Abstract
The search for biochemical abnormalities in the neuronal ceroidβlipofuscinoses (NCL) or Batten disease was initiated with the discovery of normal levels of gangliosides in juvenile amaurotic idiocy. The primary goal of most biochemical studies has been to discover the unique biochemical marker for carriers and atβrisk individuals. Ceroid, the singular pathomorphologic trait of NCL, was isolated and shown to differ from a similar but normal product of aged cells, lipofuscin. In spite of the availability of stored product, the chemical analysis of ceroid has not elucidated the unique biochemical defect in the NCL, as has been the case for other lysosomal storage disorders. The NCL were thought to be a result of lipid peroxidation because ceroid is also found in disorders of impaired vitamin E metabolism or results from a diet deficient in the antioxidant, vitamin E. In addition, tissue analysis indicated losses of polyunsaturated fatty acids in affecteds and carriers, as well as the presence of a secondary product of lipid peroxidation, 4βhydroxynonenal, in affected and carrier NCL dogs. With the exception of a fluorescent compound isolated from retinal ceroid, studies aimed at discovering the diseaseβspecific fluorophores of ceroid have been largely inconclusive. The discovery of elevated dolichols in urine and brain tissue of NCL patients led to another hypothesis, that the basic biochemical defect in NCL involved the metabolism of dolichols and retinoids. However, the more recent view is that dolichol metabolism is secondary to the unknown NCL lesion. A possible role of deficient proteases or protease inhibitors in NCL was developed after studies showed that inhibition of lysosomal thiol proteases would induce formation of autofluorescent lipopigments in brains of young rats. This initial discovery led to several reports of cathepsin deficiencies which, however, have not been reproducible. The discovery of abnormal storage of normal mitochondrial ATP synthase subunit C protein in NCL has been reported, but the reasons for the storage of this very hydrophobic protein were not apparent. A recent report found a modified amino acid, trimethyllysine in juvenile NCL ceroid. This may provide a reasonable explanation for the storage of the subunit C protein; i.e., the NCL defect may involve abnormal methylation and demethylation of proteins. Finally, localization of genes for 2 types of NCL mapping to 2 different chromosomes is a major advance in resolving the defect in NCL. Localization of genes for other inherited diseases has served as a prelude to the ultimate isolation and characterization of the genetic defect. With further progress in the biochemistry and molecular biology of NCL, the responsible gene product(s) may soon be discovered and characterized.