Galactitol, NADPH and cataracts in galactosaemia

Classic galactosaemia is an inherited deficiency (autosomal recessive, so both parents pass on a faulty gene copy) of galactose-1-phosphate uridyltransferase, an enzyme that helps convert galactose into glucose. Affected newborns have jaundice, hepatomegaly (an enlarged liver) and poor feeding within days or weeks of starting milk feeds.

With the normal route blocked, the enzyme aldose reductase (which reduces sugars to sugar alcohols) turns some of the surplus galactose into galactitol. Galactitol is poorly cleared from the lens fibres, the long cells that make up the lens, so water follows it in by osmosis. The fibres swell and lose their clarity, and a cataract develops.

Making galactitol also uses up NADPH, which the cell needs to regenerate glutathione, an antioxidant that helps clear reactive oxygen species (damaging oxygen-containing molecules). With less glutathione, these molecules are cleared less well, and the resulting oxidative damage can add to the osmotic injury. NADPH is also needed to reverse abnormal disulphide bonds (links between sulphur atoms in neighbouring proteins). If they persist, proteins cross-link, which can add to the damage.

Osmotic stress is regarded as the main mechanism, while losing NADPH can add oxidative damage. Early removal of galactose from the diet can partly prevent and reverse complications, including cataracts.