ABSTRACT
Human triosephosphate isomerase (TIM) deficiency is a very rare disease, but there are several mutations reported to be causing the illness. In this work, we produced nine recombinant human triosephosphate isomerases which have the mutations reported to produce TIM deficiency. These enzymes were characterized biophysically and biochemically to determine their kinetic and stability parameters, and also to substitute TIM activity in supporting the growth of an Escherichia coli strain lacking the tim gene. Our results allowed us to rate the deleteriousness of the human TIM mutants based on the type and severity of the alterations observed, to classify four "unknown severity mutants" with altered residues in positions 62, 72, 122 and 154 and to explain in structural terms the mutation V231M, the most affected mutant from the kinetic point of view and the only homozygous mutation reported besides E104D.
Subject(s)
Anemia, Hemolytic, Congenital Nonspherocytic/enzymology , Carbohydrate Metabolism, Inborn Errors/enzymology , Mutation , Triose-Phosphate Isomerase/chemistry , Triose-Phosphate Isomerase/deficiency , Triose-Phosphate Isomerase/metabolism , Anemia, Hemolytic, Congenital Nonspherocytic/genetics , Carbohydrate Metabolism, Inborn Errors/genetics , Enzyme Stability , Humans , Kinetics , Models, Molecular , Mutagenesis, Site-Directed , Protein Conformation , Triose-Phosphate Isomerase/geneticsABSTRACT
OBJECTIVE: To describe four infants with protracted diarrhea caused by glucose polymer intolerance resulting from congenital sucrase-isomaltase deficiency. METHODS: The diagnosis of congenital sucrase-isomaltase deficiency was established by mucosal disaccharidase assay. In each case the clinical response to discontinuation of glucose polymer was documented. RESULTS: The median age at the onset of symptoms was 3 weeks (range, 2 to 16 weeks). In three infants the formula had been prescribed for presumed postgastroenteritis diarrhea, and in a fourth it was begun after resection of a short-segment congenital ileal atresia. In each infant watery diarrhea occurred and persisted for many months, and it was assumed that the original gastrointestinal disorder was responsible. In two cases, parenteral nutrition was administered for persistent failure to thrive. Ultimately, investigation revealed the underlying congenital sucrase-isomaltase deficiency, and elimination of glucose polymer from the diet led to immediate recovery in each case. CONCLUSION: Congenital sucrase-isomaltase deficiency should be considered a possible cause of protracted diarrhea in infants receiving glucose polymer-based feedings.