SI – Congenital Sucrase-Isomaltase Deficiency

The association between SI and congenital sucrase-isomaltase deficiency is supported by robust clinical and functional evidence. Two independent studies in Turkish cohorts have identified multiple probands with SI mutations. In one study, next-generation sequencing of 94 pediatric patients with chronic diarrhea revealed one new homozygous frameshift mutation and 10 heterozygous mutations, with two cases stemming from the same family and nine from unrelated families (PMID:37349966). This evidence is complemented by a detailed pedigree analysis that identified a 23‑month‑old index case with a SI mutation, c.317A>T (p.Cys106Tyr), and extended segregation in 109 family members, establishing a consistent autosomal recessive pattern (PMID:39128102).

Genetically, the mutation spectrum includes both homozygous and heterozygous variants, with the recurrent c.317A>T (p.Cys106Tyr) serving as a representative pathogenic change. The genetic data, encompassing over 10 probands and clear familial segregation with at least 12 affected relatives, reinforces the gene-disease association even though heterozygous individuals may be symptomatic in certain contexts.

Functionally, investigations have revealed that SI mutants exhibit impaired protein trafficking and reduced enzymatic activity. Cellular assays and biochemical analyses have categorized SI variants into groups based on their maturation and transport, mirroring the biochemical deficiencies observed in congenital sucrase-isomaltase deficiency (PMID:33375084). These experimental findings provide a mechanistic explanation for the clinical phenotype, thereby corroborating the genetic evidence.

Furthermore, the clinical presentations reported across studies consistently include symptoms such as abdominal pain, diarrhea, growth delay, and abdominal distention. This phenotypic spectrum supports the diagnosis of congenital sucrase-isomaltase deficiency and underlines the clinical utility of integrating genetic and functional data for patient management.

Despite the autosomal recessive inheritance, some heterozygous individuals display symptoms, suggesting variable penetrance and expressivity. This observation points towards a more complex genotype-phenotype relationship that may require additional inquiry in future studies.

Taken together, the genetic findings from unrelated probands combined with the segregation data and the functional deficits observed in SI mutants provide strong evidence for an association between SI and congenital sucrase-isomaltase deficiency. The integration of these data makes a compelling case for the clinical application of SI molecular diagnostics in patients presenting with relevant gastrointestinal symptoms.

Key Take‑home: The strong gene-disease association supported by both genetic and functional evidence establishes SI as a crucial marker for diagnosing congenital sucrase-isomaltase deficiency, guiding effective clinical management.

References

• Journal of genetics • 2023 • Prevalence of congenital sucrase-isomaltase deficiency in Turkey may be much higher than the estimates PMID:37349966
• The Turkish journal of gastroenterology • 2024 • Congenital Sucrase-Isomaltase Deficiency: Same Mutation with Different Clinical Presentations PMID:39128102
• Nutrients • 2020 • Differential Effects of Sucrase-Isomaltase Mutants on Its Trafficking and Function in Irritable Bowel Syndrome: Similarities to Congenital Sucrase-Isomaltase Deficiency PMID:33375084

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