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Two Novel Mutations in the SI Gene Associated With Congenital Sucrase-Isomaltase Deficiency: A Case Report in China.

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.

SUBMITTER: Zhou J

PROVIDER: S-EPMC8675567 | biostudies-literature |

REPOSITORIES: biostudies-literature

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

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

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Congenital sucrase-isomaltase deficiency: identification of a common Inuit founder mutation.

Project description:BackgroundCongenital 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.MethodsWe 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.ResultsIn 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.InterpretationWe 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.

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Project description:BACKGROUND:Disaccharide Intolerance Type I (Mendelian Interance in Man database: *222900) is a rare inborn error of metabolism resulting from mutation in sucrase-isomaltase (Enzyme Catalyzed 3.2.1.48). Usually, infants with SI deficiency come to attention because of chronic diarrhea and nutritional evidence of malabsorption. CASE PRESENTATION:We describe an atypical presentation of this disorder in a 10-month-old infant. In addition to chronic diarrhea, the child displayed severe and chronic hypercalcemia, the evaluation of which was negative. An apparently coincidental right orbital hemangioma was detected. Following identification of the SI deficiency, an appropriately sucrose-restricted, but normal calcium diet regimen was instituted which led to cessation of diarrhea, substantial weight gain, and resolution of hypercalcemia. CONCLUSIONS:This case illustrates that, similar to congenital lactase deficiency (Mendelian Interance in Man database: *223000, Alactasia, Hereditary Disaccharide Intolerance Type II), hypercalcemia may complicate neonatal Sucrase-Isomaltase deficiency. Hypercalcemia in the presence of chronic diarrhea should suggest disaccharide intolerance in young infants.

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Congenital Sucrase-isomaltase Deficiency: A Novel Compound Heterozygous Mutation Causing Aberrant Protein Localization.

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

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

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Project description: Not available

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Project description: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.

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

Project description: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).

| S-EPMC6103908 | biostudies-literature

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