ascorbic-acid and Fabry-Disease

To test the hypothesis that reactive oxygen species contribute to the cerebral hyperperfusion in Fabry disease.. We examined the effect of intravenous injection of ascorbate on cerebral blood flow (CBF) using magnetic resonance arterial spin tagging. Nineteen patients with Fabry disease and 15 control subjects were studied as part of a randomized double-blind placebo-controlled trial of enzyme replacement therapy (ERT).. Vertebro-basilar hyperperfusion was observed in patients with Fabry disease. A decrease in systemic ascorbate levels relative to healthy controls was found in the patients. CBF decreased after ascorbate infusion in both control subjects and patients treated with ERT. The placebo group had a significantly delayed decrease in the CBF response after ascorbate infusion. Myeloperoxidase levels were elevated in Fabry patients, consistent with ongoing inflammatory processes in these patients.. Increased CBF in Fabry disease may be related to increased production of reactive oxygen species, while low plasma ascorbate levels suggests a global redox imbalance. These abnormalities were improved by ERT. These observations have implications regarding oxidative processes contributing to accelerated atherosclerosis in Fabry disease.

Topics: Adult; Analysis of Variance; Ascorbic Acid; Brain; Case-Control Studies; Cerebrovascular Circulation; Double-Blind Method; Fabry Disease; Humans; Image Processing, Computer-Assisted; Injections, Intravenous; Magnetic Resonance Imaging; Male; Reactive Oxygen Species; Spin Labels

Topics: alpha-Galactosidase; Ascorbic Acid; Fabry Disease; Humans; Kidney; Vitamins

Reduced plasma vitamin C concentrations in chronic diseases may result from abnormal urinary excretion of vitamin C: a renal leak. We hypothesized that vitamin C renal leak may be associated with disease-mediated renal dysregulation, resulting in aberrant vitamin C renal reabsorption and increased urinary loss.. We investigated the prevalence, clinical characteristics, and genomic associations of vitamin C renal leak in Fabry disease, an X-linked lysosomal disease associated with renal tubular dysfunction and low plasma vitamin C concentrations.. We conducted a non-randomized cross-sectional cohort study of men aged 24-42 y, with Fabry disease (n = 34) and controls without acute or chronic disease (n = 33). To match anticipated plasma vitamin C concentrations, controls were placed on a low-vitamin C diet 3 wk before inpatient admission. To determine the primary outcome of vitamin C renal leak prevalence, subjects were fasted overnight, and matched urine and fasting plasma vitamin C measurements were obtained the following morning. Vitamin C renal leak was defined as presence of urinary vitamin C at plasma concentrations below 38 μM. Exploratory outcomes assessed the association between renal leak and clinical parameters, and genomic associations with renal leak using single nucleotide polymorphisms (SNPs) in the vitamin C transporter SLC23A1.. Compared with controls, the Fabry cohort had 16-fold higher odds of renal leak (6% vs. 52%; OR: 16; 95% CI: 3.30, 162; P < 0.001). Renal leak was associated with higher protein creatinine ratio (P < 0.01) and lower hemoglobin (P = 0.002), but not estimated glomerular filtration rate (P = 0.54). Renal leak, but not plasma vitamin C, was associated with a nonsynonymous single nucleotide polymorphism in vitamin C transporter SLC23A1 (OR: 15; 95% CI: 1.6, 777; P = 0.01).. Increased prevalence of renal leak in adult men with Fabry disease may result from dysregulated vitamin C renal physiology and is associated with abnormal clinical outcomes and genomic variation.

Topics: Adult; Ascorbic Acid; Cross-Sectional Studies; Fabry Disease; Genomics; Glomerular Filtration Rate; Humans; Kidney; Male; Vitamins

There has been considerable recent progress in understanding mechanisms by which gene mutations cause degeneration of motoneurons and peripheral nerves. Novel therapies inspired by these insights have begun to yield promising results in mouse models of these genetic diseases. Among these have been the use of small molecules or proteins to suppress gain-of-function mutations (eg, ascorbic acid for Charcot-Marie-Tooth disease type 1A) or to restore enzyme activities that are deficient because of loss-of-function mutations (eg, treatment of Fabry's disease with recombinant alpha-galactosidase or with low-molecular-weight alpha-galactosidase chaperones and treatment of spinal muscular atrophy with phenylbutyrate). Some of these therapies are already being tested in humans. Equally exciting is the prospect that small molecules and proteins will be identified that exert potent therapeutic effects in a broad spectrum of inherited and acquired motoneuron and peripheral nerve disorders.

Topics: alpha-Galactosidase; Animals; Antioxidants; Ascorbic Acid; Bulbar Palsy, Progressive; Charcot-Marie-Tooth Disease; Fabry Disease; Humans; Mice; Muscular Atrophy, Spinal; Neuroprotective Agents; Phenylbutyrates; Vascular Endothelial Growth Factor A