Comprehensive Review of Galactosemia: Genotype-Phenotype Correlations, Molecular Pathophysiology, and Clinical Spectrum

Abstract

Galactosemia is a hereditary disorder of carbohydrate metabolism with autosomal recessive inheritance, resulting from a defect in an enzyme in the Leloir pathway. The most common and severe form is classical galactosemia (Type I), caused by a deficiency of the enzyme Galactose-1-Phosphate Uridyltransferase (GALT). Despite early diagnosis through newborn screening and strict dietary restriction, patients with classical galactosemia continue to face debilitating long-term complications, including cognitive impairment, speech apraxia, and premature ovarian insufficiency (POI).

This review article provides a detailed examination of the molecular genetics of the GALT gene, genotype-phenotype correlation analysis in common variants (p.Q188R, p.S135L, Duarte), and specific mutations in the Iranian population. Furthermore, cellular mechanisms of injury, including endoplasmic reticulum (ER) stress, oxidative stress, and protein glycosylation defects, are discussed as primary factors for the occurrence of complications despite treatment. The main clinical take-home message is that genotype strongly predicts long-term outcomes, and dietary restriction alone does not prevent neurological or ovarian complications; therefore, early genetic diagnosis and personalized monitoring are essential.