Quantitative assessment of whole body galactose metabolism in galactosemic patients.

We employed [1-13C] galactose in isotope kinetic studies to delineate whole body galactose metabolism in vivo in patients with galactose-1-phosphate uridyltransferase (GALT) deficiency. The data in three control and three adult galactosemic subjects, homozygous for the most common GALT gene defect, the Q188R mutation, and with absent RBC GALT activity, revealed an apparent endogenous galactose synthesis rate of 0.53-1.05 mg/kg per hour. Unlike normal children and adults who eliminated 3%-6% and 21%-47% of an intravenous bolus of [1-13C] galactose as 13CO, in expired air in 1 and 5 h respectively, classic galactosemic patients, either Q188R/Q188R or Q188R/unknown, released almost none in 1 h and 3%-6% in 5 h. In contrast, an African-American galactosemic variant patient with a S135L/S135L mutation and no residual RBC GALT activity oxidized [1-13C]galactose to 13CO2 at a rate comparable to control subjects. Individuals homozygous for the Duarte mutation, N314D/N314D and Q188R/ N314D. Q188R/+ and S135L/+ subjects also had normal breath test results. Not surprisingly, the Q188R/Q188R classic galactosemic patient cannot handle an acute galactose load, failing to match a control subject in the rapid conversion of [1-13C]galactose to [13C]glucose and 13CO2. However, classic patients synthesize substantial quantities of galactose de novo and on a lactose-free diet must oxidize comparable amounts of galactose to maintain steady-state levels of galactose and galactose metabolites such as galactose-1-phosphate, galactitol and galactonate. In vivo isotope kinetic analyses may allow us to understand better these aspects of galactose metabolism and, through the use of studies in variant galactosemics, perhaps allow us to begin to unravel the pathophysiology of galactosemia.