This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. ABSTRACT Starches and sugars make up 60-90% of human dietary energy intakes. All food carbohydrates (CHO)s are digested in the small intestine to monosaccharides before absorption by a family of membrane bound luminal enzymes called disaccharidases. The best studied disaccharidases are lactase, and sucrase-isomaltase. Because of recognizable clinical symptoms, congenital sucrase-isomaltase deficiencies (CSID) have been studied at clinical, proteomic and genomic levels. While the role of salivary and pancreatic alpha-amylase activities in starch digestion are well known, the roles of mucosal alpha-glucosidases activities are less understood. Alpha-amylases release only 4% of the glucose present in amylopectin. The remaining 96% of products are soluble glucose oligomers with a conserved pattern of lengths. These oligomers, including maltose (G2) and lengths through G40 require further digestion. Mucosal glucosidases release free glucose from the non-reducing ends of the soluble oligomers. Differentiation of amylase from glucosidases activity was first reported in 1880 after discovery of maltase activity in small intestine and its absence in the pancreas. In the 1960s Dahlqvist found that 4 different maltase activities could be identified in the human jejunum;two were isolated with sucrase-isomaltase (SI) activities and two, that were free of all other disaccharidase activities, were called maltase-glucoamylase (MGAM). In the 1980s Hermann, et al. proved that mucosal maltase activities are a subgroup of the glucosidases and that while substrate specificities of SI and MGAM are identical, the activity of MGAM was 100 fold greater and the concentration of SI peptide is 20 fold greater. This dictates that both must be investigated to understand mucosal glucose production from food starches. This protocol is a generic version of H-20932 which was written for a family with hereditary poor starch digestion. In this protocol we will study a national sample of children with similar low duodenal biopsy maltase and normal sucrase activities. The impetus for this study relates to two young siblings with failure-to-thrive that is believed to be secondary to starch intolerance. They have sought treatment for this condition that is currently managed by dietary restrictions (see H-20932). In the older child the condition has been attributed to biopsy-proven, congenital absence of the intestinal brush border enzyme called maltase. The glucosidase activities for the biopsy were, sucrase 40.6 (nl 25), maltase 87.1 (nl 100), and palatinase 6.8 (nl 5). All values were uM/min/g protein. Glucosidase enzymes reduce oligosaccharides to simple glucose that can be absorbed into the body. Failure results in undigested complex carbohydrates that pass to the colon and provoke gas, bloating, irritability and diarrhea. A similar syndrome was described by Lebenthal in 1994, nine children aged from 6-107 months were found to have clinical starch intolerance. Lebenthal used glycogen as substrate for a mucosal biopsy glucosidase assay and reported that deficient activity generally agreed with his clinical diagnosis. We now know that glycogen substrate is only about 80% specific for the MGAM activity of the mucosa. In the 14 years since Lebenthals paper we have shown that four glucosidases participate in the post-amylase digestion of oligosaccharides to glucose and that specific substrates cannot dissect these glucosidase activities. We have found that immunoprecipitation of the activities can resolve individual contributions by the different genes to starch digestion. HYPOTHESIS Supplemental oral enzyme therapy, containing fungal amyloglucosidase, will be beneficial to symptomatic children with congenital maltase glucoamylase deficiency as shown by symptom improvement and increased breath sample enrichment values (objective surrogate of brush border alpha-limit-dextrin digestion and product assimilation) . I.
SPECIFIC AIMS 1. To demonstrate that supplemental oral enzyme therapy, containing fungal amyloglucosidase, is beneficial to symptomatic children with congenital maltase glucoamylase deficiency. 2. To demonstrate symptom improvement 3. To demonstrate increased breath sample enrichment values (objective surrogate of brush border alpha-limit-dextrin digestion and product assimilation)

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