Attenuated variants of Lesch-Nyhan disease

Lesch–Nyhan disease is a neurogenetic disorder caused by deficiency of the enzyme hypoxanthine–guanine phosphoribosyltransferase. The classic form of the disease is described by a characteristic syndrome that includes overproduction of uric acid, severe generalized dystonia, cognitive disability and self-injurious behaviour. In addition to the classic disease, variant forms of the disease occur wherein some clinical features are absent or unusually mild. The current studies provide the results of a prospective and multi-centre international study focusing on neurological manifestations of the largest cohort of Lesch–Nyhan disease variants evaluated to date, with 46 patients from 3 to 65 years of age coming from 34 families. All had evidence for overproduction of uric acid. Motor abnormalities were evident in 42 (91%), ranging from subtle clumsiness to severely disabling generalized dystonia. Cognitive function was affected in 31 (67%) but it was never severe. Though none exhibited self-injurious behaviours, many exhibited behaviours that were maladaptive. Only three patients had no evidence of neurological dysfunction. Our results were compared with a comprehensive review of 78 prior reports describing a total of 127 Lesch–Nyhan disease variants. Together these results define the spectrum of clinical features associated with hypoxanthine–guanine phosphoribosyltransferase deficiency. At one end of the spectrum are patients with classic Lesch–Nyhan disease and the full clinical phenotype. At the other end of the spectrum are patients with overproduction of uric acid but no apparent neurological or behavioural deficits. Inbetween are patients with varying degrees of motor, cognitive, or behavioural abnormalities. Recognition of this spectrum is valuable for understanding the pathogenesis and diagnosis of all forms of hypoxanthine–guanine phosphoribosyltransferase deficiency

In vitro evaluation of the antioxidant and anti-inflammatory activities of sulfated metabolites of catechins

Catechins are major polyphenols in many plant foods that have been related to health promotion. In the human organism, they are largely metabolised to different conjugated metabolites (i.e. glucuronide, sulphate and methylated derivatives), which are further found in plasma and would be thus able to reach the biological targets. Therefore, in vitro assays aiming to elucidate the biological effects of dietary catechins should also consider their metabolites and not only the original compounds. In this article, the in vitro antioxidant and anti-inflammatory activities of different catechin and epicatechin sulphates, one of the less studied catechin metabolites, have been evaluated. Since these compounds are not commercially available, they had to be first synthesised in the laboratory. The in vitro antioxidant activity was assessed using the ferric reducing power (FRAP) assay and two methods based on the ability to scavenge the ABTS•+ radical cation at different pH values. Sulphation of (epi)catechin lead to a decrease in the antioxidant activity that was greater when the sulphate moiety was located in the catechin B-ring than in A-ring. Despite this, all the studied (epi)catechin sulphates still behave as better antioxidants than α-tocopherol in the radical scavenging assays carried out at pH 7.4, suggesting that they might act as efficient antioxidants in physiological conditions. The anti-inflammatory potential was assessed by evaluating the ability of the compounds to reduce the concentration of nitric oxide (NO) secreted by macrophages (RAW 264.7) after activation with a bacterial lipopolysaccharide (LPS). In the range of studied concentrations (1–300 μM), all the (epi)catechin sulphates caused a dose-dependent inhibition in NO production that even slight was statistically significant in most cases in relation to controls (LPS-activated cells without catechins), whereas the parent catechins did not show any effect in NO production in our experimental conditions. None of the assayed compounds showed any cytotoxic effect in macrophages up to the highest concentration used (300 μM). The obtained results suggested possible antioxidant and immuno-modulatory roles of the sulphated metabolites of catechins.Peer Reviewe

In vitro evaluation of the antioxidant and anti-inflammatory activities of sulphated metabolites of catechins

Catechins are major polyphenols in many plant foods that have been related to health promotion. In the human organism, they are largely metabolised to different conjugated metabolites (i.e. glucuronide, sulphate and methylated derivatives), which are further found in plasma and would be thus able to reach the biological targets. Therefore, in vitro assays aiming to elucidate the biological effects of dietary catechins should also consider their metabolites and not only the original compounds. In this article, the in vitro antioxidant and anti-inflammatory activities of different catechin and epicatechin sulphates, one of the less studied catechin metabolites, have been evaluated. Since these compounds are not commercially available, they had to be first synthesised in the laboratory. The in vitro antioxidant activity was assessed using the ferric reducing power (FRAP) assay and two methods based on the ability to scavenge the ABTS ̇+ radical cation at different pH values. Sulphation of (epi)catechin lead to a decrease in the antioxidant activity that was greater when the sulphate moiety was located in the catechin B-ring than in A-ring. Despite this, all the studied (epi)catechin sulphates still behave as better antioxidants than a-tocopherol in the radical scavenging assays carried out at pH 7.4, suggesting that they might act as efficient antioxidants in physiological conditions. The anti-inflammatory potential was assessed by evaluating the ability of the compounds to reduce the concentration of nitric oxide (NO) secreted by macrophages (RAW 264.7) after activation with a bacterial lipopolysaccharide (LPS). In the range of studied concentrations (1-300 μM), all the (epi)catechin sulphates caused a dose-dependent inhibition in NO production that even slight was statistically significant in most cases in relation to controls (LPS-activated cells without catechins), whereas the parent catechins did not show any effect in NO production in our experimental conditions. None of the assayed compounds showed any cytotoxic effect in macrophages up to the highest concentration used (300 μM). The obtained results suggested possible antioxidant and immuno-modulatory roles of the sulphated metabolites of catechins. © 2011 Taylor & Francis.Peer Reviewe