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1.
J Child Neurol ; : 8830738241279225, 2024 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-39257161

RESUMO

Objective: To determine whether there is a correlation of genetic diagnosis/result with long-term seizure freedom in pediatric epilepsy patients. Methods: This was a prospective and retrospective cohort study of children with epilepsy referred for genetic testing at a single center. The primary outcomes were presence and type of genetic diagnosis (pathogenic, benign, or variant of uncertain significance) and patient epilepsy status (seizure free, treatment failure, uncertain). Epilepsy gene panels were the primary method of genetic testing. Results: The prospective cohort had 22 patients followed for >11 years and for whom genetic testing was then performed; the retrospective cohort had 78 patients with previous genetic testing followed for >8 years. In the prospective cohort, one patient each of the seizure free or treatment failure groups had a pathogenic genetic variant; mean Combined Annotation Dependent Depletion (CADD) scores 22 and 24, respectively (P = .62). In the retrospective cohort, there was no difference in the number of variants (P = .97), the variant interpretations (P = .29 ClinVar, P = .39 lab interpretation) or mean CADD scores (P = .29) between the seizure-free, treatment failure, and uncertain epilepsy patients. Whole exome and genome sequencing identified pathogenic variants in 70% of patients with treatment failure but were not performed in seizure-free patients. Significance: Our findings show no correlation of the presence or type of epilepsy gene panel result with long-term seizure freedom in pediatric patients. The yield and specificity of pathogenic variants may be higher using whole exome and whole genome sequencing in patients with treatment-resistant epilepsy. Whole exome and whole genome sequencing, or more targeted understanding of specific variants, may be needed to improve the utility of pediatric epilepsy genetic testing.

2.
Circulation ; 119(9): 1272-83, 2009 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-19237663

RESUMO

BACKGROUND: Diabetes-associated cardiac dysfunction is associated with mitochondrial dysfunction and oxidative stress, which may contribute to left ventricular dysfunction. The contribution of altered myocardial insulin action, independent of associated changes in systemic metabolism, is incompletely understood. The present study tested the hypothesis that perinatal loss of insulin signaling in the heart impairs mitochondrial function. METHODS AND RESULTS: In 8-week-old mice with cardiomyocyte deletion of insulin receptors (CIRKO), inotropic reserves were reduced, and mitochondria manifested respiratory defects for pyruvate that was associated with proportionate reductions in catalytic subunits of pyruvate dehydrogenase. Progressive age-dependent defects in oxygen consumption and ATP synthesis with the substrate glutamate and the fatty acid derivative palmitoyl-carnitine were observed. Mitochondria also were uncoupled when exposed to palmitoyl-carnitine, in part as a result of increased reactive oxygen species production and oxidative stress. Although proteomic and genomic approaches revealed a reduction in subsets of genes and proteins related to oxidative phosphorylation, no reductions in maximal activities of mitochondrial electron transport chain complexes were found. However, a disproportionate reduction in tricarboxylic acid cycle and fatty acid oxidation proteins in mitochondria suggests that defects in fatty acid and pyruvate metabolism and tricarboxylic acid flux may explain the mitochondrial dysfunction observed. CONCLUSIONS: Impaired myocardial insulin signaling promotes oxidative stress and mitochondrial uncoupling, which, together with reduced tricarboxylic acid and fatty acid oxidative capacity, impairs mitochondrial energetics. This study identifies specific contributions of impaired insulin action to mitochondrial dysfunction in the heart.


Assuntos
Doenças Mitocondriais/metabolismo , Miocárdio/metabolismo , Estresse Oxidativo/fisiologia , Receptor de Insulina/genética , Transdução de Sinais/fisiologia , Disfunção Ventricular Esquerda/metabolismo , Adenosina Trifosfatases/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Proteínas de Transporte/metabolismo , Ecocardiografia , Complexo I de Transporte de Elétrons/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Expressão Gênica/fisiologia , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , Doenças Mitocondriais/diagnóstico por imagem , Doenças Mitocondriais/fisiopatologia , ATPases Mitocondriais Próton-Translocadoras , Miócitos Cardíacos/fisiologia , Consumo de Oxigênio/fisiologia , Fenótipo , Proteômica , Receptor de Insulina/metabolismo , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/fisiopatologia
3.
Diabetes ; 61(12): 3260-9, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22912419

RESUMO

These studies investigate the role of uncoupling protein 3 (UCP3) in cardiac energy metabolism, cardiac O(2) consumption (MVO(2)), cardiac efficiency (CE), and mitochondrial uncoupling in high fat (HF)-fed or leptin-deficient mice. UCP3KO and wild-type (WT) mice were fed normal chow or HF diets for 10 weeks. Substrate utilization rates, MVO(2), CE, and mitochondrial uncoupling were measured in perfused working hearts and saponin-permeabilized cardiac fibers, respectively. Similar analyses were performed in hearts of ob/ob mice lacking UCP3 (U3OB mice). HF increased cardiac UCP3 protein. However, fatty acid (FA) oxidation rates were similarly increased by HF diet in WT and UCP3KO mice. By contrast, MVO(2) increased in WT, but not in UCP3KO with HF, leading to increased CE in UCP3KO mice. Consistent with increased CE, mitochondrial coupling was increased in the hearts of HF-fed UCP3KO mice. Unexpectedly, UCP3 deletion in ob/ob mice reduced FA oxidation but had no effect on MVO(2) or CE. In addition, FA-induced mitochondrial uncoupling was similarly enhanced in U3OB compared with ob/ob hearts and was associated with elevated mitochondrial thioesterase-1 protein content. These studies show that although UCP3 may mediate mitochondrial uncoupling and reduced CE after HF feeding, it does not mediate uncoupling in leptin-deficient states.


Assuntos
Metabolismo Energético/fisiologia , Canais Iônicos/metabolismo , Leptina/deficiência , Proteínas Mitocondriais/metabolismo , Consumo de Oxigênio/fisiologia , Animais , Gorduras na Dieta/efeitos adversos , Metabolismo Energético/genética , Canais Iônicos/genética , Leptina/genética , Masculino , Camundongos , Camundongos Knockout , Mitocôndrias , Proteínas Mitocondriais/genética , Consumo de Oxigênio/genética , Palmitoil-CoA Hidrolase/metabolismo , Proteína Desacopladora 3
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