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Congenital Sucrase-Isomaltase Deficiency

CSID

Congenital sucrase-isomaltase deficiency (CSID) is a rare cause of incomplete carbohydrate digestion, chronic diarrhea, malabsorption and failure to thrive. The disease belongs to the heterogeneous group of congenital diarrheal disorders and is caused by mutations in the gene encoding for the enzyme sucrase-isomaltase. Anamnestic data are essential to achieve an early diagnosis and to avoid unnecessary measures like intestinal biopsies; they are to be complemented by laboratory analyses of blood and stool samples, possibly by a sucrose breath hydrogen test, and by genetic analyses. Therapy relies on dietary restrictions and enzyme replacement.


Presentation

CSID typically manifests in the infantile period. Affected children suffer from chronic diarrhea and consequences thereof, namely from malnutrition and failure to thrive. Besides diarrhea, other unspecific symptoms of indigestion can be observed. Some patients suffer from vomiting, many from abdominal pain, bloating, and flatulence. Dehydration may become an issue. Diaper rash and general malaise often cause irritability. Because CSID-associated diarrhea is caused by the ingestion of determined carbohydrates, any information on whether or not symptoms improve when the infant is given one or another formula is very helpful: In the absence of sucrase-isomaltase, sucrose-based formulas and starch are not tolerated by the patient [1]. Fruits and fruit juices constitute a common source of sugars that can't be digested by CSID patients.

In isolated cases, CSID has been diagnosed in adolescents or adults presenting with irritable bowel syndrome and meteorism [2] [3]. The fact that genetic analyses have not been carried out to confirm the respective diagnoses gives rises to the suspicion that these patients suffered from an acquired form of sucrase-isomaltase deficiency, but not from CSID.

Rigor
  • Incorporation of rigorous quality control steps throughout the workflow of the pipeline ensures the consistency, validity and accuracy of results. Our pipeline is streamlined to maximize sensitivity without sacrificing specificity.[blueprintgenetics.com]
Abdominal Pain
  • 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.[ncbi.nlm.nih.gov]
  • Typical presenting symptoms were watery diarrhoea, abdominal pain and bloating, sometimes noticeably worse after ingestion of fruit.[ncbi.nlm.nih.gov]
  • Some patients suffer from vomiting, many from abdominal pain, bloating, and flatulence. Dehydration may become an issue. Diaper rash and general malaise often cause irritability.[symptoma.com]
  • If you have symptoms of diarrhea, bloating, gaseousness, and abdominal pain or discomfort talk with your doctor to determine the diagnostic studies needed for you. Treatments - Next[iffgd.org]
Excoriation
  • In some cases, individuals may exhibit irritability; colic; abrasion and/or irritation (excoriation) of the skin on the buttocks as a result of prolonged diarrhea episodes; and/or vomiting. Symptoms of this disorder vary among affected individuals.[rarediseases.org]
Short Arm
  • Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered.[rarediseases.org]
Altered Mental Status
  • Presence of clinical alarm signs, including hypotension, anemia requiring blood transfusions, altered mental status, or inability to tolerate food and/or fluids by mouth.[clinicaltrials.gov]

Workup

Congenital diarrheal disorders are a group of inherited enteropathies that manifest early in life and are associated with unspecific symptoms such as those observed in CSID patients [4] [5]. The most direct approach to diagnosis includes sequencing of the gene(s) suspected to be defective, but targeted analyses cannot be carried out in the absence of a concrete suspicion. In this context, it may be helpful to obtain a detailed family history, to find out if any enteropathy has ever been diagnosed in a family member. If this is not the case and epidemiological data don't raise any suspicion either, a long list of differential diagnoses needs to be excluded [5]:

  • A positive family history of early-onset diarrhea argues in favor of a hereditary disorder, while infections and food allergy are other frequent causes of chronic diarrhea in infants.
  • Diagnostic imaging is very helpful to depict malformations of the gastrointestinal tract. With regards to CSID, dilated bowel loops and slightly thickened intestinal walls are frequently observed in sonography - possibly even before birth.
  • CSID causes osmotic diarrhea and thus, diarrhea should improve during fasting. This applies to all forms of osmotic diarrhea but is not the case in those suffering from secretory diarrhea. A fecal osmotic gap >50 mosm/kg is also suggestive of osmotic diarrhea.
  • Stool samples obtained from CSID patients are usually acidic with pH values <5.
  • Blood sample analyses should be performed to rule out hypoproteinemia, dyslipidemia, and other metabolic disorders.
  • Biopsies are not required to diagnose CSID, but they are often carried out to assess disaccharidase activities in the small intestine [6].
  • Specific breath tests may aid to distinguish between distinct forms of carbohydrate maldigestion and malabsorption. In case of CSID, the sucrose breath hydrogen test will yield positive results. However, it may be rather impracticable in young children.
  • Molecular analyses, particularly gene panel sequencing or whole-exome sequencing, are recommended over invasive measures like biopsies, and yield reliable results [7]. The causal mutation in the gene encoding for sucrase-isomaltase needs to be identified to confirm the diagnosis and to facilitate the identification of affected family members and carriers.
Nephrolithiasis
  • Clark JH, Fitzgerald JF, Bergstein JM: Nephrolithiasis in childhood inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 1985, 4: 829-834. 33.[bmcpediatr.biomedcentral.com]

Treatment

For a long time, treatment of CSID has solely been based on the dietary restriction of carbohydrates that can't be fully digested due to the underlying enzyme deficiency. Affected infants were to be kept on a sucrose- and starch-restricted diet. Fructose has usually been chosen as an alternative source of carbohydrates. Such dietary recommendations are still given today, but CSID treatment is generally complemented by enzyme replacement therapy [8]. Affected individuals benefit from the oral administration of sacrosidase, a yeast-derived enzyme that facilitates sucrose digestion. In some cases, dietary restrictions regarding sucrose consumption may be loosened if sacrosidase is applied, but this does not apply to all patients [1]. It should also be noted that sacrosidase does not improve maltose digestion and tolerance to starch. Whether or not starch-containing foods can be added to the diet of CSID patients depends on their residual isomaltase activity, which needs to be determined for every single patient. It may be possible to estimate a patient's residual isomaltase activity if the precise mutation of the sucrase-isomaltase gene is known [9], but further research is necessary to substantiate this hypothesis. It is generally recommended that any reintroduction of sucrose or starch is done gradually.

Prognosis

Long-term studies regarding the efficacy of sucrose- and starch-restricted diets in CSID patients have shown that many of them continue to experience diarrhea, abdominal pain and nausea. However, compliance with dietary recommendations cannot be conclusively assessed and may partially explain such "resistance to therapy" [1].

While normal growth can usually be achieved by means of dietary restrictions, persistent diarrhea significantly lowers quality of life. To this end, the approval of yeast-derived sacrosidase for CSID treatment gives new hope to these patients who show a poor response to dietary modifications. The oral application of sacrosidase improves residual symptoms of CSID and thus, quality of life [8].

Etiology

CSID patients suffer from an enzyme deficiency that results from mutations in the protein-coding sucrase-isomaltase gene. This gene is located on the long arm of chromosome 3 and comprises 99 kbp. It is mainly expressed in the small intestine, particularly in the apical membrane of enterocytes, in the brush border. To date, more than two dozen mutations affecting intracellular trafficking, subunit anchoring in the microvilli, and catalytic site architecture have been described. Several authors tried to establish genotype-phenotype relations and divided known mutations into distinct groups, thereby defining CSID phenotypes [9] [10].

The disease is inherited in an autosomal recessive manner. Both homozygosity and compound heterozygosity for pathogenic mutations may cause the disease [7].

Epidemiology

The overall incidence of CSID has been estimated to 1 in 50,000, but is known to be significantly higher in Greenland, Canada, and Alaska: In indigenous Greenlanders, the incidence of CSID amounts to 5-10%, and 3-7% of Canadian and Alaskan Inuit are assumed to be affected. Interestingly, CSID was unknown among the Inuit population before the introduction of a Western diet: Until the middle of the 19th century, they lived on a fish-and-marine mammal-based diet that was high in protein and fat but low in carbohydrates [1]. Further studies revealed that the exceptionally high incidence rates observed in the upper north of the American continent are due to the wide distribution of mutant founder alleles [11].

Sex distribution
Age distribution

Pathophysiology

The enzyme sucrase-isomaltase is required for the breakdown of distinct carbohydrates that are part of the human diet. This enzyme catalyzes the hydrolyzation of disaccharides and oligosaccharides, with part of the latter being products of the digestion of glycogen and starch. Thus, a deficiency of sucrase-isomaltase triggers a number of digestive disorders following the consumption of certain carbohydrates:

  • In CSID patients, considerable amounts of undigested sugars pass the small intestines, have an osmotic effect and pull water into the bowel. Therefore, they suffer from osmotic diarrhea.
  • Not only can't they utilize those carbohydrates, but the condition also interferes with the absorption of other nutrients. For instance, CSID may cause villous atrophy and steatorrhea [7]. This is why this disease is typically associated with malabsorption, malnutrition, and failure to thrive.
  • Those disaccharides and oligosaccharides that haven't been degraded in proximal parts of the intestinal tract are fermented by bacteria in the colon, thereby giving rise to an excessive production of gas, to abdominal distention, pain, and meteorism.

Prevention

It is highly recommended to identify the mutations accounting for individual cases of CSID. On the one hand, precise knowledge regarding the underlying gene defect facilitates the identification of carriers among family members. On the other hand, it allows for targeted prenatal - or early postnatal - analyses. This way, affected infants don't need to undergo comprehensive and often invasive procedures to determine the cause of their chronic diarrhea.

Summary

CSID has first been described by Weijers et al. in 1960 as an inherited "deficiency of sugar-splitting enzymes" [12]. In detail, affected individuals have been observed to suffer from osmotic diarrhea after ingesting sucrose, maltose, and starch. These carbohydrates are only partially degraded and thus, increased quantities of osmotically active sugars reach distal parts of the intestinal tract and pull water into its lumen.

Diagnosis of CSID is complicated by the fact that there are several congenital diarrheal disorders causing the same clinical presentation: watery diarrhea plus abdominal pain, bloating, and meteorism, entailing dehydration and malnutrition. Laboratory analyses of blood and stool samples may aid to distinguish between individual diarrheal disorders, but the identification of the causal gene defect is considered the gold standard of diagnosis. Ideally, anamnestic data allow for a tentative diagnosis and thus for targeted molecular analyses. In such cases, invasive procedures like biopsies can be avoided.

Therapy relies on dietary adjustments and enzyme replacement. CSID patients are not to consume sucrose and starches, and they may additionally benefit from the oral application of sacrosidase, a yeast-derived enzyme that enhances the digestion of sucrose. The patients' prognosis for survival and normal growth is good, but their quality of life may remain limited if symptoms cannot be controlled completely.

Of note, numerous conditions such as celiac disease, Crohn's disease, tropical sprue, giardiasis and non-infectious enteritis may cause secondary or acquired sucrase-isomaltase deficiency [13]. This condition is not reviewed in this article and usually resolves upon treatment of the underlying disorder.

Patient Information

Congenital sucrase-isomaltase deficiency (CSID) is a rare hereditary disease. It belongs to the heterogeneous group of congenital diarrheal disorders and typically manifests within the first year of a child's life in form of persistent watery diarrhea. Affected infants also suffer from abdominal pain and bloating, and possibly from vomiting. Many of them develop diaper rashes. Parents may note that their children gain little weight and grow poorly.

CSID is caused by pathogenic mutations in the gene encoding for the enzyme sucrase-isomaltase. This enzyme is required for the breakdown of certain carbohydrates that are part of the human diet, namely sucrose and starch. Under physiological conditions, these sugars are broken down into smaller molecules and are subsequently absorbed through the intestinal wall. In CSID patients, however, they cannot be degraded and absorbed, pass through to distal parts of the intestinal tract and pull water into its lumen. Therefore, the patient suffers from diarrhea. They also lose a lot of water and it is difficult to meet their calorie requirements if they can't utilize those omnipresent sugars.

Symptoms experienced by CSID patients are unspecific and commonly presented by infants suffering from other congenital diarrheal disorders, infections or food allergies. Thus, CSID diagnosis may be a rather tedious process involving laboratory analyses of blood and stool samples, specific breath tests, intestinal biopsies and/or genetic analyses. Ideally, anamnestic data suffice to raise a suspicion as to the underlying disease and prompt targeted molecular studies: In such cases, invasive procedures like biopsies can be obviated.

Therapy of CSID rests on dietary restrictions and enzyme replacement. Affected individuals are recommended not to consume foods that contain sucrose or starch. They may also benefit from the oral administration of sacrosidase, a yeast-derived enzyme that facilitates sucrose, but not starch digestion. Most patients achieve near-to-normal quality of life and normal growth if they comply with dietary recommendations and possibly sacrosidase therapy.

References

Article

  1. Treem WR. Clinical aspects and treatment of congenital sucrase-isomaltase deficiency. J Pediatr Gastroenterol Nutr. 2012; 55 Suppl 2:S7-13.
  2. Muldoon C, Maguire P, Gleeson F. Onset of sucrase-isomaltase deficiency in late adulthood. Am J Gastroenterol. 1999; 94(8):2298-2299.
  3. Ringrose RE, Preiser H, Welsh JD. Sucrase-isomaltase (palatinase) deficiency diagnosed during adulthood. Dig Dis Sci. 1980; 25(5):384-387.
  4. Overeem AW, Posovszky C, Rings EH, Giepmans BN, van ISC. The role of enterocyte defects in the pathogenesis of congenital diarrheal disorders. Dis Model Mech. 2016; 9(1):1-12.
  5. Terrin G, Tomaiuolo R, Passariello A, et al. Congenital diarrheal disorders: an updated diagnostic approach. Int J Mol Sci. 2012; 13(4):4168-4185.
  6. Chumpitazi BP, Robayo-Torres CC, Opekun AR, Nichols BL, Jr., Naim HY. Congenital sucrase-isomaltase deficiency: summary of an evaluation in one family. J Pediatr Gastroenterol Nutr. 2012; 55 Suppl 2:S36.
  7. Haberman Y, Di Segni A, Loberman-Nachum N, et al. Congenital Sucrase-isomaltase Deficiency: A Novel Compound Heterozygous Mutation Causing Aberrant Protein Localization. J Pediatr Gastroenterol Nutr. 2017; 64(5):770-776.
  8. Puntis JW, Zamvar V. Congenital sucrase-isomaltase deficiency: diagnostic challenges and response to enzyme replacement therapy. Arch Dis Child. 2015; 100(9):869-871.
  9. Gericke B, Amiri M, Scott CR, Naim HY. Molecular pathogenicity of novel sucrase-isomaltase mutations found in congenital sucrase-isomaltase deficiency patients. Biochim Biophys Acta. 2017; 1863(3):817-826.
  10. Sander P, Alfalah M, Keiser M, et al. Novel mutations in the human sucrase-isomaltase gene (SI) that cause congenital carbohydrate malabsorption. Hum Mutat. 2006; 27(1):119.
  11. Marcadier JL, Boland M, Scott CR, et al. Congenital sucrase-isomaltase deficiency: identification of a common Inuit founder mutation. Cmaj. 2015; 187(2):102-107.
  12. Weijers HA, va de KJ, Mossel DA, Dicke WK. Diarrhoea caused by deficiency of sugar-splitting enzymes. Lancet. 1960; 2(7145):296-297.
  13. Cohen SA. The clinical consequences of sucrase-isomaltase deficiency. Mol Cell Pediatr. 2016; 3(1):5.

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Last updated: 2019-07-11 19:57