Increased Formation of Methylglyoxal and Protein Glycation, Oxidation and Nitrosation in Triosephosphate Isomerase Deficiency

Triosephosphate isomerase deficiency is associated with the accumulation of dihydroxyacetonephosphate (DHAP) to abnormally high levels, congenital haemolytic anaemia and a clinical syndrome of progressive neuromuscular degeneration leading to infant mortality. DHAP degrades spontaneously to methylglyoxal (MG)--a potent precursor of advanced glycation endproducts (AGEs). MG is detoxified to D-lactate intracellularly by the glyoxalase system. We investigated the changes in MG metabolism and markers of protein glycation, oxidation and nitrosation in a Hungarian family with two germline identical brothers, compound heterozygotes for triosephosphate isomerase deficiency, one with clinical manifestations of chronic neurodegeneration and the other neurologically intact. The concentration of MG and activity of glyoxalase I in red blood cells (RBCs) were increased, and the concentrations of D-lactate in blood plasma and D-lactate urinary excretion were also increased markedly in the propositus. There were concomitant increases in MG-derived AGEs and the oxidative marker dityrosine in hemoglobin. Smaller and nonsignificant increases were found in the neurologically unaffected brother and parents. There was a marked increase (15-fold) in urinary excretion of the nitrosative stress marker 3-nitrotyrosine in the propositus. The increased derangement of MG metabolism and associated glycation, oxidative and nitrosative stress in the propositus may be linked to neurodegenerative process in triosephosphate isomerase deficiency.