Fifty years in inborn errors of metabolism : from urine ferric chloride to mass spectrometry and gene analysis

Electronic version does not contain associated previously published materialPrefatory material introducing a collection of articles spanning fifty years of research into inborn errors of metabolism. Table of Contents: 1. Introduction -- 2. Background information about inborn errors of metabolism -- 3. Lessons from phenylketonuria [PKU] -- 4. My role in developing new medical foods -- 5. My role in solving an epidemic of benzyl alcohol poisoning in premature infants -- 6. My role in galactosaemia research -- 7. My start in the metabolic world - screening tests in urine -- 8. My experiences in disaster relief -- 9. My first appearance in the medical literature -- 10. A selection of rare and unusual diseases -- 11. Tyrosinaemia type II; tyrosine aminotransferase deficiency -- 12. Iminodipeptiduria due to prolidase deficiency -- 13. Citrullinaemia -- 14. Rippling muscle disease -- 15. A fatal X-linked disorder of diarrhoea, diabetes mellitus and immune dysregulation -- 16. Infantile Refsum disease -- 17. Hereditary hypocalcuric hypercalcaemia -- 18. Carbohydrate deficient glycoprotein disease type IAPKU -- 19. Thiamine-responsive diabetes and deafness -- 20. Folinic acid-responsive seizures: a false alarm -- 21. S-adenosylmethionine hydrolase deficiency -- 22. Deficiency of complex III of the respiratory chain -- 23. Current research: quantitation of infant sucking behaviour -- 24. Discussion and summar

COPD uncovered: an international survey on the impact of chronic obstructive pulmonary disease [COPD] on a working age population

Background: Approximately 210 million people are estimated to have chronic obstructive pulmonary disease [COPD] worldwide. The burden of disease is known to be high, though less is known about those of a younger age. The aim of this study was to investigate the wider personal, economic and societal burden of COPD on a cross country working-age cohort. Methods: A cross-country [Brazil, China, Germany, Turkey, US, UK] cross-sectional survey methodology was utilised to answer the research questions. 2426 participants aged 45-67 recruited via a number of recruitment methods specific to each country completed the full survey. Inclusion criteria were a recalled physician diagnosis of COPD, a smoking history of > 10 pack years and the use of COPD medications in the previous 3 months prior to questioning. The survey included items from the validated Work Productivity and Activity Impairment [WPAI] scale and the EuroQoL 5 Dimension [EQ-5D] scale. Disease severity was measured using the 5-point MRC [Medical Research Council] dyspnoea scale as a surrogate measure. Results: 64% had either moderate [n = 1012] or severe [n = 521] COPD, although this varied by country. 75% of the cohort reported at least one comorbid condition. Quality of life declined with severity of illness [mild, mean EQ-5D score = 0.84; moderate 0.58; severe 0.41]. The annual cost of healthcare utilisation [excluding treatment costs and diagnostic tests] per individual was estimated to be $2,364 [1,500] pound. For those remaining in active employment [n: 677]: lost time from work cost the individual an average of$880 [556] pound per annum and lifetime losses of $7,365 [4,661] pound amounting to$596,000 [377,000] pound for the cohort. 447 [similar to 40%] of the working population had retired prematurely because of COPD incurring individual estimated lifetime income losses of $316,000 [200,000] pound or a combined total of$141 m [89.6 pound m]. As the mean age of retirees was 58.3 and average time since retirement was 4 years, this suggests the average age of retirement is around 54. This would mean a high societal and economic impact in all study countries, particularly where typical state retirement ages are higher, for example in Brazil, Germany and the UK [65] and the US [65,66,67], compared to Turkey [58 for women, 60 for men] and China [60]. Conclusions: Although generalisation across a broader COPD population is limited due to the varied participant recruitment methods, these data nevertheless suggest that COPD has significant personal, economic and societal burden on working age people. Further efforts to improve COPD diagnosis and management are required

Mitochondrial Encephalomyopathy and Complex III Deficiency Associated with a Stop-Codon Mutation in the Cytochrome b Gene

We have reinvestigated a young woman, originally reported by us in 1983, who presented with exercise intolerance and lactic acidosis associated with severe deficiency of complex III and who responded to therapy with menadione and ascorbate. Gradually, she developed symptoms of a mitochondrial encephalomyopathy. Immunocytochemistry of serial sections of muscle showed a mosaic of fibers that reacted poorly with antibodies to subunits of complex III but reacted normally with antibodies to subunits of complexes I, II, or IV, suggesting a mutation of mtDNA. These findings demonstrate the diagnostic value of immunocytochemistry in identifying specific respiratory-chain deficiencies and, potentially, distinguishing between nuclear- or mtDNA-encoded defects. Sequence analysis revealed a stop-codon mutation (G15242A) in the mtDNA-encoded cytochrome b gene, resulting in loss of the last 215 amino acids of cytochrome b. PCR-RFLP analysis indicated that the G15242A mutation was heteroplasmic and was present in a high percentage (87%) of affected tissue (skeletal muscle) and a low percentage (0.7%) of unaffected tissue (blood) but was not detected in controls. Analysis of microdissected muscle fibers showed a significant correlation between the immunoreactivity toward the Rieske protein of complex III and the percentage of mutant mtDNA: immunopositive fibers had a median value of 33% of the G15242A mutation, whereas immunonegative, ragged-red fibers had a median value of 89%, indicating that the stop-codon mutation was pathogenic in this patient. The G15242A mutation was also present in several other tissues, including hair roots, indicating that it must have arisen either very early in embryogenesis, before separation of the primary germ layers, or in the maternal germ line. The findings in this patient are contrasted with other recently described patients who have mutations in the cytochrome b gene