Clinical Aspects and Treatment of Congenital Sucrase‐Isomaltase Deficiency

Congenital sucrase-isomaltase deficiency (CSID) was first described by Weijers and colleagues in 1960 and has subsequently been defined as an inherited deficiency in the ability to hydrolyze sucrose, maltose, short 1–4 linked glucose oligomers, branched (1–6 linked) α-limit dextrins, and starch (1). Exposure to these nutrients provokes osmotic diarrhea with pain, bloating, and abdominal distention; rapid small bowel transit and malabsorption of other nutrients; excessive bacterial fermentation of malabsorbed carbohydrate with colonic gas production and acidification of the stools; and at times, chronic malnutrition and failure to thrive (2). After the sucrase-isomaltase (SI) gene was identified on chromosome 3 (3q25–26) and was cloned in 1992 by Chantret and colleagues, more than 25 mutations in the gene responsible for the synthesis of SI have been discovered (3–6). These mutations result in a variety of defects in the folding of the synthesized propeptide chain; the initial high mannose and then complex glycosylation; the sequential export from the endoplasmic reticulum to the Golgi apparatus, and eventually to the apical membrane; the anchoring of the N-terminal aspect of the isomaltase subunit in the enterocyte microvillus membrane; and the normal architecture of the sucrase and isomaltase catalytic sites, which are independent of each other and can be affected separately, leading to isolated deficiencies (5,6). The intracellular phenotypic heterogeneity is reflected in a range of enzymatic capability ranging from completely absent sucrase activity to low but present residual activity and from completely absent isomaltase activity to normal activity. Because SI is responsible for approximately 60% to 80% of the maltase activity in the brush border of the enterocyte, maltase activity is also significantly reduced in almost all cases. In addition to the degree of enzyme deficiency, the appearance of overt clinical manifestations of CSID is partially determined by the amount of sugar and starch being consumed. Approximately 60% of the total calories consumed in the average diet in the United States originate from carbohydrates, with 30% of carbohydrate calories deriving from sucrose (7). The typical adult consumes about 150 lb of sugar per year and 65 lb of sucrose. The influence of the dietary consumption of sucrose is best illustrated by the natural history of CSID in Greenland, where approximately 5% to 10% of Greenland Eskimos are affected (8). Before the introduction of a Western diet in the middle part of the last century provoked by the settlement of Greenland by northern Europeans from Denmark and other European countries, CSID was unknown among the indigenous population, who consumed a fish-and-marine mammal–based diet, relatively high in fat and protein and low in carbohydrates and sucrose. A marked increase in diarrhea and other gastrointestinal symptoms in the indigenous population led to studies in the 1970s that delineated the prevalence of CSID. The early introduction of sucrose and starch in the form of baby juices, baby food fruits and certain vegetables, and sucrose- and maltodextrin-containing infant formulas also plays a role in the timing of clinical manifestations of CSID. Other hormonal and dietary factors and micronutrients also influence small intestinal sucrase activity. Unlike lactase activity that is unresponsive to lactose consumption, sucrase activity is inducible by a high-sucrose, high-carbohydrate diet and reduced by a high-protein, low-carbohydrate diet (9). Both thyroxine and corticosteroids induce the expression of SI on the brush border of the enterocyte (10). In animal models, dietary-induced iron deficiency results in decreased small-bowel disaccharidase activity, with lactase affected more than SI (11). This appears to be the result of decreased gene expression caused by overexpression of PDX-1, a repressor of the lactase and sucrase promoter regions. PDX-1 overexpression can be reversed with restoration of a normal iron-containing diet and replenishment of iron stores. Naturally occurring phytochemicals in the diet (eg, cinnamon extract, onions, garlic, certain spices, mushrooms, chamomile tea) can act as inhibitors of amylase and intestinal α-glucosidases, thus influencing luminal sucrase activity (12). In patients with CSID and mutations allowing some residual SI activity, these hormonal and dietary factors may influence the onset and severity of symptoms. PREVALENCE OF CSID The actual prevalence of CSID is still a matter of debate. Substantial progress in cloning disease-causing mutations has opened the possibility of conducting large-scale population-based screening. In a recent study by Scott and colleagues, all 48 exons of the 100-kb SI gene on chromosome 3 were sequenced in 31 biopsy-proven patients with CSID and 55 different mutations were identified, with at least 1 of the 4 most common mutations found on 32 (59%) of the affected alleles (4). If one assumes the Hardy-Weinberg equilibrium for mutations in the population, then there is an 83% probability that an individual with severe clinical manifestations of CSID will have at least 1 of these 4 mutations. The results of this study raise the possibility in the near future of a genetic screening test both for population prevalence studies and to aid in the diagnosis of new cases. With the availability of DNA harvesting from buccal mucosa, the feasibility of genetic testing in young infants and children increases substantially. Studies are in progress to determine whether genetic testing also can be done on intestinal epithelial biopsy specimens opening the possibility of simultaneously determining disaccharidase levels and genetic mutations for CSID. Clinical studies of relatively homogenous selected populations have yielded high rates of CSID, ranging from 5% to 10% in Greenland Eskimos, 3% to 7% in Canadian native peoples, and about 3% in Alaskans of native ancestry (13,14); however, estimates of the prevalence of CSID in other North American and European populations generally range from 1 in 500 to 1 in 2000 among non-Hispanic whites, with a lower prevalence in African Americans and whites of Hispanic descent. These studies evolved from older studies of intestinal disaccharidase levels in adult patients undergoing endoscopy for gastrointestinal symptoms (15,16). The estimates have shown low levels of sucrase activity >1 standard deviation (SD) below the mean in mucosal biopsy specimens from 2% to 9% of patients, even in the absence of overt mucosal injury. If one assumes that some of these patients represent heterozygotes for CSID, then the prevalence quoted above seems plausible; however, the diagnosis of CSID is rarely made even in infants and young children, suggesting the possibility that the phenotype of CSID may be much broader and more variable than previously thought and that a large proportion of affected adult and pediatric patients are not being tested and diagnosed. This hypothesis receives support from the analysis of recently released whole exome sequence data (Exome Variant Server, http://evs.gs.washington.edu/EVS). Belmont and colleagues at the Children's Nutrition Research Center at the Baylor College of Medicine reviewed the SI gene sequence data in a population of approximately 3500 North American white adults ascertained as controls or with atherosclerosis and no known bias for gastrointestinal disease. These data showed 271 rare missense variants with an aggregate allelic frequency of 0.03864. Based on this allele frequency, and assuming that the alleles segregate independently, Hardy-Weinberg proportions were used to estimate the frequency of homozygotes and compound heterozygotes for rare alleles. Although it is not known whether all of these variants result in decreased enzyme activity, the large number of variants could be consistent, with an estimated frequency of 1:670 affected patients and 7% carriers in this population (personal communication, Dr John Belmont, February 28, 2012; public data at the Exome Variant Server). There are several pieces of clinical evidence that support the view that CSID is more prevalent than previously believed. Studies of disaccharidase levels from intestinal biopsy specimens sent to 2 pediatric reference laboratories have shown surprisingly frequent results for a pattern suggesting CSID. In 2 studies of almost 1000 biopsies each, sucrase deficiency was defined as >1 SD below the mean activity level in 1 study and <10% of the mean in another (17,18). As defined, sucrase deficiency was found in 11% and 13% of biopsy specimens in the 2 studies. Included were specimens with isolated sucrase or SI deficiency only (1.0% and 1.1%, respectively), SI and maltase-glucoamylase (MGAM) deficiency only (3.0% and 2.4%, respectively), and pandisaccharidase deficiency (5.8% in both studies). Pandisaccharidase deficiency was more likely accounted for by acquired diffuse intestinal villous injury. Although correlation with histology was not provided, the surprisingly high numbers of isolated SI and combined SI-MGAM deficiencies without lactase deficiency suggest that specific genetically determined enzyme deficiencies may be playing a role. Although small intestinal disaccharidases are most often investigated in the clinical setting of diarrhea in infants and young children, the role of disaccharidase deficiencies and specifically SI deficiency in other gastrointestinal syndromes also has been entertained. Small series of patients with CSID have revealed a subgroup of adolescents and even adults who present with dyspepsia, gas, and /or irritable bowel syndrome (IBS) rather than the classic presentation of watery diarrhea, failure to thrive, diaper rash, irritability, and acidic stools in infancy (2,19,20). Karnsakul and colleagues studied 44 children and adolescents with dyspepsia, only 4 of whom had intermittent diarrhea (21). Patients underwent endoscopy with small bowel biopsies and disaccharidases and one-third had low sucrase activity (>1 SD from the mean), including 4 of 44 with isolated low sucrase activity, and 11 of 44 with sucrase and pandisaccharidase deficiency, but no significant villous atrophy. In addition, in preliminary follow-up studies of families with index cases of CSID uncovered in a child, parents with a long-term diagnosis of IBS were subsequently identified as having CSID (22). After the sequencing of all of the exons of the CSID gene, most patients with CSID studied by Scott and colleagues have been found to be homozygous or compound heterozygotes for disease-causing mutations (4). Kerry and Townley showed that the parents of 4 children with CSID had intestinal sucrase activity below the lower limits of normal and a sucrase:lactase ratio <0.8, both consistent with the heterozygous state and supporting an autosomal recessive pattern of inheritance (23); however, 3 patients in Scott and colleagues’ study who presented with classical symptoms and biopsy-proven absent sucrase activity with absent or low isomaltase activity, and 2 others with milder decreases in both enzymes, appeared to be heterozygote carriers with a mutation on 1 allele and a wild-type gene on the other. These small studies lend credence to the hypothesis that CSID is more prevalent than previously thought; manifests with milder phenotypes that may even omit diarrhea as a prominent symptom; and may be transmitted in ways other than strict autosomal recessive inheritance. The combination of the “heterozygous” state with other genetic and/or dietary and nutritional interactions may provoke gastrointestinal symptoms in certain patients. PRESENTATION AND NATURAL HISTORY OF CSID The classical presentation of CSID is severe watery diarrhea, failure to gain weight, irritability, and diaper rash in a 9- to 18-month-old infant who has been exposed to sucrose and starch in the form of baby juices, baby food fruits, teething biscuits, crackers, and other starches. Factors that contribute to the predilection for a presentation during infancy include the shorter length of the colon and a decreased capacity for colonic reabsorption of fluid and electrolytes, more rapid small intestinal transit, a high carbohydrate diet, and the ontogeny of amylase activity that does not reach “adult” levels until the second year of life (24); however, clinical studies during the last 20 years and a retrospective review of 65 patients with CSID have revealed a variety of presentations that defy the conventional view (5,22,25,26). Table 1 describes the symptoms at presentation in these 65 patients. Although most have presented with the classic symptoms, a significant minority have only been diagnosed between 2 to 8 years old after normal growth and a previous diagnosis of chronic nonspecific diarrhea of childhood (“toddler's diarrhea”), or even later during adolescence or young adulthood carrying a diagnosis of diarrhea-predominant IBS. Up to one-third have had vomiting as a prominent symptom, suggesting again that dyspepsia, gas, bloating, and even reflux-like symptoms may predominate in some patients. Other anecdotal reports have mentioned hypercalcemia and nephrocalcinosis in infants with CSID, and even renal calculi in 2 adults with CSID (27,28).TABLE 1: Presenting symptoms in 65 patients with CSID (22)In a follow-up study of 65 patients with CSID who responded to a questionnaire after being identified by a record of prescriptions for enzyme replacement therapy, 53 of 65 reported the onset of symptoms before 1 year of age, 7 between 1 and 10 years old, and 5 after 10 years of age (22); however, the age at which a diagnosis was made was shifted to the right, with only 17 of 65 diagnosed in the first year, 30 between 1 and 5 years, 10 between 5 and 10 years, and 8 after 10 years of age. The potential reasons for this delay in diagnosis include a mistaken diagnosis of protein intolerance in infancy with multiple formula changes and the elimination of glucose oligomers (maltodextrin) that are partially hydrolyzed by sucrase in favor of glucose monomers in amino acid–based formulas (29). A diagnosis of food allergy often also leads to the elimination juices and baby foods that may have a high sucrose load, further masking the true underlying cause of diarrhea in patients with CSID. Later in childhood, a diagnosis of chronic nonspecific diarrhea often will result in a lower carbohydrate, higher fat diet, and the elimination of all juices with improvement in symptoms of patients with CSID (30). Older children and adolescents with CSID and diarrhea-predominant IBS may learn which foods trigger their symptoms and avoid those foods, thus masking their true diagnosis. In addition, chronic carbohydrate malabsorption may act as a prebiotic stimulus to colonic bacterial growth, creating a significant increase in the capacity to ferment and salvage malabsorbed carbohydrate, and stimulate colonic short-chain fatty synthesis and and fluid reabsorption by the bacterial may thus contribute to a in diarrhea symptoms in some patients with CSID. OF CSID the standard for the diagnosis of CSID small intestinal biopsy specimens for isomaltase and maltase activity. In the to the diagnosis of CSID include normal small bowel in the of absent or reduced sucrase activity, isomaltase activity from to activity, reduced maltase activity, and normal lactase activity, or in the setting of reduced a sucrase:lactase ratio of Table 2 the disaccharidase in patients with all were in 2 clinical as part of the new for to the and activity was absent in of patients, and in all but activity was than the of in which of small bowel biopsies from children with diarrhea and other gastrointestinal symptoms sucrase activity in patients with CSID were of had absent activity, and all but 2 were with 1 of those in the normal range and 1 with activity. activity was had absent activity, but the mean protein and the standard from the mean in but 2 patients <10% of activity. patients normal activity. There was no correlation between absent or residual sucrase activity with the of decreased maltase activity. Because the brush border enzyme is responsible for at least of maltase activity, those patients with low maltase activity may be of combined deficiencies of SI and lactase enzyme activity levels were found in 3 of patients and have been found in a small minority of patients with CSID in most studies to biopsy disaccharidase in patients with CSID studies of the SI gene in patients with intestinal disaccharidase deficiency have identified compound heterozygotes with reduced sucrase and isomaltase and even appears to be true heterozygotes with 1 normal allele and appears to be a more severe mutation on the other allele in the studies by Scott appeared to have normal wild-type on both alleles with reduced sucrase activity and symptoms provoked by sucrose consumption, which acquired sucrase deficiency even in the of normal small intestinal (4). Other of results from biopsies in the where disaccharidase levels are often only approximately of the levels found in the In addition, of biopsy specimens in of and can result in a diffuse in disaccharidase activity. Studies of intestinal biopsy disaccharidase have a of of the of the This the role of clinical in the diagnosis of CSID from mucosal disaccharidase Other of diagnosis include the sucrose study and Although relatively to the sucrose study is by significant from both sucrase deficiency from villous and bacterial and this test can provoke severe symptoms as a result of the sucrose to patients with CSID. The test the ratio of which in patients with for this test on an that is in infants and young children and the of normal intestinal 1 data from studies of the of a test to CSID This test the of a small of in in as a and the of for 2 The of in and of and to be as a of glucose As 1 the mean of in 10 patients with CSID is with in 10 A of and for CSID. Although the test 2 and it has several it is has and and of gastrointestinal symptoms of an excessive sucrose 1: from studies of the of a test to OF CSID follow-up studies of children with CSID with sucrose- and have that only 10% of patients and 60% still diarrhea, gas, and/or abdominal pain, with a lower proportion of approximately of these children are with the diet and colleagues described the of both production and gastrointestinal symptoms in 8 children with CSID with before a sucrose test a with sucrase but not maltase or isomaltase activity. specific to enzyme activity and to this activity, the food has for years been this enzyme to to and the of studies on a from the these showed that 1 of this approximately of activity glucose per per was of or maltase in mannose glycosylation; activity with and not significant activity with a to of the enzyme with at or near the for activity however, a rapid of activity. of the with a for the and of activity even at a of 2 the results of sucrose studies on the first with CSID with an from the with 2 and 4 sucrose a marked in and gastrointestinal however, by the in and the symptoms. in between the of 5 and years were with the diagnosis of CSID on chronic watery diarrhea with an a sucrase activity level of <10% of the mean of a normal lactase and a normal lactose test These studies used 3 of and an form in 4 to each in during a in which the consumed a normal and studies and without were in the first study and 3 and without and with as a in the second of sucrose studies on the first with CSID with an from the and results of these studies can be as of reduced symptoms of sucrose malabsorption provoked by both the and the of the most significantly reduced watery gas, and these symptoms and the frequency in with the of a diet and no in of patients, an diet, with during the production was by the of with and was further reduced by before sucrose A study of the test with and without these results and that all of the had with were to of and each in a and a of in a young with known who was later found to have a test for This led to the on the to on patients with before is other patients have been described with this These studies in the of an to the and of as for CSID in was by after which was for on the suggest 1 with or for patients and 2 with or for those are to be with the at the onset of a and the other the is to a higher and may be partially by other production by the of with and was further reduced by before sucrose A study of the test with and without these results and that all of the had with preliminary study was patients with CSID who prescriptions for between and are in a and in the of this (22). of were from of patients in in the United States and from patients in 4 other Included were patients and of patients than years patients 2 had it of of and 2 of The of was 3 years and one-third had been for of 65 patients were the per to to symptoms. a normal diet or a sucrose- and diet was consumed by of 65 patients, but in strict sucrose with or strict starch was to of symptoms, even Table 3 symptoms patients are being with The had bowel per and no diarrhea or diarrhea per had diarrhea 2 to 3 per and had diarrhea per In per and were not in patients >1 per and were completely absent in of patients. The most common reported in of in 5 of and in 8 of of these in of symptoms in 65 patients with CSID with Both clinical studies and suggest that CSID is a more common than previously and that genetically small intestinal SI for a of clinical including some in large of patients with chronic nonspecific diarrhea, and even The of with and and genetic of relatively common mutations in the CSID gene the of more population prevalence studies and diagnosis of classic even in adults who are to have bowel The recent of an enzyme replacement has of the previously sucrose diet and a more normal to infants and young children exposed to a high carbohydrate diet of this with the of to higher maltase and activity may be in the to patients with the of starch Research has that amylase activity the of SI and on starch and another potential addition to enzyme replacement