Myo-Inositol Deficiency, Structural Brain Changes, and Cerebral Perfusion Alterations in Classic Galactosemia:...

Classic galactosemia is a rare metabolic disorder resulting from galactose-1-phosphate uridylyltransferase deficiency, which disrupts normal galactose metabolism, leading to toxic accumulation of galactose-1-phosphate and galactitol. Despite early dietary intervention, patients remain at risk for long-term neurological impairments, including cognitive deficits, motor speech disorders, and psychiatric conditions. The mechanisms driving these persistent abnormalities remain unclear. This study investigated brain metabolic and structural alterations in adults with classic galactosemia using advanced multiparametric MRI. Six patients (3 males, 3 females; mean age 34.0 ± 7.3 years) adhering to lifelong galactose-restricted diets and six age- and sex-matched controls underwent 3T and 7T MRI, including T1-weighted imaging, pseudo-continuous arterial spin labeling, and high-resolution MR spectroscopic imaging. Patients exhibited significantly lower myo-inositol (mIns) concentrations in cerebellum (p = 0.007), putamen (p = 0.023), and cerebral white matter (p = 0.001), reflecting a chronic mIns deficiency despite dietary management. Structural analyses revealed reduced volumes of white matter (p < 0.001), bilateral putamen (p < 0.038), and left thalamus (p = 0.044); alongside increased cortical thickness and reduced cortical surface area, indicating abnormal cortical maturation, particularly in regions associated with motor and cognitive processing. Additionally, cerebral blood flow was elevated in emotion-processing regions, including bilateral amygdala (p < 0.022) and thalamus (p < 0.038). These preliminary findings highlight persistent neurological alterations in classic galactosemia despite dietary management and suggest that chronic mIns deficiency may contribute to the pathophysiology. They underscore the need for larger, longitudinal studies to confirm these results, investigate potential correlations with clinical severity and biochemical markers, and explore therapeutic strategies aimed at modulating mIns metabolism.