What Is CSID?

Congenital Sucrase-Isomaltase Deficiency (CSID) is a rare genetic disorder affecting the digestive function of sucrase and isomaltase enzymes in the small intestine. A decrease or absence of activity of these enzymes, required for the digestion of dietary sucrose and starch, is characterized by varying degrees of chronic diarrhea, abdominal pain, gas, and bloating in those who are affected. Congenital Sucrase-Isomaltase Deficiency is also referred to as Genetic Sucrase-Isomaltase Deficiency (GSID), sucrose intolerance, or disaccharide intolerance.

This autosomal recessive disorder is caused by pathogenic mutations in the sucrase-isomaltase gene (SI). The genetic condition of CSID is associated with dysfunctional SI mutations with a range of inheritance patterns – homozygotes, heterozygotes, and compound heterozygotes – with a spectrum of phenotypic expressions and CSID severity.1 This range of inheritance patterns suggest CSID may be more prevalent than originally thought.2

The Etiology of CSID

Sucrase-isomaltase consists of two integral carbohydrate-digesting glycoproteins expressed in small intestinal enterocytes and transported to the cell membranes of brush border microvilli. Sucrase-isomaltase is a heterodimer, comprised of two subunits with two active sites, sucrase and isomaltase.3 Sucrase digests sucrose (white table sugar), whereas isomaltase contributes to starch digestion. Sugar and starch are digested into monosaccharides (sucrose to fructose and glucose, starch to glucose), which are transported across the epithelial brush border for absorption.1 Unhydrolyzed disaccharides from sugars and starches cannot be absorbed and result in symptoms of malabsorption.

About CSID Sucrose into glucose and fructose

Figure 1. Sucrose digestion by sucrase into its constituent subunits, glucose and fructose, to facilitate gastrointestinal absorption.4

Absent or diminished sucrase-isomaltase enzyme activity allows undigested sugars to collect in the lumen of the small intestine and pass into the large intestine, causing colonic fermentation and acidic, watery diarrhea via osmosis. Colonic bacterial fermentation also releases methane, hydrogen, and carbon dioxide, causing abdominal gas, bloating, and pain. Symptom severity depends on the amount of sugar and starch consumed, the degree of enzyme deficiency, the buffering effect of other consumed foods, the age and GI tract length of the patient, and the rate of gastric emptying. Left untreated, the disease can lead to accelerated motility and broad malabsorption of all nutrients (not just carbohydrates) resulting in weight loss, low body mass index, dehydration, metabolic acidosis, hypercalcemia, failure to thrive, and developmental delay.1

Originally described as a homozygous recessive disorder, researchers have discovered that there are many genetic variants and combinations (genotypes) that can diminish sucrase-isomaltase activity and cause clinical symptoms. So far, at least 36 distinct pathogenic variants have been identified in patients with a confirmed diagnosis of CSID,5-13 and symptomatic genotypes include SI heterozygotes, compound heterozygotes, and homozygotes.1There are more than 2,000 identified rare variants in SI, and while most are likely benign, many have not been analyzed for possible deleterious impacts on enzyme expression or function.14

Who Is Affected by CSID?

Congenital Sucrase-Isomaltase Deficiency was first identified in 1960 among children who presented with chronic, osmotic diarrhea, irritability, and vomiting after consuming sucrose.15 Males and females are affected equally by CSID. When sucrase activity is severely diminished, gastrointestinal symptoms of CSID most clearly manifest shortly after birth, when infants are weaned from breast milk and begin eating foods that contain sucrose and starch. Children may present with symptoms that are more severe because they have a shorter small intestine.1 Patients who have CSID with moderate enzyme deficiency may not have a classic presentation of severe osmotic diarrhea in early childhood and may not be diagnosed until they are adolescents or adults. Symptom severity likely relates to the degree of enzyme deficiency and the amount of sucrose and starch consumed.

Prevalence

The actual prevalence of CSID is likely underestimated since symptoms overlap with other, more common gastrointestinal disorders.2 Patients may wait years for a diagnosis because the gold-standard diagnostic test requires an invasive duodenal mucosal biopsy sample for a disaccharidase activity assay.

Studies in select populations of endoscopic samples from adults with gastrointestinal symptoms have suggested CSID prevalence varies by ethnicity, as shown in Table 1 below:

Table 1. Previously Estimated Prevalence of CSID in Select Groups2,16

Greenland Eskimos 5-10%
Canadian natives 3-7%
Alaskans of native ancestry 3%
North Americans of European descent 0.05-0.2%

Recent Studies Indicate a Higher Possible CSID Prevalence

Since infants and young children are often misdiagnosed, the actual prevalence of CSID is likely higher than indicated above. In a recent study performed by American researchers, over 30,000 mucosal biopsy samples were collected during pediatric endoscopies and evaluated using a disaccharidase assay; 9.3% demonstrated a sucrase deficiency, which may or may not be genetic.17

References

  1. Cohen SA. The clinical consequences of sucrase-isomaltase deficiency. Mol Cell Pediatr. 2016;3:5. doi: 10.1186/s40348-015-0028-0.
  2. Treem WR. Congenital Sucrase-Isomaltase Deficiency. J Pediatr Gastroenterol Nutr. 1995;21(1):1-14.
  3. Hunziker W, Spiess M, Semenza G, Lodish HF. The sucrase-isomaltase complex: primary structure, membrane-orientation, and evolution of a stalked, intrinsic brush border protein. Cell. 1986;46(2):227-34.
  4. Gray GM. Carbohydrate digestion and absorption. Role of the small intestine. N Engl J Med.1975;292(23):1225-30.
  5. Alfalah M, Keiser M, Leeb T, et al. Compound heterozygous mutations affect protein folding and function in patients with Congenital Sucrase-Isomaltase Deficiency. Gastroenterology. 2009;136(3):883-92.
  6. Gericke B, Amiri M, Naim HY. The multiple roles of sucrase-isomaltase in the intestinal physiology. Mol Cell Pediatr. 2016;3(1):2. doi: 10.1186/s40348-016-0033-y.
  7. Jacob R, Zimmer KP, Schmitz J, et al. Congenital Sucrase-Isomaltase Deficiency arising from cleavage and secretion of a mutant form of the enzyme. J Clin Invest. 2000;106(2):281-7.
  8. Keiser M, Alfalah M, Pröpsting MJ, et al. Altered folding, turnover, and polarized sorting act in concert to define a novel pathomechanism of Congenital Sucrase-Isomaltase Deficiency. J Biol Chem. 2006;281(20):14393-9.
  9. Naim HY, Heine M, Zimmer KP. Congenital Sucrase-Isomaltase Deficiency: heterogeneity of inheritance, trafficking, and function of an intestinal enzyme complex. J Pediatr Gastroenterol Nutr. 2012;55(suppl 2):S13-20.
  10. Ritz V, Alfalah M, Zimmer KP, et al. Congenital Sucrase-Isomaltase Deficiency because of an accumulation of the mutant enzyme in the endoplasmic reticulum. Gastroenterology. 2003;125(6):1678-85.
  11. Sander P, Alfalah M, Keiser M, et al. Novel mutations in the human sucrase-isomaltase gene (SI) that cause congenital carbohydrate malabsorption. Human Mutat. 2006;27(1):119. doi: 10.1002/humu.9392.
  12. Spodsberg N, Jacob R, Alfalah M, et al. Molecular basis of aberrant apical protein transport in an intestinal enzyme disorder. J Biol Chem. 2001;276(26):23506-10.
  13. Uhrich S, Wu Z, Huang J, Scott CR. Four mutations in the SI gene are responsible for the majority of clinical symptoms of CSID. J Pediatr Gastroenterol Nutr. 2012; 55(2):S34-5.
  14. Garcia-Etxebarria K, Zheng T, Bonfiglio F, et al. Increased prevalence of rare sucrase-isomaltase (SI) pathogenic variants in irritable bowel syndrome patients. Clin Gastroenterol Hepatol. doi: 10.1016/j.cgh.2018.01.047. [Epub ahead of print]
  15. Weijers HA, van de Kamer JH, Mossel DA, Dicke WK. Diarrhoea caused by deficiency of sugar-splitting enzymes. Lancet. 1960;2(7145):296-7.
  16. Treem WR. Clinical aspects and treatment of Congenital Sucrase-Isomaltase Deficiency. J Pediatr Gastroenterol Nutr. 2012;55(suppl 2):S7-13.
  17. Nichols BL, Adams B, Roach CM, Ma CX, Baker SS. Frequency of sucrase deficiency in mucosal biopsies. J Pediatr Gastroenterol Nutr. 2012;55(suppl 2):S28-30.