenase (SSADH) deficiency (in whom supraphysiological levels of GABA accumulate), would manifest VEP anomalies. We evaluated VEPs on two patients with confirmed SSADH deficiency. Whereas the P100 latencies and amplitudes for binocular VEP analyses were within normal ranges for both patients, the P100 latencies were markedly delayed for left eye (OS) (and right eye (OD), patient 1) and monocular OS (patient 2): 134–147 ms; normal <118 ms. We hypothesize that elevated GABA in ocular tissue of SSADH patients leads to a use-dependent downregulation of the major GABAergic receptor in eye, GABAC, and that the VEP recordings’ abnormalities, as evidenced by P100 latency and/or amplitude measurements, may be reflective of abnormalities within visual systems. This is a preliminary finding that may suggest the utility of performing VEP analysis in a larger sample of SSADH-deficient patients, and encourage a neurophysiological assessment of GABAC receptor function in Aldh5a1−/− mice to reveal new pathophysiological mechanisms of this rare disorder of GABA degradation.
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Evidence for oxidative stress in tissues derived from Succinate Semialdehyde Dehydrogenase-deficient mice
Journal of Inherited Metabolic Disease, 2007Co-Authors: Alexandra Latini, KM Gibson, Karina Scussiato, Guilhian Leipnitz, Moacir WajnerAbstract:Animal models of inborn errors of metabolism are useful for investigating the pathogenesis associated with the corresponding human disease. Since the mechanisms involved in the pathophysiology of Succinate Semialdehyde Dehydrogenase (SSADH) deficiency (Aldh5a1; OMIM 271980) are still not established, in the present study we evaluated the tissue antioxidant defences and lipid peroxidation in various cerebral structures (cortex, cerebellum, thalamus and hippocampus) and in the liver of SSADH-deficient mice. The parameters analysed were total radical-trapping antioxidant potential (TRAP) and glutathione (GSH) levels, the activities of the antioxidant enzymes superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx), as well as thiobarbituric acid-reactive substances (TBARS). We first observed that the tissue nonenzymatic antioxidant defences were significantly reduced in the SSADH-deficient animals, particularly in the liver (decreased TRAP and GSH) and in the cerebral cortex (decreased GSH), as compared to the wild-type mice. Furthermore, SOD activity was significantly increased in the liver and cerebellum, whereas the activity of CAT was significantly higher in the thalamus. In contrast, GPx activity was significantly diminished in the hippocampus. Finally, we observed that lipid peroxidation (TBARS levels) was markedly increased in the liver and cerebral cortex, reflecting a high lipid oxidative damage in these tissues. Our data showing an imbalance between tissue antioxidant defences and oxidative attack strongly indicate that oxidative stress is involved in the pathophysiology of SSADH deficiency in mice, and likely the corresponding human disorder.
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Therapeutic concepts in Succinate Semialdehyde Dehydrogenase (SSADH; ALDH5a1) deficiency (γ-hydroxybutyric aciduria). Hypotheses evolved from 25 years of patient evaluation, studies in Aldh5a1 ^−/− mice and characterization of γ-
Journal of Inherited Metabolic Disease, 2007Co-Authors: I Knerr, Teodoro Bottiglieri, C. Jakobs, P. L. Pearl, O. Carter Snead, KM GibsonAbstract:We overview the pathophysiological bases, clinical approaches and potential therapeutic options for Succinate Semialdehyde Dehydrogenase (SSADH; EC1.2.1.24) deficiency (γ-hydroxybutyric aciduria, OMIM 271980, 610045) in relation to studies on SSADH gene-deleted mice, outcome data developed from 25 years of patient evaluation, and characterization of γ-hydroxybutyric acid (GHB) pharmacology in different species. The clinical picture of this disorder encompasses a wide spectrum of neurological and psychiatric dysfunction, such as psychomotor retardation, delayed speech development, epileptic seizures and behavioural disturbances, emphasizing the multifactorial pathophysiology of SSADH deficiency. The murine SSADH^−/− (e.g. Aldh5a1 ^−/−) mouse model suffers from epileptic seizures and succumbs to early lethality. Aldh5a1 ^−/− mice accumulate GHB and γ-aminobutyric acid (GABA) in the central nervous system, exhibit alterations of amino acids such as glutamine (Gln), alanine (Ala) and arginine (Arg), and manifest disturbances in other systems including dopamine, neurosteroids and antioxidant status. Therapeutic concepts in patients with SSADH deficiency and preclinical therapeutic experiments are discussed in light of data collected from research in Aldh5a1 ^−/− mice and animal studies of GHB pharmacology; these studies are the foundation for novel working approaches, including pharmacological and dietary trials, which are presented for future evaluation in this disease.
K. Michael Gibson - One of the best experts on this subject based on the ideXlab platform.
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Familial 6p22.2 duplication associates with mild developmental delay and increased SSADH activity.
American journal of medical genetics. Part B Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics, 2011Co-Authors: Linda Siggberg, K. Michael Gibson, Cornelis Jakobs, Gajja S. Salomons, Aki Mustonen, Robert Schuit, Birthe Roos, Jaakko Ignatius, Sakari KnuutilaAbstract:We present a family with mild developmental delay and a duplication (6)(p22.2). Array CGH analyses revealed this 0.7 Mb duplication in all three patients, spanning candidate genes ALDH5A1, DCDC2, and KIAA0319. Results were confirmed by MLPA analysis of the dyslexia genes DCDC2 and KIAA0319. Of interest, ALDH5A1 encodes Succinate Semialdehyde Dehydrogenase (SSADH), an enzyme responsible for γ-amino-butyric acid (GABA) degradation. Inherited deficiency of SSADH results in accumulation of the neuromodulator γ-hydroxybutyrate (GHB), which likely contributes to some aspects of the neurological phenotype of SSADH deficiency (MIM #271980). Based on autosomal-recessive inheritance, we sequenced ALDH5A1 in all patients, which revealed no pathogenic mutations. SSADH enzyme studies in cultured white cells confirmed elevated SSADH activity, consistent with the duplication, whereas concentrations of SSA were slightly elevated in urine, suggesting oxidant stress. We speculate that the duplication (6)(p22.2) and corresponding hyperactive level of SSADH activity may have negative consequences for GABA metabolism and the role of SSADH in other metabolic sequences.
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Comparative genomics of aldehyde Dehydrogenase 5a1 (Succinate Semialdehyde Dehydrogenase) and accumulation of gamma-hydroxybutyrate associated with its deficiency
Human Genomics, 2009Co-Authors: Patrizia Malaspina, O. Carter Snead, C. Jakobs, Matthew J. Picklo, K. Michael GibsonAbstract:Succinic Semialdehyde Dehydrogenase (SSADH; aldehyde Dehydrogenase 5A1 [ALDH5A1]; locus 6p22) occupies a central position in central nervous system (CNS) neurotransmitter metabolism as one of two enzymes necessary for γ -aminobutyric acid (GABA) recycling from the synaptic cleft. Its importance is highlighted by the neurometabolic disease associated with its inherited deficiency in humans, as well as the severe epileptic phenotype observed in Aldh5a1 ^-/- knockout mice. Expanding evidence now suggests, however, that even subtle decreases in human SSADH activity, associated with rare and common single nucleotide polymorphisms, may produce subclinical pathological effects. SSADH, in conjunction with aldo-keto reductase 7A2 (AKR7A2), represent two neural enzymes responsible for further catabolism of succinic Semialdehyde, producing either Succinate (SSADH) or γ -hydroxybutyrate (GHB; AKR7A2). A GABA analogue, GHB is a short-chain fatty alcohol with unusual properties in the CNS and a long pharmacological history. Moreover, SSADH occupies a further role in the CNS as the enzyme responsible for further metabolism of the lipid peroxidation aldehyde 4-hydroxy-2-nonenal (4-HNE), an intermediate known to induce oxidant stress. Accordingly, subtle decreases in SSADH activity may have the capacity to lead to regional accumulation of neurotoxic intermediates (GHB, 4-HNE). Polymorphisms in SSADH gene structure may also associate with quantitative traits, including intelligence quotient and life expectancy. Further population-based studies of human SSADH activity promise to reveal additional properties of its function and additional roles in CNS tissue.
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Neurotransmitter alterations in embryonic Succinate Semialdehyde Dehydrogenase (SSADH) deficiency suggest a heightened excitatory state during development
BMC Developmental Biology, 2008Co-Authors: Erwin E.w. Jansen, Cornelis Jakobs, O. Carter Snead, Eduard Struys, Elizabeth Hager, K. Michael GibsonAbstract:Background SSADH (aldehyde Dehydrogenase 5a1 (Aldh5a1); γ-hydroxybutyric (GHB) aciduria) deficiency is a defect of GABA degradation in which the neuromodulators GABA and GHB accumulate. The human phenotype is that of nonprogressive encephalopathy with prominent bilateral discoloration of the globi pallidi and variable seizures, the latter displayed prominently in Aldh5a1^-/- mice with lethal convulsions. Metabolic studies in murine neural tissue have revealed elevated GABA [and its derivatives Succinate Semialdehyde (SSA), homocarnosine (HC), 4,5-dihydroxyhexanoic acid (DHHA) and guanidinobutyrate (GB)] and GHB [and its analogue D-2-hydroxyglutarate (D-2-HG)] at birth. Because of early onset seizures and the neurostructural anomalies observed in patients, we examined metabolite features during Aldh5a1^-/- embryo development. Methods Embryos were obtained from pregnant dams sacrificed at E (embryo day of life) 10–13, 14–15, 16–17, 18–19 and newborn mice. Intact embryos were extracted and metabolites quantified by isotope dilution mass spectrometry (n = 5–15 subjects, Aldh5a1^+/+ and Aldh5a1^-/-) for each gestational age group. Data was evaluated using the t test and one-way ANOVA with Tukey post hoc analysis. Significance was set at the 95^th centile. Results GABA and DHHA were significantly elevated at all gestational ages in Aldh5a1^-/- mice, while GB was increased only late in gestation; SSA was not elevated at any time point. GHB and D-2-HG increased in an approximately linear fashion with gestational age. Correlative studies in human amniotic fluid from SSADH-deficient pregnancies (n = 5) also revealed significantly increased GABA. Conclusion Our findings indicate early GABAergic alterations in Aldh5a1^-/- mice, possibly exacerbated by other metabolites, which likely induce a heightened excitatory state that may predispose neural networks to epilepsy in these animals.
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Neurotransmitter alterations in embryonic Succinate Semialdehyde Dehydrogenase (SSADH) deficiency suggest a heightened excitatory state during development
BMC Developmental Biology, 2008Co-Authors: Erwin E.w. Jansen, Cornelis Jakobs, O. Carter Snead, Eduard Struys, Elizabeth J. Hager, K. Michael GibsonAbstract:Background: SSADH (aldehyde Dehydrogenase 5a1 (Aldh5a1); γ-hydroxybutyric (GHB) aciduria) deficiency is a defect of GABA degradation in which the neuromodulators GABA and GHB accumulate. The human phenotype is that of nonprogressive encephalopathy with prominent bilateral discoloration of the globi pallidi and variable seizures, the latter displayed prominently in Aldh5a1 -/- mice with lethal convulsions. Metabolic studies in murine neural tissue have revealed elevated GABA [and its derivatives Succinate Semialdehyde (SSA), homocarnosine (HC), 4,5-dihydroxyhexanoic acid (DHHA) and guanidinobutyrate (GB)] and GHB [and its analogue D-2-hydroxyglutarate (D-2-HG)] at birth. Because of early onset seizures and the neurostructural anomalies observed in patients, we examined metabolite features during Aldh5a1-/- embryo development.
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Succinate Semialdehyde Dehydrogenase deficiency does not down-regulate γ-hydroxybutyric acid binding sites in the mouse brain
Molecular Genetics and Metabolism, 2006Co-Authors: Ashok K Mehta, Maneesh Gupta, K. Michael Gibson, Lawrence P Carter, Georgianna G Gould, Maharaj K TickuAbstract:Abstract We investigated whether Succinate Semialdehyde Dehydrogenase deficiency alters γ-hydroxybutyric acid (GHB) receptor characteristics due to elevation of GHB levels in the mouse brain. The membrane homogenate binding and quantitative autoradiography using [ 3 H]NCS-382 revealed no significant changes in the affinity ( K d ), receptor density ( B max ), or displacement potency (IC 50 ) in various brain regions of Aldh5a1 −/− vs. Aldh5a1 +/+ mice.
O. Carter Snead - One of the best experts on this subject based on the ideXlab platform.
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Comparative genomics of aldehyde Dehydrogenase 5a1 (Succinate Semialdehyde Dehydrogenase) and accumulation of gamma-hydroxybutyrate associated with its deficiency
Human Genomics, 2009Co-Authors: Patrizia Malaspina, O. Carter Snead, C. Jakobs, Matthew J. Picklo, K. Michael GibsonAbstract:Succinic Semialdehyde Dehydrogenase (SSADH; aldehyde Dehydrogenase 5A1 [ALDH5A1]; locus 6p22) occupies a central position in central nervous system (CNS) neurotransmitter metabolism as one of two enzymes necessary for γ -aminobutyric acid (GABA) recycling from the synaptic cleft. Its importance is highlighted by the neurometabolic disease associated with its inherited deficiency in humans, as well as the severe epileptic phenotype observed in Aldh5a1 ^-/- knockout mice. Expanding evidence now suggests, however, that even subtle decreases in human SSADH activity, associated with rare and common single nucleotide polymorphisms, may produce subclinical pathological effects. SSADH, in conjunction with aldo-keto reductase 7A2 (AKR7A2), represent two neural enzymes responsible for further catabolism of succinic Semialdehyde, producing either Succinate (SSADH) or γ -hydroxybutyrate (GHB; AKR7A2). A GABA analogue, GHB is a short-chain fatty alcohol with unusual properties in the CNS and a long pharmacological history. Moreover, SSADH occupies a further role in the CNS as the enzyme responsible for further metabolism of the lipid peroxidation aldehyde 4-hydroxy-2-nonenal (4-HNE), an intermediate known to induce oxidant stress. Accordingly, subtle decreases in SSADH activity may have the capacity to lead to regional accumulation of neurotoxic intermediates (GHB, 4-HNE). Polymorphisms in SSADH gene structure may also associate with quantitative traits, including intelligence quotient and life expectancy. Further population-based studies of human SSADH activity promise to reveal additional properties of its function and additional roles in CNS tissue.
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Neurotransmitter alterations in embryonic Succinate Semialdehyde Dehydrogenase (SSADH) deficiency suggest a heightened excitatory state during development
BMC Developmental Biology, 2008Co-Authors: Erwin E.w. Jansen, Cornelis Jakobs, O. Carter Snead, Eduard Struys, Elizabeth Hager, K. Michael GibsonAbstract:Background SSADH (aldehyde Dehydrogenase 5a1 (Aldh5a1); γ-hydroxybutyric (GHB) aciduria) deficiency is a defect of GABA degradation in which the neuromodulators GABA and GHB accumulate. The human phenotype is that of nonprogressive encephalopathy with prominent bilateral discoloration of the globi pallidi and variable seizures, the latter displayed prominently in Aldh5a1^-/- mice with lethal convulsions. Metabolic studies in murine neural tissue have revealed elevated GABA [and its derivatives Succinate Semialdehyde (SSA), homocarnosine (HC), 4,5-dihydroxyhexanoic acid (DHHA) and guanidinobutyrate (GB)] and GHB [and its analogue D-2-hydroxyglutarate (D-2-HG)] at birth. Because of early onset seizures and the neurostructural anomalies observed in patients, we examined metabolite features during Aldh5a1^-/- embryo development. Methods Embryos were obtained from pregnant dams sacrificed at E (embryo day of life) 10–13, 14–15, 16–17, 18–19 and newborn mice. Intact embryos were extracted and metabolites quantified by isotope dilution mass spectrometry (n = 5–15 subjects, Aldh5a1^+/+ and Aldh5a1^-/-) for each gestational age group. Data was evaluated using the t test and one-way ANOVA with Tukey post hoc analysis. Significance was set at the 95^th centile. Results GABA and DHHA were significantly elevated at all gestational ages in Aldh5a1^-/- mice, while GB was increased only late in gestation; SSA was not elevated at any time point. GHB and D-2-HG increased in an approximately linear fashion with gestational age. Correlative studies in human amniotic fluid from SSADH-deficient pregnancies (n = 5) also revealed significantly increased GABA. Conclusion Our findings indicate early GABAergic alterations in Aldh5a1^-/- mice, possibly exacerbated by other metabolites, which likely induce a heightened excitatory state that may predispose neural networks to epilepsy in these animals.
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Neurotransmitter alterations in embryonic Succinate Semialdehyde Dehydrogenase (SSADH) deficiency suggest a heightened excitatory state during development
BMC Developmental Biology, 2008Co-Authors: Erwin E.w. Jansen, Cornelis Jakobs, O. Carter Snead, Eduard Struys, Elizabeth J. Hager, K. Michael GibsonAbstract:Background: SSADH (aldehyde Dehydrogenase 5a1 (Aldh5a1); γ-hydroxybutyric (GHB) aciduria) deficiency is a defect of GABA degradation in which the neuromodulators GABA and GHB accumulate. The human phenotype is that of nonprogressive encephalopathy with prominent bilateral discoloration of the globi pallidi and variable seizures, the latter displayed prominently in Aldh5a1 -/- mice with lethal convulsions. Metabolic studies in murine neural tissue have revealed elevated GABA [and its derivatives Succinate Semialdehyde (SSA), homocarnosine (HC), 4,5-dihydroxyhexanoic acid (DHHA) and guanidinobutyrate (GB)] and GHB [and its analogue D-2-hydroxyglutarate (D-2-HG)] at birth. Because of early onset seizures and the neurostructural anomalies observed in patients, we examined metabolite features during Aldh5a1-/- embryo development.
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Therapeutic concepts in Succinate Semialdehyde Dehydrogenase (SSADH; ALDH5a1) deficiency (γ‐hydroxybutyric aciduria). Hypotheses evolved from 25 years of patient evaluation, studies in Aldh5a1−/− mice and characterization of γ‐hydroxybutyric acid pha
Journal of Inherited Metabolic Disease, 2007Co-Authors: I Knerr, O. Carter Snead, Teodoro Bottiglieri, C. Jakobs, P. L. Pearl, KM GibsonAbstract:We overview the pathophysiological bases, clinical approaches and potential therapeutic options for Succinate Semialdehyde Dehydrogenase (SSADH; EC1.2.1.24) deficiency (γ-hydroxybutyric aciduria, OMIM 271980, 610045) in relation to studies on SSADH gene-deleted mice, outcome data developed from 25 years of patient evaluation, and characterization of γ-hydroxybutyric acid (GHB) pharmacology in different species. The clinical picture of this disorder encompasses a wide spectrum of neurological and psychiatric dysfunction, such as psychomotor retardation, delayed speech development, epileptic seizures and behavioural disturbances, emphasizing the multifactorial pathophysiology of SSADH deficiency. The murine SSADH−/− (e.g. Aldh5a1−/−) mouse model suffers from epileptic seizures and succumbs to early lethality. Aldh5a1−/− mice accumulate GHB and γ-aminobutyric acid (GABA) in the central nervous system, exhibit alterations of amino acids such as glutamine (Gln), alanine (Ala) and arginine (Arg), and manifest disturbances in other systems including dopamine, neurosteroids and antioxidant status. Therapeutic concepts in patients with SSADH deficiency and preclinical therapeutic experiments are discussed in light of data collected from research in Aldh5a1−/− mice and animal studies of GHB pharmacology; these studies are the foundation for novel working approaches, including pharmacological and dietary trials, which are presented for future evaluation in this disease.
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Increased guanidino species in murine and human Succinate Semialdehyde Dehydrogenase (SSADH) deficiency.
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2006Co-Authors: Erwin E.w. Jansen, Maneesh Gupta, Andreas Schulze, Nanda M. Verhoeven, Cornelis Jakobs, Henry Senephansiri, O. Carter Snead, K. Michael GibsonAbstract:Abstract Mice with targeted deletion of the GABA-degradative enzyme Succinate Semialdehyde Dehydrogenase (SSADH; Aldh5a1 ; OMIM 271980) manifest globally elevated GABA and regionally decreased arginine in brain extracts. We examined the hypothesis that arginine–glycine amidinotransferase catalyzed the formation of guanidinobutyrate (GB) from increased GABA by quantifying guanidinoacetate (GA), guanidinopropionate (GP) and GB in brain extracts employing stable isotope dilution gas chromatographic-mass spectrometry. GA and GB were up to 4- and 22-fold elevated, respectively, in total and regional (cerebellum, hippocampus, cortex) brain extracts derived from SSADH −/− mice. Corresponding analyses of urine and cerebrospinal fluid derived from SSADH-deficient patients revealed significant ( P
Cornelis Jakobs - One of the best experts on this subject based on the ideXlab platform.
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Familial 6p22.2 duplication associates with mild developmental delay and increased SSADH activity.
American journal of medical genetics. Part B Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics, 2011Co-Authors: Linda Siggberg, K. Michael Gibson, Cornelis Jakobs, Gajja S. Salomons, Aki Mustonen, Robert Schuit, Birthe Roos, Jaakko Ignatius, Sakari KnuutilaAbstract:We present a family with mild developmental delay and a duplication (6)(p22.2). Array CGH analyses revealed this 0.7 Mb duplication in all three patients, spanning candidate genes ALDH5A1, DCDC2, and KIAA0319. Results were confirmed by MLPA analysis of the dyslexia genes DCDC2 and KIAA0319. Of interest, ALDH5A1 encodes Succinate Semialdehyde Dehydrogenase (SSADH), an enzyme responsible for γ-amino-butyric acid (GABA) degradation. Inherited deficiency of SSADH results in accumulation of the neuromodulator γ-hydroxybutyrate (GHB), which likely contributes to some aspects of the neurological phenotype of SSADH deficiency (MIM #271980). Based on autosomal-recessive inheritance, we sequenced ALDH5A1 in all patients, which revealed no pathogenic mutations. SSADH enzyme studies in cultured white cells confirmed elevated SSADH activity, consistent with the duplication, whereas concentrations of SSA were slightly elevated in urine, suggesting oxidant stress. We speculate that the duplication (6)(p22.2) and corresponding hyperactive level of SSADH activity may have negative consequences for GABA metabolism and the role of SSADH in other metabolic sequences.
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Neurotransmitter alterations in embryonic Succinate Semialdehyde Dehydrogenase (SSADH) deficiency suggest a heightened excitatory state during development
BMC Developmental Biology, 2008Co-Authors: Erwin E.w. Jansen, Cornelis Jakobs, O. Carter Snead, Eduard Struys, Elizabeth Hager, K. Michael GibsonAbstract:Background SSADH (aldehyde Dehydrogenase 5a1 (Aldh5a1); γ-hydroxybutyric (GHB) aciduria) deficiency is a defect of GABA degradation in which the neuromodulators GABA and GHB accumulate. The human phenotype is that of nonprogressive encephalopathy with prominent bilateral discoloration of the globi pallidi and variable seizures, the latter displayed prominently in Aldh5a1^-/- mice with lethal convulsions. Metabolic studies in murine neural tissue have revealed elevated GABA [and its derivatives Succinate Semialdehyde (SSA), homocarnosine (HC), 4,5-dihydroxyhexanoic acid (DHHA) and guanidinobutyrate (GB)] and GHB [and its analogue D-2-hydroxyglutarate (D-2-HG)] at birth. Because of early onset seizures and the neurostructural anomalies observed in patients, we examined metabolite features during Aldh5a1^-/- embryo development. Methods Embryos were obtained from pregnant dams sacrificed at E (embryo day of life) 10–13, 14–15, 16–17, 18–19 and newborn mice. Intact embryos were extracted and metabolites quantified by isotope dilution mass spectrometry (n = 5–15 subjects, Aldh5a1^+/+ and Aldh5a1^-/-) for each gestational age group. Data was evaluated using the t test and one-way ANOVA with Tukey post hoc analysis. Significance was set at the 95^th centile. Results GABA and DHHA were significantly elevated at all gestational ages in Aldh5a1^-/- mice, while GB was increased only late in gestation; SSA was not elevated at any time point. GHB and D-2-HG increased in an approximately linear fashion with gestational age. Correlative studies in human amniotic fluid from SSADH-deficient pregnancies (n = 5) also revealed significantly increased GABA. Conclusion Our findings indicate early GABAergic alterations in Aldh5a1^-/- mice, possibly exacerbated by other metabolites, which likely induce a heightened excitatory state that may predispose neural networks to epilepsy in these animals.
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Neurotransmitter alterations in embryonic Succinate Semialdehyde Dehydrogenase (SSADH) deficiency suggest a heightened excitatory state during development
BMC Developmental Biology, 2008Co-Authors: Erwin E.w. Jansen, Cornelis Jakobs, O. Carter Snead, Eduard Struys, Elizabeth J. Hager, K. Michael GibsonAbstract:Background: SSADH (aldehyde Dehydrogenase 5a1 (Aldh5a1); γ-hydroxybutyric (GHB) aciduria) deficiency is a defect of GABA degradation in which the neuromodulators GABA and GHB accumulate. The human phenotype is that of nonprogressive encephalopathy with prominent bilateral discoloration of the globi pallidi and variable seizures, the latter displayed prominently in Aldh5a1 -/- mice with lethal convulsions. Metabolic studies in murine neural tissue have revealed elevated GABA [and its derivatives Succinate Semialdehyde (SSA), homocarnosine (HC), 4,5-dihydroxyhexanoic acid (DHHA) and guanidinobutyrate (GB)] and GHB [and its analogue D-2-hydroxyglutarate (D-2-HG)] at birth. Because of early onset seizures and the neurostructural anomalies observed in patients, we examined metabolite features during Aldh5a1-/- embryo development.
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Increased guanidino species in murine and human Succinate Semialdehyde Dehydrogenase (SSADH) deficiency.
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2006Co-Authors: Erwin E.w. Jansen, Maneesh Gupta, Andreas Schulze, Nanda M. Verhoeven, Cornelis Jakobs, Henry Senephansiri, O. Carter Snead, K. Michael GibsonAbstract:Abstract Mice with targeted deletion of the GABA-degradative enzyme Succinate Semialdehyde Dehydrogenase (SSADH; Aldh5a1 ; OMIM 271980) manifest globally elevated GABA and regionally decreased arginine in brain extracts. We examined the hypothesis that arginine–glycine amidinotransferase catalyzed the formation of guanidinobutyrate (GB) from increased GABA by quantifying guanidinoacetate (GA), guanidinopropionate (GP) and GB in brain extracts employing stable isotope dilution gas chromatographic-mass spectrometry. GA and GB were up to 4- and 22-fold elevated, respectively, in total and regional (cerebellum, hippocampus, cortex) brain extracts derived from SSADH −/− mice. Corresponding analyses of urine and cerebrospinal fluid derived from SSADH-deficient patients revealed significant ( P
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Expression profiling reveals multiple myelin alterations in murine Succinate Semialdehyde Dehydrogenase deficiency.
Journal of Inherited Metabolic Disease, 2006Co-Authors: Elizabeth A. Donarum, Maneesh Gupta, Henry Senephansiri, O. Carter Snead, P. L. Pearl, Dietrich A. Stephan, Kay Larkin, Eric J. Murphy, Robert C. Switzer, Cornelis JakobsAbstract:Succinic Semialdehyde Dehydrogenase (SSADH) deficiency, a rare genetic defect of GABA degradation recently modelled in mice (SSADH−/− mice), manifests early absence seizures that evolve into generalized convulsive seizures and lethal status epilepticus in gene-ablated mice. Disrupted GABA homeostasis, in conjunction with the epileptic phenotype and increased gamma-hydroxybutyric acid (GHB), suggested that expression profiling with the U74Av2 Affymetrix system would reveal dysregulation of receptor genes associated with GABAergic and glutamatergic neurotransmission. Unexpectedly, we found significant downregulation for genes associated with myelin biogenesis and compaction, predominantly in hippocampus and cortex. These results were confirmed by: (1) myelin basic protein (MBP) immunohistochemistry; (2) western blotting of myelin-associated glycoprotein (MAG) and MBP; (3) qRT-PCR analyses of myelin-associated oligodendrocytic basic protein (MOBP), MAG, MBP and proteolipid protein (PLP) in hippocampus, cortex and spinal cord; (4) quantitation of ethanolamine and choline plasmalogens, all core myelin components; (5) evaluation of myelin content in brain sections employing toluidine blue staining; and (6) ultrastructural evaluation of myelin sheath thickness via electron microscopy. We speculate that increased GABA/GHB, acting through GABAergic systems, results in decreased levels of the neurosteroids progesterone and allopregnanolone [Gupta et al (2003) Ann Neurol54(Supplement 6): S81–S90] and phosphorylation of mitogen-activated protein (MAP) kinase, with resulting myelin protein abnormalities primarily in the cortex of SSADH−/− mice.
Maneesh Gupta - One of the best experts on this subject based on the ideXlab platform.
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Succinate Semialdehyde Dehydrogenase deficiency does not down-regulate γ-hydroxybutyric acid binding sites in the mouse brain
Molecular Genetics and Metabolism, 2006Co-Authors: Ashok K Mehta, Maneesh Gupta, K. Michael Gibson, Lawrence P Carter, Georgianna G Gould, Maharaj K TickuAbstract:Abstract We investigated whether Succinate Semialdehyde Dehydrogenase deficiency alters γ-hydroxybutyric acid (GHB) receptor characteristics due to elevation of GHB levels in the mouse brain. The membrane homogenate binding and quantitative autoradiography using [ 3 H]NCS-382 revealed no significant changes in the affinity ( K d ), receptor density ( B max ), or displacement potency (IC 50 ) in various brain regions of Aldh5a1 −/− vs. Aldh5a1 +/+ mice.
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Increased guanidino species in murine and human Succinate Semialdehyde Dehydrogenase (SSADH) deficiency.
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2006Co-Authors: Erwin E.w. Jansen, Maneesh Gupta, Andreas Schulze, Nanda M. Verhoeven, Cornelis Jakobs, Henry Senephansiri, O. Carter Snead, K. Michael GibsonAbstract:Abstract Mice with targeted deletion of the GABA-degradative enzyme Succinate Semialdehyde Dehydrogenase (SSADH; Aldh5a1 ; OMIM 271980) manifest globally elevated GABA and regionally decreased arginine in brain extracts. We examined the hypothesis that arginine–glycine amidinotransferase catalyzed the formation of guanidinobutyrate (GB) from increased GABA by quantifying guanidinoacetate (GA), guanidinopropionate (GP) and GB in brain extracts employing stable isotope dilution gas chromatographic-mass spectrometry. GA and GB were up to 4- and 22-fold elevated, respectively, in total and regional (cerebellum, hippocampus, cortex) brain extracts derived from SSADH −/− mice. Corresponding analyses of urine and cerebrospinal fluid derived from SSADH-deficient patients revealed significant ( P
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Expression profiling reveals multiple myelin alterations in murine Succinate Semialdehyde Dehydrogenase deficiency.
Journal of Inherited Metabolic Disease, 2006Co-Authors: Elizabeth A. Donarum, Maneesh Gupta, Henry Senephansiri, O. Carter Snead, P. L. Pearl, Dietrich A. Stephan, Kay Larkin, Eric J. Murphy, Robert C. Switzer, Cornelis JakobsAbstract:Succinic Semialdehyde Dehydrogenase (SSADH) deficiency, a rare genetic defect of GABA degradation recently modelled in mice (SSADH−/− mice), manifests early absence seizures that evolve into generalized convulsive seizures and lethal status epilepticus in gene-ablated mice. Disrupted GABA homeostasis, in conjunction with the epileptic phenotype and increased gamma-hydroxybutyric acid (GHB), suggested that expression profiling with the U74Av2 Affymetrix system would reveal dysregulation of receptor genes associated with GABAergic and glutamatergic neurotransmission. Unexpectedly, we found significant downregulation for genes associated with myelin biogenesis and compaction, predominantly in hippocampus and cortex. These results were confirmed by: (1) myelin basic protein (MBP) immunohistochemistry; (2) western blotting of myelin-associated glycoprotein (MAG) and MBP; (3) qRT-PCR analyses of myelin-associated oligodendrocytic basic protein (MOBP), MAG, MBP and proteolipid protein (PLP) in hippocampus, cortex and spinal cord; (4) quantitation of ethanolamine and choline plasmalogens, all core myelin components; (5) evaluation of myelin content in brain sections employing toluidine blue staining; and (6) ultrastructural evaluation of myelin sheath thickness via electron microscopy. We speculate that increased GABA/GHB, acting through GABAergic systems, results in decreased levels of the neurosteroids progesterone and allopregnanolone [Gupta et al (2003) Ann Neurol54(Supplement 6): S81–S90] and phosphorylation of mitogen-activated protein (MAP) kinase, with resulting myelin protein abnormalities primarily in the cortex of SSADH−/− mice.
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Liver-directed adenoviral gene transfer in murine Succinate Semialdehyde Dehydrogenase deficiency.
Molecular Therapy, 2004Co-Authors: Maneesh Gupta, Erwin E.w. Jansen, Cornelis Jakobs, Henry Senephansiri, O. Carter Snead, Markus Grompe, K. Michael GibsonAbstract:Abstract Murine Succinate Semialdehyde Dehydrogenase (SSADH) deficiency (OMIM 271980; EC 1.2.1.24), a model of the corresponding human disorder, displays 100% mortality at weeks 3–4 of life, associated with lethal tonic–clonic seizures. The biochemical hallmark, γ-hydroxybutyrate (GHB), accumulates in both human and murine disorders. In the current study we evaluated rescue of the murine model with liver-directed gene therapy using the E1-deleted adenoviral vector AD:pAD-RSV-humanSSADH. Our working hypotheses were: (1) liver expresses considerable SSADH activity and therefore represents a major source of GHB output, (2) correction of liver enzyme deficiency will reduce GHB load both peripherally and in the central nervous system, and (3) SSADH expression will improve survival. SSADH −/− and SSADH +/+ mice were treated under two protocols: (A) intraperitoneal injection of 10 8 –10 11 viral particles by day 10 of life or (B) retro-orbital injection of 10 11 viral particles at day 13 of life. Intravenous administration was prohibited by the small size and fragility of the mice. Maximal survival (39%; P 8 particles) at day 10; intraperitoneal (10 10 and 10 11 particles) and retro-orbital administration (10 11 particles) yielded lower survival of 11–25% ( P +/+ liver activity (retro-orbital > ip). At various time points postinjection, ip-treated animals (10 8 viral particles) demonstrated upward of 80% reduction in liver GHB concentrations, with little impact on brain or serum GHB levels except at 48–72 h posttreatment (∼50% reduction for both tissues). Accordingly, we harvested retro-orbitally treated animals at 72 h and observed significant reductions of 60–70% for GHB in liver, kidney, serum, and brain extracts. Histochemical analysis of liver from retro-orbitally treated mutants demonstrated substantial SSADH staining, but with variability both within tissues and between animals. Our studies provide proof-of-principle that liver-mediated gene therapy has efficacy in treating SSADH deficiency and that hepatic tissue contributes significantly to the pool of GHB within the CNS.
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Seizure evolution and amino acid imbalances in murine Succinate Semialdehyde Dehydrogenase (SSADH) deficiency.
Neurobiology of Disease, 2004Co-Authors: Maneesh Gupta, Erwin E.w. Jansen, Cornelis Jakobs, Henry Senephansiri, O. Carter Snead, M. Polinsky, KM GibsonAbstract:Abstract Mice with targeted deletion of the GABA catabolic enzyme succinic Semialdehyde Dehydrogenase (SSADH) manifest lethal tonic–clonic seizures, amenable to pharmacologic rescue, at 3–4 weeks of life. In the current report, we characterized amino acid profiles in SSADH−/− brain utilizing whole brain and regional extracts (frontal and parietal cortex, hippocampus, and cerebellum) to develop hypotheses concerning epileptogenesis. Of 35 amino acids quantified, we found significant dysregulation in SSADH−/− mice for 11 (GABA, glutamate, glutamine, alanine, aspartate, serine, taurine, cystathionine, methionine, homocarnosine, and arginine) as compared to age-matched littermates both before, and following, the period of generalized convulsive seizures and status epilepticus. Our results reveal imbalanced amino acid levels potentially involved in the transition from absence seizures to generalized convulsive seizures resulting in SSADH−/− mice. We conclude that the SSADH−/− mouse represents a unique epileptic model with the potential to reveal novel aspects of excitatory/inhibitory interactions in the genesis of seizures.
