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1.
Yonsei Med J ; 60(3): 308-311, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30799594

RESUMO

Succinyl-CoA:3-ketoacid CoA transferase (SCOT) deficiency is a rare inborn error of ketone body utilization, characterized by episodic or permanent ketosis. SCOT deficiency is caused by mutations in the OXCT1 gene, which is mapped to 5p13 and consists of 17 exons. A 12-month-old girl presented with severe ketoacidosis and was treated with continuous renal replacement therapy. She had two previously unrecognized mild-form episodes of ketoacidosis followed by febrile illness. While high levels of ketone bodies were found in her blood and urine, other laboratory investigations, including serum glucose, were unremarkable. We identified novel compound heterozygous mutations in OXCT1:c.1118T>G (p.Ile373Ser) and a large deletion ranging from exon 8 to 16 through targeted exome sequencing and microarray analysis. This is the first Korean case of SCOT deficiency caused by novel mutations in OXCT1, resulting in life-threatening ketoacidosis. In patients with unexplained episodic ketosis, or high anion gap metabolic acidosis in infancy, an inherited disorder in ketone body metabolism should be suspected.


Assuntos
Acidose/genética , Coenzima A-Transferases/deficiência , Cetose/etiologia , Mutação/genética , Sequência de Bases , Coenzima A-Transferases/genética , Éxons/genética , Feminino , Heterozigoto , Humanos , Lactente , Corpos Cetônicos/sangue , Corpos Cetônicos/urina
2.
J Pediatr Endocrinol Metab ; 30(10): 1121-1124, 2017 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-28820737

RESUMO

A 9-month-old Turkish girl was admitted several times within 3 months to the hospital in reduced general condition and with extreme tachypnea. The patient had been diagnosed with phenylketonuria (PKU) in newborn screening and has been treated with a low phenylalanine diet and amino acid supplements. Each time an unexplained pronounced metabolic acidosis was noted, and the child was treated with sodium-bicarbonate and glucose-electrolyte infusions. The acidosis with only slightly abnormal glucose, normal lactate levels and pronounced ketonuria suggested a defect in ketone body utilization. Succinyl-CoA: 3-oxoacid CoA transferase (SCOT) enzyme activity was low in patient's fibroblasts. Mutation analysis of the corresponding OXCT1 gene revealed that the patient was a homozygous carrier of the mutation c.1523T>C (p.V508A). We conclude that SCOT deficiency should be considered in the differential diagnosis in patients with recurrent metabolic acidotic episodes, even if they are already known to have a metabolic disease unrelated to this.


Assuntos
Acidose/complicações , Coenzima A-Transferases/deficiência , Fenilcetonúrias/complicações , Acidose/tratamento farmacológico , Acidose/genética , Coenzima A-Transferases/genética , Análise Mutacional de DNA , Feminino , Glucose/uso terapêutico , Humanos , Lactente , Mutação , Bicarbonato de Sódio/uso terapêutico
3.
J Inherit Metab Dis ; 40(6): 845-852, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28695376

RESUMO

Succinyl-CoA:3-oxoacid CoA transferase (SCOT, gene symbol OXCT1) deficiency is an autosomal recessive disorder in ketone body utilization that results in severe recurrent ketoacidotic episodes in infancy, including neonatal periods. More than 30 patients with this disorder have been reported and to our knowledge, their heterozygous parents and siblings have had no apparent ketoacidotic episodes. Over 5 years (2008-2012), we investigated several patients that presented with severe ketoacidosis and identified a heterozygous OXCT1 mutation in four of these cases (Case1 p.R281C, Case2 p.T435N, Case3 p.W213*, Case4 c.493delG). To confirm their heterozygous state, we performed a multiplex ligation-dependent probe amplification analysis on the OXCT1 gene which excluded the presence of large deletions or insertions in another allele. A sequencing analysis of subcloned full-length SCOT cDNA showed that wild-type cDNA clones were present at reasonable rates to mutant cDNA clones. Over the following 2 years (2013-2014), we analyzed OXCT1 mutations in six more patients presenting with severe ketoacidosis (blood pH ≦7.25 and total ketone body ≧10 mmol/L) with non-specific urinary organic acid profiles. Of these, a heterozygous OXCT1 mutation was found in two cases (Case5 p.G391D, Case6 p.R281C). Moreover, transient expression analysis revealed R281C and T435N mutants to be temperature-sensitive. This characteristic may be important because most patients developed ketoacidosis during infections. Our data indicate that heterozygous carriers of OXCT1 mutations can develop severe ketoacidotic episodes in conjunction with ketogenic stresses.


Assuntos
Acidose/genética , Acidose/patologia , Acil Coenzima A/deficiência , Coenzima A-Transferases/deficiência , Cetose/genética , Cetose/patologia , Acil Coenzima A/genética , Criança , Pré-Escolar , Coenzima A-Transferases/genética , DNA Complementar/genética , Feminino , Heterozigoto , Humanos , Lactente , Corpos Cetônicos/genética , Masculino , Mutação/genética
4.
Pediatr Int ; 57(1): 41-8, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25559898

RESUMO

Succinyl-CoA:3-ketoacid CoA transferase (SCOT) deficiency and mitochondrial acetoacetyl-CoA thiolase (beta-ketothiolase or T2) deficiency are classified as autosomal recessive disorders of ketone body utilization characterized by intermittent ketoacidosis. Patients with mutations retaining no residual activity on analysis of expression of mutant cDNA are designated as severe genotype, and patients with at least one mutation retaining significant residual activity, as mild genotype. Permanent ketosis is a pathognomonic characteristic of SCOT-deficient patients with severe genotype. Patients with mild genotype, however, may not have permanent ketosis, although they may develop severe ketoacidotic episodes similar to patients with severe genotype. Permanent ketosis has not been reported in T2 deficiency. In T2-deficient patients with severe genotype, biochemical diagnosis is done on urinary organic acid analysis and blood acylcarnitine analysis to observe characteristic findings during both ketoacidosis and non-episodic conditions. In Japan, however, it was found that T2-deficient patients with mild genotype are common, and typical profiles were not identified on these analyses. Based on a clinical study of ketone body utilization disorders both in Japan and worldwide, we have developed guidelines for disease diagnosis and treatment. These diseases are treatable by avoiding fasting and by providing early infusion of glucose, which enable the patients to grow without sequelae.


Assuntos
Acidose , Coenzima A-Transferases/deficiência , DNA Complementar/genética , Corpos Cetônicos/metabolismo , Erros Inatos do Metabolismo , Mutação , Acidose/congênito , Acidose/genética , Acidose/metabolismo , Coenzima A-Transferases/genética , Coenzima A-Transferases/metabolismo , Análise Mutacional de DNA , Genótipo , Humanos , Recém-Nascido
5.
J Inherit Metab Dis ; 37(4): 541-51, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24706027

RESUMO

Acetoacetate (AcAc) and 3-hydroxybutyrate (3HB), the two main ketone bodies of humans, are important vectors of energy transport from the liver to extrahepatic tissues, especially during fasting, when glucose supply is low. Blood total ketone body (TKB) levels should be evaluated in the context of clinical history, such as fasting time and ketogenic stresses. Blood TKB should also be evaluated in parallel with blood glucose and free fatty acids (FFA). The FFA/TKB ratio is especially useful for evaluation of ketone body metabolism. Defects in ketogenesis include mitochondrial HMG-CoA synthase (mHS) deficiency and HMG-CoA lyase (HL) deficiency. mHS deficiency should be considered in non-ketotic hypoglycemia if a fatty acid beta-oxidation defect is suspected, but cannot be confirmed. Patients with HL deficiency can develop hypoglycemic crises and neurological symptoms even in adolescents and adults. Succinyl-CoA-3-oxoacid CoA transferase (SCOT) deficiency and beta-ketothiolase (T2) deficiency are two defects in ketolysis. Permanent ketosis is pathognomonic for SCOT deficiency. However, patients with "mild" SCOT mutations may have nonketotic periods. T2-deficient patients with "mild" mutations may have normal blood acylcarnitine profiles even in ketoacidotic crises. T2 deficient patients cannot be detected in a reliable manner by newborn screening using acylcarnitines. We review recent data on clinical presentation, metabolite profiles and the course of these diseases in adults, including in pregnancy.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos , Corpos Cetônicos/metabolismo , Cetose , Acetil-CoA C-Acetiltransferase/deficiência , Acetil-CoA C-Acetiltransferase/genética , Acetil-CoA C-Acetiltransferase/metabolismo , Acidose/genética , Acidose/metabolismo , Adolescente , Adulto , Erros Inatos do Metabolismo dos Aminoácidos/genética , Erros Inatos do Metabolismo dos Aminoácidos/metabolismo , Coenzima A-Transferases/deficiência , Coenzima A-Transferases/genética , Coenzima A-Transferases/metabolismo , Feminino , Humanos , Corpos Cetônicos/biossíntese , Cetose/etiologia , Gravidez
6.
J Inherit Metab Dis ; 36(6): 983-7, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23420214

RESUMO

Succinyl-CoA:3-ketoacid CoA transferase (SCOT) deficiency is a rare inherited metabolic disorder of ketone metabolism, characterized by ketoacidotic episodes and often permanent ketosis. To date there are ~20 disease-associated alleles on the OXCT1 gene that encodes the mitochondrial enzyme SCOT. SCOT catalyzes the first, rate-limiting step of ketone body utilization in peripheral tissues, by transferring a CoA moiety from succinyl-CoA to form acetoacetyl-CoA, for entry into the tricarboxylic acid cycle for energy production. We have determined the crystal structure of human SCOT, providing a molecular understanding of the reported mutations based on their potential structural effects. An interactive version of this manuscript (which may contain additional mutations appended after acceptance of this manuscript) may be found on the web address: http://www.thesgc.org/jimd/SCOT .


Assuntos
Acidose/genética , Coenzima A-Transferases/deficiência , Análise Mutacional de DNA/métodos , Mutação de Sentido Incorreto , Mapas de Interação de Proteínas , Coenzima A-Transferases/química , Coenzima A-Transferases/genética , Cristalografia por Raios X , Humanos , Modelos Moleculares , Domínios e Motivos de Interação entre Proteínas/genética , Mapas de Interação de Proteínas/genética , Multimerização Proteica/genética , Estrutura Quaternária de Proteína/genética , Estrutura Secundária de Proteína/genética , Relação Estrutura-Atividade
7.
Hum Mutat ; 34(3): 473-80, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23281106

RESUMO

The molecular basis of simultaneous two-exon skipping induced by a splice-site mutation has yet to be completely explained. The splice donor site mutation c.1248+5g>a (IVS13) of the OXCT1 gene resulted predominantly in skipping of exons 12 and 13 in fibroblasts from a patient (GS23) with succinyl-CoA:3-ketoacid CoA transferase (SCOT) deficiency. We compared heteronuclear RNA (hnRNA) intermediates between controls' and GS23's fibroblasts. Our strategy was to use RT-PCR of hnRNA to detect the presence or absence of spliced exon clusters in RNA intermediates (SECRIs) comprising sequential exons. Our initial hypothesis was that a SECRI comprising exons 12 and 13 was formed first followed by skipping of this SECRI in GS23 cells. However, such a pathway was revealed to be not a major one. Hence, we compared the intron removal of SCOT transcript between controls and GS23. In controls, intron 11 was the last intron to be spliced and the removal of intron 12 was also rather slow and occurred after the removal of intron 13 in a major pathway. However, the mutation in GS23 cells resulted in retention of intron 13, thus causing the retention of introns 12 and 11. This "splicing paralysis" may be solved by skipping the whole intron 11-exon 12-intron 12-exon 13-mutated intron 13, resulting in skipping of exons 12 and 13.


Assuntos
Acidose/genética , Coenzima A-Transferases/genética , Éxons , Fibroblastos/metabolismo , Coenzima A-Transferases/deficiência , DNA Complementar/genética , DNA Complementar/isolamento & purificação , Humanos , Immunoblotting , Lactente , Íntrons , Cetose/genética , Masculino , Mutação , Sítios de Splice de RNA , Processamento de RNA , RNA Mensageiro/genética , Análise de Sequência de DNA
8.
BMC Syst Biol ; 6: 42, 2012 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-22583864

RESUMO

BACKGROUND: Genome-scale metabolic networks and flux models are an effective platform for linking an organism genotype to its phenotype. However, few modeling approaches offer predictive capabilities to evaluate potential metabolic engineering strategies in silico. RESULTS: A new method called "flux balance analysis with flux ratios (FBrAtio)" was developed in this research and applied to a new genome-scale model of Clostridium acetobutylicum ATCC 824 (iCAC490) that contains 707 metabolites and 794 reactions. FBrAtio was used to model wild-type metabolism and metabolically engineered strains of C. acetobutylicum where only flux ratio constraints and thermodynamic reversibility of reactions were required. The FBrAtio approach allowed solutions to be found through standard linear programming. Five flux ratio constraints were required to achieve a qualitative picture of wild-type metabolism for C. acetobutylicum for the production of: (i) acetate, (ii) lactate, (iii) butyrate, (iv) acetone, (v) butanol, (vi) ethanol, (vii) CO2 and (viii) H2. Results of this simulation study coincide with published experimental results and show the knockdown of the acetoacetyl-CoA transferase increases butanol to acetone selectivity, while the simultaneous over-expression of the aldehyde/alcohol dehydrogenase greatly increases ethanol production. CONCLUSIONS: FBrAtio is a promising new method for constraining genome-scale models using internal flux ratios. The method was effective for modeling wild-type and engineered strains of C. acetobutylicum.


Assuntos
Clostridium acetobutylicum/genética , Clostridium acetobutylicum/metabolismo , Biologia Computacional/métodos , Genoma Bacteriano/genética , Engenharia Metabólica/métodos , Redes e Vias Metabólicas , Modelos Biológicos , Oxirredutases do Álcool/deficiência , Oxirredutases do Álcool/genética , Aldeído Oxirredutases/deficiência , Aldeído Oxirredutases/genética , Algoritmos , Proteínas de Bactérias/genética , Clostridium acetobutylicum/enzimologia , Coenzima A-Transferases/deficiência , Coenzima A-Transferases/genética , Técnicas de Silenciamento de Genes , Complexos Multienzimáticos/deficiência , Complexos Multienzimáticos/genética , RNA Antissenso/genética
9.
Biochim Biophys Acta ; 1812(5): 619-24, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21296660

RESUMO

Succinyl-CoA:3-ketoacid CoA transferase (SCOT) deficiency is an inborn error of ketone body metabolism and causes episodic ketoacidosis. We report clinical and molecular analyses of 5 patients with SCOT deficiency. Patients GS07, GS13, and GS14 are homozygotes of S405P, L327P, and R468C, respectively. GS17 and GS18 are compound heterozygotes for S226N and A215V, and V404F and E273X, respectively. These mutations have not been reported previously. Missense mutations were further characterized by transient expression analysis of mutant cDNAs. Among 6 missense mutations, mutants L327P, R468C, and A215V retained some residual activities and their mutant proteins were detected in immunoblot analysis following expression at 37°C. They were more stable at 30°C than 37°C, indicating their temperature sensitive character. The R468C mutant is a distinct temperature sensitive mutant which retained 12% and 51% of wild-type residual activities at 37 and 30°C, respectively. The S226N mutant protein was detected but retained no residual activity. Effects of missense mutations were predicted from the tertiary structure of the SCOT molecule. Main effects of these mutations were destabilization of SCOT molecules, and some of them also affected catalytic activity. Among 5 patients, GS07 and GS18 had null mutations in both alleles and the other three patients retained some residual SCOT activities. All 5 developed a first severe ketoacidotic crisis with blood gas pH <7.1, and experienced multiple ketoacidotic decompensations (two of them had seven such episodes). In general, the outcome was good even following multiple ketoacidotic events. Permanent ketosis or ketonuria is considered a pathognomonic feature of SCOT deficiency. However, this condition depends not only on residual activity but also on environmental factors.


Assuntos
Coenzima A-Transferases/genética , Cetose/genética , Proteínas Mutantes/genética , Mutação de Sentido Incorreto/genética , Acidose/genética , Pré-Escolar , Coenzima A-Transferases/deficiência , Feminino , Genótipo , Homozigoto , Humanos , Lactente , Recém-Nascido , Cetose/patologia , Masculino , Proteínas Mutantes/metabolismo , Fenótipo , Conformação Proteica
10.
J Inherit Metab Dis ; 33 Suppl 3: S307-13, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20652411

RESUMO

Succinyl-CoA:3-ketoacid CoA transferase (SCOT) deficiency causes episodic ketoacidotic crises and no apparent symptoms between them. Here, we report a Japanese case of neonatal-onset SCOT deficiency. The male patient presented a severe ketoacidotic crisis, with blood pH of 7.072 and bicarbonate of 5.8 mmol/L at the age of 2 days and was successfully treated with intravenous infusion of glucose and sodium bicarbonate. He was diagnosed as SCOT deficient by enzymatic assay and mutation analysis. At the age of 7 months, he developed a second ketoacidotic crisis, with blood pH of 7.059, bicarbonate of 5.4 mmol/L, and total ketone bodies of 29.1 mmol/L. He experienced two milder ketoacidotic crises at the ages of 1 year and 7 months and 3 years and 7 months. His urinary ketone bodies usually range from negative to 1+ but sometimes show 3+ (ketostix) without any symptoms. Hence, this patient does not show permanent ketonuria, which is characteristic of typical SCOT-deficient patients. He is a compound heterozygote of c.1304C > A (T435N) and c.658-666dupAACGTGATT p.N220_I222dup. mutations in the OXCT1 gene. The T435N mutation was previously reported as one which retained significant residual activity. The latter novel mutation was revealed to retain no residual activity by transient expression analysis. Both T435N and N220_I222 lie close to the SCOT dimerization interface and are not directly connected to the active site in the tertiary structure of a human SCOT dimer. In transient expression analysis, no apparent interallelic complementation or dominant negative effects were observed. Significant residual activity from the T435N mutant allele may prevent the patient from developing permanent ketonuria.


Assuntos
Acidose/genética , Coenzima A-Transferases/deficiência , Cetose/genética , Mutação , Acidose/sangue , Acidose/diagnóstico , Acidose/tratamento farmacológico , Acidose/enzimologia , Células Cultivadas , Pré-Escolar , Coenzima A-Transferases/sangue , Coenzima A-Transferases/química , Coenzima A-Transferases/genética , Análise Mutacional de DNA , Predisposição Genética para Doença , Glucose/administração & dosagem , Humanos , Lactente , Recém-Nascido , Infusões Intravenosas , Japão , Cetose/sangue , Cetose/diagnóstico , Cetose/tratamento farmacológico , Cetose/enzimologia , Masculino , Modelos Moleculares , Fenótipo , Conformação Proteica , Multimerização Proteica , Recidiva , Bicarbonato de Sódio/administração & dosagem , Fatores de Tempo , Transfecção , Resultado do Tratamento
11.
Neurobiol Dis ; 36(2): 320-30, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19660549

RESUMO

The activity of a key mitochondrial tricarboxylic acid cycle enzyme, alpha-ketoglutarate dehydrogenase complex (KGDHC), declines in many neurodegenerative diseases. KGDHC consists of three subunits. The dihydrolipoyl succinyl transferase (DLST) component is unique to KGDHC. DLST(+/-) mice showed reduced mRNA and protein levels and decreased brain mitochondrial KGDHC activity. Neurotoxic effects of mitochondrial toxins were exacerbated in DLST(+/-) mice. MPTP produced a significantly greater reduction of striatal dopamine and tyrosine hydroxylase-positive neurons in the substantia nigra pars compacta of DLST(+/-) mice. DLST deficiency enhanced the severity of lipid peroxidation in the substantia nigra after MPTP treatment. Striatal lesions induced by either malonate or 3-nitropropionic acid (3-NP) were significantly larger in DLST(+/-) mice than in wildtype controls. DLST deficiency enhanced the 3-NP inhibition of mitochondria enzymes, and 3-NP induced protein and DNA oxidations. These observations support the hypothesis that reductions in KGDHC may impair the adaptability of the brain and contribute to the pathogenesis of neurodegenerative diseases.


Assuntos
Predisposição Genética para Doença , Complexo Cetoglutarato Desidrogenase/deficiência , Complexo Cetoglutarato Desidrogenase/genética , Mitocôndrias/enzimologia , Mitocôndrias/genética , Neurotoxinas/toxicidade , Animais , Encéfalo/enzimologia , Coenzima A-Transferases/deficiência , Coenzima A-Transferases/genética , Coenzima A-Transferases/metabolismo , Metabolismo Energético/genética , Ativação Enzimática/genética , Feminino , Isoenzimas/deficiência , Isoenzimas/genética , Isoenzimas/metabolismo , Complexo Cetoglutarato Desidrogenase/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Doenças Neurodegenerativas/enzimologia , Doenças Neurodegenerativas/genética
12.
Int J Obstet Anesth ; 18(3): 280-3, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19450972

RESUMO

Succinyl-CoA transferase deficiency is a high-risk condition that pre-disposes the sufferer to severe and life-threatening ketoacidosis. An 18-year-old woman with succinyl-CoA transferase deficiency was admitted to the delivery suite for induction of labour at 38 weeks of gestation. Her management included adequate calorie intake in order to avoid fatty acid metabolism and adequate hydration along with rigorous electrolyte balance and minimisation of physiological stress by the use of epidural analgesia. The needs of the woman's condition had to be balanced against the desire to minimise gastric volume in case emergency obstetric intervention was required.


Assuntos
Anestesiologia , Coenzima A-Transferases/deficiência , Endocrinologia , Comunicação Interdisciplinar , Trabalho de Parto Induzido/métodos , Complicações na Gravidez , Adolescente , Anestesia Epidural/métodos , Anestesia Obstétrica/métodos , Feminino , Humanos , Gravidez , Complicações na Gravidez/prevenção & controle , Resultado do Tratamento
13.
An. pediatr. (2003, Ed. impr.) ; 67(4): 381-384, oct. 2007. ilus, tab
Artigo em Espanhol | IBECS | ID: ibc-056416

RESUMO

Presentamos el caso de un recién nacido de cuatro días de vida con deshidratación grave, polipnea, hipertonía y letargia. Los exámenes complementarios revelaron una acidosis metabólica grave con cetonemia, cetonuria y aumento del anión GAP. El análisis de orina reveló una excreción aumentada de ácido 2-metil-3-hidroxibutirato, tiglicina y 2-metilacetoacetato. El inicio neonatal del déficit de acetoacetil-CoA tiolasa (T2) es muy infrecuente. En la mayoría de los casos, los pacientes no presentan clínica en el período neonatal. Debemos pensar en esta entidad cuando un paciente presente una acidosis metabólica aguda, cetosis con glucemia normal y aciduria. La orina presenta aumento de las concentraciones de 2-metilacetoacetato y sus productos de descarboxilación. Este error innato del metabolismo en período neonatal puede producir graves alteraciones hidroelectrolíticas en forma de un proceso gradual o agudo que ocasionalmente puede causar la muerte del paciente


We present the case of a 4-day-old newborn with serious dehydration, polypnea, hypertonus and lethargy. Blood analysis showed severe metabolic acidosis with ketonemia, ketonuria and elevation of the GAP anion. Urine analysis revealed increased excretion of 2-methyl-3-hydroxybutyrate acid, tiglycine, and 2-methylacetoacetate acid. Neonatal onset of mitochondrial acetoacetyl-CoA thiolase (T2) deficiency is exceptional. Most patients have no clinical symptoms in the neonatal period. This entity should be considered in patients with acute metabolic acidosis and ketosis with normal glycemia and aciduria. The urine contains large amounts of 2-methylacetoacetate and its decarboxylation products. In the neonatal period, this inherited disorder of metabolism can produce severe hydroelectrolyte disorders in the form of a gradual process or acute episodes, which can occasionally be fatal


Assuntos
Recém-Nascido , Humanos , Coenzima A-Transferases/deficiência , Coenzima A-Transferases/genética , Hipoglicemia/genética , Erros Inatos do Metabolismo/enzimologia , Glicemia/metabolismo , Corpos Cetônicos/sangue , Infusões Intravenosas , Hipoglicemia/enzimologia , Índice de Gravidade de Doença
14.
Mol Genet Metab ; 90(3): 291-7, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17169596

RESUMO

Succinyl-CoA:3-ketoacid CoA transferase (SCOT, EC 2.8.3.5) is the key enzyme for ketone body utilization. Hereditary SCOT deficiency (MIM 245050) causes episodes of severe ketoacidosis. We identified a homozygous point mutation (c.671G>A) , which is a single-base substitution at the last nucleotide of exon 6, in a Turkish patient (GS12) with SCOT deficiency. This point mutation resulted in the skipping of exon 6, and exons 6 and 7 in human SCOT genes. To understand why the c.671G>A causes exons 6 and 7 skipping, nuclear RNA was separated from cytoplasmic RNA and both were analyzed by RT-PCR. In nuclear RNA, SCOT mRNA with exon 6 skipping was predominant and mRNA with exons 6 and 7 skipping was hardly detected, whereas the latter became one of major mRNA species in cytoplasmic RNA. This discrepancy was interpreted as follows: exon 6 skipping causes a frameshift and nonsense-mediated RNA decay in the cytosol, so mRNA with exon 6 skipping was unstable. On the other hand, SCOT mRNA with exons 6 and 7 is a minor transcript but it retains the reading-frame and is stable in cytosol. As a result, the latter mRNA is more abundant under steady-state conditions as compared to the former mRNA.


Assuntos
Acidose/enzimologia , Acidose/genética , Coenzima A-Transferases/deficiência , Coenzima A-Transferases/genética , Mutação Puntual , Acidose/metabolismo , Sequência de Bases , Pré-Escolar , DNA/genética , Primers do DNA/genética , Éxons , Feminino , Humanos , Processamento de RNA , Estabilidade de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
15.
Mol Genet Metab ; 89(3): 280-2, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16765626

RESUMO

Succinyl-CoA: 3-ketoacid-CoA transferase (SCOT; locus symbol OXCT, EC 2.8.3.5) deficiency is a rare genetic disorder affecting ketone body utilization in extra-hepatic tissues. A 6-bp deletion at the splice donor site of intron 1 resulted in the absence of a full-length mature SCOT mRNA with faint amounts of aberrantly spliced transcripts using a cryptic splice donor site within exon 1, which was located just 7 bases upstream from the authentic site in a SCOT deficient patient.


Assuntos
Pareamento de Bases , Coenzima A-Transferases/deficiência , Éxons/genética , Íntrons/genética , Sítios de Splice de RNA/genética , Processamento de RNA/genética , Deleção de Sequência , Sequência de Bases , Coenzima A-Transferases/genética , Análise Mutacional de DNA , Feminino , Humanos , Lactente , Dados de Sequência Molecular
17.
Anticancer Res ; 24(4): 2213-7, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15330163

RESUMO

BACKGROUND: Monoacetoacetin (MAA) has been used experimentally as a physiological energy source in parenteral nutrition. Succinyl-CoA: 3-oxoacid CoA transferase (SCOT) is a key enzyme in the metabolism of MAA. In this study, the effect of MAA on the growth of human gastric cancer cells was examined in relation to SCOT expression. MATERIALS AND METHODS: Four gastric cancer cell lines, OCUM-2M, MKN-28, MKN-45 and MKN-74, and two fibroblast cell lines were used in this study. The proliferation of gastric cancer cells was determined by MTT assay, by calculating the number of cancer cells, and by [3H]-thymidine uptake. Cells were cultured in DMEM containing 10% FBS with glucose (4.5 g/L) as the control or with MAA (4.5 g/L). SCOT mRNA expression was examined by RT-PCR. RESULTS: The growth of OCUM-2M and MKN-28 cells was significantly suppressed in MAA medium compared with glucose medium. In contrast the growth of MKN-74, MKN-45 and normal fibroblasts was not suppressed in MAA medium. SCOT mRNA was expressed in MKN-45, MKN-74 and normal fibroblasts, but not in MKN-28 or OCUM-2M. CONCLUSION: Parenteral nutrition with MAA may provide preferential energy for patients with some types of gastric cancer with SCOT deficiency.


Assuntos
Acetoacetatos/farmacologia , Coenzima A-Transferases/deficiência , Glicerídeos/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/enzimologia , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Coenzima A-Transferases/biossíntese , Coenzima A-Transferases/genética , Inibidores do Crescimento/farmacologia , Humanos , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia
18.
J Inherit Metab Dis ; 27(5): 691-2, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15669687

RESUMO

SCOT deficiency presents with persistent excess of ketones leading to ketoacidosis. Here we report patient GS15, homozygous for a novel R217X mutation, who had the first apparent ketoacidotic crisis at 8 months of age. Before confirmation of diagnosis, daily dialysis was the only mechanism by which to normalize her persistent metabolic acidosis of unknown aetiology.


Assuntos
Coenzima A-Transferases/deficiência , Coenzima A-Transferases/genética , Mutação , Acidose/genética , Pré-Escolar , Consanguinidade , Diálise , Feminino , Homozigoto , Humanos , Fatores de Tempo
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