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Background: The aim of the study was to assess the effect of chronic cardiac failure (CCF) on circulating plasma concentrations of tumour metabolic marker dimeric pyruvate kinase type M2 (M2-PK). Methods: Fifty patients with clinically stable CCF were studied. Patients with a history of past or ongoing malignancy were excluded. Dimeric M2-PK was measured by enzyme-linked immunosorbent assay in EDTA plasma. Results: Dimeric M2-PK concentration increased significantly (P = 0.005) with increasing clinical severity of CCF as assessed by the New York Heart Association classification grade. Conclusions: Chronic cardiac failure results in an increased circulating plasma concentration of M2-PK, probably related to increased glycolytic flux. The physiological significance of the results is at present unclear but may relate to maintaining a balance between energy production and the supply of glycolytic intermediates to maintain synthetic processes. The results of this investigation will also have significance in the clinical interpretation of M2-PK concentrations. [ABSTRACT FROM AUTHOR]

Nephropathic cystinosis is an autosomal recessive lysosomal storage disease characterized by renal failure at 10 years of age and other systemic complications. The gene for cystinosis, CTNS, has 12 exons. Its 2.6-kb mRNA codes for a 367-amino-acid putative cystine transporter with seven transmembrane domains. Previously reported mutations include a 65-kb "European" deletion involving marker D17S829 and 11 small mutations. Mutation analysis of 108 American-based nephropathic cystinosis patients revealed that 48 patients (44%) were homozygous for the 65-kb deletion, 2 had a smaller major deletion, 11 were homozygous and 3 were heterozygous for 753G-->A (W138X), and 24 had 21 other mutations. In 20 patients (19%), no mutations were found. Of 82 alleles bearing the 65-kb deletion, 38 derived from Germany, 28 from the British Isles, and 4 from Iceland. Eighteen new mutations were identified, including the first reported missense mutations, two in-frame deletions, and mutations in patients of African American, Mexican, and Indian ancestry. CTNS mutations are spread throughout the leader sequence, transmembrane, and nontransmembrane regions. According to a cystinosis clinical severity score, homozygotes for the 65-kb deletion and for W138X have average disease, whereas mutations involving the first amino acids prior to transmembrane domains are associated with mild disease. By northern blot analysis, CTNS was not expressed in patients homozygous for the 65-kb deletion but was expressed in all 15 other patients tested. These data demonstrate the origins of CTNS mutations in America and provide a basis for possible molecular diagnosis in this population.