Cognitive and Behavioral Manifestations of Classical Galactosemia

An autosomal recessive group of disorders, galactosemia is caused by a deficiency of one of four enzymes: galactose mutarotase (GALM), galactokinase (GALK), galactose-1-phosphate uridyltransferase (GALT), and UDP-galactose epimerase (GALE) (Holton et al. 2001). Galactose-1-phosphate uridyltransferase deficiency is clearly the most prevalent of these four and is labeled classical galactosemia. All of the information provided in this chapter refers to classical galactosemia. These four enzymes metabolize galactose to glucose. Lacking one of these enzymes, galactose accumulates in individuals with galactosemia. Treatment involves a galactose-restricted diet and, with this diet, the normally high levels of galactose that are excreted in the urine return to normal (Jakobs et al. 1995). Endogenous production of galactose, however, amounting to 1 g/day in adults, has been suggested to be a major cause of the substantial disease morbidity (Schadewaldt et al. 2004). Thus, even with strict dietary elimination of galactose, the human body produces galactose endogenously. Also due to the GALT deficiency, galactose-1-phosphate cannot be further metabolized and begins to accumulate in red blood cells and other cells and tissues. Unlike the normalization of urinary galactose excretion, galactose-1-phosphate concentrations remain elevated even with dietary treatment relative to healthy comparison subjects (Holton et al. 2001). In addition, if untreated, significantly elevated concentrations of galactitol are detected in plasma, as well as in urine in individuals with galactosemia. With treatment, plasma galactitol and the urinary excretion of galactitol decrease, yet still remain above the upper limit of normal (Jakobs et al. 1995). Thus, the pathophysiology of galactosemia is manifold and involves elevations of galactose, galactose-1-phosphate, and galactitol. Screening for galactosemia is part of newborn screening programs in all 50 states and most countries worldwide. A positive screen will be followed up with measurement of galactose-1-phosphate uridyltransferase activity in red blood cells. If done before the fifth day of life, neonatal screening can prevent acute morbidity and mortality, yet does not change the long-term outcomes of significant disease morbidity (Schweitzer-Krantz 2003).