Effect of vitamin E supplementation in patients with ataxia with vitamin E deficiency

Gabsi, S.; Gouider-Khouja, N.; Belal, Samir; Fki, Moncef; Kéfi, M.; Turki, Ilhem; Hamida, M. Ben; Kayden, Herbert J.; Mebazaa, R.; Hentati, F.

doi:10.1046/j.1468-1331.2001.00273.x

Cited by 130 publications

(82 citation statements)

References 22 publications

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“…This is despite the fact that the concentration of ␣-tocopherol in cerebellum is similar to that in the hippocampus. The presence of higher levels of lipid peroxidation in cerebellum correlates well with previous studies showing that cerebellum has the highest rate of ␣-tocopherol turnover (39) and is the primary brain region functionally affected in patients with the AVED syndrome (40,41). Based on these observations, we speculate that metabolism of ␣-tocopherol may differ between cerebellum and forebrain and that this difference underlies the unique vulnerability of cerebellum to ␣-tocopherol deficiency.…”

Section: Discussionsupporting

confidence: 88%

Crystal Structure of the VgrG1 Actin Cross-linking Domain of the Vibrio cholerae Type VI Secretion System

Durand¹,

Derrez²,

Audoly³

et al. 2012

Journal of Biological Chemistry

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Vitamin E is the major lipid-soluble chain-breaking antioxidant in mammals and plays an important role in normal development and physiology. Deficiency (whether dietary or genetic) results in primarily nervous system pathology, including cerebellar neurodegeneration and progressive ataxia (abnormal gait). However, despite the widely acknowledged antioxidant properties of vitamin E, only a few studies have directly correlated levels of reactive oxygen species with vitamin E availability in animal models. We explored the relationship between vitamin E and reactive oxygen species in two mouse models of vitamin E deficiency: dietary deficiency and a genetic model (tocopherol transfer protein, Ttp ؊/؊ mice). Both groups of mice developed nearly complete depletion of ␣-tocopherol (the major tocopherol in vitamin E) in most organs, but not in the brain, which was relatively resistant to loss of ␣-tocopherol. F4-neuroprostanes, an index of lipid peroxidation, were unexpectedly lower in brains of deficient mice compared with controls. In vivo oxidation of dihydroethidium by superoxide radical was also significantly lower in brains of deficient animals. Superoxide production by brain mitochondria isolated from vitamin E-deficient and Ttp ؊/؊ mice, measured by electron paramagnetic resonance spectroscopy, demonstrated a biphasic dependence on exogenously added ␣-tocopherol. At low concentrations, ␣-tocopherol enhanced superoxide flux from mitochondria, a response that was reversed at higher concentrations. Here we propose a mechanism, supported by molecular modeling, to explain decreased superoxide production during ␣-tocopherol deficiency and speculate that this could be a beneficial response under conditions of ␣-tocopherol deficiency.␣-Tocopherol was first discovered as a micronutrient indispensable for reproduction in female rats (1). The view that ␣-tocopherol functions solely as a chain-breaking antioxidant has prevailed, reflecting a large body of accumulated experimental evidence showing that ␣-tocopherol can reduce lipid peroxidation in many models and the observation that ␣-tocopherol inhibits lipid peroxidation by scavenging peroxyl radicals faster (10 6 M Ϫ1 s Ϫ1 ) than they can react with other lipids (ϳ10 2 M Ϫ1 s Ϫ1 ) or proteins (2). Recently, however, a broad array of "nonantioxidant" cellular functions for ␣-tocopherol have emerged (reviewed in Refs. 3-8, but see Ref. 9 for the opposing view that supports a pure antioxidative function for ␣-tocopherol). The mechanism by which these "nonantioxidant" actions factor into the observed biological effects of ␣-tocopherol is not yet known. A systematic study of the relationship between levels of ␣-tocopherol and ROS 4 production is one approach to begin to differentiate the documented ability of ␣-tocopherol to act as a lipid peroxidation inhibitor and antioxidant versus its other potential activities in vivo.In the current study, we used two mouse models of vitamin E deficiency: 1) dietary deficiency (VED) in C57BL6 mice and 2) a genetic model, ␣-tocopherol tra...

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Section: Discussionsupporting

confidence: 88%

Crystal Structure of the VgrG1 Actin Cross-linking Domain of the Vibrio cholerae Type VI Secretion System

Durand¹,

Derrez²,

Audoly³

et al. 2012

Journal of Biological Chemistry

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“…Supplementation with vitamin E is thought to be an effective chemopreventive strategy for a number of oxidative stress-related pathologies, such as ataxia (14,15), amyotrophic lateral sclerosis (16), Alzheimer disease (17,18), and Parkinson disease (19). Importantly, dietary supplementation with vitamin E was shown to inhibit carcinogenesis in a number of induced cancers (20).…”

mentioning

confidence: 99%

Tocopherol Transfer Protein Sensitizes Prostate Cancer Cells to Vitamin E

Morley

Thakur

Danielpour

et al. 2010

Journal of Biological Chemistry

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Prostate cancer is a major cause of mortality in men in developed countries. It has been reported that the naturally occurring antioxidant ␣-tocopherol (vitamin E) attenuates prostate cancer cell proliferation in cultured cells and mouse models. We hypothesized that overexpression of the tocopherol transfer protein (TTP), a vitamin E-binding protein that regulates tocopherol status, will sensitize prostate cancer cells to the antiproliferative actions of the vitamin. To test this notion, we manipulated the expression levels of TTP in cultured prostate cells (LNCaP, PC3, DU145, and RWPE-1) using overexpression and knockdown approaches. Treatment of cells with tocopherol caused a time-and dose-dependent inhibition of cell proliferation. Overexpression of TTP dramatically sensitized the cells to the apoptotic effects of ␣-tocopherol, whereas reduction ("knockdown") of TTP expression resulted in resistance to the vitamin. TTP levels also augmented the inhibitory effects of vitamin E on proliferation in semi-solid medium. The sensitizing effects of TTP were paralleled by changes in the intracellular accumulation of a fluorescent analog of vitamin E and by a reduction in intracellular levels of reactive oxygen species and were not observed when a naturally occurring, ligand bindingdefective mutant of TTP was used. We conclude that TTP sensitizes prostate cancer cells to the anti-proliferative effects of vitamin E and that this activity stems from the ability of protein to increase the intracellular accumulation of the antioxidant. These observations support the notion that individual changes in the expression level or activity of TTP may determine the responsiveness of prostate cancer patients to intervention strategies that utilize vitamin E.Prostate cancer is a major public health problem in developed countries, and it constitutes the second leading cause of cancer deaths among males in the United States. Like all malignant diseases, prostate cancer is a culmination of multiple genetic and epigenetic insults, which affect key regulatory features of cell proliferation. Although family history and ethnicity are key risk factors in the susceptibility to prostate cancer, no single gene has been identified as a high penetrance heritable prostate cancer trait to date. Current treatments of prostate cancer rely primarily on surgical and hormonal intervention strategies, coupled with sensitive diagnostic tools aimed at early detection. The incidence, prevalence, and mortality associated with prostate cancer, together with its slow progression from intraepithelial neoplasia (found in men Ͻ30 years of age) to clinical disease (found mostly in men Ͼ50 years of age), make chemoprevention an attractive therapeutic approach for this disease.Accumulation of reactive oxygen species (ROS) 3 and oxidative damage are thought to play important roles during oncogene-induced transformation (1-3) and specifically in the initiation and progression of prostate cancer (4 -6). For example, androgens are shown to increase intracellular ROS lev...

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“…Supplementation of vitamin E in most instances allowed for stabilization of the disease. At least 12 patients who were monitored during 1 year of vitamin E oral administration showed mild improvement and maintained vitamin E levels in the normal range (Gabsi et al, 2001). However, after 41 year of treatment, the findings could be different, and worsening of symptoms could occur, as reported in 6 of 16 patients by Mariotti et al (2004).…”

Section: Clinical Featuresmentioning

confidence: 92%

Molecular, clinical and peripheral neuropathy study of Tunisian patients with ataxia with vitamin E deficiency

Euch-Fayache

Bouhlal

Amouri

et al. 2013

Brain

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Ataxia with vitamin E deficiency is an autosomal recessive cerebellar ataxia caused by mutations in the a-tocopherol transfer protein coding gene localized on chromosome 8q, leading to lower levels of serum vitamin E. More than 91 patients diagnosed with ataxia with vitamin E deficiency have been reported worldwide. The majority of cases originated in the Mediterranean region, and the 744delA was the most common mutation among the 22 mutants previously described. We examined the clinical and molecular features of a large cohort of 132 Tunisian patients affected with ataxia with vitamin E deficiency. Of these patients, nerve conduction studies were performed on 45, and nerve biopsy was performed on 13. Serum vitamin E was dramatically reduced for 105 of the patients analysed. Molecular analysis revealed that 91.7% of the patients (n = 121) were homozygous for the 744delA mutation. Three other mutations were detected among the remaining patients (8.3%, n = 11) in the homozygous state. Two were previously reported (400C4T and 205-1G4T), and one was novel (553 + 1T4A). Age of onset was 13.2 AE 5.9 years, with extremes of 2 and 37 years. All described patients exhibited persistent progressive cerebellar ataxia with generally absent tendon reflexes. Deep sensory disturbances, pyramidal syndrome and skeletal deformities were frequent. Head tremor was present in 40% of the patients. Absence of neuropathy or mild peripheral neuropathy was noted in more than half of the cohort. This is the largest study of the genetic, clinical and peripheral neuropathic characteristics in patients with ataxia and vitamin E deficiency. The 744delA mutation represents the most common pathological mutation in Tunisia and worldwide, likely because of a Mediterranean founder effect. Our study led us to suggest that any patient displaying an autosomal recessive cerebellar ataxia phenotype with absent tendon reflexes and minor nerve abnormalities should first be screened for the 744delA mutation, even in the absence of a serum vitamin E measurement.

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Effect of vitamin E supplementation in patients with ataxia with vitamin E deficiency

Cited by 130 publications

References 22 publications

Crystal Structure of the VgrG1 Actin Cross-linking Domain of the Vibrio cholerae Type VI Secretion System

Crystal Structure of the VgrG1 Actin Cross-linking Domain of the Vibrio cholerae Type VI Secretion System

Tocopherol Transfer Protein Sensitizes Prostate Cancer Cells to Vitamin E

Molecular, clinical and peripheral neuropathy study of Tunisian patients with ataxia with vitamin E deficiency

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