Congenital Sucrase-Isomaltase Deficiency: Same Mutation with Different Clinical Presentations.

BACKGROUND/AIMS:  Congenital sucrase-isomaltase deficiency is an autosomal recessive inherited disaccharidase deficiency characterized by chronic osmotic diarrhea. In this study, the genotype-phenotype relationships of close relatives of an index case with congenital sucrase-isomaltase deficiency were investigated. MATERIALS AND METHODS:  A 23-month-old female patient with a sucrase-isomaltase gene c.317G>A (p.C106Y) homozygous mutation was diagnosed as an index case and her pedigree analysis was performed subsequently. The family members with and without sucrase- isomaltase gene mutations were compared in terms of clinical symptoms. RESULTS:  The study included 109 cases [mean age ± SD: 22.6 ± 17.2 years (0.1-75 years), 61 males (56%)] of 130 family members of the index case. Sucrase-isomaltase gene c.317G>A (p.C106Y) heterozygous mutation was detected in 27 cases (24.7%); 14 (51.9%) were male and had a mean age of 23.2 ± 18.3 years. The most common complaints of 12 (44.4%) symptomatic patients with mutations were abdominal pain (37%), gas irritability (33.3%), bloating (22.2%), and foul-smelling stools (18.5%). Compared with the cases without mutation, a statistically significant difference was observed in the incidence of gas irritability, foul-smelling stool, ≥2 gastrointestinal symptoms, postprandial complaints, and food allergy (P = .005, P = .047, P = .049, P = .017, P = .021, respectively). Sacrosidase enzyme replacement was applied to 7 patients whose symptoms did not improve with dietary elimination. Clinical response was obtained after enzyme treatment. CONCLUSION:  Despite its autosomal recessive inheritance, congenital sucrase-isomaltase deficiency can also be symptomatic in heterozygous individuals. Further studies are required to clarify the genotype-phenotype relationship and management of the disease.

Diagnosing sucrase-isomaltase deficiency: a comparison of a 13C-sucrose breath test and a duodenal enzyme assay.

BACKGROUND: Reduced activity of the sucrase-isomaltase (SI) enzyme can cause gastrointestinal symptoms. Biochemical measurement of SI activity in small intestinal biopsies is presently considered the gold standard for the diagnosis of SI deficiency, but this invasive test is not suitable as a routine diagnostic tool. AIM: To evaluate a 13C-sucrose-breath test (13CSBT) as a diagnostic tool for SI deficiency in an adult population. METHODS: 13CSBT results were compared to sucrase activity measured in duodenal biopsies. RESULTS: Forty patients with gastrointestinal symptoms were included in the study, 4 of whom had celiac disease and the rest (n = 36) had normal histological findings. Nine patients (22.5%) had low sucrase activity measured using duodenal biopsies. No correlation was observed between enzymatic sucrase activity and the 13CSBT results. The 13CSBT-curves for the celiac patients versus patients with normal duodenal histology demonstrated that the patients with celiac disease were within the lower range of the distribution. CONCLUSION: We observed a mismatch between the 13CSBT results and the biochemically measured sucrase activity, suggesting that SI activity is not uniformly distributed throughout the small intestines. This methodological discrepancy should be acknowledged when diagnosing SI deficiency.

[Genetics of sucrose metabolism disorders in different population groups].

The study of the genetic determinants of the disaccharidase activity opens up new prospects for improving diagnostics and choosing medical tactics in gastroenterology. The aim of the study was to systematize the data on the role of the sucrase-isomaltase gene (SI) in regulating sucrose metabolism and the contribution of SI mutations to the prevalence of sucrose malabsorption disorders (sucrase-isomaltase deficiency, SID) and certain forms of enterological pathology in different population groups. Material and methods. A review of the peer-reviewed scientific literature, mainly in the PubMed database (https://pubmed.ncbi.nlm.nih.gov) and eLibrary (https://elibrary.ru), was conducted using key words: carbohydrate malabsorption, sucrase, sucrase-isomaltase deficiency, sucrase-isomaltase SI gene. The search depth was not specified, but particular attention was paid to recent publications. The gnomAD database (https://www.ncbi.nlm. nih.gov/snp/rs781470490) was also used. Results. According to the review results, 37 out of 150 known SI gene mutations have been confirmed to contribute to reduced sucrase activity or restricted sucrase production. The prevalence of point mutations in the SI gene is estimated at 0.0006%, but carrier rates of the SI delAG deletion (rs781470490), manifested as homozygosity in SID, are very high (5-21%) in indigenous populations of Arctic regions in East Asia and America. Medicalgenetic research methods improve the accuracy of differential diagnosis of primary and secondary SID and other forms of disaccharide and polysaccharide malabsorption. The formation of databases on the prevalence of genetic determinants of sucrase-isomaltase insufficiency is a promising way to refine the epidemiology of SID. There is an increased (0.2-2.3%) risk of clinical manifestations of SID in homozygous carriers of the SI delAG mutation in the Chukotka, Kamchatka, and Northern Priochotye populations. Verification of reports on a less pronounced tendency to lipid metabolism disorders in SI delAG carriers compared with the control group is recommended. Conclusion. Manifestations of mutant SI variants in the phenotype are associated with the presence of accompanying carbohydrate malabsorption variants and specific gut microbiota. The SI 15Phe variant (rs9290264) may contribute to the development of irritable bowel syndrome.

Congenital sucrase-isomaltase deficiency in Türkiye; a single center experience.

BACKGROUND: Congenital sucrase-isomaltase deficiency (CSID) is a rare inherited carbohydrate malabsorption disorder caused by sucrase-isomaltase (SI) gene variants. In CSID, an autosomal recessively inherited disease, symptoms can also be seen in individuals with heterozygous mutations. METHODS: The variant spectrum was evaluated retrospectively in individuals who presented with chronic diarrhea between 2014 and 2022 and had undergone genetic testing of the SI gene considering CSID due to diet-related complaints. RESULTS: Ten patients with chronic diarrhea were genetically evaluated with SI gene sequencing. In patients diagnosed with CSID and whose symptoms improved with enzyme replacement therapy, the genetic mutation zygosity was found to be heterozygous at a rate of 90%. In 10% of the patients, the mutation was homozygous. Limiting consuming sucrose and isomaltose foods reduced the patients' complaints, but the symptoms did not disappear completely. With the initiation of sacrosidase enzyme replacement therapy, the patient's complaints completely disappeared. CONCLUSION: In CSID, defined as an autosomal recessive disease, clinical symptoms can also be seen in heterozygous cases previously described as carriers, and these patients also benefit from sacrosidase enzyme replacement therapy. In light of these findings, the autosomal recessive definition of CSID does not fully characterize the disease.What is Known:CSID is a rare inherited carbohydrate malabsorption disorder caused by sucrase-isomaltase gene variants.In congenital sucrase-isomaltase deficiency, an autosomal recessively inherited disorder, symptoms can also be seen in individuals with heterozygous mutations.What is new:Severe disease symptoms can also be seen in heterozygous cases, which were thought to be carriers because the disease was previously described as autosomal recessive.Sacrosidase enzyme replacement therapy also eliminates the disease symptoms in patients with heterozygous CSID mutations.This is the second study on sucrase-isomaltase enzyme deficiency pediatric groups in Türkiye and Europe.

This is the study to evaluate the congenital sucrase-isomaltase enzyme deficiency in chronic diarrhea cases covering adults and childhood in our country and the clinical features and treatment response characteristics of the variants detected in these patients.In addition, another aim of our study is that sucrase­isomaltase enzyme deficiency should be considered in the differential diagnosis and should be kept in mind, especially in cases with chronic diarrhea whose cause cannot be determined in childhood.

Genetic and acquired sucrase-isomaltase deficiency: A clinical review.

Genetic sucrase-isomaltase deficiency (GSID) is an inherited deficiency in the ability to digest sucrose and potentially starch due to mutations in the sucrase-isomaltase (SI) gene. Congenital sucrase-isomaltase deficiency is historically considered to be a rare condition affecting infants with chronic diarrhea as exposure to dietary sucrose begins. Growing evidence suggests that individuals with SI variants may present later in life, with symptoms overlapping with those of irritable bowel syndrome. The presence of SI genetic variants may, either alone or in combination, affect enzyme activity and lead to symptoms of different severity. As such, a more appropriate term for this inherited condition is GSID, with a recognition of a spectrum of severity and onset of presentation. Currently, disaccharidase assay on duodenal mucosal tissue homogenates is the gold standard in diagnosing SI deficiency. A deficiency in the SI enzyme can be present at birth (genetic) or acquired later, often in association with damage to the enteric brush-border membrane. Other noninvasive diagnostic alternatives such as sucrose breath tests may be useful but require further validation. Management of GSID is based on sucrose and potentially starch restriction tailored to the individual patients' tolerance and symptoms. As this approach may be challenging, additional treatment with commercially available sacrosidase is available. However, some patients may require continued starch restriction. Further research is needed to clarify the true prevalence of SI deficiency, the pathobiology of single SI heterozygous mutations, and to define optimal diagnostic and treatment algorithms in the pediatric population.

Severe pathogenic variants of intestinal sucrase-isomaltase interact avidly with the wild type enzyme and negatively impact its function and trafficking.

Sucrase-isomaltase (SI) is the major disaccharidase of the small intestine, exhibiting a broad α-glucosidase activity profile. The importance of SI in gut health is typified by the development of sucrose and starch maldigestion in individuals carrying mutations in the SI gene, like in congenital sucrase-isomaltase deficiency (CSID). Common and rare defective SI gene variants (SIGVs) have also been shown to increase the risk of irritable bowel syndrome (IBS) with symptoms and clinical features similar to CSID and also in symptomatic heterozygote carriers. Here, we investigate the impact of the most abundant and highly pathogenic SIGVs that occur in heterozygotes on wild type SI (SIWT) by adapting an in vitro system that recapitulates SI gene heterozygosity. Our results demonstrate that pathogenic SI mutants interact avidly with SIWT, negatively impact its enzymatic function, alter the biosynthetic pattern and impair the trafficking behavior of the heterodimer. The in vitro recapitulation of a heterozygous state demonstrates potential for SIGVs to act in a semi-dominant fashion, by further reducing disaccharidase activity via sequestration of the SIWT copy into an inactive form of the enzymatic heterodimer. This study provides novel insights into the potential role of heterozygosity in the pathophysiology of CSID and IBS.

Loss of Sucrase-Isomaltase Function Increases Acetate Levels and Improves Metabolic Health in Greenlandic Cohorts.

BACKGROUND & AIMS: The sucrase-isomaltase (SI) c.273_274delAG loss-of-function variant is common in Arctic populations and causes congenital sucrase-isomaltase deficiency, which is an inability to break down and absorb sucrose and isomaltose. Children with this condition experience gastrointestinal symptoms when dietary sucrose is introduced. We aimed to describe the health of adults with sucrase-isomaltase deficiency. METHODS: The association between c.273_274delAG and phenotypes related to metabolic health was assessed in 2 cohorts of Greenlandic adults (n = 4922 and n = 1629). A sucrase-isomaltase knockout (Sis-KO) mouse model was used to further elucidate the findings. RESULTS: Homozygous carriers of the variant had a markedly healthier metabolic profile than the remaining population, including lower body mass index (ß [standard error], -2.0 [0.5] kg/m2; P = 3.1 × 10-5), body weight (-4.8 [1.4] kg; P = 5.1 × 10-4), fat percentage (-3.3% [1.0%]; P = 3.7 × 10-4), fasting triglyceride (-0.27 [0.07] mmol/L; P = 2.3 × 10-6), and remnant cholesterol (-0.11 [0.03] mmol/L; P = 4.2 × 10-5). Further analyses suggested that this was likely mediated partly by higher circulating levels of acetate observed in homozygous carriers (ß [standard error], 0.056 [0.002] mmol/L; P = 2.1 × 10-26), and partly by reduced sucrose uptake, but not lower caloric intake. These findings were verified in Sis-KO mice, which, compared with wild-type mice, were leaner on a sucrose-containing diet, despite similar caloric intake, had significantly higher plasma acetate levels in response to a sucrose gavage, and had lower plasma glucose level in response to a sucrose-tolerance test. CONCLUSIONS: These results suggest that sucrase-isomaltase constitutes a promising drug target for improvement of metabolic health, and that the health benefits are mediated by reduced dietary sucrose uptake and possibly also by higher levels of circulating acetate.

Theories behind the effect of starch­ and sucrose­reduced diets on gastrointestinal symptoms in irritable bowel syndrome (Review).

Increased amounts of starch and sugar have been added to the diet in the Western world during the last decades. Undigested carbohydrates lead to bacterial fermentation and gas production with diffusion of water, causing abdominal bloating, pain and diarrhea. Therefore, dietary advice is the first line of treatment of irritable bowel syndrome (IBS), a disease characterized by abdominal pain and altered bowel habits without any organic findings. Recently, a diet with a reduction of starch and sucrose led to a marked effect on gastrointestinal (GI) symptoms. The mechanism is unknown, but three possible mechanisms are presented in the present review. First, functional variants of the enzyme sucrase­isomaltase (SI) have been described in IBS. A subgroup of patients with IBS may thus suffer from partial SI deficiency with reduced digestion of starch and sucrose. Second, fructose absorption is less efficient than glucose absorption, which may lead to a physiological fructose malabsorption when ingesting high amounts of sucrose. A third mechanism is that high­sugar diets causing hyperglycemia, hyperinsulinemia and weight gain have led to painful neuropathy in animal models; whereas, improved metabolic control in humans has led to improvement of neuropathy. Starch­ and sucrose­reduced diets lead to decreased levels of C­peptide, insulin, gastric inhibitory peptide, leptin and weight reduction. These metabolic changes may reduce the excitability of the hypersensitive nervous system often found in IBS and, thereby, lead to the reduced symptoms found after the diet. In conclusion, further studies are needed to investigate the pathophysiology behind development of symptoms after starch and sucrose intake, and the mechanisms behind symptom relief after reduced intake.

The glucose-regulated protein GRP94 interacts avidly in the endoplasmic reticulum with sucrase-isomaltase isoforms that are associated with congenital sucrase-isomaltase deficiency.

The glucose-regulated protein GRP94 is a molecular chaperone that is located in the endoplasmic reticulum (ER). Here, we demonstrate in pull down experiments an interaction between GRP94 and sucrase-isomaltase (SI), the most prominent disaccharidase of the small intestine. GRP94 binds to SI exclusively via its mannose-rich form compatible with an interaction occurring in the ER. We have also examined the interaction GRP94 to a panel of SI mutants that are associated with congenital sucrase-isomaltase deficiency (CSID). These mutants exhibited more efficient binding to GRP94 than wild type SI underlining a specific role of this chaperone in the quality control in the ER. In view of the hypoxic milieu of the intestine, we probed the interaction of GRP94 to SI and its mutants in cell culture under hypoxic conditions and observed a substantial increase in the binding of GRP94 to the SI mutants. The interaction of GRP94 to the major carbohydrate digesting enzyme and regulating its folding as well as retaining SI mutants in the ER points to a potential role of GRP94 in maintenance of intestinal homeostasis by chaperoning and stabilizing SI.

The patient journey to diagnosis and treatment of congenital sucrase-isomaltase deficiency.

PURPOSE: Congenital sucrase-isomaltase deficiency (CSID) is a rare genetic disorder characterized by a deficiency of the sucrase-isomaltase (SI) enzyme complex within the brush border membrane of the small intestine. Mutations in the SI gene result in abnormal synthesis and/or incorrect transport of the SI enzyme. Patients with CSID generally have reduced sucrase activity, but levels of isomaltase activity range from absent to almost normal. This study sought to better understand the experience of patients with CSID prior to, during, and after their diagnosis and its subsequent treatment with sacrosidase. METHODS: This was a cross-sectional interview study conducted in conjunction with a longitudinal, observational study of US patients prescribed and taking sacrosidase for at least three consecutive months as treatment for CSID. The observational study included both children and adults. RESULTS: This qualitative interview study explored the experiences of 43 adult and pediatric patients (n = 8 adults and n = 35 children/adolescents) with CSID pre-, during, and post-diagnosis. Findings suggest that a CSID diagnosis is particularly problematic given the disparate range of more commonly understood gastrointestinal (GI) disorders. After diagnosis and treatment with sacrosidase, participants reported considerable improvement in symptoms and health-related quality of life (HRQL), yet symptoms persist that continue to affect daily life, indicating areas of potential unmet need. CONCLUSION: Educating clinicians about CSID may help improve the overall diagnosis experience. As this research is the first of its kind in CSID, additional research, qualitative and quantitative, will be important to furthering the understanding of HRQL impact and unmet need experienced by this population and identifying ways to best meet those needs.

Differential Effects of Sucrase-Isomaltase Mutants on Its Trafficking and Function in Irritable Bowel Syndrome: Similarities to Congenital Sucrase-Isomaltase Deficiency.

Congenital sucrase-isomaltase deficiency (CSID) is a rare metabolic intestinal disorder with reduced or absent activity levels of sucrase-isomaltase (SI). Interestingly, the main symptoms of CSID overlap with those in irritable bowel syndrome (IBS), a common functional gastrointestinal disorder with unknown etiology. Recent advances in genetic screening of IBS patients have revealed rare SI gene variants that are associated with IBS. Here, we investigated the biochemical, cellular and functional phenotypes of several of these variants. The data demonstrate that the SI mutants can be categorized into three groups including immature, mature but slowly transported, and finally mature and properly transported but with reduced enzymatic activity. We also identified SI mutant phenotypes that are deficient but generally not as severe as those characterized in CSID patients. The variable effects on the trafficking and function of the mutations analyzed in this study support the view that both CSID and IBS are heterogeneous disorders, the severity of which is likely related to the biochemical phenotypes of the SI mutants as well as the environment and diet of patients. Our study underlines the necessity to screen for SI mutations in IBS patients and to consider enzyme replacement therapy as an appropriate therapy as in CSID.

Hypomorphic SI genetic variants are associated with childhood chronic loose stools.

OBJECTIVE: The SI gene encodes the sucrase-isomaltase enzyme, a disaccharidase expressed in the intestinal brush border. Hypomorphic SI variants cause recessive congenital sucrase-isomaltase deficiency (CSID) and related gastrointestinal (GI) symptoms. Among children presenting with chronic, idiopathic loose stools, we assessed the prevalence of CSID-associated SI variants relative to the general population and the relative GI symptom burden associated with SI genotype within the study population. METHODS: A prospective study conducted at 18 centers enrolled 308 non-Hispanic white children ≤18 years old who were experiencing chronic, idiopathic, loose stools at least once per week for >4 weeks. Data on demographics, GI symptoms, and genotyping for 37 SI hypomorphic variants were collected. Race/ethnicity-matched SI data from the Exome Aggregation Consortium (ExAC) database was used as the general population reference. RESULTS: Compared with the general population, the cumulative prevalence of hypomorphic SI variants was significantly higher in the study population (4.5% vs. 1.3%, P < .01; OR = 3.5 [95% CI: 6.1, 2.0]). Within the study population, children with a hypomorphic SI variant had a more severe GI symptom burden than those without, including: more frequent episodes of loose stools (P < .01), higher overall stool frequency (P < .01), looser stool form (P = .01) and increased flatulence (P = .02). CONCLUSION: Non-Hispanic white children with chronic idiopathic loose stools have a higher prevalence of CSID-associated hypomorphic SI variants than the general population. The GI symptom burden was greater among the study subjects with a hypomorphic SI variant than those without hypomorphic SI variants.

Sucrase-Isomaltase Deficiency as a Potential Masquerader in Irritable Bowel Syndrome.

BACKGROUND: Patients with irritable bowel syndrome (IBS) frequently have meal-related symptoms and can recognize specific trigger foods. Lactose intolerance is a well-established carbohydrate malabsorption syndrome that causes symptoms similar to IBS such as bloating, abdominal pain, and diarrhea. However, the prevalence of sucrase-isomaltase deficiency (SID) in this population is poorly defined. SID is a condition in which sucrase-isomaltase, an enzyme produced by brush border of small intestine to metabolize sucrose, is deficient. Just like lactase deficiency, SID causes symptoms of maldigestion syndromes including abdominal pain, bloating, gas, and diarrhea. In this study, we aim to determine the prevalence of SID in patients with presumed IBS-D/M and characterize its clinical presentation. METHODS: Patients with a presumed diagnosis of IBS-D/M based on symptoms of abdominal pain, diarrhea, and/or bloating who underwent esophagogastroduodenoscopy with duodenal biopsies and testing for disaccharidase deficiency were included. Patients with a history of inflammatory bowel disease, gastrointestinal malignancy, or celiac disease were excluded. Odds ratio was calculated for abdominal pain, diarrhea, and bloating in patients with versus without SID. RESULTS: A total of 31 patients with clinical suspicion for IBS-D/M were included with a median age of 46 years (IQR 30.5-60) and with 61% females. SID was present in 35% of patients. Among patients with SID, 63.6% had diarrhea, 45.4% had abdominal pain, and 36.4% had bloating. Patients with SID were less likely than controls to have abdominal pain (OR 0.16, 95% CI 0.03-0.81, p = 0.04) although no difference in diarrhea or bloating was found. Only two patients with SID underwent sucrose breath testing of which only one had a positive result. However, this patient also had a positive glucose breath test and may have had small intestinal bacterial overgrowth as a confounder. CONCLUSION: SID was found in 35% of patients with presumed IBS-D/M and should be considered in the differential diagnosis of patients presenting with abdominal pain, diarrhea, or bloating. Further studies should better characterize the clinical features of SID and investigate the effects of dietary modification in this group of patients.

Heterozygotes Are a Potential New Entity among Homozygotes and Compound Heterozygotes in Congenital Sucrase-Isomaltase Deficiency.

Congenital sucrase-isomaltase deficiency (CSID) is an autosomal recessive disorder of carbohydrate maldigestion and malabsorption caused by mutations in the sucrase-isomaltase (SI) gene. SI, together with maltase-glucoamylase (MGAM), belongs to the enzyme family of disaccharidases required for breakdown of -glycosidic linkages in the small intestine. The effects of homozygote and compound heterozygote inheritance trait of SI mutations in CSID patients have been well described in former studies. Here we propose the inclusion of heterozygote mutation carriers as a new entity in CSID, possibly presenting with milder symptoms. The hypothesis is supported by recent observations of heterozygote mutation carriers among patients suffering from CSID or patients diagnosed with functional gastrointestinal disorders. Recent studies implicate significant phenotypic heterogeneity depending on the character of the mutation and call for more research regarding the correlation of genetics, function at the cellular and molecular level and clinical presentation. The increased importance of SI gene variants in irritable bowel syndrome (IBS) or other functional gastrointestinal disorders FGIDs and their available symptom relief diets like fermentable oligo-, di-, mono-saccharides and polyols FODMAPs suggest that the heterozygote mutants may affect the disease development and treatment.

The Role of Disaccharidase Deficiencies in Functional Abdominal Pain Disorders-A Narrative Review.

Disaccharidase deficiencies are reportedly underdiagnosed in pediatric populations. Though typically thought to cause diarrheal disease, they can also be a cause of abdominal pain and dyspepsia, and patients diagnosed with these functional disorders may actually have associated enzyme deficiencies. While the effects of lactose deficiency have been widely studied, sucrase, maltase, and isomaltase are less frequently considered when approaching a patient with an apparent functional abdominal pain disorder. This review seeks to provide an up-to-date narrative on the current scientific literature on the possible role of sucrase, maltase, and isomaltase deficiency in pediatric functional gastrointestinal disorders.

13C-Labeled-Starch Breath Test in Congenital Sucrase-isomaltase Deficiency.

BACKGROUND AND HYPOTHESES: Human starch digestion is a multienzyme process involving 6 different enzymes: salivary and pancreatic α-amylase; sucrase and isomaltase (from sucrose-isomaltase [SI]), and maltase and glucoamylase (from maltase-glucoamylase [MGAM]). Together these enzymes cleave starch to smaller molecules ultimately resulting in the absorbable monosaccharide glucose. Approximately 80% of all mucosal maltase activity is accounted for by SI and the reminder by MGAM. Clinical studies suggest that starch may be poorly digested in those with congenital sucrase-isomaltase deficiency (CSID). Poor starch digestion occurs in individuals with CSID and can be documented using a noninvasive C-breath test (BT). METHODS: C-Labled starch was used as a test BT substrate in children with CSID. Sucrase deficiency was previously documented in study subjects by both duodenal biopsy enzyme assays and C-sucrose BT. Breath CO2 was quantitated at intervals before and after serial C-substrate loads (glucose followed 75 minutes later by starch). Variations in metabolism were normalized against C-glucose BT (coefficient of glucose absorption). Control subjects consisted of healthy family members and a group of children with functional abdominal pain with biopsy-proven sucrase sufficiency. RESULTS: Children with CSID had a significant reduction of C-starch digestion mirroring that of their duodenal sucrase and maltase activity and C-sucrase BT. CONCLUSIONS: In children with CSID, starch digestion may be impaired. In children with CSID, starch digestion correlates well with measures of sucrase activity.

Increased Prevalence of Rare Sucrase-isomaltase Pathogenic Variants in Irritable Bowel Syndrome Patients.

Patients with irritable bowel syndrome (IBS) often associate their symptoms to certain foods. In congenital sucrase-isomaltase deficiency (CSID), recessive mutations in the SI gene (coding for the disaccharidase digesting sucrose and 60% of dietary starch)1 cause clinical features of IBS through colonic accumulation of undigested carbohydrates, triggering bowel symptoms.2 Hence, in a previous study,3 we hypothesized that CSID variants reducing SI enzymatic activity may contribute to development of IBS symptoms. We detected association with increased risk of IBS for 4 rare loss-of-function variants typically found in (homozygous) CSID patients, because carriers (heterozygous) of these rare variants were more common in patients than in controls.1,4 Through a 2-step computational and experimental strategy, the present study aimed to determine whether other (dys-)functional SI variants are associated with risk of IBS in addition to known CSID mutations. We first aimed to identify all SI rare pathogenic variants (SI-RPVs) on the basis of integrated Mendelian Clinically Applicable Pathogenicity (M-CAP) and Combined Annotation Dependent Depletion (CADD) predictive (clinically relevant) scores; next, we inspected genotype data currently available for 2207 IBS patients from a large ongoing project to compare SI-RPV case frequencies with ethnically matched population frequencies from the Exome Aggregation Consortium (ExAC).

Relationships among Dietary Intakes and Persistent Gastrointestinal Symptoms in Patients Receiving Enzyme Treatment for Genetic Sucrase-Isomaltase Deficiency.

BACKGROUND: Sucrose-isomaltase deficiency (SID) remains underdiagnosed. Absent or reduced enzyme activity promotes diarrhea, abdominal bloating, and flatulence from undigested and malabsorbed disaccharides. Frequency and severity of gastrointestinal symptoms may be associated with the type of carbohydrates consumed. OBJECTIVE: To characterize the dietary intakes of patients treated with sacrosidase (Sucraid; QOL Medical) for SID and determine relationships between type of carbohydrates, sacrosidase dose, and gastrointestinal symptoms. DESIGN: A prospective 30-day observational study. PARTICIPANTS/SETTING: Forty-nine patients treated with sacrosidase for ≥3 months were recruited from the enzyme manufacturer's nationwide clinical database between November 2014 and August 2015. MAIN OUTCOME MEASURES: Dietary energy and nutrient intakes reported during 24-hour diet recall interviews, frequency and severity of gastrointestinal (GI) symptoms, and sacrosidase dose. STATISTICAL ANALYSES PERFORMED: Relationships between nutrient intakes, sacrosidase dose, and GI symptoms were evaluated using Spearman ρ correlation coefficients. RESULTS: Sacrosidase dose averaged 5.2±3.1 mL/day. Participants reported 1.3±0.9 bowel movements daily. Having less frequent GI symptoms was associated with higher sacrosidase intake. Energy intakes averaged 1,562.5±411.5 kcal/day in children, 1,964.7±823.6 kcal/day in adolescents, and 1,952.6±546.5 kcal/day in adults. Macronutrient composition averaged 44% carbohydrate, 39% fat, and 17% protein. Average carbohydrate composition was 35% starch, 8% fiber, and 59% sugars. Sucrose and fructose intakes were not associated with GI symptoms. Lactose intake was associated with diarrhea. Maltose intake was associated with nausea, distension, and reflux. CONCLUSIONS: Intakes were lower in carbohydrates and higher in fat compared with the Acceptable Macronutrient Distribution Ranges. Sucrose and fructose intakes were not associated with GI symptoms. Higher maltose and lactose intakes were associated with GI symptom frequency and severity. These findings provide evidence to guide nutrition counseling for patients treated for SID.

Functional variants in the sucrase-isomaltase gene associate with increased risk of irritable bowel syndrome.

OBJECTIVE: IBS is a common gut disorder of uncertain pathogenesis. Among other factors, genetics and certain foods are proposed to contribute. Congenital sucrase-isomaltase deficiency (CSID) is a rare genetic form of disaccharide malabsorption characterised by diarrhoea, abdominal pain and bloating, which are features common to IBS. We tested sucrase-isomaltase (SI) gene variants for their potential relevance in IBS. DESIGN: We sequenced SI exons in seven familial cases, and screened four CSID mutations (p.Val557Gly, p.Gly1073Asp, p.Arg1124Ter and p.Phe1745Cys) and a common SI coding polymorphism (p.Val15Phe) in a multicentre cohort of 1887 cases and controls. We studied the effect of the 15Val to 15Phe substitution on SI function in vitro. We analysed p.Val15Phe genotype in relation to IBS status, stool frequency and faecal microbiota composition in 250 individuals from the general population. RESULTS: CSID mutations were more common in patients than asymptomatic controls (p=0.074; OR=1.84) and Exome Aggregation Consortium reference sequenced individuals (p=0.020; OR=1.57). 15Phe was detected in 6/7 sequenced familial cases, and increased IBS risk in case-control and population-based cohorts, with best evidence for diarrhoea phenotypes (combined p=0.00012; OR=1.36). In the population-based sample, 15Phe allele dosage correlated with stool frequency (p=0.026) and Parabacteroides faecal microbiota abundance (p=0.0024). The SI protein with 15Phe exhibited 35% reduced enzymatic activity in vitro compared with 15Val (p<0.05). CONCLUSIONS: SI gene variants coding for disaccharidases with defective or reduced enzymatic activity predispose to IBS. This may help the identification of individuals at risk, and contribute to personalising treatment options in a subset of patients.