Pathophysiological Basis of Diarrhea in Classical Galactosemia: A Novel Hypothesis

Classical galactosemia (CG) is an autosomal recessive condition that results from a deficiency of galactose-1-phosphate uridyltransferase (GALT), an essential enzyme in the Leloir pathway responsible for galactose metabolism. The enzymatic defect leads to the accumulation of galactose and galactose-1-phosphate, driving activation of alternate metabolic routes and resulting in the buildup of toxic metabolites, energy depletion, and redox imbalance. More than a century after its first description in 1908, CG remains an enigmatic disorder: while its clinical spectrum is well documented, the mechanisms driving many of its manifestations are still poorly understood. Among these, diarrhea, a symptom reported in approximately 12% of symptomatic neonates, is clinically significant yet largely unexplored.

Here, we propose a novel hypothesis linking diarrhea in CG to impaired energy metabolism and injury to gastrointestinal epithelial cells. The accumulated galactose-1-phosphate disrupts phosphate homeostasis, inhibits glycolytic and glycogenolytic enzymes, contributes to mitochondrial dysfunction, and activates the futile cycle of galactose phosphorylation and dephosphorylation, etc. Along with this reduced flux through the glycolytic pathway due to non-metabolism of galactose diminishes cellular ATP level. This diminished ATP impairs the function of Na⁺/K⁺-ATPase of the intestinal basolateral membrane, thereby weakening the sodium gradient essential for SGLT1-mediated absorption of glucose and galactose across the intestinal brush border from the apical membrane. The resulting malabsorption of these osmotically active sugars draws water into the intestinal lumen, producing diarrhea. In parallel, additional stressors—including osmotic disturbances from galactitol, oxidative damage from NADPH depletion, endoplasmic reticular stress, dysregulation of the myoinositol pathway, and altered redox potential due to galactonate production—further compromise epithelial integrity and cause cell damage. This leads to impairment of fluid absorption and potentiates diarrheal symptoms.

Strikingly, dietary exclusion of lactose resolves diarrhea in CG patients, supporting our model by preventing activation of these pathogenic mechanisms. This hypothesis addresses a longstanding gap in understanding CG-associated gastrointestinal pathology and may open avenues for targeted therapeutic interventions beyond dietary restriction.