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Launay N.,L Hospitalet Of Llobregat | Launay N.,Idibell Hospital Universitari Of Bellvitge | Launay N.,Center for Biomedical Research on Rare Diseases | Aguado C.,Center for Biomedical Research on Rare Diseases | And 26 more authors.
Acta Neuropathologica | Year: 2014

X-linked adrenoleukodystrophy (X-ALD) is a rare neurometabolic disease characterized by the accumulation of very long chain fatty acids (VLCFAs) due to a loss of function of the peroxisomal transporter ABCD1. Here, using in vivo and in vitro models, we demonstrate that autophagic flux was impaired due to elevated mammalian target of rapamycin (mTOR) signaling, which contributed to X-ALD pathogenesis. We also show that excess VLCFAs downregulated autophagy in human fibroblasts. Furthermore, mTOR inhibition by a rapamycin derivative (temsirolimus) restored autophagic flux and inhibited the axonal degenerative process as well as the associated locomotor impairment in the Abcd1−/Abcd2−/− mouse model. This process was mediated through the restoration of proteasome function and redox as well as metabolic homeostasis. These findings provide the first evidence that links impaired autophagy to X-ALD, which may yield a therapy based on autophagy activators for adrenomyeloneuropathy patients. © 2014, The Author(s).

Del Mar O'Callaghan M.,Hospital Sant Joan Of Deu | Del Mar O'Callaghan M.,Institute Salud Carlos III | Emperador S.,University of Zaragoza | Emperador S.,Institute Salud Carlos III | And 22 more authors.
Neurogenetics | Year: 2012

The reported cases showed clinical, biochemical, histopathological, and molecular features lending support to the hypothesis of a pathogenic effect of the detected mutations. Case 1 was a neonatal presentation who showed multiple mitochondrial respiratory chain enzyme defects in muscle associated with a new homoplasmic m.5514A > G transition in the tRNATrp gene. Case 2 was a late infantile presentation who also showed mitochondrial respiratory chain enzyme deficiencies in muscle together with a new m.1643A > G tRNA Val mutation in homoplasmy. Case 3 showed a MERRF phenotype presented in childhood associated with the once previously reported m.15923A > G mutation in heteroplasmy in all the tissues studied. © 2012 Springer-Verlag.

Pampols T.,Institute Of Bioquimica Clinica
Advances in Experimental Medicine and Biology | Year: 2010

Inherited metabolic disorders (IMD) represent a vast, diverse and heterogeneous collection of around 700 genetic diseases. They are caused by rare mutations that affect the function of individual proteins and are a significant cause of morbidity and mortality, especially in childhood. Difficulties in ascertaining cases and the increasing number of new disorders have hampered efforts to accumulate exhaustive epidemiological data. Nonetheless, recent studies quote the cumulative incidence of IMDs at around 1 in 800 live births. To understand the epidemiology of IMD we will consider in this chapter two types of epidemiological approaches. The first type, or the Analytical approaches, includes the function of genetic factors in the natural history and clinical variability of the disease, as well as the role of epigenetic, stochastic and environmental factors. The second type, or the Descriptive approaches, comprises methods of case ascertainment through the diagnosis of symptomatic patients and population screening, mainly newborn and carrier screening, as well as measures of disease frequency and resources for disease control and prevention (primary, secondary and tertiary). © Springer Science+Business Media B.V. 2010.

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