83 results on '"congenital sucrase-isomaltase deficiency"'
Search Results
2. Healthcare Burden in Greenland of Gastrointestinal Symptoms in Adults with Inherited Loss of Sucrase-Isomaltase Function
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Andersen K, Hansen T, Jørgensen ME, and Senftleber N
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inuit ,genetic metabolism ,sucrase-isomaltase ,greenland ,congenital sucrase-isomaltase deficiency ,loss-of-function variant ,Medicine (General) ,R5-920 ,Genetics ,QH426-470 - Abstract
Kristine Andersen,1,2 Torben Hansen,3 Marit Eika Jørgensen,2,4,5 Ninna Senftleber2,4 1Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; 2Steno Diabetes Center Greenland, Nuuk, Greenland; 3Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; 4Clinical Research, Copenhagen University Hospital – Steno Diabetes Center Copenhagen, Herlev, Denmark; 5Centre for Public Health in Greenland, National Institute of Public Health, University of Southern Denmark, Odense, DenmarkCorrespondence: Kristine Andersen, Tel +45 23 61 74 11, Email Kristine.95@hotmail.comBackground: Congenital sucrase isomaltase deficiency (CSID) is in general a very rare disease. However, 2– 3% of the Greenlandic population are homozygous (HO) carriers of an Arctic-specific loss-of-function (LoF) variant in the sucrase-isomaltase (SI) encoding gene, causing CSID. The condition is characterized by gastrointestinal symptoms such as stomachache, diarrhea, and weight loss when consuming sucrose, the most common dietary sugar. However, the awareness of the condition in the population and the healthcare system seems to be limited, potentially leading to a higher healthcare burden. Hence, we aimed to investigate whether HO-carriers visit the healthcare system more with gastrointestinal symptoms compared to the control groups by using registry data.Methods: We performed a case–control study identifying cases and controls using genotype information from the 1999– 2001 and 2005– 2010 Greenlandic health population cohorts. The cases were defined as HO LoF SI-carriers and controls were defined as non-carriers and were matched (1:1) on sex, age, place of residence, and European genetic admixture. We used electronic medical records to assess the number of electronic medical record contacts (EMRc) related to gastrointestinal symptoms and the number of gastrointestinal-related diagnostic procedures.Results: A total of 80 HO-carriers and 80 non-carriers were included. The HO-carriers had 19% more EMRc related to gastrointestinal symptoms (IRR, 1.19, 95% CI [1.02;1.40], p=0.02) and had a 41% higher incidence of gastrointestinal related diagnostic procedures compared to controls (IRR, 1.41, 95% CI [1.05– 1.92], p=0.02). Only one HO-carrier was aware of the condition according to the electronic medical records.Conclusion: HO-carriers of the LoF SI-variant had both significantly more gastrointestinal-related EMRc and significantly more diagnostic procedures conducted due to gastrointestinal symptoms. Only one HO-carrier was aware of the condition. Given the high prevalence of HO-carriers in the Greenlandic population, we anticipate that diagnosing more patients with CSID and providing dietary advice could potentially reduce symptom burden and healthcare visits among HO-carriers.Keywords: Inuit, genetic metabolism, sucrase-isomaltase, Greenland, congenital sucrase-isomaltase deficiency, loss-of-function variant more...
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- 2024
Catalog
3. The effect of sucrase-isomaltase deficiency on metabolism, food intake and preferences: protocol for a dietary intervention study.
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Senftleber, Ninna Karsbæk, Skøtt Pedersen, Kristine, Schnoor Jørgensen, Cecilie, Pedersen, Hanne, Bjerg Christensen, Marie Mathilde, Kabel Madsen, Emilie, Andersen, Kristine, Jørsboe, Emil, Gillum, Matthew Paul, Frøst, Michael Bom, Hansen, Torben, and Jørgensen, Marit Eika more...
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FOOD preferences ,FOOD consumption ,WESTERN diet ,METABOLISM ,CROSSOVER trials ,TASTE testing of food - Abstract
In Greenland, traditional marine foods are increasingly being replaced by sucrose- and starch-rich foods. A knock-out c.273_274delAG variant in the sucrase-isomaltase (SI) gene is relatively common in Greenland, with homozygous carriers being unable to digest sucrose and some starch. The variant is associated with a healthier metabolic phenotype in Greenlanders, which is confirmed by SI-knockout mice. We aim to assess if the healthy phenotype is explained by metabolic and microbial differences and if food and taste preferences differ between SI-genotypes. This paper describes the protocol for a randomised cross-over trial conducted in Greenland in 2022 with two dietary interventions of three days; a traditional meat- and fish-rich diet and a starch-rich Western diet with 11 energy% sucrose. The power calculation showed that 22 homozygous SI-carriers and 22 non-carriers were sufficient to detect a 0.5 mmol/L difference in glycaemic variability (80% power, α=0.05). We enrolled 18 carriers and 20 non-carriers. We examined food preferences at baseline and collected samples before and after each intervention for metabolic, metabolome, and microbiome profiling. Analyses of samples have not been completed yet. The Ethics Committee of Greenland approved the study. Results will be disseminated in international peer-reviewed journals and to the general Greenlandic population. NCT05375656. [ABSTRACT FROM AUTHOR] more...
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- 2023
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4. Genetic Loss of Sucrase-Isomaltase Function: Mechanisms, Implications, and Future Perspectives
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Senftleber NK, Ramne S, Moltke I, Jørgensen ME, Albrechtsen A, Hansen T, and Andersen MK
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sucrase-isomaltase ,congenital sucrase-isomaltase deficiency ,loss-of-function variants ,cardiometabolic health ,sucrose ,greenland ,inuit ,Medicine (General) ,R5-920 ,Genetics ,QH426-470 - Abstract
Ninna Karsbæk Senftleber,1,* Stina Ramne,2,* Ida Moltke,3 Marit Eika Jørgensen,1,4,5 Anders Albrechtsen,3 Torben Hansen,2 Mette K Andersen2 1Clinical Research, Copenhagen University Hospital – Steno Diabetes Center Copenhagen, Herlev, Denmark; 2Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; 3Section for Computational and RNA Biology, Department of Biology, University of Copenhagen, Copenhagen, Denmark; 4Centre for Public Health in Greenland, National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark; 5Steno Diabetes Center Greenland, Nuuk, Greenland*These authors contributed equally to this workCorrespondence: Mette K Andersen, University of Copenhagen, Blegdamsvej 3B, Mærsk Tårnet, 8. sal, 2200 København N., Copenhagen, Denmark, Tel +45 35325282, Email metteandersen@sund.ku.dkAbstract: Genetic variants causing loss of sucrase-isomaltase (SI) function result in malabsorption of sucrose and starch components and the condition congenital sucrase-isomaltase deficiency (CSID). The identified genetic variants causing CSID are very rare in all surveyed populations around the globe, except the Arctic-specific c.273_274delAG loss-of-function (LoF) variant, which is common in the Greenlandic Inuit and other Arctic populations. In these populations, it is, therefore, possible to study people with loss of SI function in an unbiased way to elucidate the physiological function of SI, and investigate both short-term and long-term health effects of reduced small intestinal digestion of sucrose and starch. Importantly, a recent study of the LoF variant in Greenlanders reported that adult homozygous carriers have a markedly healthier metabolic profile. These findings indicate that SI inhibition could potentially improve metabolic health also in individuals not carrying the LoF variant, which is of great interest considering the massive number of individuals with obesity and type 2 diabetes worldwide. Therefore, the objectives of this review, are 1) to describe the biological role of SI, 2) to describe the metabolic impact of the Arctic SI LoF variant, 3) to reflect on potential mechanisms linking reduced SI function to metabolic health, and 4) to discuss what knowledge is necessary to properly evaluate whether SI inhibition is a potential therapeutic target for improving cardiometabolic health.Keywords: sucrase-isomaltase, congenital sucrase-isomaltase deficiency, loss-of-function variants, cardiometabolic health, sucrose, Greenland, Inuit more...
- Published
- 2023
5. The effect of sucrase-isomaltase deficiency on metabolism, food intake and preferences: protocol for a dietary intervention study
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Ninna Karsbæk Senftleber, Kristine Skøtt Pedersen, Cecilie Schnoor Jørgensen, Hanne Pedersen, Marie Mathilde Bjerg Christensen, Emilie Kabel Madsen, Kristine Andersen, Emil Jørsboe, Matthew Paul Gillum, Michael Bom Frøst, Torben Hansen, and Marit Eika Jørgensen more...
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Congenital sucrase-isomaltase deficiency ,inuit diet ,food preferences ,dietary intervention ,metabolism ,microbiota ,Arctic medicine. Tropical medicine ,RC955-962 - Abstract
ABSTRACTIn Greenland, traditional marine foods are increasingly being replaced by sucrose- and starch-rich foods. A knock-out c.273_274delAG variant in the sucrase-isomaltase (SI) gene is relatively common in Greenland, with homozygous carriers being unable to digest sucrose and some starch. The variant is associated with a healthier metabolic phenotype in Greenlanders, which is confirmed by SI-knockout mice. We aim to assess if the healthy phenotype is explained by metabolic and microbial differences and if food and taste preferences differ between SI-genotypes. This paper describes the protocol for a randomised cross-over trial conducted in Greenland in 2022 with two dietary interventions of three days; a traditional meat- and fish-rich diet and a starch-rich Western diet with 11 energy% sucrose. The power calculation showed that 22 homozygous SI-carriers and 22 non-carriers were sufficient to detect a 0.5 mmol/L difference in glycaemic variability (80% power, α=0.05). We enrolled 18 carriers and 20 non-carriers. We examined food preferences at baseline and collected samples before and after each intervention for metabolic, metabolome, and microbiome profiling. Analyses of samples have not been completed yet. The Ethics Committee of Greenland approved the study. Results will be disseminated in international peer-reviewed journals and to the general Greenlandic population. NCT05375656. more...
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- 2023
- Full Text
- View/download PDF
6. Nutritional and Physiological Constraints Contributing to Limitations in Small Intestinal Starch Digestion and Glucose Absorption in Ruminants.
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Trotta, Ronald J., Harmon, David L., Matthews, James C., and Swanson, Kendall C.
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SMALL intestine ,NUTRITION ,GLUCOSE ,RUMINANTS ,CARBOHYDRATES - Abstract
Increased efficiency of nutrient utilization can potentially be gained with increased starch digestion in the small intestine in ruminants. However, ruminants have quantitative limits in the extent of starch disappearance in the small intestine. The objective is to explore the nutritional and physiological constraints that contribute to limitations of carbohydrate assimilation in the ruminant small intestine. Altered digesta composition and passage rate in the small intestine, insufficient pancreatic α-amylase and/or small intestinal carbohydrase activity, and reduced glucose absorption could all be potentially limiting factors of intestinal starch assimilation. The absence of intestinal sucrase activity in ruminants may be related to quantitative limits in small intestinal starch hydrolysis. Multiple sequence alignment of the sucrase-isomaltase complex gives insight into potential molecular mechanisms that may be associated with the absence of intestinal sucrase activity, reduced capacity for intestinal starch digestion, and limitations in the efficiency of feed utilization in cattle and sheep. Future research efforts in these areas will aid in our understanding of small intestinal starch digestion and glucose absorption to optimize feeding strategies for increased meat and milk production efficiency. [ABSTRACT FROM AUTHOR] more...
- Published
- 2022
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7. The patient journey to diagnosis and treatment of congenital sucrase-isomaltase deficiency.
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Smith, Heather, Romero, Beverly, Flood, Emuella, and Boney, Anne
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- *
DIAGNOSIS , *BRUSH border membrane , *ADULTS , *QUALITY of life , *MEDICAL personnel - Abstract
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. [ABSTRACT FROM AUTHOR] more...
- Published
- 2021
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8. The effect of sucrase-isomaltase deficiency on metabolism, food intake and preferences:protocol for a dietary intervention study
- Author
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Senftleber, Ninna Karsbæk, Pedersen, Kristine Skøtt, Schnoor Jørgensen, Cecilie, Pedersen, Hanne, Bjerg Christensen, Marie Mathilde, Kabel Madsen, Emilie, Andersen, Kristine, Jørsboe, Emil, Gillum, Matthew Paul, Frøst, Michael Bom, Hansen, Torben, Jørgensen, Marit Eika, Senftleber, Ninna Karsbæk, Pedersen, Kristine Skøtt, Schnoor Jørgensen, Cecilie, Pedersen, Hanne, Bjerg Christensen, Marie Mathilde, Kabel Madsen, Emilie, Andersen, Kristine, Jørsboe, Emil, Gillum, Matthew Paul, Frøst, Michael Bom, Hansen, Torben, and Jørgensen, Marit Eika more...
- Published
- 2023
9. Genetic Loss of Sucrase-Isomaltase Function:Mechanisms, Implications, and Future Perspectives
- Author
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Senftleber, Ninna Karsbæk, Ramne, Stina, Moltke, Ida, Jørgensen, Marit Eika, Albrechtsen, Anders, Hansen, Torben, Andersen, Mette K., Senftleber, Ninna Karsbæk, Ramne, Stina, Moltke, Ida, Jørgensen, Marit Eika, Albrechtsen, Anders, Hansen, Torben, and Andersen, Mette K. more...
- Abstract
Genetic variants causing loss of sucrase-isomaltase (SI) function result in malabsorption of sucrose and starch components and the condition congenital sucrase-isomaltase deficiency (CSID). The identified genetic variants causing CSID are very rare in all surveyed populations around the globe, except the Arctic-specific c.273_274delAG loss-of-function (LoF) variant, which is common in the Greenlandic Inuit and other Arctic populations. In these populations, it is, therefore, possible to study people with loss of SI function in an unbiased way to elucidate the physiological function of SI, and investigate both short-term and long-term health effects of reduced small intestinal digestion of sucrose and starch. Importantly, a recent study of the LoF variant in Greenlanders reported that adult homozygous carriers have a markedly healthier metabolic profile. These findings indicate that SI inhibition could potentially improve metabolic health also in individuals not carrying the LoF variant, which is of great interest considering the massive number of individuals with obesity and type 2 diabetes worldwide. Therefore, the objectives of this review, are 1) to describe the biological role of SI, 2) to describe the metabolic impact of the Arctic SI LoF variant, 3) to reflect on potential mechanisms linking reduced SI function to metabolic health, and 4) to discuss what knowledge is necessary to properly evaluate whether SI inhibition is a potential therapeutic target for improving cardiometabolic health. more...
- Published
- 2023
10. Congenital sucrase–isomaltase deficiency: A case report
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Rita Santos-Silva, Marta Tavares, Eunice Trindade, and Jorge Amil-Dias
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Congenital sucrase–isomaltase deficiency ,Sacrosidase ,Baker's yeast ,Saccharomyces cerevisiae ,Diseases of the digestive system. Gastroenterology ,RC799-869 - Abstract
Background: Congenital sucrase–isomaltase deficiency (CSID) is an autosomal recessive disease characterized by absent sucrase activity with variable decrease in isomaltase activity. The prevalence of CSID in Portuguese population is unknown and there are few reported cases. Case report: We report the case of a six-month-old male infant admitted for chronic profuse diarrhea and failure to thrive that began after food diversification. The investigation showed that he had CSID. The therapeutic option was the addition of baker's yeast to the diet which was followed by complete resolution of symptoms and excellent weight recovery. Discussion: This case highlights the relevance of clinical observation and awareness in a condition where diagnosis is essentially clinical. The available therapeutic options are addressed with pragmatic use of baker's yeast. more...
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- 2014
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11. The glucose-regulated protein GRP94 interacts avidly in the endoplasmic reticulum with sucrase-isomaltase isoforms that are associated with congenital sucrase-isomaltase deficiency
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Hassan Y. Naim and Abdullah Hoter
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Gene isoform ,Protein Folding ,Camelus ,Mutant ,Congenital Sucrase-Isomaltase Deficiency ,Endoplasmic Reticulum ,Biochemistry ,Bacterial Proteins ,Structural Biology ,Chlorocebus aethiops ,Enzyme Stability ,Intestine, Small ,Animals ,Humans ,Molecular Biology ,Membrane Glycoproteins ,biology ,Chemistry ,Endoplasmic reticulum ,Wild type ,alpha-Glucosidases ,General Medicine ,Cell Hypoxia ,Sucrase-Isomaltase Complex ,Cell biology ,Chaperone (protein) ,COS Cells ,Mutation ,Unfolded protein response ,biology.protein ,Sucrase-isomaltase ,Carbohydrate Metabolism, Inborn Errors ,Protein Binding - Abstract
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. more...
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- 2021
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12. Two Novel Mutations in the SI Gene Associated With Congenital Sucrase-Isomaltase Deficiency: A Case Report in China
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Huabo Cai, Xia Qian, Jianli Zhou, Yongwei Cheng, Yu-Zhen Zhao, Mo-Xian Chen, and Shaoming Zhou
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Genetics ,Sanger sequencing ,Mutation ,business.industry ,congenital ,Congenital Sucrase-Isomaltase Deficiency ,medicine.disease_cause ,Genome ,Pediatrics ,RJ1-570 ,sucrase-isomaltase deficiency ,symbols.namesake ,Pediatrics, Perinatology and Child Health ,Failure to thrive ,medicine ,symbols ,case report ,Inherited disease ,medicine.symptom ,mutation ,business ,gene ,Gene ,Exome sequencing - Abstract
Background: Congenital sucrase-isomaltase deficiency (CSID) is an autosomal recessive inherited disease that leads to the maldigestion of disaccharides and is associated with mutation of the sucrase-isomaltase (SI) gene. Cases of CSID are not very prevalent in China or worldwide but are gradually being identified and reported.Case Presentation: We report a case involving a 14-month-old male who presented with failure to thrive that had begun after food diversification and was admitted for chronic diarrhea. We used a whole-exome sequencing (WES) approach to identify mutations in this patient's genome. WES revealed two novel heterozygous mutations in the SI gene, c.2626C > T (p.Q876*) and c.2872C > T (p.R958C), which were confirmed by Sanger DNA sequencing. With a strict sucrose- and starch-restricted diet, the patient's diarrhea was resolved, and he began to gain weight.Conclusions: We report a case of novel variants in the SI gene that caused CSID. This report provides valuable information for the clinical field, especially in China. more...
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- 2021
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13. Molecular basis of heterozygosity in congenital sucrase‐isomaltase deficiency and functional gastrointestinal disorders
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Hassan Y. Naim, Sandra Rizk‐Jamati, and Diab M Husein
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Loss of heterozygosity ,medicine.medical_specialty ,Endocrinology ,Internal medicine ,Genetics ,medicine ,Congenital Sucrase-Isomaltase Deficiency ,Biology ,Molecular Biology ,Biochemistry ,Biotechnology - Published
- 2021
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14. Sucrase-Isomaltase Deficiency Causing Persistent Bloating and Diarrhea in an Adult Female
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Varsha Chiruvella, Jacqueline T Chan, Hafiz Muhammad Sharjeel Arshad, Ayesha Cheema, and John Erikson Yap
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medicine.medical_specialty ,030204 cardiovascular system & hematology ,Congenital Sucrase-Isomaltase Deficiency ,Gastroenterology ,sucrase-isomaltase ,03 medical and health sciences ,0302 clinical medicine ,Bloating ,Internal medicine ,Medicine ,disaccharidase assay ,medicine.diagnostic_test ,business.industry ,Endocrinology/Diabetes/Metabolism ,General Engineering ,medicine.disease ,Malnutrition ,Diarrhea ,starch intolerance ,ibs ,Failure to thrive ,Sacrosidase ,Sucrase-isomaltase ,medicine.symptom ,business ,Hydrogen breath test ,030217 neurology & neurosurgery ,hydrogen breath test ,medicine.drug - Abstract
Congenital sucrase isomaltase deficiency (CSID) is an autosomal recessive disorder which leads to chronic intestinal malabsorption of nutrients from ingested starch and sucrose. Symptoms usually present after consumption of fruits, juices, grains, and starches, leading to failure to thrive and malnutrition. Diagnosis is suspected on detailed patient history and confirmed by a disaccharidase assay using small intestinal biopsies or sucrose hydrogen breath test. Treatment of CSID consists of limiting sucrose in diet and replacement therapy with sacrosidase. Due to its nonspecific symptoms, CSID may be undiagnosed in many patients for several years. We present a case of a 50-year-old woman with persistent symptoms of bloating in spite of extensive evaluation and treatment. more...
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- 2021
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15. Differential Effects of Sucrase-Isomaltase Mutants on Its Trafficking and Function in Irritable Bowel Syndrome: Similarities to Congenital Sucrase-Isomaltase Deficiency
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Diab M. Husein, Sandra Rizk, and Hassan Y. Naim
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irritable bowel syndrome ,Communication ,congenital sucrase-isomaltase deficiency ,lcsh:TX341-641 ,Oligo-1,6-Glucosidase ,sucrase-isomaltase ,Sucrase-Isomaltase Complex ,Protein Transport ,Phenotype ,COS Cells ,Chlorocebus aethiops ,Mutation ,Animals ,protein trafficking ,lcsh:Nutrition. Foods and food supply ,Carbohydrate Metabolism, Inborn Errors - Abstract
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. more...
- Published
- 2020
16. Congenital Sucrase-Isomaltase Deficiency
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Lang, Florian, editor
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- 2009
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17. Heterozygotes Are a Potential New Entity among Homozygotes and Compound Heterozygotes in Congenital Sucrase-Isomaltase Deficiency
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Husein, Diab M., Wanes, Dalanda, Marten, Lara M., Zimmer, Klaus-Peter, and Naim, Hassan Y.
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congenital sucrase-isomaltase deficiency ,lcsh:TX341-641 ,Concept Paper ,compound heterozygote ,heterozygote ,Sucrase-Isomaltase Complex ,Irritable Bowel Syndrome ,homozygote ,protein trafficking phenotypes ,Malabsorption Syndromes ,Mutation ,intestinal brush border membrane ,Humans ,Genetic Predisposition to Disease ,lcsh:Nutrition. Foods and food supply ,Carbohydrate Metabolism, Inborn Errors - Abstract
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 α-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. more...
- Published
- 2019
18. The multiple roles of sucrase-isomaltase in the intestinal physiology
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Gericke, Birthe, Amiri, Mahdi, and Naim, Hassan Y.
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- 2016
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19. Hypomorphic SI genetic variants are associated with childhood chronic loose stools
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Mauro D'Amato, Heather F. Smith, Joel A. Friedlander, Jeffery Lewis, Molly O'Gorman, Natalie A. Terry, Bruno P. Chumpitazi, Jaya Punati, Joel Lim, Ann O. Scheimann, Julie Khlevner, Derick Cooper, Yinka Davies, Neelesh A. Tipnis, Devendra Mehta, Adrian Miranda, Sandeep Gupta, Mala Setty, Carlo Di Lorenzo, and Calderaro, Adriana more...
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Male ,Heredity ,Databases, Factual ,Pathology and Laboratory Medicine ,Pediatrics ,Gastroenterology ,Oral and gastrointestinal ,Irritable Bowel Syndrome ,Database and Informatics Methods ,0302 clinical medicine ,Polymorphism (computer science) ,Genotype ,Medicine and Health Sciences ,Prevalence ,Prospective Studies ,Child ,Prospective cohort study ,Pediatric ,education.field_of_study ,Multidisciplinary ,Inborn Errors ,Single Nucleotide ,Genetic Mapping ,Diarrhea ,Carbohydrate Metabolism ,Medicine ,Population study ,Female ,030211 gastroenterology & hepatology ,Anatomy ,medicine.symptom ,Sequence Analysis ,Research Article ,Carbohydrate Metabolism, Inborn Errors ,Genotyping ,Heterozygote ,medicine.medical_specialty ,Adolescent ,Bioinformatics ,General Science & Technology ,Science ,Population ,Sequence Databases ,Variant Genotypes ,Gastroenterology and Hepatology ,Congenital Sucrase-Isomaltase Deficiency ,Research and Analysis Methods ,Polymorphism, Single Nucleotide ,Databases ,03 medical and health sciences ,Signs and Symptoms ,Diagnostic Medicine ,Clinical Research ,030225 pediatrics ,Internal medicine ,Genetics ,medicine ,Humans ,Polymorphism ,Molecular Biology Techniques ,education ,Molecular Biology ,Factual ,business.industry ,Biology and Life Sciences ,Sucrase-Isomaltase Complex ,Brain Disorders ,Gastrointestinal Tract ,Biological Databases ,Digestive Diseases ,Flatulence ,business ,Digestive System - Abstract
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. more...
- Published
- 2020
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20. (13)C-Labeled-Starch Breath Test in Congenital Sucrase-Isomaltase Deficiency
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Buford L. Nichols, Susan S. Baker, Claudia C. Robayo-Torres, Antone R. Opekun, Bruno P. Chumpitazi, Bruce R. Hamaker, and Marisela Diaz-Sotomayor
- Subjects
Male ,Adolescent ,Starch ,Duodenum ,Congenital Sucrase-Isomaltase Deficiency ,Carbohydrate metabolism ,Article ,Sucrase ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,030225 pediatrics ,medicine ,Humans ,Child ,Breath test ,chemistry.chemical_classification ,Carbon Isotopes ,medicine.diagnostic_test ,business.industry ,Gastroenterology ,Infant ,Sucrase-Isomaltase Complex ,Enzyme ,chemistry ,Biochemistry ,Breath Tests ,Case-Control Studies ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,030211 gastroenterology & hepatology ,Digestion ,Female ,Maltase ,business ,Isomaltase ,Carbohydrate Metabolism, Inborn Errors - Abstract
BACKGROUND: Human starch digestion is a multi-enzyme process involving six 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). HYPOTHESES: Poor starch digestion occurs in individuals with CSID and can be documented using a noninvasive 13C-breath test (BT). METHODS: 13C-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 13C-sucrose BT. Breath 13CO2 was quantitated at intervals before and after serial 13C-substrate loads (glucose followed 75 minutes later by starch). Variations in metabolism were normalized against 13C-glucose BT (Coefficient of glucose absorption, CGO). 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 13C-starch digestion mirroring that of their duodenal sucrase and maltase activity and 13C-sucrase BT. CONCLUSION: In children with CSID, starch digestion may be impaired. In children with CSID, starch digestion correlates well with measures of sucrase activity. more...
- Published
- 2018
21. Increased Prevalence of Rare Sucrase-isomaltase Pathogenic Variants in Irritable Bowel Syndrome Patients
- Author
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Koldo Garcia-Etxebarria, Susanna Walter, Peter T. Schmidt, Mauro D'Amato, William D. Chey, Paolo Usai-Satta, Shanti Eswaran, Francesca Galeazzi, Magnus Simren, Guy E. Boeckxstaens, Matteo Neri, Emeran A. Mayer, Rosario Cuomo, Piero Portincasa, Daisy Jonkers, Aldona Dlugosz, Mira M. Wouters, Ferdinando Bonfiglio, Purna C. Kashyap, Michael Camilleri, Lin Chang, Greger Lindberg, Gerardo Nardone, Massimo Bellini, Bodil Ohlsson, Pontus Karling, Andre Franke, Tenghao Zheng, Luis Bujanda, Giovanni Barbara, Garcia-Etxebarria, Koldo, Zheng, Tenghao, Bonfiglio, Ferdinando, Bujanda, Lui, Dlugosz, Aldona, Lindberg, Greger, Schmidt, Peter T, Karling, Pontu, Ohlsson, Bodil, Simren, Magnu, Walter, Susanna, Nardone, Gerardo, Cuomo, Rosario, Usai-Satta, Paolo, Galeazzi, Francesca, Neri, Matteo, Portincasa, Piero, Bellini, Massimo, Barbara, Giovanni, Jonkers, Daisy, Eswaran, Shanti, Chey, William D, Kashyap, Purna, Chang, Lin, Mayer, Emeran A, Wouters, Mira M, Boeckxstaens, Guy, Camilleri, Michael, Franke, Andre, D'Amato, Mauro, Interne Geneeskunde, and RS: NUTRIM - R2 - Liver and digestive health more...
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Genotype ,Population ,Clinical Sciences ,Gastroenterology and Hepatology ,Congenital Sucrase-Isomaltase Deficiency ,Gastroenterology ,Hepatology ,Article ,Irritable Bowel Syndrome ,03 medical and health sciences ,symbols.namesake ,0302 clinical medicine ,Gene Frequency ,Internal medicine ,Gastroenterologi ,Prevalence ,Medicine ,Humans ,education ,Exome ,Allele frequency ,Irritable bowel syndrome ,education.field_of_study ,030109 nutrition & dietetics ,Science & Technology ,Gastroenterology & Hepatology ,business.industry ,medicine.disease ,Sucrase-Isomaltase Complex ,Mendelian inheritance ,symbols ,030211 gastroenterology & hepatology ,NA ,Sucrase-isomaltase ,business ,Life Sciences & Biomedicine - Abstract
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). ispartof: CLINICAL GASTROENTEROLOGY AND HEPATOLOGY vol:16 issue:10 pages:1673-1676 ispartof: location:United States status: published more...
- Published
- 2018
22. Congenital Sucrase-isomaltase Deficiency: A Novel Compound Heterozygous Mutation Causing Aberrant Protein Localization
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Batia Weiss, Ortal Barel, Michael Schvimer, Brigitte Kochavi, Camila Avivi, Yael Haberman, Iris Barshack, Yair Anikster, Gideon Rechavi, Vered Kunik, Ayelet Di Segni, Nurit Loberman-Nachum, Nitzan Kol, Goni Hout-Siloni, and Eran Eyal more...
- Subjects
0301 basic medicine ,Genetic Markers ,Male ,Heterozygote ,Congenital Sucrase-Isomaltase Deficiency ,Compound heterozygosity ,medicine.disease_cause ,Article ,Sucrase-isomaltase complex ,03 medical and health sciences ,Exome Sequencing ,Medicine ,Humans ,Exome sequencing ,Genetics ,Mutation ,business.industry ,Gastroenterology ,Infant ,Heterozygote advantage ,Sucrase-Isomaltase Complex ,030104 developmental biology ,Parenteral nutrition ,Pediatrics, Perinatology and Child Health ,Female ,Sucrase-isomaltase ,business ,Carbohydrate Metabolism, Inborn Errors - Abstract
OBJECTIVES: Congenital diarrheal disorders is a group of inherited enteropathies presenting in early life and requiring parenteral nutrition. In most cases, genetics may be the key for precise diagnosis. We present an infant girl with chronic congenital diarrhea that resolved after introduction of fructose-based formula but had no identified mutation in the SLC5A1 gene. Using whole exome sequencing (WES) we identified other mutations that better dictated dietary adjustments. METHODS: WES of the patient and her parents was performed. The analysis focused on recessive model including compound heterozygous mutations. Sanger sequencing was used to validate identified mutations and to screen the patient’s newborn sister and grandparents. Expression and localization analysis were performed in the patient’s duodenal biopsies using immunohistochemistry. RESULTS: Using WES we identified a new compound heterozygote mutation in sucrase-isomaltase (SI) gene; a maternal inherited known V577G mutation, and a novel paternal inherited C1531W mutation. Importantly, the newborn offspring carried similar compound heterozygous mutations. Computational predictions suggest that both mutations highly destabilize the protein. SI expression and localization studies determined that the mutated SI protein was not expressed on the brush border membrane in the patient’s duodenal biopsies, verifying the diagnosis of congenital sucrase-isomaltase deficiency (CSID). CONCLUSIONS: The novel compound heterozygote V577G/C1531W SI mutations lead to lack of SI expression in the duodenal brush border, confirming the diagnosis of CSID. These cases of CSID extend the molecular spectrum of this condition, further directing a more adequate dietary intervention for the patient and newborn sibling. more...
- Published
- 2017
23. Congenital sucrase–isomaltase deficiency: identification of a common Inuit founder mutation
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Kheirie Issa, Margaret Boland, Michael T. Geraghty, C. Ronald Scott, Zaining Wu, Adam D. McIntyre, Robert A. Hegele, Matthew A. Lines, and Julien L. Marcadier
- Subjects
Proband ,medicine.medical_specialty ,Pediatrics ,Malabsorption ,Research ,General Medicine ,Biology ,Congenital Sucrase-Isomaltase Deficiency ,medicine.disease ,Frameshift mutation ,Sucrase-isomaltase complex ,Endocrinology ,Internal medicine ,Failure to thrive ,medicine ,medicine.symptom ,Allele frequency ,Founder effect - Abstract
Background Congenital sucrase-isomaltase deficiency is a rare hereditary cause of chronic diarrhea in children. People with this condition lack the intestinal brush-border enzyme required for digestion of di- and oligosaccharides, including sucrose and isomaltose, leading to malabsorption. Although the condition is known to be highly prevalent (about 5%-10%) in several Inuit populations, the genetic basis for this has not been described. We sought to identify a common mutation for congenital sucrase-isomaltase deficiency in the Inuit population. Methods We sequenced the sucrase-isomaltase gene, SI, in a single Inuit proband with congenital sucrase-isomaltase deficiency who had severe fermentative diarrhea and failure to thrive. We then genotyped a further 128 anonymized Inuit controls from a variety of locales in the Canadian Arctic to assess for a possible founder effect. Results In the proband, we identified a novel, homozygous frameshift mutation, c.273_274delAG (p.Gly92Leufs*8), predicted to result in complete absence of a functional protein product. This change was very common among the Inuit controls, with an observed allele frequency of 17.2% (95% confidence interval [CI] 12.6%-21.8%). The predicted Hardy-Weinberg prevalence of congenital sucrase-isomaltase deficiency in Inuit people, based on this single founder allele, is 3.0% (95% CI 1.4%-4.5%), which is comparable with previous estimates. Interpretation We found a common mutation, SI c.273_274delAG, to be responsible for the high prevalence of congenital sucrase-isomaltase deficiency among Inuit people. Targeted mutation testing for this allele should afford a simple and minimally invasive means of diagnosing this condition in Inuit patients with chronic diarrhea. more...
- Published
- 2014
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24. Differential Effects of Sucrase-Isomaltase Mutants on Its Trafficking and Function in Irritable Bowel Syndrome: Similarities to Congenital Sucrase-Isomaltase Deficiency.
- Author
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Husein, Diab M., Rizk, Sandra, and Naim, Hassan Y.
- Abstract
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. [ABSTRACT FROM AUTHOR] more...
- Published
- 2021
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25. Congenital sucrase–isomaltase deficiency: diagnostic challenges and response to enzyme replacement therapy
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J W L Puntis and V Zamvar
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Diarrhea ,Male ,Sucrose ,medicine.medical_specialty ,Abdominal pain ,Congenital Sucrase-Isomaltase Deficiency ,Gastroenterology ,Feces ,Bloating ,Internal medicine ,medicine ,Humans ,Enzyme Replacement Therapy ,Adverse effect ,beta-Fructofuranosidase ,business.industry ,Dietary management ,Infant ,Enzyme replacement therapy ,Sucrase-Isomaltase Complex ,Surgery ,Treatment Outcome ,Child, Preschool ,Diarrhea, Infantile ,Pediatrics, Perinatology and Child Health ,Female ,Sacrosidase ,medicine.symptom ,business ,Carbohydrate Metabolism, Inborn Errors ,Follow-Up Studies ,medicine.drug - Abstract
Congenital sucrase–isomaltase (SI) deficiency is a rare genetic condition characterised by a deficiency in the brush-border SI enzyme, resulting in an inability to metabolise sucrose and starches. Six cases of congenital SI deficiency treated with Sucraid (sacrosidase, a yeast-derived enzyme that facilitates sucrose digestion) are described. Typical presenting symptoms were watery diarrhoea, abdominal pain and bloating, sometimes noticeably worse after ingestion of fruit. Diagnosis is challenging since conventional hydrogen breath testing after an oral sucrose load is impractical in young children, and many laboratories no longer look for maldigested sucrose using faecal sugar chromatography. Confirmation is by disaccharidase assay of duodenal or jejunal mucosa obtained endoscopically. All six patients showed little improvement following advice regarding dietary management, but experienced a marked reduction in symptoms with sacrosidase administration; no adverse events were reported. Sacrosidase is an effective and well-tolerated treatment for patients with congenital SI deficiency. Gene testing and clinical trial of sacrosidase may become an alternative to endoscopic biopsies for diagnosis. more...
- Published
- 2015
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26. Molecular pathogenicity of novel sucrase-isomaltase mutations found in congenital sucrase-isomaltase deficiency patients
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C. Ronald Scott, Birthe Gericke, Hassan Y. Naim, and Mahdi Amiri
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0301 basic medicine ,Mutant ,Biology ,Congenital Sucrase-Isomaltase Deficiency ,03 medical and health sciences ,0302 clinical medicine ,Chlorocebus aethiops ,medicine ,Animals ,Humans ,Amino Acid Sequence ,Molecular Biology ,Gene ,Cellular localization ,Genetics ,Genetic disorder ,Wild type ,medicine.disease ,Phenotype ,Molecular biology ,Sucrase-Isomaltase Complex ,Protein Transport ,030104 developmental biology ,COS Cells ,Mutation ,Molecular Medicine ,030211 gastroenterology & hepatology ,Sucrase-isomaltase ,Carbohydrate Metabolism, Inborn Errors - Abstract
Background & aims Congenital sucrase-isomaltase deficiency (CSID) is a genetic disorder associated with mutations in the sucrase-isomaltase ( SI ) gene. The diagnosis of congenital diarrheal disorders like CSID is difficult due to unspecific symptoms and usually requires invasive biopsy sampling of the intestine. Sequencing of the SI gene and molecular analysis of the resulting potentially pathogenic SI protein variants may facilitate a diagnosis in the future. This study aimed to categorize SI mutations based on their functional consequences. Methods cDNAs encoding 13 SI mutants were expressed in COS-1 cells. The molecular pathogenicity of the resulting SI mutants was defined by analyzing their biosynthesis, cellular localization, structure and enzymatic functions. Results Three biosynthetic phenotypes for the novel SI mutations were identified. The first biosynthetic phenotype was defined by mutants that are intracellularly transported in a fashion similar to wild type SI and with normal, but varying, levels of enzymatic activity. The second biosynthetic phenotype was defined by mutants with delayed maturation and trafficking kinetics and reduced activity. The third group of mutants is entirely transport incompetent and functionally inactive. Conclusions The current study unraveled CSID as a multifaceted malabsorption disorder that comprises three major classes of functional and trafficking mutants of SI and established a gradient of mild to severe functional deficits in the enzymatic functions of the enzyme. General significance This novel concept and the existence of mild consequences in a number of SI mutants strongly propose that CSID is an underdiagnosed and a more common intestinal disease than currently known. more...
- Published
- 2016
27. Clinical Aspects and Treatment of Congenital Sucrase-Isomaltase Deficiency
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William R. Treem
- Subjects
Sucrose ,Sucrose metabolism ,medicine.medical_specialty ,business.industry ,Starch metabolism ,Gastroenterology ,Starch ,Congenital Sucrase-Isomaltase Deficiency ,Carbohydrate metabolism ,Sucrase-Isomaltase Complex ,Endocrinology ,Internal medicine ,Pediatrics, Perinatology and Child Health ,Dietary Carbohydrates ,Prevalence ,Humans ,Medicine ,business ,Carbohydrate Metabolism, Inborn Errors - Published
- 2012
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28. 50 Years of Progress Since Congenital Sucrase-Isomaltase Deficiency Recognition
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Buford L. Nichols and Salvatore Auricchio
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Adult ,Diarrhea ,business.industry ,Starch metabolism ,Gastroenterology ,Infant ,Physiology ,Starch ,Carbohydrate metabolism ,Congenital Sucrase-Isomaltase Deficiency ,Sucrase-Isomaltase Complex ,Mice ,Pediatrics, Perinatology and Child Health ,Dietary Carbohydrates ,Animals ,Humans ,Medicine ,Inborn errors metabolism ,business ,Carbohydrate Metabolism, Inborn Errors - Published
- 2012
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29. Congenital Sucrase-Isomaltase Deficiency
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Hassan Y. Naim, Martin Heine, and Klaus-Peter Zimmer
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Sucrose ,medicine.medical_specialty ,Starch metabolism ,Congenital Sucrase-Isomaltase Deficiency ,medicine.disease_cause ,Internal medicine ,Dietary Carbohydrates ,medicine ,Humans ,Intestinal Mucosa ,Genetics ,Mutation ,Sucrose metabolism ,Intestinal enzymes ,business.industry ,Gastroenterology ,Inheritance (genetic algorithm) ,Starch ,Sucrase-Isomaltase Complex ,Endocrinology ,Pediatrics, Perinatology and Child Health ,Inborn errors metabolism ,business ,Function (biology) ,Carbohydrate Metabolism, Inborn Errors - Published
- 2012
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30. Differential Effects of Sucrase-Isomaltase Mutants on Its Trafficking and Function in Irritable Bowel Syndrome: Similarities to Congenital Sucrase-Isomaltase Deficiency.
- Author
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Husein DM, Rizk S, and Naim HY
- Subjects
- Animals, COS Cells, Chlorocebus aethiops, Oligo-1,6-Glucosidase genetics, Oligo-1,6-Glucosidase metabolism, Phenotype, Sucrase-Isomaltase Complex genetics, Sucrase-Isomaltase Complex metabolism, Carbohydrate Metabolism, Inborn Errors genetics, Carbohydrate Metabolism, Inborn Errors metabolism, Irritable Bowel Syndrome genetics, Irritable Bowel Syndrome metabolism, Mutation, Protein Transport, Sucrase-Isomaltase Complex deficiency
- Abstract
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. more...
- Published
- 2020
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31. Compound Heterozygous Mutations Affect Protein Folding and Function in Patients With Congenital Sucrase-Isomaltase Deficiency
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Klaus Peter Zimmer, Markus Keiser, Marwan Alfalah, Tosso Leeb, and Hassan Y. Naim
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Protein Folding ,Sucrose ,Congenital Sucrase-Isomaltase Deficiency ,Biology ,Transfection ,Compound heterozygosity ,Gene Expression Regulation, Enzymologic ,Sucrase-isomaltase complex ,Sucrase ,Genetic Heterogeneity ,Chlorocebus aethiops ,Animals ,Humans ,Point Mutation ,Amino Acid Sequence ,Hepatology ,Point mutation ,Gastroenterology ,Apical membrane ,Molecular biology ,Protein Structure, Tertiary ,Sucrase-Isomaltase Complex ,Enzyme Activation ,Protein Transport ,COS Cells ,Mutagenesis, Site-Directed ,Sucrase-isomaltase ,Isomaltase ,Carbohydrate Metabolism, Inborn Errors - Abstract
BACKGROUND & AIMS: Congenital sucrase-isomaltase (SI) deficiency is an autosomal-recessive intestinal disorder characterized by a drastic reduction or absence of sucrase and isomaltase activities. Previous studies have indicated that single mutations underlie individual phenotypes of the disease. We investigated whether compound heterozygous mutations, observed in some patients, have a role in disease pathogenesis. METHODS: We introduced mutations into the SI complementary DNA that resulted in the amino acid substitutions V577G and G1073D (heterozygous mutations found in one group of patients) or C1229Y and F1745C (heterozygous mutations found in another group). The mutant genes were expressed transiently, alone or in combination, in COS cells and the effects were assessed at the protein, structural, and subcellular levels. RESULTS: The mutants SI-V577G, SI-G1073D, and SI-F1745C were misfolded and could not exit the endoplasmic reticulum, whereas SI-C1229Y was transported only to the Golgi apparatus. Co-expression of mutants found on each SI allele in patients did not alter the protein's biosynthetic features or improve its enzymatic activity. Importantly, the mutations C1229Y and F1745C, which lie in the sucrase domains of SI, prevented its targeting to the cell's apical membrane but did not affect protein folding or isomaltase activity. CONCLUSIONS: Compound heterozygosity is a novel pathogenic mechanism of congenital SI deficiency. The effects of mutations in the sucrase domain of SIC1229Y and SIF1745C indicate the importance of a direct interaction between isomaltase and sucrose and the role of sucrose as an intermolecular chaperone in the intracellular transport of SI. more...
- Published
- 2009
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32. Sacrosidase Trial in Chronic Nonspecific Diarrhea in Children
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Warren P. Bishop and Riad Rahhal
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Pediatrics ,medicine.medical_specialty ,Malabsorption ,business.industry ,digestive, oral, and skin physiology ,Congenital Sucrase-Isomaltase Deficiency ,medicine.disease ,Sucrase ,Diarrhea ,Etiology ,Medicine ,Sacrosidase ,Sucrose intake ,Toddler ,medicine.symptom ,business ,medicine.drug - Abstract
Chronic nonspecific diarrhea in children, or toddler's diarrhea, is a frequently encountered entity in pediatric clinical practice. This disorder remains poorly understood. Suggested etiologies include malabsorption, dietary intake and motility abnormalities. We investigated the use of sacrosidase (a yeast sucrase supplement) in children with toddler's diar- rhea. The study outcome was clinical response to sacrosidase supplementation. Children, 1-6 years of age, with toddler's diarrhea were enrolled in an open prospective trial. Stooling patterns were obtained at baseline and while on supplementa- tion. Twelve patients were enrolled out of 40 patients who presented with chronic diarrhea. Eight patients did not respond to standard diet changes and were entered into the trial. With supplementation, 4 out of the 8 patients responded clinically with a decrease in mean daily stool frequency and an improvement in the mean daily stool consistency. Sacrosidase sup- plementation demonstrated a potential benefit in a subset of children with toddler's diarrhea. Response to sacrosidase may suggest excessive sucrose intake or unrecognized partial or complete sucrase deficiency in some children with toddler's diarrhea. more...
- Published
- 2008
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33. Congenital sucrase-isomaltase deficiency because of an accumulation of the mutant enzyme in the endoplasmic reticulum
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Valentina Ritz, Marwan Alfalah, Hassan Y. Naim, Ralf Jacob, Klaus-Peter Zimmer, and Jacques Schmitz
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DNA, Complementary ,Hepatology ,Immunoprecipitation ,Endoplasmic reticulum ,Immunoelectron microscopy ,Gastroenterology ,Biology ,Apical membrane ,Congenital Sucrase-Isomaltase Deficiency ,Endoplasmic Reticulum ,Subcellular localization ,Molecular biology ,Sucrase-Isomaltase Complex ,Sucrase-isomaltase complex ,Protein Transport ,COS Cells ,Animals ,Humans ,Point Mutation ,Sucrase-isomaltase - Abstract
Background & Aims: Congenital sucrase-isomaltase deficiency (CSID) is an autosomal recessive human disorder characterized by reduced activities of the brush border enzyme sucrase-isomaltase (SI). Here, we elucidate the pathogenesis of a new variant of CSID at the cellular and molecular level. Methods: Assessment of the CSID phenotype was achieved by enzymatic activity measurements, biosynthetic labeling of intestinal biopsy specimens, immunoprecipitation of SI, and immunoelectronmicroscopy. The putative mutation was identified by sequencing of the SI cDNA isolated by RT-PCR from intestinal biopsy samples. The function of the mutation was verified by immunoprecipitation and confocal microscopy of transiently transfected cells. Results: Biosynthetic labeling and immunoelectron microscopy reveal a predominant localization of SI in the endoplasmic reticulum (ER) similar to phenotype I of CSID. Unlike phenotype I, however, a partial conversion of SI to a complex glycosylated mature form takes place. The SI cDNA in this phenotype revealed 3 mutations, 2 of which, Val to Phe at residue 15 and Ala to Thr at residue 231, had no effect on the structure or function of SI. By contrast, the third mutation resulted in an exchange of leucine by proline at position 620 (L620P) and revealed in transfected COS cells structural features and subcellular localization similar to the phenotype identified in the patient's enterocytes. Conclusions: This is the first identification at the molecular and subcellular levels of a novel variant of CSID in which SI accumulates predominantly in the ER, and a minor proportion is further processed and transported to the apical membrane of enterocytes. more...
- Published
- 2003
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34. Congenital Sucrase-Isomaltase Deficiency
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Ann R McMeans
- Subjects
Nutrition assessment ,business.industry ,Gastroenterology ,Infant ,Physiology ,Congenital Sucrase-Isomaltase Deficiency ,Diet assessment ,Carbohydrate metabolism ,Sucrase-Isomaltase Complex ,Nutrition Assessment ,Patient Education as Topic ,Practice Guidelines as Topic ,Pediatrics, Perinatology and Child Health ,Humans ,Medicine ,Child ,business ,Carbohydrate Metabolism, Inborn Errors - Published
- 2012
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35. Our Cases with Sucrase Isomaltase Deficiency
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Sema Aydogdu, Fatih Ünal, Maşallah Baran, Miray Karakoyun, Yasemin Özdemir Şahan, and Erhan Kilicoglu
- Subjects
medicine.medical_specialty ,Lactose intolerance ,Pediatrics ,business.industry ,Standard treatment ,Hepatology ,Congenital Sucrase-Isomaltase Deficiency ,medicine.disease ,Gastroenterology ,Malnutrition ,Internal medicine ,medicine ,Vomiting ,Sacrosidase ,medicine.symptom ,business ,Pediatric gastroenterology ,medicine.drug - Abstract
Objectives: Individuals affected with sucrase isomaltase deficiency are unable to digest sucrose-containing foods. Primary symptoms include watery diarrhea, abdominal discomfort and vomiting. Secondary symptoms include retarded growth and malnutrition. Nonspecific symptoms may lead to lengthy delays in diagnosis. The objective of this report is to describe the clinical presentation, diagnosis and treatment of five Turkish children with sucrase isomaltase deficiency. Methods: This is a series of three male and two female patients that presented to the Department of Pediatric Gastroenterology, Hepatology, and Nutrition at Ege University between 2008 and 2014. Results: Patient ages ranged from 6 months to 9 years and symptoms began after the introduction of food or formula into the diet at 1 week to 6 months of age. Presenting symptoms included growth retardation, decreased weight gain, watery diarrhea and vomiting. Four patients were previously misdiagnosed with GERD, celiac disease, lactose intolerance and food allergy but they did not respond to standard treatment. Routine clinical laboratory assessments including hematology, renal, thyroid and hepatic function, renal tubular function were normal. A detailed history revealed the association between the onset of illness and dietary changes leading to the diagnosis of congenital sucrase isomaltase deficiency. All five patients responded to treatment with sacrosidase oral solution. Conclusion: This is the first case series of pediatric patients with sucrase isomaltase deficiency in Turkey. The actual prevalence of the disease in Turkey is unknown, probably due incorrect diagnoses. Four of our patients were previously misdiagnosed with other gastrointestinal disorders leading to delayed treatment. We suggest that sucrase isomaltase deficiency should be considered in pediatric patients presenting with chronic watery diarrhea. more...
- Published
- 2015
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36. Prevalence of Known Congenital Sucrase-Isomaltase Deficiency Gene Mutations in Children with Functional Abdominal Pain and/or Functional Diarrhea
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Mauro D'Amato, Jeffery D. Lewis, Derick Cooper, Heather Elser, Carlo Di Lorenzo, and Bruno P. Chumpitazi
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Abdominal pain ,Pathology ,Hepatology ,business.industry ,Gastroenterology ,Functional diarrhea ,Gene mutation ,Congenital Sucrase-Isomaltase Deficiency ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Internal medicine ,Medicine ,030211 gastroenterology & hepatology ,medicine.symptom ,business - Published
- 2017
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37. Congenital sucrase-isomaltase deficiency: A case report
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Santos-Silva, Rita, Tavares, Marta, Trindade, Eunice, and Amil-Dias, Jorge
- Subjects
Deficiência congénita de sacarase-isomaltase ,Fermento ,Baker’s yeast ,Congenital sucrase-isomaltase deficiency ,Sacrosidase ,Saccharomyces cerevisiae ,Bakers yeast - Abstract
Background: Congenital sucrase-isomaltase deficiency (CSID) is an autosomal recessive disease characterized by absent sucrase activity with variable decrease in isomaltase activity. The prevalence of CSID in Portuguese population is unknown and there are few reported cases. Case report: We report the case of a six-month-old male infant admitted for chronic profuse diarrhea and failure to thrive that began after food diversification. The investigation showed that he had CSID. The therapeutic option was the addition of baker’s yeast to the diet which was followed by complete resolution of symptoms and excellent weight recovery. Discussion: This case highlights the relevance of clinical observation and awareness in a condition where diagnosis is essentially clinical. The available therapeutic options are addressed with pragmatic use of baker’s yeast. Introdução: O défice congénito de sacarase-isomaltase é uma doença autossómica recessiva caraterizada pela ausência da atividade da sacarase e diminuição variável da atividade da isomaltase. A prevalência desta patologia na população portuguesa é desconhecida e há poucos casos divulgados. Relato de caso: Lactente masculino de 6 meses, internado para estudo de diarreia crónica profusa coincidente com o início da diversificação alimentar e associada a má evolução ponderal. A investigação mostrou tratar-se de uma deficiência congénita de sacarase-isomaltase. A medida terapêutica escolhida foi a adição de fermento de padeiro na dieta, com resolução da sintomatologia e excelente recuperação ponderal. Discussão: Discute-se a importância de uma elevada suspeição clínica numa patologia cujo diagnóstico é essencialmente clínico e também as opções terapêuticas disponíveis, com ênfase no uso do fermento de padeiro. more...
- Published
- 2014
38. Sacrosidase Therapy for Congenital Sucrase-Isomaltase Deficiency
- Author
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Geraldine Kastoff, Luanne McAdams, Christopher J. Justinich, William R. Treem, Lesley Stanford, and Jeffrey S. Hyams
- Subjects
Diarrhea ,Sucrose ,medicine.medical_specialty ,medicine.medical_treatment ,Saccharomyces cerevisiae ,Congenital Sucrase-Isomaltase Deficiency ,Placebos ,Bloating ,Double-Blind Method ,Internal medicine ,Animals ,Humans ,Medicine ,In patient ,Child ,Chemotherapy ,business.industry ,Gastroenterology ,Infant ,Abdominal distension ,Sucrase-Isomaltase Complex ,Kinetics ,Milk ,Endocrinology ,Breath Tests ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,Sucrase activity ,Sacrosidase ,medicine.symptom ,business ,Carbohydrate Metabolism, Inborn Errors ,Hydrogen ,Sucrase ,medicine.drug - Abstract
The purpose of this study was to determine if sacrosidase, a liquid produced from Saccharomyces cerevisiae containing 6000 IU of sucrase activity per mg protein, prevented symptoms of diarrhea, abdominal cramps, gas, and bloating in patients with congenital sucrase-isomaltase deficiency (CSID) consuming a normal sucrose and carbohydrate-containing diet.Twenty-eight children (aged 5 months to 11 years) underwent a randomized, double-blind trial consisting of two phases: 1) three sucrose breath H2 tests with three single-dose treatments (placebo, sacrosidase, and sacrosidase plus milk), and 2) a dose-response phase consisting of four multidose treatments, each for 10 days of full-strength sacrosidase, 1:10 dilution, 1:100 dilution, and 1:1000 dilution. Patients who weighed less than or equal to 15 kg received a dose of sacrosidase and those who weighed more than 15 kg received 2 ml. For the dose-response phase each patient consumed a normal diet. The number of stools and severity of symptoms were recorded daily for each concentration of sacrosidase administered and compared to a baseline period during which the patient took no sacrosidase and consumed a sucrose/starch-free diet. Data were analyzed using an ANOVA model and the nonparameter Wilcoxon signed-rank test.Breath H2 excretion decreased significantly when patients received sacrosidase or sacrosidase plus milk compared to placebo during sucrose breath tests. During the dose-response phase significant treatment differences were observed between the two higher concentrations and the two lower concentrations of sacrosidase for both total stools (p0.001) and total symptom score (p = 0.003). Higher concentrations of sacrosidase were associated with fewer stools and a greater number of formed or hard stools compared to lower concentrations and compared to the baseline period. Higher concentrations were also associated with fewer symptoms of gas, abdominal cramps, or bloating, but no differences in vomiting. The only significant adverse event was wheezing in one child with a history of asthma.Sacrosidase is a safe, effective, well-accepted treatment to prevent gastrointestinal symptoms in patients with CSID consuming a normal diet. more...
- Published
- 1999
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39. Glucose polymer as a cause of protracted diarrhea in infants with unsuspected congenital sucrase-isomaltase deficiency
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M. Stephen Murphy, Tina Newton, and Ian W. Booth
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Male ,medicine.medical_specialty ,Congenital Sucrase-Isomaltase Deficiency ,Gastroenterology ,Diagnosis, Differential ,Internal medicine ,medicine ,Humans ,Intestinal Mucosa ,Glucans ,business.industry ,Infant, Newborn ,Infant ,Disaccharidase ,Failure to Thrive ,Sucrase-Isomaltase Complex ,Discontinuation ,Diarrhea ,Endocrinology ,Parenteral nutrition ,Gastrointestinal disorder ,Diarrhea, Infantile ,Pediatrics, Perinatology and Child Health ,Failure to thrive ,Female ,Infant Food ,medicine.symptom ,Complication ,business ,Carbohydrate Metabolism, Inborn Errors - Abstract
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. (J PEDIATR 1996;128:753-6) more...
- Published
- 1996
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40. Congenital sucrase-isomaltase deficiency. Identification of a glutamine to proline substitution that leads to a transport block of sucrase-isomaltase in a pre-Golgi compartment
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Cornelis P. Hollenberg, J. Ouwendijk, Wilma Peters, L.A. Ginsel, Jack A.M. Fransen, Hassan Y. Naim, and C.E.C. Moolenaar
- Subjects
Enzyme complex ,een molecualir celbiologisch onderzoek [Expressie van brush-border en lysosomale enzymen in gepolariseerde epitheelcellen] ,Biopsy ,Molecular Sequence Data ,Mutant ,Fluorescent Antibody Technique ,Congenital Sucrase-Isomaltase Deficiency ,Biology ,Endoplasmic Reticulum ,Transfection ,Sucrase-isomaltase complex ,Sucrase ,symbols.namesake ,a molecular-cell biological [Expression of brush-border and lysosomal enzymes in polarized epithelial cells] ,Malabsorption Syndromes ,Humans ,Amino Acid Sequence ,Base Sequence ,Biological Transport ,General Medicine ,Golgi apparatus ,Molecular biology ,Cell Compartmentation ,Sucrase-Isomaltase Complex ,Breath Tests ,Biochemistry ,Mutation ,symbols ,Sucrase-isomaltase ,Isomaltase ,Hydrogen ,Research Article - Abstract
Congenital sucrase-isomaltase deficiency is an example of a disease in which mutant phenotypes generate transport-incompetent molecules. Here, we analyze at the molecular level a phenotype of congenital sucrase-isomaltase deficiency in which sucrase-isomaltase (SI) is not transported to the brush border membrane but accumulates as a mannose-rich precursor in the endoplasmic reticulum (ER), ER-Golgi intermediate compartment, and the cis-Golgi, where it is finally degraded. A 6-kb clone containing the full-length cDNA encoding SI was isolated from the patient's intestinal tissue and from normal controls. Sequencing of the cDNA revealed a single mutation, A/C at nucleotide 3298 in the coding region of the sucrase subunit of the enzyme complex. The mutation leads to a substitution of the glutamine residue by a proline at amino acid 1098 (Q1098P). The Q1098P mutation lies in a region that is highly conserved between sucrase and isomaltase from different species and several other structurally and functionally related proteins. This is the first report that characterizes a point mutation in the SI gene that is responsible for the transport incompetence of SI and for its retention between the ER and the Golgi. more...
- Published
- 1996
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41. Congenital Sucrase-Isomaltase Deficiency: Summary of an Evaluation in One Family
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Hassan Y. Naim, Claudia C. Robayo-Torres, Bruno P. Chumpitazi, Buford L. Nichols, and Antone R. Opekun
- Subjects
medicine.medical_specialty ,Sucrose ,Congenital Sucrase-Isomaltase Deficiency ,Compound heterozygosity ,medicine.disease_cause ,Gastroenterology ,Article ,Sucrase-isomaltase complex ,Fathers ,Internal medicine ,Dietary Carbohydrates ,Medicine ,Humans ,Exome ,Breath test ,Genetics ,chemistry.chemical_classification ,Mutation ,medicine.diagnostic_test ,business.industry ,Siblings ,Disaccharidase ,Sucrase-Isomaltase Complex ,Enzyme ,chemistry ,Pediatrics, Perinatology and Child Health ,business ,Carbohydrate Metabolism, Inborn Errors - Abstract
Evaluation for congenital sucrase-isomaltase deficiency (CSID) historically has been performed using duodenal enzyme disaccharidase assays, in which the Dahlqvist method is used to assess the activities of the disaccharidases in vitro (1, 2). Meanwhile, noninvasive means have been developed to test for CSID (3). One of these methods is the 13C-based breath test, the results of which have been found to correlate well with duodenal mucosal enzyme analysis (4). Another approach is SI exome genetic sequencing, which has identified both homozygous mutations and compound heterozygote mutations that cause CSID (5–7). more...
- Published
- 2012
42. 13C-breath tests for sucrose digestion in congenital sucrase isomaltase-deficient and sacrosidase-supplemented patients
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Claudia C. Robayo-Torres, Susan S. Baker, Xavier Villa, E O Smith, Roberto Quezada-Calvillo, Antone R. Opekun, Buford L. Nichols, and Marilyn Navarrete
- Subjects
Male ,medicine.medical_specialty ,Sucrose ,Adolescent ,Diet therapy ,Biopsy ,Congenital Sucrase-Isomaltase Deficiency ,Article ,Sucrase-isomaltase complex ,Sucrase ,Internal medicine ,Medicine ,Humans ,Child ,Sucrose alpha-glucosidase ,Breath test ,Carbon Isotopes ,medicine.diagnostic_test ,beta-Fructofuranosidase ,business.industry ,Gastroenterology ,Infant ,Carbon Dioxide ,Sucrase-Isomaltase Complex ,Endocrinology ,Glucose ,Breath Tests ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,Dietary Supplements ,Sacrosidase ,Female ,Sucrase-isomaltase ,business ,medicine.drug ,Carbohydrate Metabolism, Inborn Errors - Abstract
Congenital sucrase-isomaltase deficiency (CSID) is characterized by absence or deficiency of the mucosal sucrase-isomaltase enzyme. Specific diagnosis requires upper gastrointestinal biopsy with evidence of low to absent sucrase enzyme activity and normal histology. The hydrogen breath test (BT) is useful, but is not specific for confirmation of CSID. We investigated a more specific 13C-sucrose labeled BT.Determine whether CSID can be detected with the 13C-sucrose BT without duodenal biopsy sucrase assay, and if the 13C-sucrose BT can document restoration of sucrose digestion by CSID patients after oral supplementation with sacrosidase (Sucraid).Ten CSID patients were diagnosed by low biopsy sucrase activity. Ten controls were children who underwent endoscopy and biopsy because of dyspepsia or chronic diarrhea with normal mucosal enzymes activity and histology. Uniformly labeled 13C-glucose and 13C-sucrose loads were orally administered. 13CO2 breath enrichments were assayed using an infrared spectrophotometer. In CSID patients, the 13C-sucrose load was repeated adding Sucraid. Sucrose digestion and oxidation were calculated as a mean percent coefficient of glucose oxidation averaged between 30 and 90 minutes.Classification of patients by 13C-sucrose BT percent coefficient of glucose oxidation agreed with biopsy sucrase activity. The breath test also documented the return to normal of sucrose digestion and oxidation after supplementation of CSID patients with Sucraid.13C-sucrose BT is an accurate and specific noninvasive confirmatory test for CSID and for enzyme replacement management. more...
- Published
- 2009
43. MG-107 Congenital sucrase-isomaltase deficiency: Identification of the common inuit founder mutation
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Julien L. Marcadier, Kheirie Issa, Robert A. Hegele, Matthew A. Lines, C. Ronald Scott, Michael T. Geraghty, Margaret Boland, Zaining Wu, and Adam D. McIntyre
- Subjects
Proband ,Genetics ,medicine.medical_specialty ,Malabsorption ,business.industry ,Congenital Sucrase-Isomaltase Deficiency ,medicine.disease ,Gastroenterology ,Frameshift mutation ,Internal medicine ,Failure to thrive ,medicine ,medicine.symptom ,Allele ,business ,Allele frequency ,Genetics (clinical) ,Founder effect - Abstract
Objective Congenital sucrase-isomaltase deficiency (CSID) is a rare hereditary cause of chronic diarrhoea in children. Persons with CSID lack the intestinal brush-border enzyme required for digestion of di- and oligosaccharides, including sucrose and isomaltose. Malabsorption results in abdominal pain, distention, copious diarrhoea, and failure to thrive. If recognised, dietary avoidance of the offending carbohydrates is highly effective. Although CSID is known to be highly prevalent (˜5–10%) in several Inuit populations, the genetic basis for this condition has not been described. Methods We sequenced the sucrase-isomaltase gene, SI, in a single Inuit CSID proband with severe fermentative diarrhoea and failure to thrive. We then genotyped a further 128 anonymized Inuit control individuals from a variety of circumpolar locales to assess for a possible founder effect. Results We identified a novel, homozygous frameshift mutation, c.273_274delAG (p. Gly92Leufs*8) in exon 4 of SI in the proband, that is predicted to result in complete absence of functional protein product. This change is indeed very common among Inuit control specimens, with an observed allele frequency of 0.17 (95% confidence interval 0.13–0.22). The predicted Hardy-Weinberg prevalence of CSID in the Inuit, based on this single founder allele is ˜3% (95% confidence interval 1.6–5.0%), comparable with previous estimates. Interpretation Targeted mutation testing for the c.273_274delAG allele should afford a simple and minimally invasive means of diagnosing CSID in persons of Inuit descent. Because CSID is a readily treatable disorder, such testing should be considered at an early stage in the assessment of Inuit patients with chronic diarrhoea. more...
- Published
- 2015
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44. Altered folding, turnover, and polarized sorting act in concert to define a novel pathomechanism of congenital sucrase-isomaltase deficiency
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Deborah Castelletti, Marwan Alfalah, Marcus J. Pröpsting, Hassan Y. Naim, and Markus Keiser
- Subjects
Adult ,Male ,Enzyme complex ,Protein Folding ,Octoxynol ,Mutant ,Detergents ,Molecular Sequence Data ,Biology ,Congenital Sucrase-Isomaltase Deficiency ,Endoplasmic Reticulum ,Biochemistry ,symbols.namesake ,Animals ,Humans ,Amino Acid Sequence ,Molecular Biology ,Sequence Homology, Amino Acid ,Endoplasmic reticulum ,Wild type ,Cell Biology ,Golgi apparatus ,Sucrase-Isomaltase Complex ,Intestines ,Secretory protein ,symbols ,Isomaltase ,Epitope Mapping ,Carbohydrate Metabolism, Inborn Errors - Abstract
Naturally occurring mutants of membrane and secretory proteins are often associated with the pathogenesis of human diseases. Here, we describe the molecular basis of a novel phenotype of congenital sucrase-isomaltase deficiency (CSID), a disaccharide malabsorption disorder of the human intestine in which several structural features and functional capacities of the brush-border enzyme complex sucrase-isomaltase (SI) are affected. The cDNA encoding SI from a patient with CSID reveals a mutation in the isomaltase subunit of SI that results in the substitution of a cysteine by an arginine at amino acid residue 635 (C635R). When this mutation is introduced into the wild type cDNA of SI a mutant enzyme, SI(C635R), is generated that shows a predominant localization in the endoplasmic reticulum. Nevertheless, a definite localization of SI(C635R) in the Golgi apparatus and at the cell surface could be also observed. Epitope mapping with conformation-specific mAbs protease sensitivity assays, and enzymatic activity measurements demonstrate an altered folding pattern of SI(C635R) that is responsible for a substantially increased turnover rate and an aberrant sorting profile. Thus, SI(C635R) becomes distributed also at the basolateral membrane in contrast to wild type SI. Concomitant with the altered sorting pattern, the partial detergent extractability of wild type SI shifts to a complete detergent solubility with Triton X-100. The mutation has therefore affected an epitope responsible for the apical targeting fidelity of SI. Altogether, the combined effects of the C635R mutation on the turnover rate, function, polarized sorting, and detergent solubility of SI constitute a unique and novel pathomechanism of CSID. more...
- Published
- 2006
45. Clinical heterogeneity in congenital sucrase-isomaltase deficiency
- Author
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Treem Wr
- Subjects
medicine.medical_specialty ,business.industry ,Internal medicine ,Pediatrics, Perinatology and Child Health ,Clinical heterogeneity ,medicine ,Congenital Sucrase-Isomaltase Deficiency ,business ,Gastroenterology - Published
- 1996
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46. Four Mutations in the SI Gene Are Responsible for the Majority of Clinical Symptoms of CSID
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Zaining Wu, C. Ronald Scott, Stefanie B. Uhrich, and Jie Yu Huang
- Subjects
medicine.medical_specialty ,Starch digestion ,Congenital Sucrase-Isomaltase Deficiency ,Gastroenterology ,Sucrase ,chemistry.chemical_compound ,Isomaltulose ,Internal medicine ,Dietary Carbohydrates ,medicine ,Humans ,Genetic Testing ,Exocrine pancreatic insufficiency ,Alleles ,Irritable bowel syndrome ,Genetics ,business.industry ,DNA ,medicine.disease ,Disaccharidase ,Sucrase-Isomaltase Complex ,chemistry ,Mutation ,Pediatrics, Perinatology and Child Health ,business ,Isomaltase ,Carbohydrate Metabolism, Inborn Errors - Abstract
1. Prader A, Auricchio S, Muerset G. D rchfall infolge hereditaren Mangels an intestinaler Saccharaseaktivitat (Saccharoseintoleranz). Schweizerischen Mediz Wochenschr 1961;91:465–75. 2. Robayo-Torres CC, Opekun AR, Quezada-Calvillo R, et al. 13C-breath tests for sucrose digestion in congenital sucrase isomaltase-deficient and sacrosidase-supplemented patients. J Pediatr Gastroenterol Nutr 2009; 48:412–8. 3. Auricchio S, Ciccimarra F, Moauro L, et al. Intraluminal and mucosal starch digestion in congenital deficiency of intestinal sucrase and isomaltase activities. Pediatr Res 1972;6:832–9. 4. Dahlqvist A. Assay of intestinal disaccharidases. Anal Biochem 1968; 22:99–107. 5. Talley NJ, Stanghellini V, Heading RC, et al. Functional gastroduodenal disorders. In: Drossman DA, Corazziari E, Talley NJ, et al, eds. Rome II: The Functional Gastrointestinal Disorders. 2nd ed. McLean, VA: Degnon Associates; 2000: 302. 6. Karnsakul W, Luginbuehl U, Hahn D, et al. Disaccharidase activities in dyspeptic children: biochemical and molecular investigations of maltaseglucoamylase activity. J Pediatr Gastroenterol Nutr 2002;35:551–6. 7. Dahlqvist A, Auricchio S, Semenza G, et al. Human intestinal disaccharidases and hereditary disaccharide intolerance. The hydrolysis of sucrose, isomaltose, palatinose (isomaltulose), and a 1,6-alpha-oligosaccharide (isomalto-oligosaccharide) preparation. J Clin Invest 1963;42:556–62. 8. Leeds JS, Hopper AD, Sidhu R, et al. Some patients with irritable bowel syndrome may have exocrine pancreatic insufficiency. Clin Gastroenterol Hepatol 2010;8:433–8. more...
- Published
- 2012
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47. Transient Sucrose and Starch Intolerance
- Author
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Hassan Y. Naim, Dietmar Scholz, and Klaus-Peter Zimmer
- Subjects
Sucrose ,medicine.medical_specialty ,Starch ,Starch metabolism ,Congenital Sucrase-Isomaltase Deficiency ,Disaccharidases ,Gastroenterology ,chemistry.chemical_compound ,Internal medicine ,Dietary Carbohydrates ,medicine ,Humans ,Sucrose metabolism ,business.industry ,Disaccharidase ,Celiac Disease ,Intestinal Diseases ,chemistry ,Dietary Reference Intake ,Pediatrics, Perinatology and Child Health ,Sacrosidase ,business ,medicine.drug - Abstract
9. Protein and amino acids. In: Otten JJ, Hellwig JP, Meyers LD, eds. Dietary Reference Intakes: The Essential Guide to Nutrient Requirements. Washington DC: The National Academies Press; 2006: 144–155. 10. Congenital sucrase-isomaltase deficiency. www.CSIDinfo.com. Published December 18, 2006. Accessed February 15, 2012. 11. Sucrose and starch in foods. www.CSIDinfo.com. Published December 18, 2006. Accessed February 15, 2012. 12. Treem WR, McAdams L, Stanford L, et al. Sacrosidase therapy for congenital sucrase-isomaltase deficiency. J Pediatr Gastroenterol Nutr 1999;28:137–42. 13. Genetics Home Reference. Congenital sucrase isomaltase deficiency. http://ghr.nlm.nih.gov/condition/congenital-sucrase-isomaltase-deficiency. Published July 2008. Accessed September 16, 2011. more...
- Published
- 2012
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48. Congenital sucrase-isomaltase deficiency arising from cleavage and secretion of a mutant form of the enzyme
- Author
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Klaus-Peter Zimmer, Hassan Y. Naim, Jacques Schmitz, and Ralf Jacob
- Subjects
Models, Molecular ,Biopsy ,Golgi Apparatus ,Biology ,Congenital Sucrase-Isomaltase Deficiency ,Article ,Sucrase-isomaltase complex ,Sucrase ,symbols.namesake ,Intestine, Small ,Humans ,Point Mutation ,Secretion ,Protein Precursors ,Endoplasmic reticulum ,Membrane Proteins ,Biological Transport ,General Medicine ,Golgi apparatus ,Cell biology ,Cell Compartmentation ,Sucrase-Isomaltase Complex ,Phenotype ,Biochemistry ,Membrane protein ,Child, Preschool ,symbols ,Isomaltase ,Protein Processing, Post-Translational ,Carbohydrate Metabolism, Inborn Errors - Abstract
Congenital sucrase-isomaltase deficiency (CSID) is an autosomal recessive human intestinal disorder that is clinically characterized by fermentative diarrhea, abdominal pain, and cramps upon ingestion of sugar. The symptoms are the consequence of absent or drastically reduced enzymatic activities of sucrase and isomaltase, the components of the intestinal integral membrane glycoprotein sucrase-isomaltase (SI). Several known phenotypes of CSID result from an altered posttranslational processing of SI. We describe here a novel CSID phenotype, in which pro-SI undergoes an unusual intracellular cleavage that eliminates its transmembrane domain. Biosynthesis of pro-SI in intestinal explants and in cells transfected with the SI cDNA of this phenotype demonstrated a cleavage occurring within the endoplasmic reticulum due to a point mutation that converts a leucine to proline at residue 340 of isomaltase. Cleaved pro-SI is transported to and processed in the Golgi apparatus and is ultimately secreted into the exterior milieu as an active enzyme. To our knowledge this is the first report of a disorder whose pathogenesis results not from protein malfolding or mistargeting, but from the conversion of an integral membrane glycoprotein into a secreted species that is lost from the cell surface. more...
- Published
- 2000
49. Analysis of a naturally occurring mutation in sucrase-isomaltase: glutamine 1098 is not essential for transport to the surface of COS-1 cells
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R.A. van de Vorstenbosch, J. Ouwendijk, R.H.M. te Morsche, Wilma Peters, Jack A.M. Fransen, Hassan Y. Naim, and L.A. Ginsel
- Subjects
Proline ,Glutamine ,Lysine ,Mutant ,Molecular Sequence Data ,Biology ,Transfection ,symbols.namesake ,Accumulation ,Golgi ,Animals ,Humans ,Protein folding ,Amino Acid Sequence ,Molecular Biology ,Alanine ,Membrane Glycoproteins ,Cell Membrane ,Wild type ,Biological Transport ,Golgi apparatus ,Congenital sucrase–isomaltase deficiency ,Precipitin Tests ,Intestine ,Rats ,Sucrase-Isomaltase Complex ,Biochemistry ,Amino Acid Substitution ,Microscopy, Fluorescence ,COS Cells ,Mutation ,symbols ,Mutagenesis, Site-Directed ,Molecular Medicine ,Rabbits ,Sucrase-isomaltase - Abstract
A glutamine for proline substitution at position 1098 was previously shown to result in accumulation of brush-border sucrase–isomaltase in the Golgi apparatus. The substitution is present in a highly homologous region of the protein, and results in a comparable accumulation when introduced into the same region in lysosomal α-glucosidase. To study the importance of the glutamine-1098, we analyzed the transport compatibility of two mutants in which glutamine-1098 is substituted by lysine or alanine. Both mutants were transported to the cell surface and processed comparable to wild type. We concluded that glutamine-1098 is not essential for transport to the cell surface. more...
- Published
- 1998
50. Congenital sucrase-isomaltase deficiency: an under-diagnosed disease in Chinese children
- Author
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Qunying Yang, Peiyu Chen, Tiefu Fang, Min Yang, Lanlan Geng, Sitang Gong, Wenji Ou, and Ding-You Li
- Subjects
Male ,medicine.medical_specialty ,China ,Sucrose ,Colonoscopy ,Disease ,Congenital Sucrase-Isomaltase Deficiency ,Gastroenterology ,Sucrase-isomaltase complex ,Chinese children ,Internal medicine ,medicine ,Glucose test ,Humans ,Pediatrics, Perinatology, and Child Health ,Glucose tolerance test ,medicine.diagnostic_test ,business.industry ,Infant ,Glucose Tolerance Test ,medicine.disease ,Sucrose tolerance test ,Sucrase-Isomaltase Complex ,Endocrinology ,Glucose-galactose malabsorption ,Sucrase-isomaltase deficiency ,Pediatrics, Perinatology and Child Health ,Failure to thrive ,medicine.symptom ,business ,Research Article ,Carbohydrate Metabolism, Inborn Errors - Abstract
Background Congenital sucrase-isomaltase deficiency (CSID) is a rare genetic disorder. The prevalence of CSID in Chinese population is unknown and no single case has been reported. Methods Sucrose tolerance tests were performed in three children suspected of CSID. Glucose tolerance tests were performed to exclude glucose malabsorption. Blood glucose was measured at fasting and at 30 min, 60 min, 120 min, and 180 min of the study. Gastrointestinal symptoms were recorded up to 4 hours after the study. Results From December 2008 to June 2011, three children, ranging from 16 to 19 months old, were referred to our tertiary children’s hospital due to chronic watery diarrhea and failure to thrive. Laboratory investigations including complete blood counts, ESR, CRP, and serum immunoglobulins were normal. Routine stool culture for bacteria and exam for parasites were negative. Upper endoscopy, colonoscopy and histology were unremarkable. All children failed lactose-free and amino acid-based formulas. All three children had flat sucrose tolerance tests and began to have watery stool 2–4 hours after feeding sucrose test solution. The glucose tolerance tests were normal and no children developed watery stools up to 4 hours after feeding glucose test solution. Conclusions This is the first case series of CSID in Chinese children. The diagnosis of CSID can be made based on clinical suspicion and sucrose tolerance test. CSID is probably an under-diagnosed or misdiagnosed disease in Chinese children and should be considered in children with chronic watery diarrhea. more...
- Published
- 2014
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