The role of polyols in the pathophysiology of hypergalactosemia

Abstract

Cellular accumulation of galactitol has been suggested to cause the apparent dietary-independent, long-term complications in classic galactosemia. Experimental animals rendered hypergalactosemic by galactose feeding accumulate tissue galactitol, as well as millimolar quantities of galactose, and manifest biochemical, physiological and pathological abnormalities which are generally eliminated or curtailed by the concomitant administration of an aldose reductase inhibitor. This includes reduced cellular content of the cyclic polyol, myo-inositol, which like galactitol may function as an alternate intracellular osmolyte. However, the abnormalities detected in experimental galactosemic animals are more compatible with findings in experimental diabetes mellitus than in human galactosemia. Because patients with galactokinase deficiency fail to manifest the CNS and ovarian complications which characterize classic galactosemia, yet during long-term lactose restriction excrete comparable urinary quantities of galactitol, this polyol alone is not likely to play an important role during postnatal life in the pathogenesis of long-term complications. Notwithstanding, a role for either galactitol or myo-inositol in an intrauterine toxicity cannot be dismissed.

Verbal Dyspraxia and Galactosemia

“…Galactitol accumulation in lens fibers is associated with cataract formation in human galactokinase and hGALT deficiencies (2,31,32). Galactitol is produced from excess Dgalactose by aldose reductase, when intracellular concentrations of D-galactose exceed the capacity of hGALT or human galactokinase (33). Because galactitol is not further metabolized, it accumulates in cells, produces osmotic effects that alter selective cell permeability, and consequently promotes cell death.…”

Is prenatal myo‐inositol deficiency a mechanism of CNS injury in galactosemia?

“…In other words, as the content of galactitol rises, myo-inositol levels decrease. As discussed below, this is not surprising, and quite expected based on the polyol literature (Berry 1995).…”

Galactosemia: The good, the bad, and the unknown

“…One study reported elevated galactitol in the amniotic fluid of a galactosemic fetus at 10 weeks gestation, and the elevated levels of galactose, gal-1P, and galactitol measured in the livers of two galactosemic fetuses at 20 weeks gestation were comparable to those found in neonatal infants dying of the disorder (reviewed in Holton et al, 2000). Elevated levels of gal-1P have been detected even in the cord blood of galactosemic infants born to mothers who abstained from galactose consumption during pregnancy (Gitzelmann, 1995), perhaps reflecting the capacity for endogenous production of galactose demonstrated originally by Berry and colleagues (Berry, 1995;Berry et al, 2004).…”