Background and pathophysiology of congenital sucrase-isomaltase deficiency (CSID)
An uncommon hereditary condition known as CSID affects around 0.05%–0.2% non-Hispanic Whites; meanwhile, African-Americans and White Hispanics exhibit a lower prevalence. As many as 5 in 100 people may be affected by this disorder in the native communities of Canada, Alaska, and Greenland1. CSID is characterized by a lack of the sucrase-isomaltase (SI) enzyme complex, usually present in the brush border of the small intestine, which is necessary for the dissociation of α-glycosidic bonds in sucrose and maltose.
At the molecular level, homozygous or heterozygous mutations on chromosome 3q25-q26 lead to improper synthesis and transportation of the SI gene. Ouwendijk et al2 were the first to describe a mutation in the SI gene linked to CSID. Such mutations have also been demonstrated to increase the incidence of irritable bowel syndrome (IBS), which shares symptoms and clinical characteristics with CSID3. Over 40 known mutations in the SI gene cause CSID4. Sucrase activity is typically decreased in CSID patients, but the activity of isomaltase varies from nonexistent to fairly normal, due to which nutrients from ingested starch and sucrose cannot be adequately absorbed when this enzyme complex is insufficient5.
Clinical presentation and diagnosis of CSID
A lack of SI can result in carbohydrate malabsorption, characterized by cramping, bloating, gas, and watery, osmotic-fermentative diarrhea6. Patients may suffer from persistent malnutrition and failure to thrive in more complicated situations7. After an infant is weaned and is introduced to a starch-rich and sucrose-rich diet, such as sugar, grains, and fruits, CSID gradually becomes apparent. However, others may have milder gastrointestinal symptoms either from start or for a long time before they are identified in early adulthood8.
Health care professionals have several options to help them diagnose CSID. Any infant who develops severe, watery diarrhea after consuming milk and glucose should be evaluated for CSID. Clinical evaluation, distinctive symptoms, a full patient history, or specialist testing may all help confirm a diagnosis of this illness. However, a small intestinal biopsy checked for disaccharidase activity is the standard test for CSID diagnosis; other less invasive investigations are the 13C-sucrose or sucrose hydrogen methane breath test. Another approach can be gene sequencing1.
Current treatment guidelines for CSID
Dietary management with a low-sucrose or sucrose-free diet is the primary treatment for CSID. Starch-free or a low-starch diet may also be recommended, particularly during the initial years of life. While some affected persons may develop sucrose tolerance in their 20s, others may remain sucrose intolerant throughout their lives.
In 1998, the Food and Drug Administration (FDA) authorized using multidose sacrosidase oral solution (Sucraid) to treat CSID. This oral solution contains sacrosidase derived from baker’s yeast and glycerin and is used as an enzyme replacement therapy9. Sacrosidase is a β-fructofuranoside fructohydrolase that hydrolyzes sucrose. It does not interact with oligosaccharides having 1,6 glucosyl linkages, in contrast to human intestine SI. In vitro, it is exceedingly potent, with 9000 IU of activity per milliliter and about 6000 IU of sucrase activity per milligram of protein. When combined with water, it has no flavor and is stable when refrigerated. This formulation has also shown tolerance to pH variations down to a pH of 1.5, and taking the enzyme with extra protein prevents the enzyme from being degraded by intragastric pepsin10. Many of the symptoms brought on by sucrose consumption can be alleviated with the use of Sucraid for those with this illness.
Sucraid approval was based on the 3 clinical trials that evaluated the efficacy of sacrosidase in patients with CSID. In the first trial by Treem et al11, the sucrose hydrogen breath test results showed a dramatic increase in sugar digestion efficiency. Sacrosidase was found to be most effective at higher doses. Similar findings were reported by Treem et al10 in another study. Moreover, sacrosidase significantly reduced both the frequency and intensity of gastrointestinal discomfort, as demonstrated by the long-term study conducted by QOL Medical, LLC12.
On September 7, 2022, the FDA approved Sucraid single-use containers to treat CSID in patients who weigh more than 15Â kg or 33 pounds. Sacrosidase is now marketed in both multidose and single-use vials. These new single-use containers would be much more practical and facilitate patient medication management13.
Limitations of sacrosidase (Sucraid)
The introduction of single-use containers means greater convenience for patients and reduced cost. Sacrosidase, as of now, is the only treatment for CSID, but it comes with limitations, such as its inability to break down certain sugars produced during starch digestion, so the diet’s starch intake may need to be limited. People with diabetes mellitus need to consult their doctors before taking Sucraid to avoid unannounced fluctuations in blood glucose levels. Patients can also experience some adverse effects, such as allergic reactions, which may cause swelling or difficulty breathing. Furthermore, QOL Medical is the only authorized manufacturer of the approved drug. News by FDA in 2018 reported a shortage in the production of Sucraid, which led to the distribution of an unapproved batch for patients with severe CSID14.
In 2021, a cross-sectional study led by Smith and colleagues demonstrated a significant improvement in patients’ symptoms and quality of life after treatment with sacrosidase. However, more than 85% of participants indicated that CSID had various effects on their daily lives even after receiving treatment. The majority complained that living with CSID harmed their social lives. Irritability, awkwardness, and feeling left out were the top 3 reported emotional effects8.
Conclusion
The drug’s limitations, impact on patient’s quality of life, and psychological well-being demands an alternative, better, and more efficient treatment option for CSID. Until then, the production of Sucraid should be doubled since the latest FDA approval means increased demand. A phase 4 trial is underway consisting of 1100 pediatric patients to evaluate the therapeutic dose of Sucraid15. Hopefully, this trial’s results will help transform an efficient version of the drug. Lastly, for primary prevention, there should be awareness programs and genetic counseling to guide people about CSID, which would help in early diagnosis, ultimately making treatment more accessible.
Ethical approval
Not applicable.
Source of funding
None.
Author contributions
S.T.A. and M.A.S. have done the conceptualization. M.S.M., A.M., and M.M.N.U. conducted the literature and drafting of the manuscript. M.A.S. performed the editing and supervision. All authors have read and agreed to the final version of the manuscript.
Conflict of interest disclosure
The authors declare that they have no financial conflict of interest with regard to the content of this report.
Research registration unique identifying number (UIN)
Not applicable.
Guarantor
All authors take responsibility for the work, access to data and decision to publish.
References
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2. Ouwendijk J, Moolenaar CE, Peters WJ, et al. 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. J Clin Invest 1996;97:633–41.
3. Garcia-Etxebarria K, Zheng T, Bonfiglio F, et al. Increased prevalence of rare sucrase-isomaltase pathogenic variants in irritable bowel syndrome patients. Clin Gastroenterol Hepatol 2018;16:1673–6.
4. Stenson PD, Mort M, Ball EV, et al. The Human Gene Mutation Database: towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies. Hum Genet 2017;136:665–77.
5. Chiruvella V, Cheema A, Arshad HM, et al. Sucrase-isomaltase deficiency causing persistent bloating and diarrhea in an adult female. Cureus 2021;4:14349.
6. Cohen SA. The clinical consequences of sucrase-isomaltase deficiency. Mol Cell Pediatr 2016;3:1–4.
7. Belmont JW, Reid B, Taylor W, et al. Congenital sucrase-isomaltase deficiency presenting with failure to thrive, hypercalcemia, and nephrocalcinosis. BMC Pediatr 2002;2:1–7.
8. Smith H, Romero B, Flood E, et al. The patient journey to diagnosis and treatment of congenital sucrase-isomaltase deficiency. Qual Life Res 2021;30:2329–38.
9. FDA Drug Approval Package. 1998. Accessed December 2, 2022.
https://www.accessdata.fda.gov/drugsatfda_docs/nda/98/20772.cfm
10. Treem WR, McAdams L, Stanford L, et al. Sacrosidase therapy for congenital sucrase-isomaltase deficiency. J Pediatr Gastroenterol Nutr 1999;28:137–42.
11. Treem WR, Ahsan N, Sullivan B, et al. Evaluation of liquid yeast-derived sucrase enzyme replacement in patients with sucrase-isomaltase deficiency. Gastroenterology 1993;105:1061–8.
12. QOL Medical, LLC. Open-label, long-term study of sucrase enzyme therapy for Congenital Sucrase-Isomaltase Deficiency. Data on file, OMC-SUC-3. 1997.
14. Related Information for Sacrosidase Oral Solution. 2018. Accessed December 2, 2022.
https://www.fda.gov/drugs/drug-shortages/related-information-sacrosidase-oral-solution
15. 7-day trial of sucraid for alleviating CSID symptoms in subjects with low, moderate, and normal sucrase levels. 2022. Accessed December 2, 2022.
https://www.clinicaltrials.gov/ct2/show/NCT05480761
