Pyruvate kinase deficient hemolytic anemia in the Northern Irish population.

A common cause of hereditary nonspherocytic hemolytic anemia is pyruvate kinase deficiency, which is associated with lifelong chronic hemolysis. Pyruvate kinase deficiency has a worldwide distribution with a higher prevalence in the Caucasian population, and especially in Europe and North America. It is inherited in an autosomal fashion and over 180 different mutations have been described. Investigation of hemolytic anemia in Northern Ireland has uncovered 4 new cases of pyruvate kinase deficiency. Molecular investigation revealed a total of six different mutations. One mutation (p.Arg495Val) is reported here for the first time in a homozygous patient. Another mutant PKLR allele harbored a nonsense and frameshift mutation in cis: c.[721G>T; 826delG]. Considering the three previously described Irish cases of pyruvate kinase deficiency, this study raises the total number of pyruvate kinase-deficient Irish patients to seven in which a total of nine mutant PKLR alleles were identified. This indicates the absence of a founder pyruvate kinase mutation in the Northern Ireland population. Although pyruvate kinase deficiency is prevalent in the Caucasian population it is not reflected in the number of individuals diagnosed in Northern Ireland. Hence, many cases of pyruvate kinase deficiency may remain undetected possibly due to the resultant anemia being mild.

Pre-operative plasma erythropoietin concentration and survival following surgery for non-small cell lung cancer.

BACKGROUND: Suppression of the effect of the hormone erythropoietin (EPO) on the bone marrow, and an inadequate EPO response to anaemia have been shown to be factors in the genesis of cancer related anaemia. Low haemoglobin (Hb) concentration pre-operatively has been shown to have prognostic significance in patients with surgically resected NSCLC. This study investigates the relationship between pre-operative EPO and survival in patients having surgery for NSCLC. METHODS: Pre-operative plasma EPO concentration and haemoglobin concentration were analysed in patients undergoing surgery for NSCLC between April 1998 and January 1999. Full follow-up was available for all patients. RESULTS: Forty two patients were included. Median EPO concentration was 9.4 mIU/ml, range (3.7-56.4) with 17 patients (40.4%) having values above the normal range. Median haemoglobin concentration was 13.3g/dl (range 8.5-16.8) with 15 patients (26%) anaemic pre-operatively. Pathological staging revealed 17 (40.4%) patients with stage I, 6 (14.3%) with stage II, 19 (45.3%) with stage III disease. Ten patients had irresectable disease. There was a significant difference in median EPO but not haemoglobin concentration, between the different pathological stages. Survival was significantly lower in patients with pre-operative EPO >10.5 mIU. CONCLUSIONS: Raised pre-operative EPO is associated with reduced survival in patients having surgery for NSCLC. Its measurement should be considered in the pre-operative assessment of patients undergoing surgery for NSCLC. Further research is required to further investigate the biological relationship between EPO and NSCLC.

Recessive congenital methaemoglobinaemia: functional characterization of the novel D239G mutation in the NADH-binding lobe of cytochrome b5 reductase.

Type I recessive congenital methaemoglobinaemia (RCM), caused by the reduced form of nicotinamide adenine dinucleotide (NADH)-cytochrome b(5) reductase (cytb(5)r) deficiency, manifests clinically as cyanosis without neurological dysfunction. Two mutations, E255- and G291D, have been identified in the NADH-binding lobe of cytb(5)r in previously reported patients, and we have detected a further novel mutation, D239G, in this lobe in two unrelated Irish families. Although one family belongs to the genetically isolated Traveller Community, which separated from the general Irish population during the 1845-48 famine, the D239G mutation was present on the same haplotype in both families. Three known cytb(5)r mutations were also identified, including the R159- mutation, which causes loss of the entire NADH-binding lobe and had previously been reported in an individual with type II RCM. Characterization of the three NADH-binding lobe mutants using a heterologous expression system revealed that all three variants retained stoichiometric levels of flavin adenine dinucleotide with spectroscopic and thermodynamic properties comparable with those of native cytb(5)r. In contrast to the E255- and G291D variants, the novel D239G mutation had no adverse impact on protein thermostability. The D239G mutation perturbed substrate binding, causing both decreased specificity for NADH and increased specificity for NADPH. Thus cytb(5)r deficient patients who are heterozygous for an NADH-binding lobe mutation can exhibit the clinically less severe type I phenotype, even in association with heterozygous deletion of the NADH-binding lobe.