Vitamin E deficiency and metabolic deficits in neuronal ceroid lipofuscinosis described by bioinformatics.

The mnd mouse, a model of neuronal ceroid lipofusinosis (NCL), has a profound vitamin E deficiency in sera and brain, associated with cerebral deterioration characteristic of NCL. In this study, the vitamin E deficiency is corrected using dietary supplementation. However, the histopathological features associated with NCL remained. With use of a bioinformatics approach based on high-resolution solid and solution state 1H-NMR spectroscopy and principal component analysis (PCA), the deficits associated with NCL are defined in terms of a metabolic phenotype. Although vitamin E supplementation reversed some of the metabolic abnormalities, in particular the concentration of phenylalanine in extracts of cerebral tissue, PCA demonstrated that metabolic deficits associated with NCL were greater than any effects produced from vitamin E supplementation. These deficits included increased glutamate and N-acetyl-L-aspartate and decreased creatine and glutamine concentrations in aqueous extracts of the cortex, as well as profound accumulation of lipid in intact cerebral tissue. This is discussed in terms of faulty production of mitochondrial-associated membranes, thought to be central to the deficits in mnd mice.

Altered elemental profiles in neuronal ceroid lipofuscinosis.

The elemental profiles of thrombocytes and mononuclear cells were investigated in five patients with Infantile and eight with Juvenile Neuronal Ceroid Lipofuscinosis. The patients with the infantile form had suffered from the disease for a year and those with the juvenile form for some six years. The thrombocytes exhibited increased concentrations of calcium and magnesium, but the same concentrations of iron and zinc as found in healthy subjects. The mononuclear cells exhibited an increased concentration of iron and a reduced concentration of zinc. The elevated concentrations of magnesium, calcium and iron in the thrombocytes and mononuclear cells may represent the end products of ceroid pigmentation. Five patients with Juvenile and one with Infantile Neuronal Ceroid Lipofuscinosis were treated with antioxidants along with vitamins E, B2 and B6, but this treatment did not affect significantly the concentration of iron in the mononuclear cells. However, selenium was detected in some mononuclear cells in all the patients so treated. This was unexpected since iron (III), being antagonistic to selenium in the form of selenite--which was the antioxidant given--forms a stable complex which cannot be broken down biologically.

Selenium treatment in neuronal ceroid-lipofuscinosis.

Neuronal ceroid-lipofuscinosis (NCL) refers to a group of disorders with devastating effects on the central nervous system. The accumulation of autofluorescent lipopigments containing lipid peroxides is considered a pathogenetic mechanism of the cell damage seen in NCL. Therapy aimed at preventing further lipid peroxidation, such as the Zeman regimen, did not slow progression of the disease. Therefore, Santavuori and Westermarck [Santavuori and Westermarck 1984] introduced treatment with a combination of selenium and vitamin E and reported favorable results with few side effects. We present information on the rationale for the use of selenium, recommendations on the daily intake, and reported side effects. However, our limited experience with selenium in this disorder does not permit conclusions. Additionally, careful studies are indicated before this treatment is dispensed routinely.

Selenium in chronic neurologic diseases. Multiple sclerosis and Batten's disease.

The selenium levels in whole blood and the activity of glutathione peroxidase in hematogenous cells of normal Danes have been defined taking into account sex and confounding factors such as smoking and aging. No differences related to sex could be found with regard to the selenium level, and peroxidase activity assayed with hydrogen peroxide. However, the peroxidase activity assayed with t-butyl hydroperoxide was higher in females than in males (p less than .05). The peroxidase activities are dependent on age. Thus, the peroxidase levels assayed with both substrates show a minimum value in the age group from 40 to 50 yr for both smokers and nonsmokers. Smokers did show more homogeneous values as a function of age than nonsmokers. Smokers had significantly lower selenium values than nonsmokers, but glutathione peroxidase values identical with those of nonsmokers. Multiple sclerosis (MS) patients suffer from a chronic relapsing/remitting demyelinating disease. A theory explaining the pathogenesis of MS concerns increased stickiness of cellular plasma membranes, hampering normal vascular function of the brain. In agreement with that theory, the present communication demonstrates significantly lowered selenium values and lowered glutathione peroxidase activities of major types of hematogenous cells. In close agreement with these findings, hematogenous cells in MS show increased peroxidation rates. A nonblinded biochemical dietary experiment on MS patients showed that all abnormalities could be normalized by daily intake of selenium, vitamin E, and vitamin C. Batten's disease is a recessive inherited neurodegenerative disorder clinically characterized by progressive loss of vision, epilepsy, and dementia. Neuropathologically, this disease is characterized by storage of lipofuscin in nervous tissue. We have in a few cases documented a low selenium status and low glutathione peroxidase activities of hematogenous cells. As in MS, we normalized the biochemical abnormalities by an antioxidative treatment. Like in similar Finnish studies, the biochemical parameters can be normalized. Further, the Finnish studies indicate it possible by an antioxidative treatment to inhibit progression of the mental deterioration. The data presented will be discussed in relationship both to specific pathological parameters of the diseases and to the low dietary energy expenditures of handicapped immobile patients.

Leucocyte glutathione peroxidase activity and selenium level in Batten's disease.

The glutathione peroxidase (GSHPx) activity was found significantly reduced in whole lymphocytes from patients suffering from Batten's disease. By means of two different procedures for isolation of subcellular fractions of lymphocytes it was possible to demonstrate an increased GSHPx activity of the particulate fractions (20.000 g-av and 105.000 g-av precipitates). However, the GSHPx activity of the supernatants was decreased. The GSHPx activity of the 20.000 g-av supernatant correlated significantly with the serum selenium content both in normal controls and in Batten's disease. A similar correlation was traced with GSHPx activity of erythrocyte haemolysate and serum selenium level in Batten's disease but not in normal controls. The GSHPx activity was also found decreased in the 20.000 g-av and 105.000 g-av supernatants of granulocytes. The abnormal subcellular distribution of GSHPx activities was related to the distribution of enzymes which were used as markers for different subcellular components. The data presented are discussed in relationship to the theory that Batten's disease is due to an increased peroxidation damaging the cellular membranes.