Galactose breath testing distinguishes variant and severe galactose-1-phosphate uridyltransferase genotypes

A galactose breath test that quantitates [1-C-13]galactose conversion to (C O2)-C-13 provides information on the whole body galactose oxidative capacit y. As there is little information on the relationship between whole body ox idation and the genotype in patients with galactosemia, we measured the (CO 2)-C-13 excretion for 2 h after administration of [1-C-13]galactose in 37 p atients (3-48 y old) with galactose-l-phosphate uridyltransferase (GALT) de ficiency and 20 control subjects (3-37 y old). Eleven patients with the com mon Q188R/Q188R genotype and no detectable erythrocyte GALT activity elimin ated <2% of a bolus of [1-C-13]galactose as (CO2)-C-13 compared with 8.47 t o 28.23% in controls. This defines a severe metabolic phenotype. Seven pati ents with one Q188R allele and a second mutant allele such as L195P, E308K, V151A, M142K, or O344K and one patient with a K285N/unknown genotype also released <2% as (CO2)-C-13 in 2 k The presence of N314D or S135L as the sec ond mutant allele does not impair total body galactose oxidation, as indivi duals with the GALT genotype of Q188R/N314D, K285N/N314D, and Q188R/S135L h ad normal 2-h galactose breath tests. Subjects with S135L/S135L, N314D/N314 D, S135/Delta T2359 as well as other rarer genotypes such as R258C/Y209C, E 203 K/IVSC-N314D, K285N/T138M, Q188R/D113N, S135L/F171S, R148W/N314D, and I VSC-N314D/N314D oxidized galactose comparable to controls. The dissociation of residual erythrocyte GALT activity and whole body galactose oxidative c apacity is exemplified by blacks with a S135L/S135L genotype and absent ery throcyte GALT activity. An oral 2-h [1-C-13]galactose breath test distingui shes severe and Variant GALT genotypes and enables delineation of the exten t of impaired galactose metabolism in an array of patients who possess dive rse GALT mutations. It may prove to be useful in establishing whether a pat ient is capable of manifesting disease similar to patients with a Q188WQ188 R genotype.