Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vitamin E is essential for neurological function. This fact, together with a growing body of evidence indicating that neurodegenerative processes are associated with oxidative stress, lead to the convincing idea that several neurological disorders may be prevented and/or cured by the antioxidant properties of vitamin E. In this review, some aspects related to the role of vitamin E against Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and ataxia with vitamin E deficiency will be presented.
 ...
PMID:Vitamin E and neurodegenerative diseases. 1730 57

We report a 53-year-old woman with probable Bassen-Kornzweig syndrome. Her parents were a consanguineous marriage. At two years of age, she developed night blindness. During her childhood she had severe diarrhea that disappeared in adulthood. At 26 years of age, she was diagnosed as having retinitis pigmentosa and her visual acuity became worse thereafter. She noted tremor in the right hand at 37 years of age, gait ataxia at 42, and developed tremor in the bilateral lower extremities at 48. On admission, bilateral visual disturbance, resting and postural tremor, moderately poor coordination, mild distal dominant sensory impairment, an absence of tendon reflex in all four extremities, moderate to severe gait ataxia, and positive Romberg sign were found. Muscle rigidity and akinesia were not observed. Intelligence and muscle power were normal and pathological reflexes were absent. Acanthocytes were found in blood. Serum chemistry showed remarkable decreases in total cholesterol (54 mg/dl, normal 180-220), triglyceride (0 mg/dl, normal 30-150), beta-lipoprotein (3 mg/dl, normal 190-500), apoA-1 protein (66 mg/dl, normal 105-184), apoA-2 protein (11 mg/dl, normal 26-46), apoB protein (0 mg/dl, normal 38-104), apoC-2 protein (1.1 mg/dl, normal 1.2-6.4), vitamin A (297 ng/ml, normal 431-1,041), and vitamin E (0.19 ng/dl, normal 0.75-1.41). While, a marked increase in PIVKA II (703 mAU/ml, normal<40) due to a decrease in vitamin K was found. She was thus diagnosed as having Bassen-Kornzweig syndrome or hypo-betalipoproteinemia. Although brain MRI was normal, single-photon emission CT (SPECT) showed mildly decreased perfusion in the left parietal cortex and right striatum. Motor nerve conduction velocities were normal, but sensory nerve action potentials were not evoked in all four extremities. Surface EMG recorded on the right radial extensor and flexor carpi muscles at rest showed a 4.5 Hz tremor. Vitamin replacement therapy with vitamin A (10,000 IU/day), E (200 mg/day), and K (10 mg/day) was initiated. Several days after treatment, amplitude of resting tremor ameliorated mildly. Clonazepam was administered (0.5 mg/day) for further treatment. After one-month of treatment, vitamin A (656 ng/ml) and E (0.39 mg/dl) levels were elevated and PIVKA II level (29 mAU/ml) decreased. Only a mild right hand tremor remained, but sensory impairment and gait ataxia were not changed. The cause of Bassen-Kornzweig syndrome is a deletion of the microsomal triglyceride transfer protein (MTP) gene. While, familial hypo-betalipoproteinemia, due to a mutation of apolipoprotein B gene, is known to show the same phenotype. Because of the patient's refusal of genetic examination, which disease she has cannot be conclusively determined. Intention tremor was reported in Bassen-Kornzweig syndrome. However, her 4.5 Hz tremor was also present at rest, which resembled resting tremor in Parkinson's disease. Pathophysiology of Bassen-Kornzweig syndrome is known to be due to hypo-vitaminosis. Decreased [18F]-dopa uptake in striatum of patients with long-term hypo-vitamin E has been reported in PET study. Mild hypoperfusion was found in the striatum of the present cases: indicating that her tremor was associated with striatonigral damage. Thus, careful observation of extrapyramidal signs is necessary in abeta- or hypo-betalipoproteinemia.
 ...
PMID:[An adult case of probable Bassen-Kornzweig syndrome, presenting resting tremor]. 1732 79

Friedreich Ataxia (FRDA), the most frequent inherited ataxia, is not only characterized by progressive gait and limb ataxia, but in most cases is also accompanied by a severe hypertrophic cardiomyopathy. This life threatening symptom can be ameliorated by the administration of idebenone, a short chain quinone antioxidant, supporting additional evidence that oxidative stress plays a major role in the pathogenesis of this disease. In this study we analyze the combinatorial effect of different antioxidants on cell viability of FRDA fibroblasts and of RAT-1 immortalized fibroblasts exposed to oxidative stress. We find that an equimolar mixture of idebenone and vitamin E is more potent than each of the compound alone. Increased potency was also obtained with a novel synthetic antioxidant (Fe-Aox29) combining the active groups from both idebenone and vitamin E. These results indicate, that idebenone and vitamin E might act synergistically to counteract oxidative stress in fibroblasts from FRDA patients.
 ...
PMID:Protective effects of Fe-Aox29, a novel antioxidant derived from a molecular combination of Idebenone and vitamin E, in immortalized fibroblasts and fibroblasts from patients with Friedreich Ataxia. 1747 63

During the last 90 years since the discovery of vitamin E, research has focused on different properties of this molecule, the focus often depending on the specific techniques and scientific knowledge present at each time. Originally discovered as a dietary factor essential for reproduction in rats, vitamin E has revealed in the meantime many more important molecular properties, such as the scavenging of reactive oxygen and nitrogen species with consequent prevention of oxidative damage associated with many diseases, or the modulation of signal transduction and gene expression in antioxidant and non-antioxidant manners. Research over the last 30 years has also resolved the biosynthesis and occurrence of vitamin E in plants, the proteins involved in the cellular uptake, tissue distribution and metabolism, and defined a congenital recessive neurological disease, ataxia with vitamin E deficiency (AVED), characterized by impaired enrichment of alpha-tocopherol in plasma as a result of mutations in the liver alpha-tocopherol transfer gene. This review is giving a brief introduction about vitamin E by following the major research directions since its discovery with a historical perspective.
 ...
PMID:Vitamin E: an overview of major research directions. 1762 18

Human alpha-tocopherol transfer protein (alpha-TTP) plays a central role in vitamin E homeostasis: mutations in the protein are a cause of a progressive neurodegenerative disorder known as ataxia with vitamin E deficiency (AVED). Despite normal dietary intake of vitamin E, affected individuals suffer from a relative deficiency of this essential lipophilic antioxidant. Disease-associated mutations in alpha-TTP impair its ability to prevent the degradation and excretion of alpha-T. Recently, we and others solved the crystal structures of alpha-TTP bound to a molecule of (2R, 4'R, 8'R)-alpha-T, which has led to a better understanding of the molecular basis of its biochemical activity. Surprisingly, the ligand was found buried in the hydrophobic core of the protein, completely sequestered from the aqueous milieu. In this chapter, the implications of the structure of alpha-TTP bound to its ligand regarding the mechanism of alpha-T retention are discussed. A comparison to a crystal structure of the apo form of alpha-TTP indicates a possible specific conformational change that allows the entry and exit of the ligand. The effect of known disease-associated point mutations is examined in light of the crystal structure as well as recent biochemical studies. Despite the knowledge gained from these studies, the exact molecular mechanism by which alpha-TTP retains alpha-T remains enigmatic and will likely prove a fruitful area for future research.
 ...
PMID:Structure and function of alpha-tocopherol transfer protein: implications for vitamin E metabolism and AVED. 1762 70

Almost a century ago, plant extracts were documented to be critical for the fertility of rodents. This activity was later ascribed to vitamin E, a term comprising a number of structurally related plant lipids that function as fat soluble antioxidants. The alpha-tocopherol transfer protein (TTP) is a critical regulator of vitamin E status that stimulates the movement of vitamin E between membrane vesicles in vitro and facilitates the secretion of tocopherol from hepatocytes. Heritable mutations in the ttpA gene cause ataxia with vitamin E deficiency (AVED), an autosomal recessive disorder characterized by low plasma vitamin E levels and progressive neurodegeneration. This chapter summarizes recent advances in our understanding of the molecular and physiological aspects of TTP activity.
 ...
PMID:The alpha-tocopherol transfer protein. 1762 71

Vitamin E refers to a family of tocopherol and tocotrienol isomers discovered in 1922 as anti-infertility factor. Vitamin E deficiency causes infertility and delayed-onset ataxia in experimental animals, and it leads to neuronal dysfunctions in humans. However, based largely on its radical-scavenging antioxidant activity in vitro, vitamin E supplements are commonly thought to provide health benefits against diseases associated with oxidative damage, most notably cardiovascular diseases. Contrary to this belief, the outcome of recent large, prospective, randomized and placebo-controlled clinical studies does not encourage the use of vitamin E supplements. These overall disappointing results can be explained and substantiated by scientific data critically testing the strengths of evidence for many of the underlying assumptions and examining the possibility that in vivo vitamin E may have function(s) other than, or in addition to, acting as an antioxidant.
 ...
PMID:Vitamin E. 1791 25

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 alpha-tocopherol (the major tocopherol in vitamin E) in most organs, but not in the brain, which was relatively resistant to loss of alpha-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 alpha-tocopherol. At low concentrations, alpha-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 alpha-tocopherol deficiency and speculate that this could be a beneficial response under conditions of alpha-tocopherol deficiency.
 ...
PMID:Prolonged alpha-tocopherol deficiency decreases oxidative stress and unmasks alpha-tocopherol-dependent regulation of mitochondrial function in the brain. 1818 Mar 6

alpha-Tocopherol is a member of the vitamin E family that functions as the principal fat-soluble antioxidant in vertebrates. Body-wide distribution of tocopherol is regulated by the hepatic alpha-tocopherol transfer protein (alphaTTP), which stimulates secretion of the vitamin from hepatocytes to circulating lipoproteins. This biological activity of alphaTTP is thought to stem from its ability to facilitate the transfer of vitamin E between membranes, but the mechanism by which the protein exerts this activity remains poorly understood. Using a fluorescence energy transfer methodology, we found that the rate of tocopherol transfer from lipid vesicles to alphaTTP increases with increasing alphaTTP concentration. This concentration dependence indicates that ligand transfer by alphaTTP involves direct protein-membrane interaction. In support of this notion, equilibrium analyses employing filtration, dual polarization interferometry, and tryptophan fluorescence demonstrated the presence of a stable alphaTTP-bilayer complex. The physical association of alphaTTP with membranes is markedly sensitive to the presence of vitamin E in the bilayer. Some naturally occurring mutations in alphaTTP that cause the hereditary disorder ataxia with vitamin E deficiency diminish the effect of tocopherol on the protein-membrane association, suggesting a possible mechanism for the accompanying pathology.
 ...
PMID:Mechanisms of ligand transfer by the hepatic tocopherol transfer protein. 1845 85

Ataxia with isolated vitamin E deficiency is a rare autosomal recessive neurodegenerative disease due to mutations in the alpha-tocopherol transfer protein gene. In ataxia with isolated vitamin E deficiency, the biochemical hallmark is the low plasmatic levels of vitamin E and, in most of the patients, vitamin E supplementation allows a stabilization of the neurologic conditions. We have investigated the genetic cause of ataxia and reduced levels of vitamin E, and apolipoproteins A1 and B in a 16-y-old patient. Results revealed that our propositus is a compound heterozygote for the c.227_229delinsATT/c.744delA mutations in the alpha-tocopherol transfer protein gene, each inherited from one of the two parents. His sister is also a compound heterozygote for both mutations, and she presents a biochemical pattern similar to that of his brother. After receiving the vitamin E supplementation, plasmatic levels of vitamin E and apolipoprotein A1 have been normalized in the propositus. The detected mutations would justify the undetectable levels of vitamin E, but would not explain the also decreased levels of the apolipoproteins, as neither that after treatment with vitamin E, the levels of apolipoprotein B do not become normal. These findings suggest that other genes may play a role in producing this atypical biochemical profile.
 ...
PMID:A novel delins mutation in the alpha-TTP gene in a family segregating ataxia with isolated vitamin E deficiency. 1845 55


<< Previous 1 2 3 4 5 6 7 8 9 10