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Shigeo Kure - One of the best experts on this subject based on the ideXlab platform.
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paradoxical increase in seizure frequency with valproate in nonketotic hyperGlycinemia
Brain & Development, 2012Co-Authors: Yu Tsuyusaki, Shigeo Kure, Hiroko Shimbo, Takahito Wada, Mizue Iai, Megumi Tsuji, Sumimasa Yamashita, Noriko Aida, Hitoshi OsakaAbstract:Nonketotic hyperGlycinemia (NKH), or Glycine Encephalopathy, is an autosomal recessive disorder caused by a defect in the Glycine cleavage enzyme system. In neonatal-onset NKH, patients manifest lethargy, hypotonia, apnea, and intractable epileptic seizures that are not specific to this disease. We experienced a 6-year-old girl with spastic quadriplegia, intractable epilepsy, and mental retardation, all initially regarded as sequelae of neonatal meningitis. The seizure frequency was transiently increased when valproate was started. Head MRI revealed progressive brain atrophy and white matter loss with high intensity signals on T2-weighted and diffusion-weighted images, which prompted us to conduct further metabolic workups. High Glycine levels led us to suspect NKH, and we confirmed this diagnosis by the non-invasive, (13)C-Glycine breath test. DNA sequencing revealed novel Leu885Pro/Trp897Cys mutations in the Glycine decarboxylase gene that were transmitted from both parents. Sodium benzoate and dextromethorphan dramatically decreased her hypertonicity. Our case shows that paradoxical increases in seizure frequency following valproate can be a clue for a diagnosis of NKH, and that a correct diagnosis of NKH can greatly alter the quality of life in such patients.
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two novel laboratory tests facilitating diagnosis of Glycine Encephalopathy nonketotic hyperGlycinemia
Brain & Development, 2011Co-Authors: Shigeo KureAbstract:Glycine Encephalopathy (GE), also known as non-ketotic hyperGlycinemia, is a life-threatening metabolic disease caused by inherited deficiency of the Glycine cleavage system (GCS). GE is characterized by accumulation of a large amount of Glycine in serum and cerebrospinal fluids. In typical cases with GE, coma, profound hypotonia, and intractable seizures develop within several days of life. Patients with atypical symptoms may have delayed or missed diagnosis because of non-specific symptoms. It is sometimes problematic to confirm the diagnosis of GE since it requires either invasive liver biopsy for measurement of GCS activity or exhaustive mutational screening of three GCS genes, GLDC, AMT, and GCSH. We herein describe two novel laboratory tests for diagnosis of GE, [1-(13)C]Glycine breath test and the multiplex ligation-dependent probe amplification (MLPA) for detection of large deletions in GLDC. The [1-(13)C]Glycine breath test has been developed for noninvasive enzymatic diagnosis of GE. Because the GCS generates CO(2) by degradation of Glycine, the GCS activity could be evaluated in vivo by measurement of exhaled (13)CO(2) after administration of a stable isotope, [1-(13)C]Glycine. The MLPA has been developed for improvement in mutation detection rate in GE: Deletions involving multiple GDLC exons are prevalent among GE patients, but cannot be detected by the exon-sequencing analysis. Two novel diagnosis methods would facilitate diagnosis of hyperGlycinemic patients as having GE.
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Model Mice for Mild-Form Glycine Encephalopathy: Behavioral and Biochemical Characterizations and Efficacy of Antagonists for the Glycine Binding Site of N-Methyl D-Aspartate Receptor
Pediatric Research, 2008Co-Authors: Kanako Kojima-ishii, Shigeo Kure, Akiko Ichinohe, Toshikatsu Shinka, Ayumi Narisawa, Shoko Komatsuzaki, Junnko Kanno, Fumiaki Kamada, Yoko Aoki, Hiroyuki YokoyamaAbstract:Glycine Encephalopathy (GE) is caused by an inherited deficiency of the Glycine cleavage system (GCS) and characterized by accumulation of Glycine in body fluids and various neurologic symptoms. Coma and convulsions develop in neonates in typical GE while psychomotor retardation and behavioral abnormalities in infancy and childhood are observed in mild GE. Recently, we have established a transgenic mouse line (low-GCS) with reduced GCS activity (29% of wild-type (WT) C57BL/6) and accumulation of Glycine in the brain (Stroke, 2007; 38:2157). The purpose of the present study is to characterize behavioral features of the low-GCS mouse as a model of mild GE. Two other transgenic mouse lines were also analyzed: high-GCS mice with elevated GCS activity and low-GCS-2 mice with reduced GCS activity. As compared with controls, low-GCS mice manifested increased seizure susceptibility, aggressiveness and anxiety-like activity, which resembled abnormal behaviors reported in mild GE, whereas high-GCS mice were less sensitive to seizures, hypoactive and less anxious. Antagonists for the Glycine-binding site of the N-methyl-D-aspartate receptor significantly ameliorated elevated locomotor activity and seizure susceptibility in the low-GCS mice. Our results suggest the usefulness of low-GCS mice as a mouse model for mild GE and a novel therapeutic strategy.
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treatment from birth of nonketotic hyperGlycinemia due to a novel gldc mutation
Annals of Neurology, 2006Co-Authors: Stanley H Korman, Isaiah D Wexler, Alisa Gutman, Marieodile Rolland, Junko Kanno, Shigeo KureAbstract:Objective To determine whether the devastating outcome of neonatal-onset Glycine Encephalopathy (NKH) could be improved by instituting treatment immediately at birth rather than after symptoms are already well established. Methods A newborn with NKH diagnosed prenatally following the neonatal death of a previous affected sibling was treated from birth with oral sodium benzoate (250mg/kg/day) and the NMDA receptor antagonist ketamine (15mg/kg/day) immediately after sampling cord blood and cerebrospinal fluid (CSF) for Glycine determination. Glycine cleavage system (CGS) activity was determined in placental tissue. Mutation analysis was performed by sequencing all GLDC, GCSH and AMT exons. Results CSF Glycine (99 μmol/L, reference 3.8–8.0) was already markedly elevated at birth. GCS activity in placental tissue was severely reduced (2.6% of controls). A novel homozygous GLDC c.482AG(Y161C) missense mutation was identified. Neonatal hypotonia and apnea did not occur but the long-term outcome was poor, with intractable seizures and severe psychomotor retardation. This contrasts with the favorable outcome with early treatment in variant NKH with mild GCS deficiency (Ann Neuol 2004;56:139–143). Interpretation Prospective treatment with this regimen can favorably modify the early neonatal course of severe NKH but does not prevent the poor long-term outcome, suggesting Glycine-induced prenatal injury and/or ongoing postnatal damage. Ann Neurol 2006
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novel mutations in the p protein Glycine decarboxylase gene in patients with Glycine Encephalopathy non ketotic hyperGlycinemia
Molecular Genetics and Metabolism, 2002Co-Authors: Shigeo Kure, Kanako Kojima, Derek A Applegarth, Jennifer R Toone, Marion B Coultermackie, Payam Sazegar, Akiko IchinoheAbstract:Eight novel mutations were found in the P-protein (Glycine decarboxylase) gene (GLDC) of the Glycine cleavage system (EC 2.1.1.10) by screening five exons of the gene in patients with Glycine Encephalopathy (NKH). The mutations identified were of eight single base changes: a one-base deletion 1054del A, a splice site mutation IVS18-2A-->G and six amino acid substitutions A283P, A313P, P329T, R410K, P700A, and G762R.
Jennifer R Toone - One of the best experts on this subject based on the ideXlab platform.
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natural history of nonketotic hyperGlycinemia in 65 patients
Neurology, 2004Co-Authors: Julie Hooverfong, S Shah, J L K Van Hove, Derek A Applegarth, Jennifer R Toone, Ada HamoshAbstract:Background: Glycine Encephalopathy, also known as nonketotic hyperGlycinemia (NKH), is an autosomal recessive disorder caused by a defect in the Glycine cleavage system. NKH is classically associated with neonatal apnea, lethargy, hypotonia, and seizures, followed by severe psychomotor retardation in those who survive. Methods: To determine the natural history of NKH, the authors mailed a 44-question survey to 170 households in the International NKH Family Network. Results: Data for 65 patients (36 boys, 29 girls) were collected from 58 families. One-third of the subjects died; 8 girls died during the neonatal period, and 14 patients died thereafter (2 girls, 12 boys). Median age of death for boys was 2.6 years vs p = 0.02). Mean birth weight and length, occipitofrontal circumference, and gestation duration were normal. Two-thirds of infants were ventilated during the neonatal period; of these, 40% died. Ninety percent had confirmed seizures, 75% during the first month of life. Interestingly, three NKH patients never developed seizures. An abnormal corpus callosum and/or hydrocephalus were associated with especially poor gross motor and speech development. Of 25 patients living ≥3 years, 10 were able to walk and say/sign words; all were boys. In six families with more than one affected child, disease course and mortality were similar within each family. Conclusions: This study reveals a striking and unexpected gender difference in mortality and developmental progress. Of the two-thirds of nonketotic hyperGlycinemia patients surviving the newborn period, up to 20% (mostly boys) may learn to walk and communicate by saying or signing words.
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novel mutations in the p protein Glycine decarboxylase gene in patients with Glycine Encephalopathy non ketotic hyperGlycinemia
Molecular Genetics and Metabolism, 2002Co-Authors: Shigeo Kure, Kanako Kojima, Derek A Applegarth, Jennifer R Toone, Marion B Coultermackie, Payam Sazegar, Akiko IchinoheAbstract:Eight novel mutations were found in the P-protein (Glycine decarboxylase) gene (GLDC) of the Glycine cleavage system (EC 2.1.1.10) by screening five exons of the gene in patients with Glycine Encephalopathy (NKH). The mutations identified were of eight single base changes: a one-base deletion 1054del A, a splice site mutation IVS18-2A-->G and six amino acid substitutions A283P, A313P, P329T, R410K, P700A, and G762R.
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nonketotic hyperGlycinemia Glycine Encephalopathy laboratory diagnosis
Molecular Genetics and Metabolism, 2001Co-Authors: Derek A Applegarth, Jennifer R TooneAbstract:Nonketotic hyperGlycinemia (NKH) is an autosomal recessive disorder of Glycine metabolism caused by a defect in the Glycine cleavage enzyme complex (GCS). GCS is a complex of four proteins encoded on four different chromosomes. In classical neonatal NKH, levels of cerebrospinal fluid (CSF) Glycine and CSF/plasma Glycine ratio are very high but the CSF results, in particular, may be more difficult to interpret in later-onset, milder, or otherwise atypical NKH. Enzymatic confirmation of NKH requires a liver sample. Delineation of which protein of the complex is defective is necessary to screen for mutations in the appropriate gene. Except for Finnish NKH patients, few recurrent mutations have yet been found, although analysis of the P-protein gene (the site of the defect in the majority of patients) is at an early stage. Prenatal diagnosis by GCS assay in chorionic villus biopsies is not completely reliable and will be replaced by molecular analysis in families where the mutations are known.
Derek A Applegarth - One of the best experts on this subject based on the ideXlab platform.
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natural history of nonketotic hyperGlycinemia in 65 patients
Neurology, 2004Co-Authors: Julie Hooverfong, S Shah, J L K Van Hove, Derek A Applegarth, Jennifer R Toone, Ada HamoshAbstract:Background: Glycine Encephalopathy, also known as nonketotic hyperGlycinemia (NKH), is an autosomal recessive disorder caused by a defect in the Glycine cleavage system. NKH is classically associated with neonatal apnea, lethargy, hypotonia, and seizures, followed by severe psychomotor retardation in those who survive. Methods: To determine the natural history of NKH, the authors mailed a 44-question survey to 170 households in the International NKH Family Network. Results: Data for 65 patients (36 boys, 29 girls) were collected from 58 families. One-third of the subjects died; 8 girls died during the neonatal period, and 14 patients died thereafter (2 girls, 12 boys). Median age of death for boys was 2.6 years vs p = 0.02). Mean birth weight and length, occipitofrontal circumference, and gestation duration were normal. Two-thirds of infants were ventilated during the neonatal period; of these, 40% died. Ninety percent had confirmed seizures, 75% during the first month of life. Interestingly, three NKH patients never developed seizures. An abnormal corpus callosum and/or hydrocephalus were associated with especially poor gross motor and speech development. Of 25 patients living ≥3 years, 10 were able to walk and say/sign words; all were boys. In six families with more than one affected child, disease course and mortality were similar within each family. Conclusions: This study reveals a striking and unexpected gender difference in mortality and developmental progress. Of the two-thirds of nonketotic hyperGlycinemia patients surviving the newborn period, up to 20% (mostly boys) may learn to walk and communicate by saying or signing words.
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novel mutations in the p protein Glycine decarboxylase gene in patients with Glycine Encephalopathy non ketotic hyperGlycinemia
Molecular Genetics and Metabolism, 2002Co-Authors: Shigeo Kure, Kanako Kojima, Derek A Applegarth, Jennifer R Toone, Marion B Coultermackie, Payam Sazegar, Akiko IchinoheAbstract:Eight novel mutations were found in the P-protein (Glycine decarboxylase) gene (GLDC) of the Glycine cleavage system (EC 2.1.1.10) by screening five exons of the gene in patients with Glycine Encephalopathy (NKH). The mutations identified were of eight single base changes: a one-base deletion 1054del A, a splice site mutation IVS18-2A-->G and six amino acid substitutions A283P, A313P, P329T, R410K, P700A, and G762R.
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nonketotic hyperGlycinemia Glycine Encephalopathy laboratory diagnosis
Molecular Genetics and Metabolism, 2001Co-Authors: Derek A Applegarth, Jennifer R TooneAbstract:Nonketotic hyperGlycinemia (NKH) is an autosomal recessive disorder of Glycine metabolism caused by a defect in the Glycine cleavage enzyme complex (GCS). GCS is a complex of four proteins encoded on four different chromosomes. In classical neonatal NKH, levels of cerebrospinal fluid (CSF) Glycine and CSF/plasma Glycine ratio are very high but the CSF results, in particular, may be more difficult to interpret in later-onset, milder, or otherwise atypical NKH. Enzymatic confirmation of NKH requires a liver sample. Delineation of which protein of the complex is defective is necessary to screen for mutations in the appropriate gene. Except for Finnish NKH patients, few recurrent mutations have yet been found, although analysis of the P-protein gene (the site of the defect in the majority of patients) is at an early stage. Prenatal diagnosis by GCS assay in chorionic villus biopsies is not completely reliable and will be replaced by molecular analysis in families where the mutations are known.
Akiko Ichinohe - One of the best experts on this subject based on the ideXlab platform.
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Model Mice for Mild-Form Glycine Encephalopathy: Behavioral and Biochemical Characterizations and Efficacy of Antagonists for the Glycine Binding Site of N-Methyl D-Aspartate Receptor
Pediatric Research, 2008Co-Authors: Kanako Kojima-ishii, Shigeo Kure, Akiko Ichinohe, Toshikatsu Shinka, Ayumi Narisawa, Shoko Komatsuzaki, Junnko Kanno, Fumiaki Kamada, Yoko Aoki, Hiroyuki YokoyamaAbstract:Glycine Encephalopathy (GE) is caused by an inherited deficiency of the Glycine cleavage system (GCS) and characterized by accumulation of Glycine in body fluids and various neurologic symptoms. Coma and convulsions develop in neonates in typical GE while psychomotor retardation and behavioral abnormalities in infancy and childhood are observed in mild GE. Recently, we have established a transgenic mouse line (low-GCS) with reduced GCS activity (29% of wild-type (WT) C57BL/6) and accumulation of Glycine in the brain (Stroke, 2007; 38:2157). The purpose of the present study is to characterize behavioral features of the low-GCS mouse as a model of mild GE. Two other transgenic mouse lines were also analyzed: high-GCS mice with elevated GCS activity and low-GCS-2 mice with reduced GCS activity. As compared with controls, low-GCS mice manifested increased seizure susceptibility, aggressiveness and anxiety-like activity, which resembled abnormal behaviors reported in mild GE, whereas high-GCS mice were less sensitive to seizures, hypoactive and less anxious. Antagonists for the Glycine-binding site of the N-methyl-D-aspartate receptor significantly ameliorated elevated locomotor activity and seizure susceptibility in the low-GCS mice. Our results suggest the usefulness of low-GCS mice as a mouse model for mild GE and a novel therapeutic strategy.
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novel mutations in the p protein Glycine decarboxylase gene in patients with Glycine Encephalopathy non ketotic hyperGlycinemia
Molecular Genetics and Metabolism, 2002Co-Authors: Shigeo Kure, Kanako Kojima, Derek A Applegarth, Jennifer R Toone, Marion B Coultermackie, Payam Sazegar, Akiko IchinoheAbstract:Eight novel mutations were found in the P-protein (Glycine decarboxylase) gene (GLDC) of the Glycine cleavage system (EC 2.1.1.10) by screening five exons of the gene in patients with Glycine Encephalopathy (NKH). The mutations identified were of eight single base changes: a one-base deletion 1054del A, a splice site mutation IVS18-2A-->G and six amino acid substitutions A283P, A313P, P329T, R410K, P700A, and G762R.
Elena Buglo - One of the best experts on this subject based on the ideXlab platform.
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elevated preoptic brain activity in zebrafish glial Glycine transporter mutants is linked to lethargy like behaviors and delayed emergence from anesthesia
Scientific Reports, 2021Co-Authors: Michael J Venincasa, Owen Randlett, Sureni Sumathipala, Richard Bindernagel, Matthew Stark, Qing Yan, Steven A Sloan, Elena BugloAbstract:Delayed emergence from anesthesia was previously reported in a case study of a child with Glycine Encephalopathy. To investigate the neural basis of this delayed emergence, we developed a zebrafish glial Glycine transporter (glyt1 - / -) mutant model. We compared locomotor behaviors; dose-response curves for tricaine, ketamine, and 2,6-diisopropylphenol (propofol); time to emergence from these anesthetics; and time to emergence from propofol after craniotomy in glyt1-/- mutants and their siblings. To identify differentially active brain regions in glyt1-/- mutants, we used pERK immunohistochemistry as a proxy for brain-wide neuronal activity. We show that glyt1-/- mutants initiated normal bouts of movement less frequently indicating lethargy-like behaviors. Despite similar anesthesia dose-response curves, glyt1-/- mutants took over twice as long as their siblings to emerge from ketamine or propofol, mimicking findings from the human case study. Reducing Glycine levels rescued timely emergence in glyt1-/- mutants, pointing to a causal role for elevated Glycine. Brain-wide pERK staining showed elevated activity in hypnotic brain regions in glyt1-/- mutants under baseline conditions and a delay in sensorimotor integration during emergence from anesthesia. Our study links elevated activity in preoptic brain regions and reduced sensorimotor integration to lethargy-like behaviors and delayed emergence from propofol in glyt1-/- mutants.