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1.
Medicine (Baltimore) ; 100(38): e27231, 2021 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-34559118

RESUMO

BACKGROUND: Hepatitis B cirrhosis with hyperalphafetoproteinemia is the intermediate stage of liver cirrhosis progressing to hepatocellular carcinoma (HCC), there is no effective way to treat precancerous lesions of liver in modern medicine. In recent decades, clinical and experimental evidence shows that Chinese medicine (CM) has a certain beneficial effect on Hepatitis B Cirrhosis. Therefore, this trial aims to evaluate the efficacy and safety of a CM erzhu jiedu recipe (EZJDR) for the treatment of Hepatitis B Cirrhosis with Hyperalphafetoproteinemia. METHODS: We designed a randomized, double blind, placebo-controlled clinical trial. A total of 72 patients of Hepatitis B Cirrhosis with hyperalphafetoproteinemia were randomized in 2 parallel groups. Patients in the control group received placebo granules similar to the EZJDR. In the EZJDR group, patients received EZJDR twice a day, after meals, for 48 weeks. The primary efficacy measures were changes in serum alpha-fetoprotein (AFP) and alpha-fetoprotein alloplasm (AFP-L3); The secondary indicators of efficacy are changes in liver function indicators, HBV-DNA level; Liver stiffness measurement (LSM); Hepatic portal vein diameter; T lymphocyte subgroup indexes during treatment. All data will be recorded in case report forms and analyzed by Statistical Analysis System software. Adverse events will also be evaluated. RESULTS: The results showed that EZJDR can significantly inhibit the levels of AFP and AFP-L3 in patients with hepatitis B cirrhosis and hyperalphafetoproteinemia and have good security. ETHICS AND DISSEMINATION: The study protocol was approved by the Medical Ethics Committee of Shuguang Hospital, affiliated with University of Traditional Chinese Medicine, Shanghai (NO.2018-579-08-01). TRIAL REGISTRATION: This trial was registered on Chinese Clinical Trial Center (NO.ChiCTR1800017165).


Assuntos
Proteínas de Transferência de Ésteres de Colesterol/deficiência , Erros Inatos do Metabolismo Lipídico/tratamento farmacológico , Erros Inatos do Metabolismo Lipídico/etiologia , Medicina Tradicional Chinesa/normas , Distribuição de Qui-Quadrado , Método Duplo-Cego , Fibrose/complicações , Fibrose/tratamento farmacológico , Hepatite B/complicações , Hepatite B/tratamento farmacológico , Humanos , Medicina Tradicional Chinesa/métodos , Medicina Tradicional Chinesa/estatística & dados numéricos , Placebos
2.
Cell Mol Life Sci ; 78(14): 5631-5646, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34110423

RESUMO

Peroxisomes play an essential role in the ß-oxidation of dicarboxylic acids (DCAs), which are metabolites formed upon ω-oxidation of fatty acids. Genetic evidence linking transporters and enzymes to specific DCA ß-oxidation steps is generally lacking. Moreover, the physiological functions of DCA metabolism remain largely unknown. In this study, we aimed to characterize the DCA ß-oxidation pathway in human cells, and to evaluate the biological role of DCA metabolism using mice deficient in the peroxisomal L-bifunctional protein (Ehhadh KO mice). In vitro experiments using HEK-293 KO cell lines demonstrate that ABCD3 and ACOX1 are essential in DCA ß-oxidation, whereas both the bifunctional proteins (EHHADH and HSD17B4) and the thiolases (ACAA1 and SCPx) have overlapping functions and their contribution may depend on expression level. We also show that medium-chain 3-hydroxydicarboxylic aciduria is a prominent feature of EHHADH deficiency in mice most notably upon inhibition of mitochondrial fatty acid oxidation. Using stable isotope tracing methodology, we confirmed that products of peroxisomal DCA ß-oxidation can be transported to mitochondria for further metabolism. Finally, we show that, in liver, Ehhadh KO mice have increased mRNA and protein expression of cholesterol biosynthesis enzymes with decreased (in females) or similar (in males) rate of cholesterol synthesis. We conclude that EHHADH plays an essential role in the metabolism of medium-chain DCAs and postulate that peroxisomal DCA ß-oxidation is a regulator of hepatic cholesterol biosynthesis.


Assuntos
Colesterol/metabolismo , Ácidos Dicarboxílicos/urina , Erros Inatos do Metabolismo Lipídico/patologia , Hepatopatias/patologia , Mitocôndrias/patologia , Enzima Bifuncional do Peroxissomo/fisiologia , Animais , Feminino , Células HEK293 , Homeostase , Humanos , Erros Inatos do Metabolismo Lipídico/etiologia , Hepatopatias/etiologia , Hepatopatias/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/metabolismo
3.
Br J Nutr ; 123(12): 1365-1372, 2020 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-32077392

RESUMO

Vegetable lipid emulsions (LE) contain non-declared phytosterols (PS). We aimed to determine PS content depending on the brand and LE batch, and in adult hospitalised patients treated with parenteral nutrition (PN), to establish the association between plasma and administered PS. Part I was the LE study: totals and fractions of PS in three to four non-consecutive batches from six LE were analysed. Part II was the patient study: patients with at least 7 previous days of PN with 0·8 g/kg per d of an olive/soyabean (O/S) LE were randomised (day 0) 1:1 to O/S or 100 % fish oil (FO) at a dose of 0·4 g/kg per d for 7 d (day 7). Plasma PS, its fractions, total cholesterol on days 0 and 7, their clearance and their association with PS administered by LE were studied. In part I, LE study: differences were found in the total PS, their fractions and cholesterol among different LE brands and batches. Exclusive soyabean LE had the highest content of PS (422·36 (sd 130·46) µg/ml). In part II, patient study: nineteen patients were included. In the O/S group, PS levels were maintained (1·11 (sd 6·98) µg/ml) from day 0 to 7, while in the FO group, significant decreases were seen in total PS (-6·21 (sd 4·73) µg/ml) and their fractions, except for campesterol and stigmasterol. Plasma PS on day 7 were significantly associated with PS administered (R2 0·443). PS content in different LE brands had great variability. PS administered during PN resulted in accumulation and could be prevented with the exclusive administration of FO LE.


Assuntos
Emulsões Gordurosas Intravenosas/análise , Hipercolesterolemia/etiologia , Enteropatias/etiologia , Erros Inatos do Metabolismo Lipídico/etiologia , Soluções de Nutrição Parenteral/química , Nutrição Parenteral/efeitos adversos , Fitosteróis/efeitos adversos , Fitosteróis/análise , Adulto , Colesterol/análogos & derivados , Colesterol/análise , Colesterol/sangue , Feminino , Óleos de Peixe/análise , Humanos , Pacientes Internados , Masculino , Óleos de Plantas/análise , Estudos Prospectivos , Estigmasterol/análise , Verduras/química
4.
Am J Phys Med Rehabil ; 99(6): e71-e74, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31136308

RESUMO

Multiple acyl-CoA dehydrogenase deficiency is a rare autosomal recessive inborn error of metabolism. The late-onset multiple acyl-CoA dehydrogenase deficiency is frequently caused by mutations in ETFDH gene. Because of its clinical heterogeneity, diagnosis and treatment of late-onset multiple acyl-CoA dehydrogenase deficiency are often delayed. The authors described a previously healthy 40-yr-old Thai woman presenting with subacute severe weakness of bulbar-limb muscles and elevated serum creatine kinase. The authors emphasized the importance of needle EMG and prompt muscle histopathological evaluation, which rapidly led to the diagnosis and riboflavin therapy, resulting in a dramatic and rapid improvement before genetic study disclosed mutation in ETFDH gene.


Assuntos
Eletromiografia/métodos , Erros Inatos do Metabolismo Lipídico/etiologia , Erros Inatos do Metabolismo Lipídico/fisiopatologia , Deficiência Múltipla de Acil Coenzima A Desidrogenase/complicações , Deficiência Múltipla de Acil Coenzima A Desidrogenase/fisiopatologia , Distrofias Musculares/etiologia , Distrofias Musculares/fisiopatologia , Adulto , Feminino , Humanos , Erros Inatos do Metabolismo Lipídico/tratamento farmacológico , Erros Inatos do Metabolismo Lipídico/genética , Deficiência Múltipla de Acil Coenzima A Desidrogenase/tratamento farmacológico , Deficiência Múltipla de Acil Coenzima A Desidrogenase/genética , Distrofias Musculares/tratamento farmacológico , Distrofias Musculares/genética , Riboflavina/uso terapêutico
5.
J Clin Endocrinol Metab ; 104(9): 3610-3613, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-30990523

RESUMO

CONTEXT: Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency (LCHADD) affects oxidation of long-chain fatty acids (FAO) and is associated with risk of metabolic crises and episodic rhabdomyolysis. CASE DESCRIPTION: We present the cases of two patients with LCHADD. Patient 1 (male, 26 years old) was severely affected by muscle weakness and neuropathy. He was diagnosed at age 20 years and was nonadherent to standard dietary management. MRI revealed significant fat replacement of muscle in both calves. Patient 2 (female, 15 years old) was diagnosed at age 1 year. She had no muscle weakness and was compliant with the recommended diet. Compared with healthy persons, both patients had reduced FAO and palmitate oxidation, measured with indirect calorimetry and stable isotope technique during a submaximal cycle ergometer test. Patient 2 had some residual capacity to increase FAO and a compensatory higher carbohydrate oxidation, which ensured a near-normal exercise capacity. Patient 1 was unable to increase FAO and could only complete 23 minutes of exercise, vs 60 minutes by patient 2 and healthy persons. In both, 10% IV infusion of glucose (IV-glucose) during exercise increased carbohydrate oxidation slightly, but endurance was not improved, which likely relates to the fixed weakness in patient 1 and because the residual FAO was suppressed by the glucose infusion in both. CONCLUSION: The two patients illustrate that FAO is impaired and carbohydrate oxidation is elevated during exercise in patients affected by LCHADD, compared with healthy persons, but IV-glucose has no beneficial effect on exercise tolerance in LCHADD.


Assuntos
Cardiomiopatias/complicações , Exercício Físico , Ácidos Graxos/metabolismo , Glucose/administração & dosagem , Erros Inatos do Metabolismo Lipídico/tratamento farmacológico , Miopatias Mitocondriais/complicações , Proteína Mitocondrial Trifuncional/deficiência , Debilidade Muscular/tratamento farmacológico , Músculo Esquelético/efeitos dos fármacos , Doenças do Sistema Nervoso/complicações , Rabdomiólise/complicações , Adolescente , Adulto , Estudos de Casos e Controles , Feminino , Seguimentos , Humanos , Erros Inatos do Metabolismo Lipídico/complicações , Erros Inatos do Metabolismo Lipídico/etiologia , Erros Inatos do Metabolismo Lipídico/patologia , Masculino , Debilidade Muscular/etiologia , Debilidade Muscular/patologia , Músculo Esquelético/patologia , Oxirredução , Prognóstico , Edulcorantes/administração & dosagem , Adulto Jovem
6.
Hum Mol Genet ; 28(6): 928-941, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30445591

RESUMO

Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is the most common defect of mitochondrial long-chain fatty acid ß-oxidation. Patients present with heterogeneous clinical phenotypes affecting heart, liver and skeletal muscle predominantly. The full pathophysiology of the disease is unclear and patient response to current therapeutic regimens is incomplete. To identify additional cellular alterations and explore more effective therapies, mitochondrial bioenergetics and redox homeostasis were assessed in VLCAD-deficient fibroblasts, and several protective compounds were evaluated. The results revealed cellular and tissue changes, including decreased respiratory chain (RC) function, increased reactive oxygen species (ROS) production and altered mitochondrial function and signaling pathways in a variety of VLCAD-deficient fibroblasts. The mitochondrially enriched electron and free radical scavengers JP4-039 and XJB-5-131 improved RC function and decreased ROS production significantly, suggesting that they are viable candidate compounds to further develop to treat VLCAD-deficient patients.


Assuntos
Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Antioxidantes/farmacologia , Síndrome Congênita de Insuficiência da Medula Óssea/metabolismo , Transporte de Elétrons/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Erros Inatos do Metabolismo Lipídico/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Doenças Mitocondriais/metabolismo , Doenças Musculares/metabolismo , Acil-CoA Desidrogenase de Cadeia Longa/metabolismo , Trifosfato de Adenosina/metabolismo , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Síndrome Congênita de Insuficiência da Medula Óssea/etiologia , Retículo Endoplasmático/metabolismo , Erros Inatos do Metabolismo Lipídico/etiologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Doenças Mitocondriais/etiologia , Dinâmica Mitocondrial/efeitos dos fármacos , Doenças Musculares/etiologia , Oxirredução/efeitos dos fármacos , Consumo de Oxigênio , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais
7.
Acta Clin Belg ; 74(6): 451-455, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30451603

RESUMO

Muscle weakness is a nonspecific finding of myopathy of any etiology that include iatrogenic, toxic, endocrinological, infectious, immunologic, and metabolic disorders. Among the metabolic myopathies glutaric aciduria type II (GAII) is an autosomal recessively inherited rare disorder of fatty acid and amino acid metabolisms. The late onset form is heterogeneous in terms of symptomatology and severity and for the cases that chronic manifestations of lipid storage myopathy are the only clues for the disease, differential diagnosis can be challenging. Here we report two cases of GAII: the first one was 18-year old boy who presented with proximal muscle weakness and in another center, he was diagnosed as polymyositis and treated with immunosuppressive therapies. He admitted to our clinic with ongoing muscle weakness and symptoms that were related to the side effects of immunosuppressive therapies. The second case was also presented with muscle weakness. For both cases, muscle biopsies and urinary organic acid analyses were consistent with the diagnosis of GAII. To differentiate inflammatory myositis from non-inflammatory myopathies; rheumatic symptoms, accompanying complaints of the patient and autoantibody positivity can be helpful. To our knowledge this is the first report to underline the differential diagnosis of inflammatory myopathies from metabolic myopathies.


Assuntos
Acil-CoA Desidrogenase/deficiência , Transtornos de Início Tardio , Erros Inatos do Metabolismo Lipídico , Deficiência Múltipla de Acil Coenzima A Desidrogenase , Músculo Esquelético/patologia , Distrofias Musculares , Miosite/diagnóstico , Adolescente , Biópsia/métodos , Carnitina/administração & dosagem , Diagnóstico Diferencial , Feminino , Humanos , Transtornos de Início Tardio/diagnóstico , Transtornos de Início Tardio/fisiopatologia , Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/etiologia , Erros Inatos do Metabolismo Lipídico/fisiopatologia , Masculino , Micronutrientes/administração & dosagem , Deficiência Múltipla de Acil Coenzima A Desidrogenase/diagnóstico , Deficiência Múltipla de Acil Coenzima A Desidrogenase/metabolismo , Deficiência Múltipla de Acil Coenzima A Desidrogenase/fisiopatologia , Debilidade Muscular/diagnóstico , Debilidade Muscular/etiologia , Distrofias Musculares/diagnóstico , Distrofias Musculares/etiologia , Distrofias Musculares/fisiopatologia , Riboflavina/administração & dosagem , Índice de Gravidade de Doença , Urinálise/métodos , Adulto Jovem
9.
J Atheroscler Thromb ; 25(8): 741-746, 2018 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-29353827

RESUMO

AIM: Sitosterolemia is an extremely rare, autosomal recessive disease characterized by high plasma cholesterols and plant sterols because of increased absorption of dietary cholesterols and sterols from the intestine, and decreased excretion from biliary tract. Previous study indicated that sitosterolemic patients might be vulnerable to post-prandial hyperlipidemia, including high remnant-like lipoprotein particles (RLP) level. Here we evaluate whether a loading dietary fat increases a post-prandial RLP cholesterol level in sitosterolemic patients compared to heterozygous familial hypercholesterolemic patients (FH). METHODS: We recruit total of 20 patients: 5 patients with homozygous sitosterolemia, 5 patients with heterozygous sitosterolemia, and 10 patients with heterozygous FH as controls from May 2015 to March 2018 at Kanazawa University Hospital, Japan. All patients receive Oral Fat Tolerance Test (OFTT) cream (50 g/body surface area square meter, orally only once, and the cream includes 34% of fat, 74 mg of cholesterol, and rich in palmitic and oleic acids. The primary endpoint is the change of a RLP cholesterol level after OFTT cream loading between sitosterolemia and FH. We measure them at baseline, and 2, 4, and 6 hours after the oral fat loading. RESULTS: This is the first study to evaluate whether sitosterolemia patients have a higher post-prandial RLP cholesterol level compared to heterozygous FH patients. CONCLUSION: The result may become an additional evidence to restrict dietary cholesterols for sitosterolemia. This study is registered at University Hospital Medical Information Network (UMIN) Clinical Trials Registry (UMIN ID: UMIN000020330).


Assuntos
Colesterol/sangue , Gorduras na Dieta/efeitos adversos , Hipercolesterolemia/diagnóstico , Hiperlipoproteinemia Tipo II/diagnóstico , Enteropatias/diagnóstico , Erros Inatos do Metabolismo Lipídico/diagnóstico , Fitosteróis/efeitos adversos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Colesterol/administração & dosagem , Feminino , Seguimentos , Humanos , Hipercolesterolemia/sangue , Hipercolesterolemia/etiologia , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/etiologia , Enteropatias/sangue , Enteropatias/etiologia , Japão , Erros Inatos do Metabolismo Lipídico/sangue , Erros Inatos do Metabolismo Lipídico/etiologia , Lipoproteínas/sangue , Masculino , Pessoa de Meia-Idade , Fitosteróis/sangue , Período Pós-Prandial , Prognóstico , Triglicerídeos/sangue , Adulto Jovem
11.
Biochim Biophys Acta ; 1857(9): 1363-1372, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27240720

RESUMO

Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is biochemically characterized by tissue accumulation of octanoic (OA), decanoic (DA) and cis-4-decenoic (cDA) acids, as well as by their carnitine by-products. Untreated patients present episodic encephalopathic crises and biochemical liver alterations, whose pathophysiology is poorly known. We investigated the effects of OA, DA, cDA, octanoylcarnitine (OC) and decanoylcarnitine (DC) on critical mitochondrial functions in rat brain and liver. DA and cDA increased resting respiration and diminished ADP- and CCCP-stimulated respiration and complexes II-III and IV activities in both tissues. The data indicate that these compounds behave as uncouplers and metabolic inhibitors of oxidative phosphorylation. Noteworthy, metabolic inhibition was more evident in brain as compared to liver. DA and cDA also markedly decreased mitochondrial membrane potential, NAD(P)H content and Ca(2+) retention capacity in Ca(2+)-loaded brain and liver mitochondria. The reduction of Ca(2+) retention capacity was more pronounced in liver and totally prevented by cyclosporine A and ADP, as well as by ruthenium red, demonstrating the involvement of mitochondrial permeability transition (mPT) and Ca(2+). Furthermore, cDA induced lipid peroxidation in brain and liver mitochondria and increased hydrogen peroxide formation in brain, suggesting the participation of oxidative damage in cDA-induced alterations. Interestingly, OA, OC and DC did not alter the evaluated parameters, implying lower toxicity for these compounds. Our results suggest that DA and cDA, in contrast to OA and medium-chain acylcarnitines, disturb important mitochondrial functions in brain and liver by multiple mechanisms that are possibly involved in the neuropathology and liver alterations observed in MCAD deficiency.


Assuntos
Acil-CoA Desidrogenase/deficiência , Encéfalo/efeitos dos fármacos , Cálcio/metabolismo , Ácidos Decanoicos/farmacologia , Metabolismo Energético/efeitos dos fármacos , Ácidos Graxos Monoinsaturados/farmacologia , Erros Inatos do Metabolismo Lipídico/etiologia , Fígado/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Proteínas de Transporte da Membrana Mitocondrial/efeitos dos fármacos , Animais , Encéfalo/metabolismo , Fígado/metabolismo , Mitocôndrias/metabolismo , Poro de Transição de Permeabilidade Mitocondrial , NADP/análise , Ratos , Ratos Wistar
12.
Muscle Nerve ; 52(2): 289-93, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25556768

RESUMO

INTRODUCTION: The lipid storage myopathies, primary carnitine deficiency, neutral lipid storage disease, and multiple acyl coenzyme A dehydrogenase deficiency (MADD), are progressive disorders that cause permanent weakness. These disorders of fatty acid metabolism and intracellular triglyceride degradation cause marked fat deposition and damage to muscle cells. METHODS: We describe a rapidly progressive myopathy in a previously healthy 33-year-old woman. Over 4 months, she developed a proximal and axial myopathy associated with diffuse myalgia and dysphagia, ultimately leading to respiratory failure and death. RESULTS: Muscle biopsy showed massive accumulation of lipid. Plasma acylcarnitine and urine organic acid analysis was consistent with MADD. This was confirmed by molecular genetic testing, which revealed 2 pathogenic mutations in the ETFDH gene. CONCLUSIONS: This report illustrates a late-onset case of MADD and reviews the differential diagnosis and evaluation of patients with proximal myopathy and excessive accumulation of lipid on muscle biopsy.


Assuntos
Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/etiologia , Deficiência Múltipla de Acil Coenzima A Desidrogenase/complicações , Deficiência Múltipla de Acil Coenzima A Desidrogenase/diagnóstico , Distrofias Musculares/diagnóstico , Distrofias Musculares/etiologia , Adulto , Feminino , Humanos
13.
J Lipid Res ; 52(1): 6-34, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20929975

RESUMO

Cholesterol homeostasis is critical for normal growth and development. In addition to being a major membrane lipid, cholesterol has multiple biological functions. These roles include being a precursor molecule for the synthesis of steroid hormones, neuroactive steroids, oxysterols, and bile acids. Cholesterol is also essential for the proper maturation and signaling of hedgehog proteins, and thus cholesterol is critical for embryonic development. After birth, most tissues can obtain cholesterol from either endogenous synthesis or exogenous dietary sources, but prior to birth, the human fetal tissues are dependent on endogenous synthesis. Due to the blood-brain barrier, brain tissue cannot utilize dietary or peripherally produced cholesterol. Generally, inborn errors of cholesterol synthesis lead to both a deficiency of cholesterol and increased levels of potentially bioactive or toxic precursor sterols. Over the past couple of decades, a number of human malformation syndromes have been shown to be due to inborn errors of cholesterol synthesis. Herein, we will review clinical and basic science aspects of Smith-Lemli-Opitz syndrome, desmosterolosis, lathosterolosis, HEM dysplasia, X-linked dominant chondrodysplasia punctata, Congenital Hemidysplasia with Ichthyosiform erythroderma and Limb Defects Syndrome, sterol-C-4 methyloxidase-like deficiency, and Antley-Bixler syndrome.


Assuntos
Colesterol/biossíntese , Anormalidades Congênitas/etiologia , Erros Inatos do Metabolismo Lipídico/complicações , Anormalidades Múltiplas/etiologia , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/metabolismo , Animais , Condrodisplasia Punctata/etiologia , Condrodisplasia Punctata/genética , Condrodisplasia Punctata/metabolismo , Humanos , Erros Inatos do Metabolismo Lipídico/etiologia , Erros Inatos do Metabolismo Lipídico/genética , Erros Inatos do Metabolismo Lipídico/metabolismo , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/deficiência , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/genética , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/metabolismo , Síndrome de Smith-Lemli-Opitz/etiologia , Síndrome de Smith-Lemli-Opitz/genética , Síndrome de Smith-Lemli-Opitz/metabolismo , Erros Inatos do Metabolismo de Esteroides , Síndrome
14.
J Inherit Metab Dis ; 31 Suppl 2: S293-7, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18500571

RESUMO

Wolcott-Rallison syndrome (WRS) (OMIM 226980) is a rare, autosomal recessive disorder with infancy-onset diabetes mellitus, multiple epiphyseal dysplasia, osteopenia, mental retardation or developmental delay, and hepatic and renal dysfunction as main clinical findings. Patients with WRS have mutations in the EIF2AK3 gene, which encodes the pancreatic eukaryotic translation initiation factor 2-alpha kinase 3. We report a female patient who developed insulin-requiring diabetes at 2.5 months of age. Multiple epiphyseal dysplasia was diagnosed at age 2 years. At age 5.5 years she developed a Reye-like syndrome with hypoketotic hypoglycaemia and renal and hepatic insufficiency and died. A partial autopsy showed fat infiltration in the liver and kidneys. Examination of urine by gas chromatography and mass spectrometry showed large amounts of C(6)-dicarboxylic acid (adipic acid), 3-hydroxy-C(8)-dicarboxylic acid, 3-hydroxy-C(10)-dicarboxylic acid, and 3-hydroxydecenedioic acid. Acetoacetate and 3-hydroxybutyrate were absent. The findings suggested a metabolic block in mitochondrial fatty acid oxidation, but lack of material precluded enzyme analyses. The clinical diagnosis of WRS was suggested in retrospect, and confirmed by sequencing of DNA extracted from stored autopsy material. The patient was compound heterozygous for the novel EIF2AK3 mutations c.1694_1695delAT (Y565X) and c.3044T > C (F1015S). Our data suggest that disruption of the EIF2AK3 gene may lead to defective mitochondrial fatty acid oxidation and hypoglycaemia, thus adding to the heterogeneous phenotype of WRS.


Assuntos
Diabetes Mellitus Tipo 1/diagnóstico , Ácidos Dicarboxílicos/urina , Hidroxiácidos/urina , Erros Inatos do Metabolismo Lipídico/etiologia , Osteocondrodisplasias/diagnóstico , Adipatos/urina , Biomarcadores/urina , Pré-Escolar , Análise Mutacional de DNA , Diabetes Mellitus/etiologia , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/enzimologia , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/urina , Progressão da Doença , Epífises/anormalidades , Epífises/enzimologia , Evolução Fatal , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Insuficiência Hepática/etiologia , Humanos , Lactente , Erros Inatos do Metabolismo Lipídico/genética , Erros Inatos do Metabolismo Lipídico/urina , Mutação , Osteocondrodisplasias/complicações , Osteocondrodisplasias/enzimologia , Osteocondrodisplasias/etiologia , Osteocondrodisplasias/genética , Osteocondrodisplasias/urina , Insuficiência Renal/etiologia , eIF-2 Quinase/genética
15.
Mol Genet Metab ; 92(4): 346-50, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17825594

RESUMO

Patients with mitochondrial long-chain fat oxidation deficiencies are usually treated with diets containing reduced fat and increased carbohydrate, at times via gastrostomy feeding. To ensure adequate intake of essential fatty acids, supplements are provided to their diets using commercially available oils. These oils contain large quantities of non-essential fats that are preferentially oxidized and produce disease-specific metabolites (acyl-CoA intermediates) due to the genetic defect. This study describes the concentrations of these intermediates as reflected by acylcarnitines as well as the % contribution from each of four fatty acids: palmitate, oleate, linoleate, and alpha-linolenate when incubated with fibroblasts from patients with VLCAD, LCHAD, and trifunctional protein (TFP) deficiencies. Palmitate and oleate produce the majority of disease-specific acylcarnitines with these defective cell lines (79-94%) whereas linoleate and linolenate produced less (6-21%). On average, the amount of acylcarnitines decreased with increasing unsaturation (C18:1>C18:2>C18:3:34%>11%>3%, respectively. This relationship may reflect the "gatekeeper" role of carnitine palmitoyltransferase I (CPT I). A diet comparison between Canola and a combination of Flax/Walnut oils revealed that the latter, containing the least amount of non-essential fats, reduced blood acylcarnitine levels by 33-36%. The etiology of the severe peripheral neuropathy of TFP deficiency may result from the unique metabolite, 3-keto-acyl-CoA, after conversion to a methylketone via spontaneous decarboxylation. Essential fatty acid supplementation with oils should consider these findings to decrease production of disease-specific acyl-CoA intermediates.


Assuntos
Acil-CoA Desidrogenase de Cadeia Longa/metabolismo , Carnitina/análogos & derivados , Dietoterapia , Erros Inatos do Metabolismo Lipídico/dietoterapia , Complexos Multienzimáticos/deficiência , Carnitina/metabolismo , Linhagem Celular , Dietoterapia/métodos , Gorduras na Dieta , Ingestão de Energia , Fibroblastos/metabolismo , Erros Inatos do Metabolismo Lipídico/etiologia , Complexos Multienzimáticos/genética , Óleos , Oxirredução , Polineuropatias/genética , Polineuropatias/metabolismo
16.
J Invest Dermatol ; 126(9): 2032-8, 2006 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16741516

RESUMO

Neutral lipid storage disease with ichthyosis (NLSDI; Chanarin-Dorfman syndrome) is an ichthyosiform syndrome, often associated with mutations in a lipid hydrolase, CGI-58. The presence of oil red O-positive, neutral lipid droplets in tissue biopsies, and/or in leukocytes on blood smears, coupled with a constellation of multisystem abnormalities and a pruritic ichthyosiform erythroderma, are together diagnostic of NLSDI. We investigated the pathogenesis of the ichthyosiform erythroderma in patients from three unrelated kindreds with a clinical diagnosis of NLSDI. Basal permeability barrier function and stratum corneum (SC) integrity were abnormal, but barrier recovery rates were faster than normal, as in atopic dermatitis. The basal barrier abnormality was linked to the secretion of lipid micro-inclusions, first segregated within lamellar bodies (LB), which then form a non-lamellar phase within the SC interstices, shown by combined ruthenium tetroxide post-fixation and lipid-retaining resin-white embedding. With colloidal lanthanum nitrate perfusion, excess water/solute movement was restricted to the SC interstices, and further localized to non-lamellar domains. Phase separation of excess stored lipid provides a unifying pathogenic mechanism not only for NLSDI, but also in several other inherited ichthyosiform disorders of lipid metabolism, such as recessive X-linked ichthyosis and type 2 Gaucher's disease.


Assuntos
Eritrodermia Ictiosiforme Congênita/etiologia , Eritrodermia Ictiosiforme Congênita/patologia , Erros Inatos do Metabolismo Lipídico/etiologia , Erros Inatos do Metabolismo Lipídico/patologia , 1-Acilglicerol-3-Fosfato O-Aciltransferase , Adulto , Criança , Epiderme/patologia , Epiderme/ultraestrutura , Esterases/genética , Saúde da Família , Feminino , Humanos , Eritrodermia Ictiosiforme Congênita/genética , Corpos de Inclusão/patologia , Corpos de Inclusão/ultraestrutura , Lipase/genética , Metabolismo dos Lipídeos , Erros Inatos do Metabolismo Lipídico/genética , Microscopia Eletrônica , Permeabilidade , Síndrome , Água/metabolismo
17.
PLoS Genet ; 1(2): e23, 2005 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16121256

RESUMO

Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is the most common inherited disorder of mitochondrial fatty acid beta-oxidation in humans. To better understand the pathogenesis of this disease, we developed a mouse model for MCAD deficiency (MCAD-/-) by gene targeting in embryonic stem (ES) cells. The MCAD-/- mice developed an organic aciduria and fatty liver, and showed profound cold intolerance at 4 degrees C with prior fasting. The sporadic cardiac lesions seen in MCAD-/- mice have not been reported in human MCAD patients. There was significant neonatal mortality of MCAD-/- pups demonstrating similarities to patterns of clinical episodes and mortality in MCAD-deficient patients. The MCAD-deficient mouse reproduced important aspects of human MCAD deficiency and is a valuable model for further analysis of the roles of fatty acid oxidation and pathogenesis of human diseases involving fatty acid oxidation.


Assuntos
Acil-CoA Desidrogenase/deficiência , Erros Inatos do Metabolismo Lipídico/etiologia , Animais , Temperatura Baixa , Modelos Animais de Doenças , Embrião de Mamíferos/citologia , Ácidos Graxos/metabolismo , Fígado Gorduroso , Camundongos , Camundongos Knockout , Oxirredução , Células-Tronco , Taxa de Sobrevida
18.
Adv Neonatal Care ; 4(1): 26-32, 2004 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-14988877

RESUMO

Acute fatty liver disease of pregnancy has been recognized as a clinical problem since the 1980s. In the past 8 years, the association of this disease with a genetic inborn error of metabolism in the infant has been recognized. Women who are heterozygous for this disorder are usually asymptomatic until the capacity of their livers to metabolize free fatty acids (FFA) is overwhelmed by a homozygous fetus. The inborn error of metabolism, long-chain 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD) deficiency, may not be immediately recognizable in the infant. Symptoms in the infant are often triggered by an increased long-chain fatty acid load in the diet, or by illness that results in breakdown of endogenous fat. The following case study reviews the clinical pathophysiology of this perinatal health problem and highlights the priorities for the care of infants born to mothers with acute fatty liver disease of pregnancy.


Assuntos
3-Hidroxiacil-CoA Desidrogenases/deficiência , Fígado Gorduroso/metabolismo , Erros Inatos do Metabolismo Lipídico/etiologia , Complicações na Gravidez/metabolismo , 3-Hidroxiacil-CoA Desidrogenases/metabolismo , Adulto , Coagulação Intravascular Disseminada/etiologia , Fígado Gorduroso/complicações , Fígado Gorduroso/diagnóstico , Feminino , Síndrome HELLP/complicações , Síndrome HELLP/diagnóstico , Síndrome HELLP/metabolismo , Humanos , Recém-Nascido , Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/enzimologia , 3-Hidroxiacil-CoA Desidrogenase de Cadeia Longa , Gravidez , Complicações na Gravidez/diagnóstico , Fatores de Risco
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