Journal of Pharmacological Reports
Open Access
+44-77-2385-9429
+44-77-2385-9429
Riccardo Perfetti*, Susan E Waisbren, Jonathan W Mink, Evan Bailey and Shoshana Shendelman
Galactosemia confers long-term Central Nervous System (CNS) complications and other difficulties in most affected individuals, despite newborn screening and dietary galactose restriction allowing survival into adulthood. These complications include speech, cognition, motor, and behavioral deficits, as well as cataracts and ovarian insufficiency in women. Endogenous synthesis of galactose far exceeds the level achieved through a galactose-restricted diet, limiting the long-term benefits of dietary control. Thus, an urgent medical need exists for those with this disorder. Although our understanding of Galactosemia has evolved over the last two decades, its pathophysiology has not been fully elucidated. Proposed causes of the complex symptomatology include newborn galactose exposure, nonadherence to the galactose-restricted diet, and Galactose-1-phosphate (Gal-1p) accumulation. However, none of these have been shown to account for the long-term complications of disease. Galactitol, an abnormal metabolite found in the blood of individuals with both Galactokinase (GALK) and Galactose-1-phosphate uridyltransferase (GALT) deficiencies, is a critical pathogenic cause of these complications. Galactitol is a toxic metabolite of galactose, produced by the enzyme aldose reductase only in the presence of excess galactose and is not found in healthy individuals. Several lines of evidence support the galactitol hypothesis of galactosemia-associated CNS complications, including animal models and clinical findings in individuals with galactosemia. Understanding the role of galactitol may provide a pathway to preserve CNS function in galactosemia.
Published Date: 2024-08-26; Received Date: 2024-07-23