*) partly presented at the EGS Annual Meeting, June 2001

In patients with classical galactosaemia, i.e. galactose-1-phosphate uridyltransferase (GALT) deficiency (McKusik 230400), long-term disturbances emerge even when the patients are on an extremely galactose restricted diet. This might - at least in part - be attributable to the production of free galactose from endogenous sources leading to a so-called 'autointoxication' in the patients.

We now addressed the question of quantity and age dependency of endogenous galactose production in galactosaemia. The rate of release of galactose from intracellular sources into plasma is assessed in overnight fasted healthy adults and galactosemic patients by galactose turnover measurements in vivo using stable isotope (1-13C)-labelled galactose as substrate and the primed continuous infusion approach ([1-13C]galactose priming i.v., 1 mg/kg body weight; i.v. infusion; 0.15 mg/kg body weight per h for 6 h). According to our experience, stable metabolic conditions are reached within 3 h after start of 13C-label infusion.

The main findings of these ongoing investigations are as follows (as of August 2001): In controls, the release of endogenous galactose into plasma in controls was about 0.05 mg/kg body weight per h, equivalent to about 1.3 mg/kg per d, under steady state conditions. Galactose disposal by oxidation - as estimated from the 13C-label enrichment in plasma galactose and expired carbon dioxide - accounted for about 99 percent of whole body galactose disposal. In accordance, only minor amounts of endogenous galactose were found to be disposed by the kidneys (< 2 percent).

Up to now, in vivo turnover studies have been performed in 20 galactosemic patients. Seven patients (4-30 years) were homozygous for the most common Q188R mutation, six (4-29) were compound heterozygous for Q188R, and seven (6-29 years) exhibited a non-Q188R genotype. The galactose-1-phosphate concentration was < 5 mg/dl red blood cells (RBC) in all patients, indicating good to moderate dietary control. As yet, only part of the experiments have been evaluated. Therefore, the data presented herein (rates per day as extrapolated from the experimental data) are necessarily preliminary results.

In any case, in patients exhibiting GALT activity in RBC of less than 1 % of control, the release of galactose from endogenous intracellular sources ranged from 10 to 20 mg/kg body weight per d. In addition, about 3 to 10 mg/kg body weight per d of galactose was obviously converted intracellularly to yield galactitol prior to the release into the plasma compartment and subsequent excretion by the kidneys. Thus, estimates for total endogenous galactose production ranged from 12 to 25 mg/kg body weight per d (about 800 - 1800 mg/d at 70 kg).

Importantly, a statistically highly significant correlation (p < 0.0001) was found between age and endogenous galactose production. According to the currently available data, the production apparently decreased gradually with age, amounting to 20-25 mg/kg body weight per d in young children < 6 years and to generally less than 10 mg/kg body weight per d in adult patients. Somewhat unexpectedly, we found a significant increase in 13C-label incorporation into expired carbon dioxide in all but one patient (of the < 1% GALT activity group) accounting for a residual whole body galactose oxidation of 1-5 mg/kg body weight per d, i.e. about 10-20% of the endogenous galactose release. Galactose clearance by the kidney accounted for 1-5%. The metabolic fate of the remainder is now under investigation.

An interesting but yet individual finding was made in a variant form of galactosaemia. On occasion of the galactose turnover study, a patient with a Q188R/I32N genotype and a residual GALT activity of just 12 percent of control not only exhibited normal galactose metabolite levels (galactose, galactitol, galactose-1-phosphat) but also perfectly normal turnover rates, including galactose production and oxidation and renal metabolite disposal. This indicates that only a few percent of residual GALT activity may be sufficient for maintenance of normal whole body galactose turnover rates. Detection of the appropriate threshold value would be important in this context.

In conclusion, our preliminary data suggest (1) that free galactose is produced from endogenous sources at a (patho)physiologically relevant rate in galactosaemia, (2) that endogenous galactose production decreases significantly with age and (3) that (near) normal whole body galactose turnover rates can be achieved even at low - yet to be defined - residual GALT activities.