SLC5A1 – Glucose-Galactose Malabsorption

Glucose-galactose malabsorption (GGM; MONDO:0011731) is a rare autosomal recessive disorder characterized by life-threatening osmotic diarrhea and dehydration in neonates. Affected infants present with severe diarrhea on ingestion of glucose or galactose, leading to hypernatremic dehydration and malnutrition without prompt dietary intervention (HP:0002014, HP:0001944, HP:0003228). Diagnosis relies on clinical presentation, carbohydrate elimination diets, and definitive molecular testing of SLC5A1.

Clinical Validity

Category: Definitive

Rationale: Over 300 reported cases spanning >30 years, including >107 unrelated probands in a literature review (PMID:32946683) with robust segregation in consanguineous and founder families, plus concordant functional defects in 46 patients screened (PMID:12139397).

Genetic Evidence

GGM follows an autosomal recessive inheritance pattern. Segregation analysis in an Old Order Amish pedigree documented 33 affected relatives carrying homozygous SLC5A1 mutations and four private founder alleles (PMID:20486940). Case series include 16 unrelated Saudi patients from consanguineous families (PMID:28753187) and multiple single cases worldwide. The variant spectrum comprises missense (e.g., c.82G>A (p.Asp28Asn)), nonsense (c.187C>T (p.Arg63Ter)), in-frame deletions (c.1107_1109del (p.Val371del)), and splice/frameshift mutations across all 15 exons. Recurrent alleles such as p.Cys255Trp and p.Gln457Arg have population-specific frequencies, with p.Gln457Arg enriched in Northern Sweden (PMID:34485913).

Functional / Experimental Evidence

Extensive in vitro studies demonstrate that most pathogenic missense variants cause defective trafficking of SGLT1 to the plasma membrane, abrogating Na⁺/sugar cotransport (e.g., p.Cys355Ser, p.Leu147Arg) (PMID:9098004; PMID:10036327). Some mutants (e.g., p.Gln457Arg) reach the membrane but are locked in an outward-facing conformation, preventing sugar translocation (PMID:34485913). Chemical rescue experiments and electrophysiological assays in Xenopus oocytes and mammalian cells consistently recapitulate the human phenotype, confirming haploinsufficiency as the mechanism of pathogenicity.

Conflicting Evidence

A minority of clinically suspected GGM cases lacked SLC5A1 mutations, underscoring the need for proper clinical evaluation (e.g., breath tests, dietary trials) before molecular testing (PMID:16446504).

Integration & Clinical Utility

SLC5A1 mutations definitively cause GGM via loss of SGLT1 function. Genetic diagnosis enables prenatal and early postnatal screening, guiding prompt initiation of glucose-free, galactose-free diets to prevent morbidity and mortality. Functional assay concordance underpins the reliability of variant interpretation in diagnostic and commercial genetic testing.

Key Take-home: Definitive evidence supports autosomal recessive SLC5A1 mutations as the cause of GGM; molecular diagnosis is essential for early dietary management and improved outcomes.

References

• Prenatal diagnosis • 1996 • Prenatal identification of a heterozygous status in two fetuses at risk for glucose-galactose malabsorption. PMID:8844006
• Gastroenterology • 1997 • Compound missense mutations in the sodium/D-glucose cotransporter result in trafficking defects. PMID:9098004
• Cell biochemistry and biophysics • 2002 • Molecular basis for glucose-galactose malabsorption. PMID:12139397
• Journal of paediatrics and child health • 2020 • Literature review on congenital glucose-galactose malabsorption from 2001 to 2019. PMID:32946683
• Function (Oxford, England) • 2021 • The Molecular Basis of Glucose Galactose Malabsorption in a Large Swedish Pedigree. PMID:34485913

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