The long tem objectives of this proposal are to define the biochemical defect(s) in patients with various phenotypic types of the neuronal ceroid- lipofuscinoses (NCL) or Batten disorders, a common group of inherited neurodegenerative storage disorders of children. This will lead to the presymptomatic detection of affecteds and the early and reliable diagnosis of carriers, which is not available at the present time. Our major hypothesis is that a primary defect in lipid peroxidation leads to the generation of secondary lipid oxidation products, the 4-hydroxyalkenals, which go on to form autofluorescent chromolipids or ceroid which is pathognomic for NCL. Our preliminary data supports this idea. Gas chromatographic analysis has revealed, in agonist-stimulated activation (ASA) of blood cells from a well-documented canine model of NCL, that affected, carrier and normal dogs were clearly distinguishable by their HNE levels. A major aim is to classify NCL patients on a biochemical basis in order to set the stage for their study on a molecular level. To this end we have established a Repository of 100 immortalized human lymphocytes and DNAs from NCL patients and their unaffected family members. These cell lines have been used in our assays and have been provided to investigators throughout the world. We propose to expand our collection such that each type of NCL is well represented. This is especially important since all of these patients are moribund and there is a need to have standardized reference facilities for all investigators to examine. Further, these studies will indicate which types of hum NCL correspond to the dog model. In addition, a biochemical understanding of how ceroid, the characteristic marker for NCL, is formed will have implications for understanding the natural process of cell aging.
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