The Experts below are selected from a list of 81 Experts worldwide ranked by ideXlab platform
Turgay Coşkun - One of the best experts on this subject based on the ideXlab platform.
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Genetic basis of Hyperlysinemia
Orphanet Journal of Rare Diseases, 2013Co-Authors: Sander M Houten, Heleen Te Brinke, Simone Denis, Jos Pn Ruiter, Alida C Knegt, Johannis Bc De Klerk, Persephone Augoustides-savvopoulou, Johannes Häberle, Matthias R Baumgartner, Turgay CoşkunAbstract:Background Hyperlysinemia is an autosomal recessive inborn error of L-lysine degradation. To date only one causal mutation in the AASS gene encoding α-aminoadipic semialdehyde synthase has been reported. We aimed to better define the genetic basis of Hyperlysinemia. Methods We collected the clinical, biochemical and molecular data in a cohort of 8 Hyperlysinemia patients with distinct neurological features. Results We found novel causal mutations in AASS in all affected individuals, including 4 missense mutations, 2 deletions and 1 duplication. In two patients originating from one family, the Hyperlysinemia was caused by a contiguous gene deletion syndrome affecting AASS and PTPRZ1 . Conclusions Hyperlysinemia is caused by mutations in AASS . As Hyperlysinemia is generally considered a benign metabolic variant, the more severe neurological disease course in two patients with a contiguous deletion syndrome may be explained by the additional loss of PTPRZ1 . Our findings illustrate the importance of detailed biochemical and genetic studies in any Hyperlysinemia patient.
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genetic basis of Hyperlysinemia
Orphanet Journal of Rare Diseases, 2013Co-Authors: Sander M Houten, Heleen Te Brinke, Simone Denis, Jos Pn Ruiter, Alida C Knegt, Johannis Bc De Klerk, Johannes Häberle, Matthias R Baumgartner, Persephone Augoustidessavvopoulou, Turgay CoşkunAbstract:Background Hyperlysinemia is an autosomal recessive inborn error of L-lysine degradation. To date only one causal mutation in the AASS gene encoding α-aminoadipic semialdehyde synthase has been reported. We aimed to better define the genetic basis of Hyperlysinemia.
Sander M Houten - One of the best experts on this subject based on the ideXlab platform.
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mitochondrial nadp h deficiency due to a mutation in nadk2 causes dienoyl coa reductase deficiency with Hyperlysinemia
Human Molecular Genetics, 2014Co-Authors: Sander M Houten, Heleen Te Brinke, Simone Denis, Aldo Jongejan, Antoine H C Van Kampen, Edward J Bradley, Frank Baas, Raoul C M Hennekam, David S Millington, Sarah P YoungAbstract:Dienoyl-CoA reductase (DECR) deficiency with Hyperlysinemia is a rare disorder affecting the metabolism of polyunsaturated fatty acids and lysine. The molecular basis of this condition is currently unknown. We describe a new case with failure to thrive, developmental delay, lactic acidosis and severe encephalopathy suggestive of a mitochondrial disorder. Exome sequencing revealed a causal mutation in NADK2. NADK2 encodes the mitochondrial NAD kinase, which is crucial for NADP biosynthesis evidenced by decreased mitochondrial NADP(H) levels in patient fibroblasts. DECR and also the first step in lysine degradation are performed by NADP-dependent oxidoreductases explaining their in vivo deficiency. DECR activity was also deficient in lysates of patient fibroblasts and could only be rescued by transfecting patient cells with functional NADK2. Thus NADPH is not only crucial as a cosubstrate, but can also act as a molecular chaperone that activates and stabilizes enzymes. In addition to polyunsaturated fatty acid oxidation and lysine degradation, NADPH also plays a role in various other mitochondrial processes. We found decreased oxygen consumption and increased extracellular acidification in patient fibroblasts, which may explain why the disease course is consistent with clinical criteria for a mitochondrial disorder. We conclude that DECR deficiency with Hyperlysinemia is caused by mitochondrial NADP(H) deficiency due to a mutation in NADK2.
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Genetic basis of Hyperlysinemia
Orphanet Journal of Rare Diseases, 2013Co-Authors: Sander M Houten, Heleen Te Brinke, Simone Denis, Jos Pn Ruiter, Alida C Knegt, Johannis Bc De Klerk, Persephone Augoustides-savvopoulou, Johannes Häberle, Matthias R Baumgartner, Turgay CoşkunAbstract:Background Hyperlysinemia is an autosomal recessive inborn error of L-lysine degradation. To date only one causal mutation in the AASS gene encoding α-aminoadipic semialdehyde synthase has been reported. We aimed to better define the genetic basis of Hyperlysinemia. Methods We collected the clinical, biochemical and molecular data in a cohort of 8 Hyperlysinemia patients with distinct neurological features. Results We found novel causal mutations in AASS in all affected individuals, including 4 missense mutations, 2 deletions and 1 duplication. In two patients originating from one family, the Hyperlysinemia was caused by a contiguous gene deletion syndrome affecting AASS and PTPRZ1 . Conclusions Hyperlysinemia is caused by mutations in AASS . As Hyperlysinemia is generally considered a benign metabolic variant, the more severe neurological disease course in two patients with a contiguous deletion syndrome may be explained by the additional loss of PTPRZ1 . Our findings illustrate the importance of detailed biochemical and genetic studies in any Hyperlysinemia patient.
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genetic basis of Hyperlysinemia
Orphanet Journal of Rare Diseases, 2013Co-Authors: Sander M Houten, Heleen Te Brinke, Simone Denis, Jos Pn Ruiter, Alida C Knegt, Johannis Bc De Klerk, Johannes Häberle, Matthias R Baumgartner, Persephone Augoustidessavvopoulou, Turgay CoşkunAbstract:Background Hyperlysinemia is an autosomal recessive inborn error of L-lysine degradation. To date only one causal mutation in the AASS gene encoding α-aminoadipic semialdehyde synthase has been reported. We aimed to better define the genetic basis of Hyperlysinemia.
Moacir Wajner - One of the best experts on this subject based on the ideXlab platform.
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Neurochemical Evidence that Lysine Inhibits Synaptic Na^+,K^+-ATPase Activity and Provokes Oxidative Damage in Striatum of Young Rats In vivo
Neurochemical Research, 2011Co-Authors: Bianca Seminotti, Guilhian Leipnitz, Alexandre Umpierrez Amaral, Carolina Gonçalves Fernandes, Ângela Zanatta, Moacir WajnerAbstract:Lysine (Lys) accumulation in tissues and biological fluids is the biochemical hallmark of patients affected by familial Hyperlysinemia (FH) and other inherited metabolic disorders. In the present study we investigated the effects of acute administration of Lys on relevant parameters of energy metabolism and oxidative stress in striatum of young rats. We verified that Lys in vivo intrastriatal injection did not change the citric acid cycle function and creatine kinase activity, but, in contrast, significantly inhibited synaptic Na^+,K^+-ATPase activity in striatum prepared 2 and 12 h after injection. Moreover, Lys induced lipid peroxidation and diminished the concentrations of glutathione 2 h after injection. These effects were prevented by the antioxidant scavengers melatonin and the combination of α-tocopherol and ascorbic acid. Lys also inhibited glutathione peroxidase activity 12 h after injection. Therefore it is assumed that inhibition of synaptic Na^+,K^+-ATPase and oxidative damage caused by brain Lys accumulation may possibly contribute to the neurological manifestations of FH and other neurometabolic conditions with high concentrations of this amino acid.
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Neurochemical Evidence that Lysine Inhibits Synaptic Na+,K+-ATPase Activity and Provokes Oxidative Damage in Striatum of Young Rats In vivo
Neurochemical Research, 2010Co-Authors: Bianca Seminotti, Guilhian Leipnitz, Alexandre Umpierrez Amaral, Carolina Gonçalves Fernandes, Ângela Zanatta, Moacir WajnerAbstract:Lysine (Lys) accumulation in tissues and biological fluids is the biochemical hallmark of patients affected by familial Hyperlysinemia (FH) and other inherited metabolic disorders. In the present study we investigated the effects of acute administration of Lys on relevant parameters of energy metabolism and oxidative stress in striatum of young rats. We verified that Lys in vivo intrastriatal injection did not change the citric acid cycle function and creatine kinase activity, but, in contrast, significantly inhibited synaptic Na+,K+-ATPase activity in striatum prepared 2 and 12 h after injection. Moreover, Lys induced lipid peroxidation and diminished the concentrations of glutathione 2 h after injection. These effects were prevented by the antioxidant scavengers melatonin and the combination of α-tocopherol and ascorbic acid. Lys also inhibited glutathione peroxidase activity 12 h after injection. Therefore it is assumed that inhibition of synaptic Na+,K+-ATPase and oxidative damage caused by brain Lys accumulation may possibly contribute to the neurological manifestations of FH and other neurometabolic conditions with high concentrations of this amino acid.
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Inhibition of creatine kinase activity by lysine in rat cerebral cortex
Metabolic Brain Disease, 2009Co-Authors: Anelise Miotti Tonin, Bianca Seminotti, Guilhian Leipnitz, Ângela Zanatta, Gustavo Costa Ferreira, Patrícia Fernanda Schuck, Carolina Maso Viegas, Clóvis Milton Duvall Wannmacher, Moacir WajnerAbstract:Accumulation of lysine (Lys) in tissues and biochemical fluids is the biochemical hallmark of patients affected by familial Hyperlysinemia (FH) and also by other inherited neurometabolic disorders. In the present study, we investigated the in vitro effect of Lys on various parameters of energy metabolism in cerebral cortex of 30-day-old Wistar rats. We verified that total (tCK) and cytosolic creatine kinase activities were significantly inhibited by Lys, in contrast to the mitochondrial isoform which was not affected by this amino acid. Furthermore, the inhibitory effect of Lys on tCK activity was totally prevented by reduced glutathione, suggesting a possible role of reactive species oxidizing critical thiol groups of the enzyme. In contrast, Lys did not affect ^14CO_2 production from [U-^14C] glucose (aerobic glycolytic pathway) and [1-^14C] acetic acid (citric acid cycle activity) neither the various activities of the electron transfer chain and synaptic Na^+K^+-ATPase at concentrations as high as 5.0 mM. Considering the importance of creatine kinase (CK) activity for brain energy metabolism homeostasis and especially ATP transfer and buffering, our results suggest that inhibition of this enzyme by Lys may contribute to the neurological signs presented by symptomatic patients affected by FH and other neurodegenerative disorders in which Lys accumulates.
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Lysine induces lipid and protein damage and decreases reduced glutathione concentrations in brain of young rats.
International Journal of Developmental Neuroscience, 2008Co-Authors: Bianca Seminotti, Guilhian Leipnitz, Alexandre Umpierrez Amaral, Carolina Gonçalves Fernandes, Lucila De Bortoli Da Silva, Anelise Miotti Tonin, Carmen Regla Vargas, Moacir WajnerAbstract:Abstract The present work investigated the in vitro effects of lysine on important parameters of oxidative stress in cerebral cortex of young rats. Our results show that lysine significantly induced lipid peroxidation, as determined by increase of thiobarbituric acid-reactive substances and chemiluminescence levels, as well as protein oxidative damage since carbonyl formation and sulfhydryl oxidation were enhanced by this amino acid. Furthermore, the addition of free radical scavengers significantly prevented lysine-induced lipid oxidative damage, suggesting that free radicals were involved in this effect. Lysine also significantly diminished glutathione levels in cortical supernatants, decreasing, therefore, the major brain antioxidant defense. Finally, lysine markedly oxidized a glutathione commercial solution in a medium devoid of brain supernatants, indicating that it behaved as a direct acting oxidant. The present data indicate that lysine induces oxidative stress in cerebral cortex of young rats. Therefore, it is presumed that this pathomechanism may be involved at least in part in the neurological damage found in patients affected by disorders with Hyperlysinemia.
Simone Denis - One of the best experts on this subject based on the ideXlab platform.
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mitochondrial nadp h deficiency due to a mutation in nadk2 causes dienoyl coa reductase deficiency with Hyperlysinemia
Human Molecular Genetics, 2014Co-Authors: Sander M Houten, Heleen Te Brinke, Simone Denis, Aldo Jongejan, Antoine H C Van Kampen, Edward J Bradley, Frank Baas, Raoul C M Hennekam, David S Millington, Sarah P YoungAbstract:Dienoyl-CoA reductase (DECR) deficiency with Hyperlysinemia is a rare disorder affecting the metabolism of polyunsaturated fatty acids and lysine. The molecular basis of this condition is currently unknown. We describe a new case with failure to thrive, developmental delay, lactic acidosis and severe encephalopathy suggestive of a mitochondrial disorder. Exome sequencing revealed a causal mutation in NADK2. NADK2 encodes the mitochondrial NAD kinase, which is crucial for NADP biosynthesis evidenced by decreased mitochondrial NADP(H) levels in patient fibroblasts. DECR and also the first step in lysine degradation are performed by NADP-dependent oxidoreductases explaining their in vivo deficiency. DECR activity was also deficient in lysates of patient fibroblasts and could only be rescued by transfecting patient cells with functional NADK2. Thus NADPH is not only crucial as a cosubstrate, but can also act as a molecular chaperone that activates and stabilizes enzymes. In addition to polyunsaturated fatty acid oxidation and lysine degradation, NADPH also plays a role in various other mitochondrial processes. We found decreased oxygen consumption and increased extracellular acidification in patient fibroblasts, which may explain why the disease course is consistent with clinical criteria for a mitochondrial disorder. We conclude that DECR deficiency with Hyperlysinemia is caused by mitochondrial NADP(H) deficiency due to a mutation in NADK2.
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Genetic basis of Hyperlysinemia
Orphanet Journal of Rare Diseases, 2013Co-Authors: Sander M Houten, Heleen Te Brinke, Simone Denis, Jos Pn Ruiter, Alida C Knegt, Johannis Bc De Klerk, Persephone Augoustides-savvopoulou, Johannes Häberle, Matthias R Baumgartner, Turgay CoşkunAbstract:Background Hyperlysinemia is an autosomal recessive inborn error of L-lysine degradation. To date only one causal mutation in the AASS gene encoding α-aminoadipic semialdehyde synthase has been reported. We aimed to better define the genetic basis of Hyperlysinemia. Methods We collected the clinical, biochemical and molecular data in a cohort of 8 Hyperlysinemia patients with distinct neurological features. Results We found novel causal mutations in AASS in all affected individuals, including 4 missense mutations, 2 deletions and 1 duplication. In two patients originating from one family, the Hyperlysinemia was caused by a contiguous gene deletion syndrome affecting AASS and PTPRZ1 . Conclusions Hyperlysinemia is caused by mutations in AASS . As Hyperlysinemia is generally considered a benign metabolic variant, the more severe neurological disease course in two patients with a contiguous deletion syndrome may be explained by the additional loss of PTPRZ1 . Our findings illustrate the importance of detailed biochemical and genetic studies in any Hyperlysinemia patient.
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genetic basis of Hyperlysinemia
Orphanet Journal of Rare Diseases, 2013Co-Authors: Sander M Houten, Heleen Te Brinke, Simone Denis, Jos Pn Ruiter, Alida C Knegt, Johannis Bc De Klerk, Johannes Häberle, Matthias R Baumgartner, Persephone Augoustidessavvopoulou, Turgay CoşkunAbstract:Background Hyperlysinemia is an autosomal recessive inborn error of L-lysine degradation. To date only one causal mutation in the AASS gene encoding α-aminoadipic semialdehyde synthase has been reported. We aimed to better define the genetic basis of Hyperlysinemia.
Heleen Te Brinke - One of the best experts on this subject based on the ideXlab platform.
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mitochondrial nadp h deficiency due to a mutation in nadk2 causes dienoyl coa reductase deficiency with Hyperlysinemia
Human Molecular Genetics, 2014Co-Authors: Sander M Houten, Heleen Te Brinke, Simone Denis, Aldo Jongejan, Antoine H C Van Kampen, Edward J Bradley, Frank Baas, Raoul C M Hennekam, David S Millington, Sarah P YoungAbstract:Dienoyl-CoA reductase (DECR) deficiency with Hyperlysinemia is a rare disorder affecting the metabolism of polyunsaturated fatty acids and lysine. The molecular basis of this condition is currently unknown. We describe a new case with failure to thrive, developmental delay, lactic acidosis and severe encephalopathy suggestive of a mitochondrial disorder. Exome sequencing revealed a causal mutation in NADK2. NADK2 encodes the mitochondrial NAD kinase, which is crucial for NADP biosynthesis evidenced by decreased mitochondrial NADP(H) levels in patient fibroblasts. DECR and also the first step in lysine degradation are performed by NADP-dependent oxidoreductases explaining their in vivo deficiency. DECR activity was also deficient in lysates of patient fibroblasts and could only be rescued by transfecting patient cells with functional NADK2. Thus NADPH is not only crucial as a cosubstrate, but can also act as a molecular chaperone that activates and stabilizes enzymes. In addition to polyunsaturated fatty acid oxidation and lysine degradation, NADPH also plays a role in various other mitochondrial processes. We found decreased oxygen consumption and increased extracellular acidification in patient fibroblasts, which may explain why the disease course is consistent with clinical criteria for a mitochondrial disorder. We conclude that DECR deficiency with Hyperlysinemia is caused by mitochondrial NADP(H) deficiency due to a mutation in NADK2.
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Genetic basis of Hyperlysinemia
Orphanet Journal of Rare Diseases, 2013Co-Authors: Sander M Houten, Heleen Te Brinke, Simone Denis, Jos Pn Ruiter, Alida C Knegt, Johannis Bc De Klerk, Persephone Augoustides-savvopoulou, Johannes Häberle, Matthias R Baumgartner, Turgay CoşkunAbstract:Background Hyperlysinemia is an autosomal recessive inborn error of L-lysine degradation. To date only one causal mutation in the AASS gene encoding α-aminoadipic semialdehyde synthase has been reported. We aimed to better define the genetic basis of Hyperlysinemia. Methods We collected the clinical, biochemical and molecular data in a cohort of 8 Hyperlysinemia patients with distinct neurological features. Results We found novel causal mutations in AASS in all affected individuals, including 4 missense mutations, 2 deletions and 1 duplication. In two patients originating from one family, the Hyperlysinemia was caused by a contiguous gene deletion syndrome affecting AASS and PTPRZ1 . Conclusions Hyperlysinemia is caused by mutations in AASS . As Hyperlysinemia is generally considered a benign metabolic variant, the more severe neurological disease course in two patients with a contiguous deletion syndrome may be explained by the additional loss of PTPRZ1 . Our findings illustrate the importance of detailed biochemical and genetic studies in any Hyperlysinemia patient.
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genetic basis of Hyperlysinemia
Orphanet Journal of Rare Diseases, 2013Co-Authors: Sander M Houten, Heleen Te Brinke, Simone Denis, Jos Pn Ruiter, Alida C Knegt, Johannis Bc De Klerk, Johannes Häberle, Matthias R Baumgartner, Persephone Augoustidessavvopoulou, Turgay CoşkunAbstract:Background Hyperlysinemia is an autosomal recessive inborn error of L-lysine degradation. To date only one causal mutation in the AASS gene encoding α-aminoadipic semialdehyde synthase has been reported. We aimed to better define the genetic basis of Hyperlysinemia.