RESUMO
Bi-allelic variants in Iron-Sulfur Cluster Scaffold (NFU1) have previously been associated with multiple mitochondrial dysfunctions syndrome 1 (MMDS1) characterized by early-onset rapidly fatal leukoencephalopathy. We report 19 affected individuals from 10 independent families with ultra-rare bi-allelic NFU1 missense variants associated with a spectrum of early-onset pure to complex hereditary spastic paraplegia (HSP) phenotype with a longer survival (16/19) on one end and neurodevelopmental delay with severe hypotonia (3/19) on the other. Reversible or irreversible neurological decompensation after a febrile illness was common in the cohort, and there were invariable white matter abnormalities on neuroimaging. The study suggests that MMDS1 and HSP could be the two ends of the NFU1-related phenotypic continuum.
Assuntos
Paraplegia Espástica Hereditária , Humanos , Fenótipo , Paraplegia Espástica Hereditária/genética , Mutação de Sentido Incorreto , Alelos , Ferro/metabolismo , Proteínas de Transporte/genéticaRESUMO
This review highlights the current knowledge of epigenetic targets of anticancer therapy and outlines the current limitations of epigenetic approaches and the difficulties in defining preventive tools and strategies. Promising strategies towards achieving the goal of developing effective epigenetic treatments are discussed, including restoration or enhancement of sensitivity to other treatment modalities, and combinations with other agents and new therapeutic areas.
Assuntos
Antineoplásicos/farmacologia , Epigênese Genética , Neoplasias/tratamento farmacológico , Ensaios Clínicos como Assunto , Sistemas de Liberação de Medicamentos , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Neoplasias/genéticaRESUMO
A long path, initiated more than 40 years ago, has led to a deeper understanding of the complexity of gene regulation in eukaryotic genomes. In addition to genetic mechanisms, the imbalance in the epigenetic control of gene expression may profoundly alter the finely tuned machinery leading to gene regulation. Here, we review the impact of the studies on DNA methylation, the "primadonna" in the epigenetic scenario, on the understanding of basic phenomena, such as X inactivation and genomic imprinting. The effect of deregulation of DNA methylation on human health, will be also discussed. Finally, an attempt to predict future directions of this rapidly evolving field has been proposed, with the certainty that, fortunately, science is always better than predictions.