Galactose mutarotase deficiency as the galactosemia type IV

Galactose, a monosaccharide, plays diverse biological roles in energy production, especially in the glycolysis and glycosylation of proteins and lipids. Galactose metabolism is mediated by the Leloir pathway, which comprises four key enzymes. Following lactose hydrolysis, galactose mutarotase (GALM) catalyzes the anomerization of β-D-galactose to α-D-galactose, providing a substrate for the downstream pathway. In 2019, GALM deficiency was defined as the fourth type of galactosemia. Affected individuals may develop cataracts similar to those observed in individuals with galactokinase deficiency, disrupting the subsequent steps in the Leloir pathway. However, cataracts generally occur less frequently and tend to be milder in patients with GALM deficiency, likely because of the partial compensation provided by spontaneous galactose mutarotation in aqueous solutions. Because lactose, the primary dietary source of galactose, is the predominant carbohydrate consumed until weaning, the timely initiation of lactose restriction can prevent or even reverse cataract formation. To date, other complications or adverse events, including those in heterozygous carriers of GALM variants, have not been clearly demonstrated. This review aims to synthesize current knowledge and findings of GALM deficiency on molecular mechanisms, clinical presentation, diagnostic approaches, carrier risk, and dietary management, with particular emphasis on cataract prevention and reversibility through early lactose restriction. By consolidating available evidence, we propose future research directions, with broader implications for newborn screening programs, clinical decision-making, and a deeper understanding of galactose metabolism.