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1.
Int J Mol Sci ; 21(7)2020 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-32276429

RESUMO

Patients with very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) can present with life-threatening cardiac arrhythmias. The pathophysiological mechanism is unknown. We reprogrammed fibroblasts from one mildly and one severely affected VLCADD patient, into human induced pluripotent stem cells (hiPSCs) and differentiated these into cardiomyocytes (VLCADD-CMs). VLCADD-CMs displayed shorter action potentials (APs), more delayed afterdepolarizations (DADs) and higher systolic and diastolic intracellular Ca2+ concentration ([Ca2+]i) than control CMs. The mitochondrial booster resveratrol mitigated the biochemical, electrophysiological and [Ca2+]i changes in the mild but not in the severe VLCADD-CMs. Accumulation of potentially toxic intermediates of fatty acid oxidation was blocked by substrate reduction with etomoxir. Incubation with etomoxir led to marked prolongation of AP duration and reduced DADs and [Ca2+]i in both VLCADD-CMs. These results provide compelling evidence that reduced accumulation of fatty acid oxidation intermediates, either by enhanced fatty acid oxidation flux through increased mitochondria biogenesis (resveratrol) or by inhibition of fatty acid transport into the mitochondria (etomoxir), rescues pro-arrhythmia defects in VLCADD-CMs and open doors for new treatments.


Assuntos
Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Arritmias Cardíacas/prevenção & controle , Síndrome Congênita de Insuficiência da Medula Óssea/fisiopatologia , Compostos de Epóxi/farmacologia , Ácidos Graxos/química , Erros Inatos do Metabolismo Lipídico/fisiopatologia , Mitocôndrias/fisiologia , Doenças Mitocondriais/fisiopatologia , Doenças Musculares/fisiopatologia , Miócitos Cardíacos/fisiologia , Resveratrol/farmacologia , Potenciais de Ação , Arritmias Cardíacas/etiologia , Eletrofisiologia Cardíaca , Síndrome Congênita de Insuficiência da Medula Óssea/complicações , Ácidos Graxos/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas , Erros Inatos do Metabolismo Lipídico/complicações , Doenças Mitocondriais/complicações , Doenças Musculares/complicações , Miócitos Cardíacos/efeitos dos fármacos , Oxirredução
3.
Muscle Nerve ; 61(2): 253-257, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31729045

RESUMO

BACKGROUND: Neutral lipid storage disease with myopathy (NLSDM) is a rare lipid metabolism disorder. In this study, we evaluated some circulating miRNAs levels in serum samples and the MRI of three affected siblings. METHODS: Three members of one NLSDM family were identified: two brothers and one sister. Muscles of lower and right upper extremities were studied by MRI. Expression profile of miRNAs, obtained from serum samples, was detected using qRT-PCR. RESULTS: Two brothers presented with progressive skeletal myopathy, while the sister had severe hepatosteatosis and diabetes. NLSDM patients showed a significant increase of muscle-specific miRNAs expression compared with healthy subjects. We found a correlation between hepatic damage and elevation of miRNAs expression profile of liver origin. CONCLUSIONS: The dysregulation of miRNAs might represent an indicator of skeletal and hepatic damage and it might be useful to monitor the progression of NLSDM.


Assuntos
Biomarcadores/sangue , Erros Inatos do Metabolismo Lipídico/sangue , Erros Inatos do Metabolismo Lipídico/genética , MicroRNAs/sangue , Doenças Musculares/sangue , Doenças Musculares/genética , Idade de Início , Feminino , Humanos , Lipase/genética , Erros Inatos do Metabolismo Lipídico/diagnóstico por imagem , Fígado/metabolismo , Fígado/patologia , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/diagnóstico por imagem , Doenças Musculares/diagnóstico por imagem , Mutação/genética , Irmãos , Tomografia Computadorizada por Raios X
4.
Toxicol In Vitro ; 62: 104665, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31629068

RESUMO

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 Wistar
6.
Lipids Health Dis ; 18(1): 232, 2019 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-31883530

RESUMO

BACKGROUND: Chanarin Dorfman Syndrome (CDS) is a rare autosomal recessive disorder characterized by the multisytemic accumulation of neutral lipids inside the cytoplasmic lipid droplets. This condition is caused by mutations in the abhydrolase domain containing 5 gene (ABHD5). In CDS the skin involvement is the prevalent and always observed clinical feature, consisting of a non-bullous congenital ichthyosiform erythroderma (NCIE). Moreover, a variable involvement of the liver and neuromuscular system can be also observed. In this report, we aimed to perform the clinical and genetic characterization of a patient affected by CDS with atypical dermatological findings, considering this rare inborn error of neutral lipid metabolism. METHODS: Genomic DNA samples obtained from patient and his parents were used to perform the sequencing of the ABHD5 exons and their intron/exon boundaries. Bioinformatic analyses were performed to investigate the possible effect of the identified mutation on protein structure. RESULTS: Here we present the case of a 29-year-old male patient with CDS, who, for long time, has been misdiagnosed as pityriasis rubra pilaris (PRP). He has a history of increasing hyperlipidemia; hepatomegaly associated with hepatosteatosis was also detected. ABHD5 molecular analysis revealed a novel missense mutation, the c.811G > A (p.G271R). Bioinformatic investigations showed that the variant has a deleterious effect on ABHD5 function, probably causing an incorrect folding of the mutant protein. CONCLUSIONS: These results highlihts the importance of genetic testing for ABHD5 in unresolved cases of patients presenting unusual skin lesions, that resemble PRP, associated with a history of hyperlipidemia and nonalcoholic fatty liver.


Assuntos
1-Acilglicerol-3-Fosfato O-Aciltransferase/genética , Eritrodermia Ictiosiforme Congênita/diagnóstico , Ictiose Lamelar/diagnóstico , Erros Inatos do Metabolismo Lipídico/diagnóstico , Doenças Musculares/diagnóstico , Pitiríase Rubra Pilar/diagnóstico , Adulto , Erros de Diagnóstico , Predisposição Genética para Doença , Humanos , Eritrodermia Ictiosiforme Congênita/genética , Eritrodermia Ictiosiforme Congênita/patologia , Ictiose Lamelar/genética , Ictiose Lamelar/patologia , Gotículas Lipídicas/metabolismo , Erros Inatos do Metabolismo Lipídico/genética , Erros Inatos do Metabolismo Lipídico/patologia , Lipídeos/genética , Masculino , Doenças Musculares/genética , Doenças Musculares/patologia , Mutação de Sentido Incorreto , Pitiríase Rubra Pilar/genética , Pitiríase Rubra Pilar/patologia , Dobramento de Proteína
7.
Pediatr Ann ; 48(11): e441-e447, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31710363

RESUMO

Exocrine pancreatic insufficiency in children can lead to lifelong complications related to malnutrition and poor growth. The clinical presentation can be subtle in the early stages of insufficiency as the large functional capacity of the pancreas is gradually lost. The pediatrician plays a crucial role in the early identification of these children to ensure a timely referral so that a diagnosis can be made and therapy initiated. Early nutritional therapy allows for prevention and correction of deficiencies, which leads to improved outcomes and survival. When insufficiency is suspected, the workup should start with an indirect test of exocrine pancreatic function, such as fecal elastase, to establish the diagnosis. Once a diagnosis is established, further testing to delineate the etiology should be pursued, with cystic fibrosis being high on the differential list and assessed for with a sweat test. Assessment of anthropometry at every visit is key, as is monitoring of laboratory parameters and physical examination findings that are suggestive of malabsorption and malnutrition. The mainstay of management is administration of exogenous pancreatic enzymes to facilitate digestion and absorption. [Pediatr Ann. 2019;48(11):e441-e447.].


Assuntos
Transtornos da Nutrição Infantil/etiologia , Insuficiência Pancreática Exócrina/diagnóstico , Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Anus Imperfurado/complicações , Criança , Transtornos da Nutrição Infantil/diagnóstico , Transtornos da Nutrição Infantil/terapia , Quimotripsina/metabolismo , Síndrome Congênita de Insuficiência da Medula Óssea/complicações , Fibrose Cística/complicações , Gorduras na Dieta/metabolismo , Displasia Ectodérmica/complicações , Terapia de Reposição de Enzimas , Insuficiência Pancreática Exócrina/etiologia , Insuficiência Pancreática Exócrina/terapia , Fezes/enzimologia , Transtornos do Crescimento/complicações , Perda Auditiva Neurossensorial/complicações , Humanos , Hipotireoidismo/complicações , Deficiência Intelectual/complicações , Erros Inatos do Metabolismo Lipídico/complicações , Doenças Mitocondriais/complicações , Doenças Musculares/complicações , Nariz/anormalidades , Avaliação Nutricional , Pâncreas/diagnóstico por imagem , Pâncreas/fisiologia , Pancreatopatias/complicações , Elastase Pancreática/metabolismo , Testes de Função Pancreática , Pancreatite Crônica/complicações , Pancreatite Crônica/etiologia , Síndrome de Shwachman-Diamond/complicações , Esteatorreia/etiologia , Tripsinogênio/sangue
8.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(11): 1067-1072, 2019 Nov 10.
Artigo em Chinês | MEDLINE | ID: mdl-31703127

RESUMO

OBJECTIVE: To determine the incidence and mutational types of fatty acid oxidation disorders (FAOD) in central-northern region of Guangxi. METHODS: A total of 62 953 neonates were screened for FAOD during December 2012 and December 2017. Acyl-carnitine profiling of neonatal blood sample was performed by tandem mass spectrometry using dry blood spots on a filter paper. The diagnosis of FAOD was confirmed by organic acid profiling of urea and genetic testing. RESULTS: Eighteen cases of FAOD were diagnosed among the 62 953 neonates. Among these, primary carnitine deficiency (PCD) was the most common type (n=13), which was followed by short-chain acyl-CoA dehydrogenase deficiency (SCADD) (n=2), medium-chain acyl-CoA dehydrogenase deficiency (MCADD) (n=1), multiple acyl-CoA dehydrogenase deficiency (MADD) (n=1), and carnitine palmitoyltransferase II deficiency (CPT II D) (n=1). Genetic testing has revealed two previously unreported variants, i.e., c.337G to A (p.Gly113Arg) of ACADS gene and c.737G TO T (p.Gly246Val) of ETFA gene. CONCLUSION: PCD is the most common FAOD in central-northern Guangxi. Tandem mass spectrometry combined with genetic testing may facilitate early diagnosis of FAOD.


Assuntos
Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/genética , Acil-CoA Desidrogenase/deficiência , Acil-CoA Desidrogenase/genética , Carnitina/sangue , Carnitina O-Palmitoiltransferase/deficiência , China , Flavoproteínas Transferidoras de Elétrons/genética , Humanos , Recém-Nascido , Erros Inatos do Metabolismo/diagnóstico , Deficiência Múltipla de Acil Coenzima A Desidrogenase/diagnóstico , Triagem Neonatal , Espectrometria de Massas em Tandem
9.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(10): 1002-1005, 2019 Oct 10.
Artigo em Chinês | MEDLINE | ID: mdl-31598946

RESUMO

OBJECTIVE: To detect potential variation in an ethnic Han Chinese family affected with late-onset lipid storage myopathy. METHODS: Next generation sequencing (NGS) was used to screen disease-related genes in the proband. Suspected mutation was validated with PCR and Sanger sequencing in two patients, their father, and 100 healthy controls. RESULTS: Heterozygous c.770A>G (p.Tyr257Cys) and c.1395dupT (p.Gly466Tryfs) mutation were detected in the two patients. Their father was found to be heterozygous for the c.770A>G (p.Tyr257Cys) mutation, while the c.1395dupT (p.Gly466Tryfs) variation was not reported previously and not found among the healthy controls. CONCLUSION: Mutations of the ETFDH gene probably underlie the pathogenesis in this family. The novel c.1395dupT (p.Gly466Tryfs) has enriched the mutation spectrum of EDFDH gene.


Assuntos
Flavoproteínas Transferidoras de Elétrons/genética , Proteínas com Ferro-Enxofre/genética , Erros Inatos do Metabolismo Lipídico/genética , Distrofias Musculares/genética , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/genética , Grupo com Ancestrais do Continente Asiático , Heterozigoto , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação
10.
J Pediatr Ophthalmol Strabismus ; 56: e60-e64, 2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31622479

RESUMO

Retinopathy of prematurity (ROP) is a biphasic disease in which the first phase is characterized by high oxygen tension leading to vaso-obliteration in the retina. Pearson syndrome is a rare multisystem mitochondrial disease with a defect in cellular respiration. The authors describe a patient with Pearson syndrome and delayed onset of ROP at a postconceptual age of 42 weeks. The proposed mechanistic theory was the increased oxygen use associated with the metabolic impairments in Pearson syndrome counterbalancing the effects of supplemental oxygen during the vaso-obliterative stage of ROP. [J Pediatr Ophthalmol Strabismus. 2019;56:e60-e64.].


Assuntos
Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Síndrome Congênita de Insuficiência da Medula Óssea/diagnóstico , Recém-Nascido de Baixo Peso , Erros Inatos do Metabolismo Lipídico/diagnóstico , Doenças Mitocondriais/diagnóstico , Doenças Musculares/diagnóstico , Oxigênio/metabolismo , Retinopatia da Prematuridade/diagnóstico , Acil-CoA Desidrogenase de Cadeia Longa/metabolismo , Síndrome Congênita de Insuficiência da Medula Óssea/metabolismo , Progressão da Doença , Feminino , Angiofluoresceinografia/métodos , Seguimentos , Fundo de Olho , Idade Gestacional , Humanos , Recém-Nascido , Erros Inatos do Metabolismo Lipídico/metabolismo , Doenças Mitocondriais/metabolismo , Doenças Musculares/metabolismo , Retinopatia da Prematuridade/metabolismo , Fatores de Tempo
11.
Biochem Soc Trans ; 47(5): 1259-1268, 2019 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-31654053

RESUMO

The ABCG5/G8 heterodimer is the primary neutral sterol transporter in hepatobiliary and transintestinal cholesterol excretion. Inactivating mutations on either the ABCG5 or ABCG8 subunit cause Sitosterolemia, a rare genetic disorder. In 2016, a crystal structure of human ABCG5/G8 in an apo state showed the first structural information on ATP-binding cassette (ABC) sterol transporters and revealed several structural features that were observed for the first time. Over the past decade, several missense variants of ABCG5/G8 have been associated with non-Sitosterolemia lipid phenotypes. In this review, we summarize recent pathophysiological and structural findings of ABCG5/G8, interpret the structure-function relationship in disease-causing variants and describe the available evidence that allows us to build a mechanistic view of ABCG5/G8-mediated sterol transport.


Assuntos
Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/química , Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/química , Sistema Biliar/metabolismo , Colesterol/metabolismo , Lipoproteínas/química , Fígado/metabolismo , Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/biossíntese , Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/biossíntese , Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Catálise , Homeostase , Humanos , Hipercolesterolemia/metabolismo , Enteropatias/metabolismo , Erros Inatos do Metabolismo Lipídico/metabolismo , Lipoproteínas/biossíntese , Lipoproteínas/metabolismo , Fitosteróis/efeitos adversos , Fitosteróis/metabolismo
12.
PLoS One ; 14(9): e0221829, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31479473

RESUMO

Mitochondrial DNA (mtDNA) genome integrity is essential for proper mitochondrial respiratory chain function to generate cellular energy. Nuclear genes encode several proteins that function at the mtDNA replication fork, including mitochondrial single-stranded DNA-binding protein (SSBP1), which is a tetrameric protein that binds and protects single-stranded mtDNA (ssDNA). Recently, two studies have reported pathogenic variants in SSBP1 associated with hearing loss, optic atrophy, and retinal degeneration. Here, we report a 14-year-old Chinese boy with severe and progressive mitochondrial disease manifestations across the full Pearson, Kearns-Sayre, and Leigh syndromes spectrum, including infantile anemia and bone marrow failure, growth failure, ptosis, ophthalmoplegia, ataxia, severe retinal dystrophy of the rod-cone type, sensorineural hearing loss, chronic kidney disease, multiple endocrine deficiencies, and metabolic strokes. mtDNA genome sequencing identified a single large-scale 5 kilobase mtDNA deletion (m.8629_14068del5440), present at 68% and 16% heteroplasmy in the proband's fibroblast cell line and blood, respectively, suggestive of a mtDNA maintenance defect. On trio whole exome blood sequencing, the proband was found to harbor a novel de novo heterozygous mutation c.79G>A (p.E27K) in SSBP1. Size exclusion chromatography of p.E27K SSBP1 revealed it remains a stable tetramer. However, differential scanning fluorimetry demonstrated p.E27K SSBP1 relative to wild type had modestly decreased thermostability. Functional assays also revealed p.E27K SSBP1 had altered DNA binding. Molecular modeling of SSBP1 tetramers with varying combinations of mutant subunits predicted general changes in surface accessible charges, strength of inter-subunit interactions, and protein dynamics. Overall, the observed changes in protein dynamics and DNA binding behavior suggest that p.E27K SSBP1 can interfere with DNA replication and precipitate the introduction of large-scale mtDNA deletions. Thus, a single large-scale mtDNA deletion (SLSMD) with manifestations across the clinical spectrum of Pearson, Kearns-Sayre, and Leigh syndromes may result from a nuclear gene disorder disrupting mitochondrial DNA replication.


Assuntos
Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Síndrome Congênita de Insuficiência da Medula Óssea/genética , DNA Mitocondrial/genética , Proteínas de Ligação a DNA/genética , Síndrome de Kearns-Sayre/genética , Doença de Leigh/genética , Erros Inatos do Metabolismo Lipídico/genética , Doenças Mitocondriais/genética , Proteínas Mitocondriais/genética , Doenças Musculares/genética , Mutação , Acil-CoA Desidrogenase de Cadeia Longa/genética , Adolescente , Sequência de Aminoácidos , Linhagem Celular , Criança , Síndrome Congênita de Insuficiência da Medula Óssea/complicações , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/metabolismo , Heterozigoto , Humanos , Síndrome de Kearns-Sayre/complicações , Doença de Leigh/complicações , Erros Inatos do Metabolismo Lipídico/complicações , Masculino , Doenças Mitocondriais/complicações , Proteínas Mitocondriais/química , Proteínas Mitocondriais/metabolismo , Simulação de Dinâmica Molecular , Doenças Musculares/complicações , Fenótipo , Estabilidade Proteica , Estrutura Quaternária de Proteína , Deleção de Sequência , Sequenciamento Completo do Exoma
13.
Curr Opin Cardiol ; 34(6): 706-713, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31436558

RESUMO

PURPOSE OF REVIEW: This review is a comprehensive update on recent discoveries on the genetics of early-onset coronary artery disease (EOCAD), and how those findings can be translated to advance its medical management. RECENT FINDINGS: To date, a total of 266 common variants of modest effect size have been reported to be associated with CAD, but many still warrant functional studies. Rare variants impacting the function of at least 10 genes are now well characterized in Mendelian EOCAD. Estimations of minor allele frequencies in multiple ancestries from large genetic databases have allowed us to estimate the prevalence of Mendelian forms of EOCAD. In fact, the prevalence of Mendelian mutations varies markedly between ancestries, ranging from 1 : 289 to 1 : 153 for familial hypercholesterolemia. Mendelian forms of EOCAD support three major biological pathways, including lipid metabolism, vascular wall integrity and function, and thrombosis. Furthermore, combining common variants of modest effect into polygenic risk scores (PRS) has shown to be effective at identifying individuals at high risk of CAD. SUMMARY: Mendelian forms of EOCAD highlight the importance of lipid metabolism, yet prevalence in many non-European populations remains to be clarified. Polygenic EOCAD affects more individuals and, in many cases, confers a higher risk of EOCAD than rare Mendelian mutations. Thus, sequencing of target genes and the derivation of PRSs can be used to identify high-risk patients, leading to more personalized therapeutic approaches.


Assuntos
Doença da Artéria Coronariana/genética , Idade de Início , Testes Genéticos , Genética Populacional , Humanos , Erros Inatos do Metabolismo Lipídico/genética , Fatores de Risco , Trombofilia/genética , Doenças Vasculares/genética
14.
Biochim Biophys Acta Mol Cell Biol Lipids ; 1864(11): 1591-1605, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31394165

RESUMO

Medium-chain-triglycerides (MCT) are widely applied in the treatment of long-chain fatty acid oxidation disorders (lcFAOD). Long-term treatment with MCT led to a sexually dimorphic response in the mouse model of very-long-chain-acyl-CoA-dehydrogenase-deficiency (VLCAD-/-) with the subsequent development of a metabolic syndrome in female mice. In order to evaluate the molecular mechanisms responsible for this sex specific response we performed a comprehensive metabolic phenotyping, SILAC-based quantitative proteomics and characterized the involved signaling pathways by western blot analysis and gene expression. WT and VLCAD-/- mice showed strong sex-dependent differences in basal metabolism and expression of proteins involved in the distinct metabolic pathways, even more prominent after treatment with octanoate. The investigation of molecular mechanisms responsible for the sexual dimorphisms delineated the selective activation of the ERK/mTORc1 signaling pathway leading to an increased biosynthesis and elongation of fatty acids in VLCAD-/- females. In contrast, octanoate induced the activation of ERK/PPARγ pathway and the subsequent upregulation of peroxisomal ߭oxidation in males. We here provide first evidence that sex has to be considered as important variable in disease phenotype. These findings may have implications on treatment strategies in the different sexes.


Assuntos
Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Acil-CoA Desidrogenase de Cadeia Longa/metabolismo , Síndrome Congênita de Insuficiência da Medula Óssea/metabolismo , Ácidos Graxos/metabolismo , Erros Inatos do Metabolismo Lipídico/metabolismo , Doenças Mitocondriais/metabolismo , Doenças Musculares/metabolismo , Acil-CoA Desidrogenase de Cadeia Longa/genética , Animais , Caprilatos/metabolismo , Caprilatos/uso terapêutico , Síndrome Congênita de Insuficiência da Medula Óssea/genética , Síndrome Congênita de Insuficiência da Medula Óssea/terapia , Feminino , Deleção de Genes , Humanos , Erros Inatos do Metabolismo Lipídico/genética , Erros Inatos do Metabolismo Lipídico/terapia , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos , Doenças Mitocondriais/genética , Doenças Mitocondriais/terapia , Doenças Musculares/genética , Doenças Musculares/terapia , Oxirredução , PPAR gama/metabolismo , Fatores Sexuais , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo
15.
Mol Genet Metab ; 128(1-2): 122-128, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31399326

RESUMO

Newborn screening is an incredibly useful tool for the early identification of many metabolic disorders, including fatty acid oxidation (FAO) disorders. In many cases, molecular tests are necessary to reach a final diagnosis, highlighting the need for a thorough evaluation of genes implicated in FAO disorders. Using the ClinGen (Clinical Genome Resource) clinical validity framework, thirty genes were analyzed for the strength of evidence supporting their association with FAO disorders. Evidence was gathered from the literature by biocurators and presented to disease experts for review in order to assign a clinical validity classification of Definitive, Strong, Moderate, Limited, Disputed, Refuted, or No Reported Evidence. Of the gene-disease relationships evaluated, 22/30 were classified as Definitive, three as Moderate, one as Limited, three as No Reported Evidence and one as Disputed. Gene-disease relationships with a Limited, Disputed, and No Reported Evidence were found on two, six, and up to four panels out of 30 FAO disorder-specific panels, respectively, in the National Institute of Health Genetic Testing Registry, while over 70% of the genes on panels are definitively associated with an FAO disorder. These results highlight the need to systematically assess the clinical relevance of genes implicated in fatty acid oxidation disorders in order to improve the interpretation of genetic testing results and diagnosis of patients with these disorders.


Assuntos
Ácidos Graxos/metabolismo , Testes Genéticos , Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/genética , Predisposição Genética para Doença , Humanos , Recém-Nascido , Triagem Neonatal , Oxirredução , Reprodutibilidade dos Testes
17.
Mol Genet Metab ; 127(4): 327-335, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31279622

RESUMO

BACKGROUND: Childhood fasting intolerance is a life-threatening problem associated with various inborn errors of metabolism. Plasma acylcarnitines reflect fatty acid oxidation and help determine fasting intolerance etiology. Pediatric reference values of plasma acylcarnitines upon fasting are not available, complicating interpretation of stress samples. METHODS: Retrospective analysis of supervised clinical fasting studies between 01/2005-09/2012. Exclusion criteria involved patients with (suspected) disorders, repeated tests or incomplete results. Remaining children were grouped according to age: group A (≤24 months), B (25-84 months) and C (≥85 months). Median and 2.5th to 97.5th percentiles of basic metabolic parameters and acylcarnitines were determined at start and end of testing on the ward and analyzed for significant differences (p<0.05). RESULTS: Out of 127 fasting studies, 48 were included: group A (n=13), B (n=23) and C (n=12). Hypoglycemia occurred in 21%. Children from group C demonstrated significantly higher end glucose concentrations while end ketone body concentrations were significantly lower compared to younger children. In all groups, free carnitine and C3-carnitine significantly decreased upon fasting, while C2-, C6-, C12:1-, C12-, C14:1-, C14-, C16:1- and C16-carnitine significantly increased. End concentrations of C6-, C12:1-, C12-, C14:1-, C14-, C16:1-, C16- and C18:1-carnitine were significantly lower in children ≥85 months compared to younger children. CONCLUSIONS: Fasting-induced counter-regulatory mechanisms to maintain energy homeostasis are age-dependent. This influences the changes in basic metabolic parameters and acylcarnitine profiles. Our data enable improved interpretation of the individual fasting response and may support assessment of minimal safe fasting times or treatment responses in patients.


Assuntos
Carnitina/análogos & derivados , Jejum/sangue , Hipoglicemia/sangue , Estresse Fisiológico , Glicemia/análise , Carnitina/sangue , Criança , Pré-Escolar , Feminino , Homeostase , Humanos , Lactente , Erros Inatos do Metabolismo Lipídico/sangue , Masculino , Estudos Retrospectivos
18.
Pediatrics ; 144(1)2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31227563

RESUMO

A 2-day old term male infant was found to be hypotonic and minimally reactive during routine nursing care in the newborn nursery. At 40 hours of life, he was hypoglycemic and had intermittent desaturations to 70%. His mother had an unremarkable pregnancy and spontaneous vaginal delivery. The mother's prenatal serology results were negative for infectious risk factors. Apgar scores were 9 at 1 and 5 minutes of life. On day 1 of life, he fed, stooled, and voided well. Our expert panel discusses the differential diagnosis of hypotonia in a neonate, offers diagnostic and management recommendations, and discusses the final diagnosis.


Assuntos
Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Síndrome Congênita de Insuficiência da Medula Óssea/diagnóstico , Letargia/etiologia , Erros Inatos do Metabolismo Lipídico/diagnóstico , Doenças Mitocondriais/diagnóstico , Hipotonia Muscular/etiologia , Doenças Musculares/diagnóstico , Síndrome Congênita de Insuficiência da Medula Óssea/terapia , Diagnóstico Diferencial , Humanos , Hipotermia/etiologia , Recém-Nascido , Erros Inatos do Metabolismo Lipídico/terapia , Masculino , Doenças Mitocondriais/terapia , Doenças Musculares/terapia
19.
Internist (Berl) ; 60(8): 871-877, 2019 Aug.
Artigo em Alemão | MEDLINE | ID: mdl-31254003

RESUMO

Sitosterolemia or phytosterolemia is a rare autosomal recessive hereditary lipid storage disorder. It is caused by homozygous or compound heterozygous mutations in one of the two ABCG5 and ABCG8 genes encoding the intestinal and hepatic heterodimer ABCG5 (sterolin 1)/ABCG8 (sterolin 2) efflux transporters. These mutations lead to intestinal hyperabsorption and reduced hepatic secretion of cholesterol and plant sterols with subsequent accumulation of phytosterols and cholesterol in plasma and deposition in tissue (xanthoma). Phytosterols are found mainly in vegetable oils, margarine, nuts, grains, soybeans and avocados. Patients with sitosterolemia show extreme phenotypic heterogeneity from almost asymptomatic individuals to those with combined severe hypercholesterolemia at a young age, leading to increased atherosclerosis and premature cardiac death. Early abnormalities include hemolytic anemia with stomatocytosis, macrothrombocytopenia and splenomegaly. In addition to strict avoidance of phytosterol-containing foods, the use of the sterol absorption inhibitor ezetimibe, possibly in combination with the bile acid-binding resin cholestyramine, is the most effective treatment option.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Hipercolesterolemia/patologia , Enteropatias/patologia , Erros Inatos do Metabolismo Lipídico/genética , Mutação/genética , Fitosteróis/efeitos adversos , Fitosteróis/sangue , Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Humanos , Hipercolesterolemia/sangue , Erros Inatos do Metabolismo Lipídico/complicações , Erros Inatos do Metabolismo Lipídico/patologia
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