Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025362 (mental retardation)
 15,878 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Approximately 10% of newborns are born prematurely. Of these children, more than 10% will sustain neurological injuries leading to significant learning disabilities, cerebral palsy, or mental retardation, with very low birth weight infants having an even higher incidence of brain injury. Whereas intraventricular hemorrhage was the most common form of serious neurological injury a decade ago, periventricular white matter injury (PWMI) is now the most common cause of brain injury in preterm infants. The spectrum of chronic PWMI includes focal cystic necrotic lesions (periventricular leukomalacia; PVL) and diffuse myelination disturbances. Recent neuroimaging studies support that the incidence of PVL is declining, whereas diffuse cerebral white matter injury is emerging as the predominant lesion. Factors that predispose to PVL include prematurity, hypoxia, ischemia, and inflammation. It is believed that injury to oligodendrocyte (OL) progenitors contributes to the pathogenesis of myelination disturbances in PWMI by disrupting the maturation of myelin-myelin-forming oligodendrocytes. Other potential mechanisms of injury include activation of microglia and axonal damage. Chemical mediators that may contribute to white matter injury include reactive oxygen (ROS) and nitrogen species (RNS), glutamate, cytokines, and adenosine. As our understanding of the pathogenesis of PWMI improves, it is anticipated that new strategies for directly preventing brain injury in premature infants will evolve.
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PMID:Emerging concepts in periventricular white matter injury. 1569 97

DS (Down's syndrome) is the most common human aneuploidy associated with mental retardation and early neurodegeneration. Mitochondrial dysfunction has emerged as a crucial factor in the pathogenesis of numerous neurological disorders including DS, but the cause of mitochondrial damage remains elusive. In the present study, we identified new molecular events involved in mitochondrial dysfunction which could play a role in DS pathogenesis. We analysed mitochondrial respiratory chain function in DS-HSFs (Down's syndrome human foetal skin fibroblasts; human foetal skin fibroblasts with chromosome 21 trisomy) and found a selective deficit in the catalytic efficiency of mitochondrial complex I. The complex I deficit was associated with a decrease in cAMP-dependent phosphorylation of the 18 kDa subunit of the complex, due to a decrease in PKA (protein kinase A) activity related to reduced basal levels of cAMP. Consistently, exposure of DS-HSFs to db-cAMP (dibutyryl-cAMP), a membrane-permeable cAMP analogue, stimulated PKA activity and consequently rescued the deficit of both the cAMP-dependent phosphorylation and the catalytic activity of complex I; conversely H89, a specific PKA inhibitor, suppressed these cAMP-dependent activations. Furthermore, in the present paper we report a 3-fold increase in cellular levels of ROS (reactive oxygen species), in particular superoxide anion, mainly produced by DS-HSF mitochondria. ROS accumulation was prevented by db-cAMP-dependent activation of complex I, suggesting its involvement in ROS production. Taken together, the results of the present study suggest that the drastic decrease in basal cAMP levels observed in DS-HSFs participates in the complex I deficit and overproduction of ROS by DS-HSF mitochondria.
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PMID:Deficit of complex I activity in human skin fibroblasts with chromosome 21 trisomy and overproduction of reactive oxygen species by mitochondria: involvement of the cAMP/PKA signalling pathway. 2133 38