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PubMed1990

Results of newborn screening for galactose metabolic disorders.

A screening strategy has been used which uses the Paigen and Beutler methods for the determination of galactose and galactose-1-phosphate. A blood spot test for epimerase has also been developed. In the last 10 years, 265,019 samples from newborns have been tested by these methods. Among the 154 screening positives, we have detected seven cases of epimerase-deficient galactosaemia (Type III), seven cases of Duarte/galactosaemia heterozygotes, 48 cases of other various types of heterozygotes, four cases of persistent hypergalactosaemia, three cases of hepatitis and one case of congenital atresia of the bile duct. These results indicate that our screening system has effectively detected the infants with galactose metabolic disorders.

Carbohydrate Metabolism, Inborn Errors↗
PubMed1986

Gonadal function in patients with galactosaemia.

Gonadal function was followed in 26 females and 12 males with galactosaemia due to deficiency of the enzyme galactose-1-phosphate (Gal-1-P) uridyl transferase over a 4 year period. Gonadal function was normal in males, but all females except two had evidence of acquired ovarian failure. Twelve females with ovarian failure documented at the beginning of this study continued to have either primary or secondary amenorrhoea on follow-up. Five of six patients, who previously had normal gonadal function developed either hypergonadotrophic hypogonadism or an abnormal response to gonadotrophin-releasing hormone (LRH) indicative of acquired ovarian damage. Seven of eight female patients, 1-12 years of age, who were evaluated for the first time had an exaggerated release of gonadotrophins during LRH stimulation tests diagnostic of gonadal insufficiency. The pathogenesis of ovarian failure remains unknown, but it appears likely that galactose or Gal-1-P is toxic to the ovary. The source of galactose metabolites, which may begin to accumulate prenatally and continue to damage the gonad in the postnatal period, is likely to be derived from the diet and from the endogenous synthesis of Gal-1-P from glucose via a variety of metabolic pathways. The testis appears to be relatively resistant to the effects of abnormal galactose metabolism.

Adolescent↗
PubMed1990

Regulation of galactose metabolism: implications for therapy.

In view of evidence that dietary therapy of galactose-1-phosphate uridyltransferase deficiency has failed to prevent complications of the disorder, there is a need for new strategies in treatment. The enhancement of residual enzyme activity in tissues of galactosaemic patients should provide such an approach. This possibility is derived from knowledge of the regulation of transferase activity in normal animal tissues. The pertinent observations summarized herein are: (1) that hepatic transferase activity is modulated by various cellular metabolites, uridine nucleotides being of particular significance; (2) that transferase activity in the young rat liver is subject to developmental programming with a several-fold increase after birth; (3) that transferase activity in pregnant rat liver is significantly increased which may be related to hormonal effects of progesterone; and (4) that pharmacological doses of folic acid may increase transferase activity. The basis of such regulation can give insight into sufficient augmentation of the residual activity to increase galactose utilization and thereby better the long-term outcome.

Animals↗
PubMed1996

Molecular characterization of Duarte-1 and Duarte-2 variants of galactose-1-phosphate uridyltransferase.

The N314D polymorphism was found in two different alleles of the galactose-1-phosphate uridyltransferase (GALT) gene, Duarte-1 (D1) and Duarte-2 (D2). Although both variants have identical electrophoretic mobility and isoelectro-focusing points, the galactose-1-phosphate uridyltransferase (GALT) activity varies: D1 alleles showed 110-130% of the normal RBC activity, but D2 alleles only 40-50%. We found that D1 alleles also carried a silent mutation in exon 7 (L218L) in addition to N314D. In contrast, besides N314D, D2 alleles carried two regulatory mutations, G1105C and G1391A, in introns D and E, respectively. In normal and Q188R alleles none of the above four mutations coexisted. However, some galactosaemia alleles with mutations other than Q188R, such as W316X and E340X of exon 10, also carried the N314D mutation. The W316X alleles existed in cis with the intron mutations (G1105C and G1391A), whereas those with E340X are in cis with L218L. In all cases examined, the intron mutations were not found in D1 alleles and no D2 alleles had the silent mutation of L218L. These results suggest that the decrease in the GALT activity in D2 may be due to regulation of the GALT gene expression. The G1105C site may be critical to the function of erythroid transcription factor NF-E1, since it flanks the core consensus sequence for one of its binding sites. The G1391A mutation may affect another cis-acting regulatory sequence. Alternatively, both mutations may be involved in an aberrant splice processing, which possibly results in a low level of correctly spliced mRNA.

Alleles↗
PubMed1987

Galactose metabolism in transferase-deficient galactosaemic and normal long-term lymphoid cell lines.

The activity (mean +/- SD) of galactose-1-phosphate uridyl transferase in two long-term lymphoid cell lines from Caucasian patients with transferase deficiency galactosaemia, a heterozygote, and eight normal subjects was 0, 78 and 168 +/- 55 nmol UDPG consumed (mg protein)-1h-1, respectively. Also, no activity was found in erythrocytes and cultured fibroblasts from the patients. A small number of cells of the galactosaemic lines cultured in medium, in which galactose was substituted for glucose, survived for 37 days. Normal and galactosaemic lines incubated with D-galactose-[1-14C] liberated 218.2 +/- 65.6 and 18.1 pmol 14CO2 (mg cellular protein)-1 (6h)-1, respectively. The evolution of 14CO2 from D-glucose-[1-14C] was similar in normal and galactosaemic lines. In the presence of [3H]galactose the radioactivity incorporated into TCA-precipitated material of the galactosaemic lines was 6.8% of the normal lines. Approximately 26% and 1.3% of the total radioactivity was incorporated into molecular species with a molecular weight greater than 400,000 daltons in normal and galactosaemic cells, respectively. Similar molecules were identified in the cell-free medium of both normal and deficient cells except for an 18,000 daltons molecule identified only in the medium of the normal cells. These findings indicate that a small amount of galactose is metabolized in galactosaemic lines with no transferase activity.

Carbon Dioxide↗
PubMed1990

Culture of galactosaemic fibroblasts in the presence of galactose: effect of inosine.

Fibroblasts from three galactosaemics had no galactose-1-phosphate uridyltransferase (GALT) activity. These fibroblasts cells were cultured in different media supplemented with dialysed fetal calf serum. Galactosaemic and control cell strains stopped growing in hexose-free medium. In glucose-free medium containing galactose, galatosaemic cells, in contrast to control cells, stopped growing after two days and died. In the same medium supplemented with inosine, they exhibited the same growth pattern as the control cell strains although in the presence of high concentrations of galactose-1-phosphate (Gal-1-P). These findings indicated that the glucose-free medium containing galactose supplemented with dialysed fetal calf serum and inosine, as a ribose donor, was appropriate for further in vitro investigations of galactose metabolism in galactosaemic cells.

Cell Division↗
PubMed1992

Erythrocytic uridine diphosphate galactose in galactosaemia.

An earlier claim of a deficiency of uridine diphosphate galactose in erythrocytes of galactosaemia patients was not confirmed. Enzymic techniques similar to those of the earlier investigators were used to determine not only the concentration of uridine diphosphate galactose but also the ratio of this concentration to the sum of the uridine sugar diphosphates (uridine diphosphate galactose and uridine diphosphate glucose). The values in erythrocytes of galactosaemic subjects were similar to those of non-galactosaemic children on a galactose-restricted diet and to those of normal adults. These results cast doubt on the claim of a major deficiency of uridine diphosphate galactose in galactosaemia and on the need for treating galactosaemic children with uridine.

Adult↗
PubMed1991

Fruits and vegetables are a source of galactose: implications in planning the diets of patients with galactosaemia.

It has become apparent that removing dairy products from the diets of patients with galactosaemia does not sufficiently diminish the deleterious signs. We have determined the amount of soluble monomeric galactose in 45 fruits and vegetables using capillary gas chromatography and selective ion monitoring. Galactose contents ranged from less than 0.1 mg per 100 g of tissue in artichoke, mushroom, olive, and peanut to 35.4 mg per 100 g in persimmon. Fruits and vegetables with over 10 mg per 100 g included date, papaya, bell pepper, tomato and watermelon. These results will provide important data for planning the diets of patients with galactosaemia.

Fruit↗
PubMed1989

Uridine nucleotide sugars in erythrocytes of patients with galactokinase deficiency.

The levels of UDPglucose and UDPgalactose (UDPGal) have been measured in erythrocytes of seven patients with galactokinase deficiency. Normal levels of UDPGal were found in all patients with galactokinase deficiency (McKusick 23020). This is in contrast with reduced values of UDPGal found in patients with classical galactosaemia who have complete absence of galactose-1-phosphate uridyl transferase activity. It was demonstrated that patients with galactokinase deficiency had an incomplete enzyme block in erythrocytes by direct enzyme assay, by 14CO2 production from [1-14C]galactose, and by the appearance of labelled intermediates, notably galactose-1-phosphate and UDPhexose.

Adolescent↗