QUANTITATIVE ASSESSMENT OF WHOLE-BODY GALACTOSE METABOLISM IN GALACTOSEMIC PATIENTS

We employed [1-C-13]galactose in isotope kinetic studies to delineate whole body galactose metabolism in vivo in patients with galactose-l-p hosphate uridyltransferase (GALT) deficiency. The data in three contro l and three adult galactosemic subjects, homozygous for the most commo n GALT gene defect, the Q188R mutation, and with absent RBC GALT activ ity, 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-C-13] galactose as (CO 2)-C-13 in expired air in 1 and 5 h respectively, classic galactosemic patients, either Q188R/Q188R or Q188R/unknown, released almost none i n Ih and 3%-6% in 5h. In contrast, an African-American galactosemic va riant patient with a S135L/S135L mutation and no residual RBC GALT act ivity oxidized [1-C-13]galactose to (CO2)-C-13 at a rate comparable to control subjects. Individuals homozygous for the Duarte mutation, N31 4D/N314D and Q188R/N314D, Q188R/+ and S135L/+ subjects also had normal breath test results. Not surprisingly, the Q188R/Q188R classic galact osemic patient cannot handle an acute galactose load, failing to match a control subject in the rapid conversion of [1-C-13]galactose to [C- 13]glucose and (CO2)-C-13. However, classic patients synthesize substa ntial quantities of galactose de novo and on a lactose-free diet must oxidize comparable amounts of galactose to maintain steady-state level s of galactose and galactose metabolites such as galactose-l-phosphate , galactitol and galactonate. In vivo isotope kinetic analyses may all ow 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.