RESUMEN
Leigh syndrome represents a complex inherited neurometabolic and neurodegenerative disorder associated with different clinical, genetic and neuroimaging findings in the context of bilateral symmetrical lesions involving the brainstem and basal ganglia. Heterogeneous neurological manifestations such as spasticity, cerebellar ataxia, dystonia, choreoathetosis and parkinsonism are associated with multisystemic and ophthalmological abnormalities due to >75 different monogenic causes. Here, we describe the clinical and genetic features of a Brazilian cohort of patients with Leigh Syndrome in which muscle biopsy analysis showed mitochondrial DNA defects and determine the utility of whole exome sequencing for a final genetic diagnostic in this cohort.
Asunto(s)
ADN Mitocondrial/genética , ADN Mitocondrial/metabolismo , Secuenciación del Exoma , Enfermedad de Leigh/genética , Enfermedad de Leigh/metabolismo , Adolescente , Adulto , Anciano , Brasil , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Enfermedad de Leigh/diagnóstico , Masculino , Persona de Mediana EdadRESUMEN
The mitochondrial respiratory chain in vertebrates and arthropods is different from that of most other eukaryotes because they lack alternative enzymes that provide electron transfer pathways additional to the oxidative phosphorylation (OXPHOS) system. However, the use of diverse experimental models, such as human cells in culture, Drosophila melanogaster and the mouse, has demonstrated that the transgenic expression of these alternative enzymes can impact positively many phenotypes associated with human mitochondrial and other cellular dysfunction, including those typically presented in complex IV deficiencies, Parkinson's, and Alzheimer's. In addition, these enzymes have recently provided extremely valuable data on how, when, and where reactive oxygen species, considered by many as "by-products" of OXPHOS, can contribute to animal longevity. It has also been shown that the expression of the alternative enzymes is thermogenic in cultured cells, causes reproductive defects in flies, and enhances the deleterious phenotype of some mitochondrial disease models. Therefore, all the reported beneficial effects must be considered with caution, as these enzymes have been proposed to be deployed in putative gene therapies to treat human diseases. Here, we present a brief review of the scientific data accumulated over the past decade that show the benefits and the risks of introducing alternative branches of the electron transport into mammalian and insect mitochondria, and we provide a perspective on the future of this research field.
Asunto(s)
Animales Modificados Genéticamente/metabolismo , Proteínas del Complejo de Cadena de Transporte de Electrón/metabolismo , Mitocondrias/metabolismo , Translocador 1 del Nucleótido Adenina/genética , Translocador 1 del Nucleótido Adenina/metabolismo , Animales , Animales Modificados Genéticamente/crecimiento & desarrollo , Proteínas del Complejo de Cadena de Transporte de Electrón/genética , Humanos , NADH Deshidrogenasa/genética , NADH Deshidrogenasa/metabolismo , Fosforilación Oxidativa , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Las enfermedades mitocondriales son un grupo de desórdenes clínicamente heterogéneo con manifestaciones clínicas muy variables y alta tasa de morbi-mortalidad. Tienen complejas implicancias en la reproducción, ya que los riesgos de repetición en la familia son variables, 25% en las formas autosómicas recesivas, alrededor de 4% en los casos de mutaciones mitocondriales de novo, y un riesgo incierto pero elevado si la madre es portadora de las mutaciones mitocondriales. Por ello, se proponen distintas técnicas de diagnóstico preimplantacional, prenatal o de reproducción asistida a fin de evitar el nacimiento de niños con esta patología. En el presente trabajo se describen y analizan las implicancias científicas y éticas de las nuevas técnicas de reproducción asistida que se proponen a las familias con alto riesgo.
Mitochondrial diseases are a clinically heterogeneous group of disorders with variable clinical features and high morbidity and mortality. As there are different hereditary patterns, complex implications in reproduction are expected; the recurrence risk may be about 25% in autosomal recessive inheritance, 4% in de novo mitochondrial mutations, and an uncertain, but high risk, when the mother is carrier of mitochondrial mutations. Thus, different preimplantation and prenatal diagnosis or assisted reproductive techniques are proposed to avoid the birth of children with these diseases. In this paper scientific and ethical implications of new assisted reproductive techniques offer to high risk families are describe and analyzed.
As enfermidades mitocondriais são um grupo de desordens clinicamente heterogêneos com manifestações clínicas muito variáveis e alta taxa de morbi-mortalidade. Têm complexas implicações na reprodução, já que os riscos de repetição na família são variáveis, 25% nas formas autossômicas recessivas, ao redor de 4% nos casos de mutações mitocondriais de novo, e um risco incerto porém elevado se a mãe é portadora das mutações mitocondriais. Por isso, se propõem distintas técnicas de diagnóstico pré-implantacional, pré-natal ou de reprodução assistida a fim de evitar o nascimento de crianças com esta patologia. No presente trabalho se descrevem e analisam as implicações científicas e éticas das novas técnicas de reprodução assistida que se propõem às famílias com alto risco.