Turkes F.,Imperial College Medical School |
Murphy E.,Charles Dent Metabolic Unit
Toxicology Mechanisms and Methods | Year: 2013
Elevated plasma homocysteine (Hcy) has been detected in patients with various neurodegenerative conditions. Studies on neurones and cerebral tissue have revealed that hyperhomocystinaemia may inhibit mitochondrial electron transport chain (ETC) enzyme activity resulting in neuronal morbidity. As astrocytes convey a protective and supportive role towards neurones, we postulated that Hcy-induced astrocytic ETC inhibition may contribute to neurological dysfunction. In order to investigate this hypothesis, we established a cellular model of hyperhomocystinaemia using primary rat astrocytes. Which were incubated were incubated with 200μM, 500μM Hcy and the Hcy metabolite, thiolactone (10 ̄M). Following 96 h of incubation with 200μM and 500μM Hcy, an approximate two-fold (1.11 nmol/mg) and three-fold (1.45 nmol/mg) increase in mitochondrial levels of Hcy, respectively, were detected compared to control levels (0.54 nmol/mg). However, on exposure to Hcy (200 or 500μM) and Hcy-thiolactone (10μM), the activities of astrocytic ETC complex I, II-III and IV were found to be comparable to control levels. In addition, the extracellular lactate:pyruvate ratio and the intracellular glutathione status of primary rat astrocytes were not significantly different between Hcy (200 or 500μM) treated and controls. In conclusion, the results of this study suggest that Hcy induced impairment of astrocytic ETC function may not contribute to the pathophysiology of hyperhomocystinaemia. © 2013 Informa Healthcare USA, Inc. All rights reserved: reproduction in whole or part not permitted.
Adam S.,Royal Infirmary |
Carbasius Weber E.,University Utrecht |
Champion H.,University of Cambridge |
Chan H.,Charles Dent Metabolic Unit |
And 35 more authors.
Molecular Genetics and Metabolism | Year: 2013
Background: Within Europe, the management of pyridoxine (B6) non-responsive homocystinuria (HCU) may vary but there is limited knowledge about treatment practice. Aim: A comparison of dietetic management practices of patients with B6 non-responsive HCU in European centres. Methods: A cross-sectional audit by questionnaire was completed by 29 inherited metabolic disorder (IMD) centres: (14 UK, 5 Germany, 3 Netherlands, 2 Switzerland, 2 Portugal, 1 France, 1 Norway, 1 Belgium). Results: 181 patients (73% >. 16. years of age) with HCU were identified. The majority (66%; n=119) were on dietary treatment (1-10. years, 90%; 11-16. years, 82%; and >. 16. years, 58%) with or without betaine and 34% (n=62) were on betaine alone. The median natural protein intake (g/day) on diet only was, by age: 1-10. years, 12. g; 11-16. years, 11. g; and >. 16. years, 45. g. With diet and betaine, median natural protein intake (g/day) by age was: 1-10. years, 13. g; 11-16. years, 20. g; and >. 16. years, 38. g. Fifty-two percent (n=15) of centres allocated natural protein by calculating methionine rather than a protein exchange system. A methionine-free l-amino acid supplement was prescribed for 86% of diet treated patients. Fifty-two percent of centres recommended cystine supplements for low plasma concentrations. Target treatment concentrations for homocystine/homocysteine (free/total) and frequency of biochemical monitoring varied. Conclusion: In B6 non-responsive HCU the prescription of dietary restriction by IMD centres declined with age, potentially associated with poor adherence in older patients. Inconsistencies in biochemical monitoring and treatment indicate the need for international consensus guidelines. © 2013 Elsevier Inc.