RESUMO
Mitochondrial fatty acid ß-oxidation disorders (FAODs) are a group of about 20 diseases which are caused by specific mutations in genes that codify proteins or enzymes involved in the fatty acid transport and mitochondrial ß-oxidation. As a consequence of these inherited metabolic defects, fatty acids can not be used as an appropriate energetic source during special conditions, such as prolonged fasting, exercise or other catabolic states. Therefore, patients usually present hepatopathy, cardiomyopathy, severe skeletal myopathy and neuropathy, besides biochemical features like hypoketotic hypoglycemia, metabolic acidosis, hypotony and hyperammonemia. This set of symptoms seems to be related not only with the energy deficiency, but also with toxic effects provoked by fatty acids and carnitine derivatives accumulated in the tissues of the patients. The understanding of the mechanisms by which these metabolites provoke tissue injury in FAODs is crucial for the developmental of novel therapeutic strategies that promote increased life expectancy, as well as improved life quality for patients. In this sense, the objective of this review is to present evidence from the scientific literature on the role of oxidative damage and mitochondrial dysfunction in the pathogenesis of the most prevalent FAODs: medium-chain acyl-CoA dehydrogenase (MCAD), long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) and very long-chain acyl-CoA dehydrogenase (VLCAD) deficiencies. It is expected that the findings presented in this review, obtained from both animal model and patients studies, may contribute to a better comprehension of the pathophysiology of these diseases.
Assuntos
Acidose , Erros Inatos do Metabolismo Lipídico , Doenças Musculares , Acidose/metabolismo , Animais , Ácidos Graxos , Humanos , Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/genética , Erros Inatos do Metabolismo Lipídico/metabolismo , Mitocôndrias/metabolismo , Doenças Musculares/metabolismo , Oxirredução , Estresse OxidativoRESUMO
cis-5-Tetradecenoic (cis-5) and myristic (Myr) acids predominantly accumulate in patients affected by very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency. They commonly manifest myopathy with muscular pain and rhabdomyolysis, whose underlying mechanisms are poorly known. Thus, in the present study we investigated the effects of cis-5 and Myr on mitochondrial bioenergetics and Ca2+ homeostasis in rat skeletal muscle. cis-5 and Myr decreased ADP-stimulated (state 3) and CCCP-stimulated (uncoupled) respiration, especially when mitochondria were supported by NADH-linked as compared to FADH2-linked substrates. In contrast, these fatty acids increased resting respiration (state 4). Similar effects were observed in skeletal muscle fibers therefore validating the data obtained with isolated mitochondria. Furthermore, cis-5 and Myr markedly decreased mitochondrial membrane potential and Ca2+ retention capacity that were avoided by cyclosporin A plus ADP and ruthenium red, indicating that cis-5 and Myr induce mitochondrial permeability transition (MPT). Finally, docosanoic acid did not disturb mitochondrial homeostasis, indicating selective effects for Myr and cis-5. Taken together, our findings indicate that major long-chain fatty acids accumulating in VLCAD deficiency behave as metabolic inhibitors, uncouplers of oxidative phosphorylation and MPT inducers. It is presumed that these pathomechanisms contribute to the muscular symptoms and rhabdomyolysis observed in patients affected by VLCAD deficiency.
Assuntos
Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Síndrome Congênita de Insuficiência da Medula Óssea/metabolismo , Erros Inatos do Metabolismo Lipídico/metabolismo , Mitocôndrias/efeitos dos fármacos , Doenças Mitocondriais/metabolismo , Músculo Esquelético/efeitos dos fármacos , Doenças Musculares/metabolismo , Ácidos Mirísticos/toxicidade , Acil-CoA Desidrogenase de Cadeia Longa/metabolismo , Animais , Cálcio/metabolismo , Metabolismo Energético/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/fisiologia , Músculo Esquelético/metabolismo , Consumo de Oxigênio/efeitos dos fármacos , Permeabilidade/efeitos dos fármacos , Ratos WistarRESUMO
We studied the effects of the major long-chain fatty acids accumulating in very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency, namely cis-5-tetradecenoic acid (Cis-5) and myristic acid (Myr), on important mitochondrial functions in isolated mitochondria from cardiac fibers and cardiomyocytes of juvenile rats. Cis-5 and Myr at pathological concentrations markedly reduced mitochondrial membrane potential (ΔΨm ), matrix NAD(P)H pool, Ca2+ retention capacity, ADP- (state 3) and carbonyl cyanide 3-chlorophenyl hydrazine-stimulated (uncoupled) respiration, and ATP generation. By contrast, these fatty acids increased resting (state 4) respiration (uncoupling effect) with the involvement of the adenine nucleotide translocator because carboxyatractyloside significantly attenuated the increased state 4 respiration provoked by Cis-5 and Myr. Furthermore, the classical inhibitors of mitochondrial permeability transition (MPT) pore cyclosporin A plus ADP, as well as the Ca2+ uptake blocker ruthenium red, fully prevented the Cis-5- and Myr-induced decrease in ΔΨm in Ca2+ -loaded mitochondria, suggesting, respectively, the induction of MPT pore opening and the contribution of Ca2+ toward these effects. The findings of the present study indicate that the major long-chain fatty acids that accumulate in VLCAD deficiency disrupt mitochondrial bioenergetics and Ca2+ homeostasis, acting as uncouplers and metabolic inhibitors of oxidative phosphorylation, as well as inducers of MPT pore opening, in the heart at pathological relevant concentrations. It is therefore presumed that a disturbance of bioenergetics and Ca2+ homeostasis may contribute to the cardiac manifestations observed in VLCAD deficiency.
Assuntos
Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Cálcio/metabolismo , Metabolismo Energético , Homeostase , Erros Inatos do Metabolismo Lipídico/metabolismo , Mitocôndrias Cardíacas/metabolismo , Doenças Mitocondriais/metabolismo , Doenças Musculares/metabolismo , Miocárdio/metabolismo , Acil-CoA Desidrogenase de Cadeia Longa/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Linhagem Celular , Síndrome Congênita de Insuficiência da Medula Óssea , Ácidos Graxos/metabolismo , Potencial da Membrana Mitocondrial , Miocárdio/citologia , Fosforilação Oxidativa , Consumo de Oxigênio , Ratos WistarRESUMO
The pathogenesis of the muscular symptoms and recurrent rhabdomyolysis that are commonly manifested in patients with mitochondrial trifunctional protein (MTP) and long-chain 3-hydroxy-acyl-CoA dehydrogenase (LCHAD) deficiencies is still unknown. In this study we investigated the effects of the major long-chain monocarboxylic 3-hydroxylated fatty acids (LCHFA) accumulating in these disorders, namely 3-hydroxytetradecanoic (3HTA) and 3-hydroxypalmitic (3HPA) acids, on important mitochondrial functions in rat skeletal muscle mitochondria. 3HTA and 3HPA markedly increased resting (state 4) and decreased ADP-stimulated (state 3) and CCCP-stimulated (uncoupled) respiration. 3HPA provoked similar effects in permeabilized skeletal muscle fibers, validating the results obtained in purified mitochondria. Furthermore, 3HTA and 3HPA markedly diminished mitochondrial membrane potential, NAD(P)H content and Ca(2+) retention capacity in Ca(2+)-loaded mitochondria. Mitochondrial permeability transition (mPT) induction probably underlie these effects since they were totally prevented by cyclosporin A and ADP. In contrast, the dicarboxylic analogue of 3HTA did not alter the tested parameters. Our data strongly indicate that 3HTA and 3HPA behave as metabolic inhibitors, uncouplers of oxidative phosphorylation and mPT inducers in skeletal muscle. It is proposed that these pathomechanisms disrupting mitochondrial homeostasis may be involved in the muscle alterations characteristic of MTP and LCHAD deficiencies.
Assuntos
Cardiomiopatias/metabolismo , Erros Inatos do Metabolismo Lipídico/metabolismo , Mitocôndrias Musculares/efeitos dos fármacos , Miopatias Mitocondriais/metabolismo , Proteína Mitocondrial Trifuncional/deficiência , Ácidos Mirísticos/farmacologia , Doenças do Sistema Nervoso/metabolismo , Ácidos Palmíticos/farmacologia , Rabdomiólise/metabolismo , Animais , Cálcio/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias Musculares/metabolismo , Mitocôndrias Musculares/fisiologia , Proteína Mitocondrial Trifuncional/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , NADP/metabolismo , Consumo de Oxigênio/efeitos dos fármacos , Ratos WistarRESUMO
Mitochondrial trifunctional protein and long-chain 3-hydroxyacyl-CoA dehydrogenase deficiencies are fatty acid oxidation disorders biochemically characterized by tissue accumulation of long-chain fatty acids and derivatives, including the monocarboxylic long-chain 3-hydroxy fatty acids (LCHFAs) 3-hydroxytetradecanoic acid (3HTA) and 3-hydroxypalmitic acid (3HPA). Patients commonly present severe cardiomyopathy for which the pathogenesis is still poorly established. We investigated the effects of 3HTA and 3HPA, the major metabolites accumulating in these disorders, on important parameters of mitochondrial homeostasis in Ca(2+) -loaded heart mitochondria. 3HTA and 3HPA significantly decreased mitochondrial membrane potential, the matrix NAD(P)H pool and Ca(2+) retention capacity, and also induced mitochondrial swelling. These fatty acids also provoked a marked decrease of ATP production reflecting severe energy dysfunction. Furthermore, 3HTA-induced mitochondrial alterations were completely prevented by the classical mitochondrial permeability transition (mPT) inhibitors cyclosporin A and ADP, as well as by ruthenium red, a Ca(2+) uptake blocker, indicating that LCHFAs induced Ca(2+)-dependent mPT pore opening. Milder effects only achieved at higher doses of LCHFAs were observed in brain mitochondria, implying a higher vulnerability of heart to these fatty acids. By contrast, 3HTA and docosanoic acids did not change mitochondrial homeostasis, indicating selective effects for monocarboxylic LCHFAs. The present data indicate that the major LCHFAs accumulating in mitochondrial trifunctional protein and long-chain 3-hydroxyacyl-CoA dehydrogenase deficiencies induce mPT pore opening, compromising Ca(2+) homeostasis and oxidative phosphorylation more intensely in the heart. It is proposed that these pathomechanisms may contribute at least in part to the severe cardiac alterations characteristic of patients affected by these diseases.
Assuntos
Sinalização do Cálcio , 3-Hidroxiacil-CoA Desidrogenase de Cadeia Longa/metabolismo , Mitocôndrias Cardíacas/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Ácidos Mirísticos/metabolismo , Fosforilação Oxidativa , Ácidos Palmíticos/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Bloqueadores dos Canais de Cálcio/farmacologia , Sinalização do Cálcio/efeitos dos fármacos , Cardiomiopatias/enzimologia , Cardiomiopatias/metabolismo , Permeabilidade da Membrana Celular/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Humanos , Erros Inatos do Metabolismo Lipídico/enzimologia , Erros Inatos do Metabolismo Lipídico/metabolismo , 3-Hidroxiacil-CoA Desidrogenase de Cadeia Longa/deficiência , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Cardíacas/enzimologia , Membranas Mitocondriais/efeitos dos fármacos , Membranas Mitocondriais/metabolismo , Miopatias Mitocondriais/enzimologia , Miopatias Mitocondriais/metabolismo , Poro de Transição de Permeabilidade Mitocondrial , Dilatação Mitocondrial/efeitos dos fármacos , Proteína Mitocondrial Trifuncional/deficiência , Proteína Mitocondrial Trifuncional/metabolismo , NADP/metabolismo , Doenças do Sistema Nervoso/enzimologia , Doenças do Sistema Nervoso/metabolismo , Especificidade de Órgãos , Fosforilação Oxidativa/efeitos dos fármacos , Ratos Wistar , Rabdomiólise/enzimologia , Rabdomiólise/metabolismoRESUMO
Patients with long-chain 3-hydroxy-acyl-CoA dehydrogenase (LCHAD) deficiency commonly present liver dysfunction whose pathogenesis is unknown. We studied the effects of long-chain 3-hydroxylated fatty acids (LCHFA) that accumulate in LCHAD deficiency on liver bioenergetics using mitochondrial preparations from young rats. We provide strong evidence that 3-hydroxytetradecanoic (3HTA) and 3-hydroxypalmitic (3HPA) acids, the monocarboxylic acids that are found at the highest tissue concentrations in this disorder, act as metabolic inhibitors and uncouplers of oxidative phosphorylation. These conclusions are based on the findings that these fatty acids decreased ADP-stimulated (state 3) and uncoupled respiration, mitochondrial membrane potential and NAD(P)H content, and, in contrast, increased resting (state 4) respiration. We also verified that 3HTA and 3HPA markedly reduced Ca2+ retention capacity and induced swelling in Ca2+-loaded mitochondria. These effects were mediated by mitochondrial permeability transition (MPT) induction since they were totally prevented by the classical MPT inhibitors cyclosporin A and ADP, as well as by ruthenium red, a Ca2+ uptake blocker. Taken together, our data demonstrate that the major monocarboxylic LCHFA accumulating in LCHAD deficiency disrupt energy mitochondrial homeostasis in the liver. It is proposed that this pathomechanism may explain at least in part the hepatic alterations characteristic of the affected patients.
Assuntos
3-Hidroxiacil-CoA Desidrogenases/deficiência , Cardiomiopatias/patologia , Permeabilidade da Membrana Celular/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Ácidos Graxos/farmacologia , Erros Inatos do Metabolismo Lipídico/patologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias Hepáticas/efeitos dos fármacos , Miopatias Mitocondriais/patologia , Dilatação Mitocondrial/efeitos dos fármacos , Doenças do Sistema Nervoso/patologia , Rabdomiólise/patologia , 3-Hidroxiacil-CoA Desidrogenases/metabolismo , Animais , Transporte Biológico , Cálcio/metabolismo , Cardiomiopatias/metabolismo , Erros Inatos do Metabolismo Lipídico/metabolismo , Mitocôndrias Hepáticas/metabolismo , Membranas Mitocondriais/metabolismo , Miopatias Mitocondriais/metabolismo , Proteína Mitocondrial Trifuncional/deficiência , NADP/metabolismo , Doenças do Sistema Nervoso/metabolismo , Fosforilação Oxidativa/efeitos dos fármacos , Consumo de Oxigênio/efeitos dos fármacos , Ratos , Ratos Wistar , Rabdomiólise/metabolismoRESUMO
Cardiomyopathy is a common clinical feature of some inherited disorders of mitochondrial fatty acid ß-oxidation including mitochondrial trifunctional protein (MTP) and isolated long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiencies. Since individuals affected by these disorders present tissue accumulation of various fatty acids, including long-chain 3-hydroxy fatty acids, in the present study we investigated the effect of 3-hydroxydecanoic (3 HDCA), 3-hydroxydodecanoic (3 HDDA), 3-hydroxytetradecanoic (3 HTA) and 3-hydroxypalmitic (3 HPA) acids on mitochondrial oxidative metabolism, estimated by oximetry, NAD(P)H content, hydrogen peroxide production, membrane potential (ΔΨ) and swelling in rat heart mitochondrial preparations. We observed that 3 HTA and 3 HPA increased resting respiration and diminished the respiratory control and ADP/O ratios using glutamate/malate or succinate as substrates. Furthermore, 3 HDDA, 3 HTA and 3 HPA decreased ΔΨ, the matrix NAD(P)H pool and hydrogen peroxide production. These data indicate that these fatty acids behave as uncouplers of oxidative phosphorylation. We also verified that 3 HTA-induced uncoupling-effect was not mediated by the adenine nucleotide translocator and that this fatty acid induced the mitochondrial permeability transition pore opening in calcium-loaded organelles since cyclosporin A prevented the reduction of mitochondrial ΔΨ and swelling provoked by 3 HTA. The present data indicate that major 3-hydroxylated fatty acids accumulating in MTP and LCHAD deficiencies behave as strong uncouplers of oxidative phosphorylation potentially impairing heart energy homeostasis.
Assuntos
3-Hidroxiacil-CoA Desidrogenases/metabolismo , Cardiomiopatias/metabolismo , Ácidos Graxos/metabolismo , Erros Inatos do Metabolismo Lipídico/metabolismo , Potencial da Membrana Mitocondrial/fisiologia , Mitocôndrias Cardíacas/metabolismo , Proteínas Mitocondriais/metabolismo , Proteínas Musculares/metabolismo , Miocárdio/metabolismo , Fosforilação Oxidativa , Doenças do Sistema Nervoso Periférico/metabolismo , Retinose Pigmentar/metabolismo , 3-Hidroxiacil-CoA Desidrogenases/deficiência , Animais , Peróxido de Hidrogênio/metabolismo , 3-Hidroxiacil-CoA Desidrogenase de Cadeia Longa , Miopatias Mitocondriais , Proteína Mitocondrial Trifuncional/deficiência , Doenças do Sistema Nervoso , Oxirredução , Consumo de Oxigênio , Ratos , Ratos Wistar , RabdomióliseRESUMO
The accumulation of octanoic (OA) and decanoic (DA) acids in tissue is the common finding in medium-chain acyl-coenzyme A dehydrogenase deficiency (MCADD), the most frequent defect of fatty acid oxidation. Affected patients present hypoketotic hypoglycemia, rhabdomyolysis, hepatomegaly, seizures and lethargy, which may progress to coma and death. At present, the pathophysiological mechanisms underlying hepatic and skeletal muscle alterations in affected patients are poorly known. Therefore, in the present work, we investigated the in vitro effects of OA and DA, the accumulating metabolites in MCADD, on various bioenergetics and oxidative stress parameters. It was verified that OA and DA decreased complexes I-III, II-III and IV activities in liver and also inhibit complex IV activity in skeletal muscle. In addition, DA decreased complexes II-III activity in skeletal muscle. We also verified that OA and DA increased TBA-RS levels and carbonyl content in both tissues. Finally, DA, but not OA, significantly decreased GSH levels in rat skeletal muscle. Our present data show that the medium-chain fatty acids that accumulate in MCADD impair electron transfer through respiratory chain and elicit oxidative damage in rat liver and skeletal muscle. It may be therefore presumed that these mechanisms are involved in the pathophysiology of the hepatopathy and rhabdomyolysis presented by MCADD-affected patients.
Assuntos
Caprilatos/metabolismo , Decanoatos/metabolismo , Fígado/metabolismo , Músculo Esquelético/metabolismo , Estresse Oxidativo , Acil-CoA Desidrogenase/deficiência , Acil-CoA Desidrogenase/metabolismo , Animais , Caprilatos/farmacologia , Creatina Quinase/metabolismo , Decanoatos/farmacologia , Transporte de Elétrons , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Glutationa/metabolismo , Erros Inatos do Metabolismo Lipídico/metabolismo , Fígado/efeitos dos fármacos , Fígado/enzimologia , Masculino , Mitocôndrias/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/enzimologia , Oxirredução , Carbonilação Proteica , Ratos , Ratos Wistar , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismoRESUMO
Patients affected by medium-chain acyl CoA dehydrogenase (MCAD) deficiency, a frequent inborn error of metabolism, suffer from acute episodes of encephalopathy. However, the mechanisms underlying the neuropathology of this disease are poorly known. In the present study, we investigated the in vitro effect of the medium-chain fatty acids (MCFA), at concentrations varying from 0.01 to 3 mM, accumulating in MCAD deficiency on some parameters of energy metabolism in cerebral cortex of young rats. (14)CO(2) production from [U(14)] glucose, [1-(14)C] acetate and [1,5-(14)C] citrate was evaluated by incubating cerebral cortex homogenates from 30-day-old rats in the absence (controls) or presence of octanoic acid, decanoic acid or cis-4-decenoic acid. OA and DA significantly reduced (14)CO(2) production from acetate by around 30-40%, and from glucose by around 70%. DA significantly reduced (14)CO(2) production from citrate by around 40%, while OA did not affect this parameter. cDA inhibited (14)CO(2) production from all tested substrates by around 30-40%. The activities of the respiratory chain complexes and of creatine kinase were also tested in the presence of DA and cDA. Both metabolites significantly inhibited cytochrome c oxidase activity (by 30%) and complex II-III activity (DA, 25%; cDA, 80%). Furthermore, only cDA inhibited complex II activity (by 30%), while complex I-III and citrate synthase were not affected by these MCFA. On the other hand, only cDA reduced the activity of creatine kinase in total homogenates, as well as in mitochondrial and cytosolic fractions from cerebral cortex (by 50%). The data suggest that the major metabolites which accumulate in MCAD deficiency, with particular emphasis to cDA, compromise brain energy metabolism. We presume that these findings may contribute to the understanding of the pathophysiology of the neurological dysfunction of MCAD deficient patients.
Assuntos
Acil-CoA Desidrogenase/deficiência , Córtex Cerebral/metabolismo , Metabolismo Energético/fisiologia , Ácidos Graxos/metabolismo , Erros Inatos do Metabolismo Lipídico/metabolismo , Acetatos/metabolismo , Fatores Etários , Animais , Antifúngicos/farmacologia , Anti-Hipertensivos/farmacologia , Caprilatos/farmacologia , Radioisótopos de Carbono , Citrato (si)-Sintase/metabolismo , Creatina Quinase/metabolismo , Ácidos Decanoicos/farmacologia , Transporte de Elétrons/fisiologia , Metabolismo Energético/efeitos dos fármacos , Ratos , Ratos WistarRESUMO
Las miopatías por depósito de lípidos son la expresión fundamental de los trastornos del metabolismo lipídico muscular. En el presente estudio exponemos cuatro casos de la entidad y señalamos las características clínicas, histopatológicas y bioquímicas que están presentes en los defectos genéticos del metabolismo de los ácidos grasos del músculo esquelético. En tres casos los hallazgos fueron compatibles con el diagnóstico de la entidad por déficit de carnitina y en uno por déficit de flavoproteínas. Tres correspondieron a pacientes del sexo femenino. Concluimos que con una correlación sistemática de los datos clínicos y paraclínicos, así como también del estudio morfológico, se puede inferir la posible etiología de estas miopatías, cuyo diagnóstico definitivo es por medio del análisis bioquímico
Assuntos
Humanos , Masculino , Adolescente , Adulto , Feminino , Lactente , Doenças Metabólicas/diagnóstico , Doenças Metabólicas/etiologia , Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/metabolismo , Erros Inatos do Metabolismo Lipídico/patologia , Doenças Musculares , Músculo Esquelético/anormalidades , Medicina , VenezuelaRESUMO
OBJECTIVE: Fatty acid oxidation (FAO) disorders are frequently reported as the cause of sudden and unexpected death, but their postmortem recognition remains difficult. We have devised a biochemical protocol in which informative findings in liver tissue are microvesicular steatosis, elevated concentrations of C8-C16 fatty acids, glucose depletion, and low carnitine concentration. STUDY DESIGN: We analyzed 27 cases representing five FAO disorders and compared the results with those obtained in a retrospective blinded analysis of 418 cases of sudden infant death (313 SIDS, 45 infections, and 34 accidents and abuse). RESULTS: All cases of accidents and abuse correctly tested negative. Among the others, 25 (6%) showed at least two abnormal findings. Of these, 14 closely matched the biochemical profiles seen in specific FAO disorders. These included 2 cases with medium-chain acyl-CoA dehydrogenase deficiency, 4 cases consistent with glutaric acidemia type 2, 4 cases with either very long-chain acylcoenzyme A dehydrogenase deficiency or long-chain 3-hydroxy-acyl-coenzyme A dehydrogenase deficiency, and 4 cases predicted to be affected with carnitine uptake defect. CONCLUSION: The results of this study support the view that approximately 5% of all cases of sudden infant death are likely caused by an FAO disorder.
Assuntos
Ácidos Graxos/metabolismo , Erros Inatos do Metabolismo Lipídico/complicações , Fígado/patologia , Morte Súbita do Lactente/etiologia , 3-Hidroxiacil-CoA Desidrogenases/deficiência , Acil-CoA Desidrogenase , Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Carnitina/metabolismo , Estudos de Casos e Controles , Feminino , Glutaratos/sangue , Humanos , Lactente , Recém-Nascido , Erros Inatos do Metabolismo Lipídico/metabolismo , Erros Inatos do Metabolismo Lipídico/patologia , Fígado/metabolismo , Masculino , Triagem Neonatal/métodos , Oxirredução , Estudos Retrospectivos , Morte Súbita do Lactente/patologiaRESUMO
An 18-month-old girl with an oxidative phosphorylation defect had neonatal onset of chronic lactic acidosis, lipid storage myopathy, bilateral cataracts, and primary adrenal insufficiency. Chronic lactic acidosis responded to treatment with dichloroacetate. Sequential muscle biopsies demonstrated resolution of the lipid storage myopathy associated with the return to normal muscle free carnitine levels. This case demonstrates a new clinical phenotype associated with a defect in oxidative phosphorylation and the need to consider mitochondrial disorders in the differential diagnosis of primary adrenal insufficiency in childhood.
Assuntos
Acidose Láctica/metabolismo , Hormônio Adrenocorticotrópico/deficiência , Erros Inatos do Metabolismo Lipídico/metabolismo , Mitocôndrias Musculares/metabolismo , Fosforilação Oxidativa , Acidose Láctica/complicações , Acidose Láctica/tratamento farmacológico , Catarata/complicações , Ácido Dicloroacético/uso terapêutico , Feminino , Humanos , Recém-Nascido , Erros Inatos do Metabolismo Lipídico/complicações , FenótipoRESUMO
Reverse cholesterol transport from peripheral tissues, including the arterial wall, involves high density lipoprotein (HDL) uptake of unesterified cell cholesterol, its esterification by lecithin-cholesterol-acyl-transferase (LCAT), direct HDL-cholesteryl ester uptake by the liver and the indirect pathway consisting of the cholesteryl ester transfer protein (CETP)-mediated transfer of HDL-cholesteryl ester to apolipoprotein (apo) B-containing lipoproteins (very low density lipoprotein (VLDL) and LDL). Although the first route should be regarded as anti-atherogenic, ambiguous interpretations are drawn from the indirect pathway since it is potentially atherogenic to the extent that it may raise the plasma cholesteryl ester concentration in lipoproteins that are taken up by arterial wall macrophages. In addition, controversial roles are played in reverse cholesterol transport by LCAT and liver uptake of HDL-cholesteryl ester mediated by hepatic lipase (HL). HDL may exert several antiatherogenic effects unrelated to its role in cell cholesterol removal.
Assuntos
Arteriosclerose/prevenção & controle , Colesterol/metabolismo , Glicoproteínas , Fígado/metabolismo , Animais , Apolipoproteínas/genética , Apolipoproteínas/metabolismo , Arteriosclerose/genética , Arteriosclerose/metabolismo , Transporte Biológico , Proteínas de Transporte/metabolismo , Proteínas de Transferência de Ésteres de Colesterol , Ésteres do Colesterol/metabolismo , HDL-Colesterol/metabolismo , Suscetibilidade a Doenças/metabolismo , Predisposição Genética para Doença , Humanos , Lipase/deficiência , Lipase/genética , Lipase/metabolismo , Erros Inatos do Metabolismo Lipídico/genética , Erros Inatos do Metabolismo Lipídico/metabolismo , Fosfatidilcolina-Esterol O-Aciltransferase/metabolismoAssuntos
Encefalopatias/metabolismo , Cianose/metabolismo , Deficiência de Citocromo-c Oxidase , Erros Inatos do Metabolismo Lipídico/metabolismo , Malonatos/urina , Doenças Musculares/metabolismo , Púrpura/metabolismo , Encefalopatias/genética , Cianose/genética , Extremidades , Humanos , Lactente , Erros Inatos do Metabolismo Lipídico/genética , Masculino , Doenças Musculares/genética , Púrpura/genética , SíndromeRESUMO
A term neonate became lethargic and hypotonic at 46 hours of age and died 10 hours later despite supportive therapy. Urinary organic acids indicated medium-chain acyl-coenzyme A dehydrogenase deficiency, and DNA studies confirmed this disorder. Neonatal symptoms in this enzyme deficiency have rarely been reported, and recent reviews have ignored or discounted this presentation.
Assuntos
DNA/genética , Ácidos Graxos Dessaturases/deficiência , Erros Inatos do Metabolismo Lipídico/metabolismo , Acil-CoA Desidrogenase , Ácidos Graxos Dessaturases/análise , Ácidos Graxos Dessaturases/genética , Ácidos Graxos/urina , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Recém-Nascido , Erros Inatos do Metabolismo Lipídico/genética , Erros Inatos do Metabolismo Lipídico/patologia , Masculino , Mutação , Reação em Cadeia da Polimerase , Espectrometria de Massas de Bombardeamento Rápido de ÁtomosRESUMO
Today, the long-chain polyunsaturated fatty acids, omega 6 and omega 3, are of special interest to different research groups, all over the world, due to its physiological and metabolic importance. This paper presents different cases of fatty acids deficiency from which the cases of premature low-birth-weight neonates and children under 5 years old presenting severe malnutrition, stand out. In addition, various inherited pathological processes that involve the mechanism of oxidation of these nutrients, are also described.
Assuntos
Transtornos da Nutrição Infantil/metabolismo , Ácidos Graxos Insaturados/metabolismo , Erros Inatos do Metabolismo Lipídico/metabolismo , Pré-Escolar , Crescimento , Humanos , Lactente , OxirreduçãoRESUMO
Cholesterol ester storage disease (CESD) is infrequent in children. Four new cases in two nonrelated families are presented. Acid lipase deficiency in the leukocytes of the patients and reduced activity (50%) in those of parents were demonstrated. Clinical manifestations varied from neonatal cholestasis to asymptomatic hepatomegaly. Hepatic histology showed lipid vacuoles and cholesterol ester storage in hepatocytes and Kupffer cells. Increased levels of cholesterol and hepatomegaly were the first findings. There is as yet no specific treatment for CESD; however, the early detection of cases would make possible the timely control of complications.
Assuntos
Ésteres do Colesterol/metabolismo , Erros Inatos do Metabolismo Lipídico , Criança , Feminino , Hepatomegalia/enzimologia , Homozigoto , Humanos , Hipercolesterolemia/metabolismo , Células de Kupffer/enzimologia , Leucócitos/enzimologia , Erros Inatos do Metabolismo Lipídico/genética , Erros Inatos do Metabolismo Lipídico/metabolismo , Erros Inatos do Metabolismo Lipídico/patologia , Lipase Lipoproteica/deficiência , Fígado/enzimologia , Fígado/patologia , MasculinoRESUMO
Five patients aged 7 to 21 months are described who developed attacks of coma after a short prodromal illness with diarrhea or vomiting or both. Four had concomitant hypoglycemia, and all had hypoketonemia, with excessive urinary excretion of medium-chain dicarboxylic acids, medium-chain (omega-1)-hydroxyacids, suberylglycine, hexanoylglycine, and octanoylcarnitine. All patients accumulated octanoic acid, decanoic acid, and cis-4-decenoic acid in plasma. Fibroblasts from three patients showed a decreased rate of octanoate oxidation (10%, 12%, and 29% of control values, respectively). These findings suggest a deficiency of medium-chain acyl-CoA dehydrogenase, most probably an autosomal recessive inherited metabolic disorder. Two of the patients died during an acute attack, and a third had severe neurologic sequelae; the two remaining patients recovered. Plasma free carnitine levels were low, but total carnitine was normal. The three surviving patients underwent a fasting test, which did not lead to hypoglycemia, although hypoketonemia, dicarboxylic aciduria, and excessive mobilization of fatty acids did occur. The surviving patients were maintained on frequent carbohydrate-enriched meals.