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PubMed1999

The molecular basis of transferase galactosaemia in South African negroids.

Transferase galactosaemia is an autosomal recessively inherited disorder caused by a deficiency of galactose-1-phosphate uridyltransferase (GALT). Manifestations include jaundice, vomiting, cataracts, mental retardation, speech abnormalities and poor growth. The GALT gene has been mapped and sequenced. The S135L mutation accounts for approximately 48% of galactosaemia alleles in African Americans and has been found to account for about 91% of galactosaemia alleles in negroid South African patients which suggested that the mutation had an African origin. We have calculated the S135L allele frequency (+/- 1SE) in a sample of healthy unrelated negroid South Africans to be 0.0067 (+/- 0.0024). The S135L mutation was also detected in negroid populations from other regions of Africa confirming its African origin.

Alleles↗
PubMed1999

Biochemical monitoring of treatment for galactosaemia: biological variability in metabolite concentrations.

Red cell galactose 1-phosphate (Gal-1-P) concentrations and urinary galactitol excretion have been suggested as biochemical indices of dietary compliance in classical transferase-deficient galactosaemia. We report our experience of measuring both in 32 patients over 0-10.9 years (median 3.45). A total of 438 blood specimens for Gal-1-P and 383 urine specimens for galacitol assay were received; 317 pairs of specimens were collected at the same time. Concentrations of both analytes fell rapidly over the first 2-3 months following dietary intervention, to mean (geometric SD) levels of 225 (1.60) mumol/L red cells for Gal-1-P and 388 (1.19) mumol/mmol creatinine for galactitol. Concentrations then fell exponentially over the next 7-8 years, with times to half-disappearance of 6.3 years for Gal-1-P and 6.4 years for galactitol, to levels of 104 (1.58) and 193 (1.36) respectively in patients aged over 10 years. Concentrations of both analytes were independent of the presence of the common Q188R mutation. Mean intra- and inter-individual coefficients of variation (CV) across the range of values studied were 36% and 61% for Gal-1-P, and 37% and 42% for galactitol. Analytical CVs were 3.6% for Gal-1-P and 5.5% for galactitol, indicating that the major source of variability is biological. The correlation coefficient between Gal-1-P and galactitol in paired samples overall was 0.33; the regression equation being [Galactitol] = 0.84[Gal-1-P] + 176. Serial measurements of both Gal-1-P and galactitol may be valuable in monitoring galactosaemia, but high intra-individual biological variability limits their usefulness. Standardization of sample collection times may improve this. Further work is needed to assess the predictive values of both analytes for long-term outcome.

Adolescent↗
PubMed2001

Congenital porto-left renal venous shunt as a cause of galactosaemia.

Congenital porto left renal venous (PRV) shunt was found to be the cause of galactosaemia in four galactosaemic neonates detected by mass screening (Paigen method). The patients did not have hereditary galactosaemias and were diagnosed as having galactosaemia of unknown cause, because porto-systemic venous (PS) shunts had not been recognized. At the time of diagnosis, hypergalactosaemia was not severe (0.44-0.55 mmol/L; 8-10 mg/dl) and plasma concentration of total bile acids (TBA) did not suggest a PS shunt (46-50 micromol/L). However, slightly but consistently increased concentrations of galactose and TBA strongly suggested the presence of a PS shunt, and careful ultrasonographic investigation revealed PRV shunt. We conclude that PRV shunt should be suspected in patients with hypergalactosaemia of unknown cause.

Female↗
PubMed2000

Studies of the V94M-substituted human UDPgalactose-4-epimerase enzyme associated with generalized epimerase-deficiency galactosaemia.

Impairment of the human enzyme UDPgalactose 4-epimerase (hGALE) results in epimerase-deficiency galactosaemia, an inborn error of metabolism with variable biochemical presentation and clinical outcomes reported to range from benign to severe. Molecular studies of the hGALE loci from patients with epimerase deficiency reveal significant allelic heterogeneity, raising the possibility that variable genotypes may constitute at least one factor contributing to the biochemical and clinical heterogeneity observed. Previously we have identified a single substitution mutation, V94M, present in the homozygous state in all patients genotyped with the severe, generalized form of epimerase-deficiency galactosaemia. We report here further studies of the V94M-hGALE enzyme, overexpressed and purified from a null-background yeast expression system. Our results demonstrate that the mutant protein is impaired relative to the wild-type enzyme predominantly at the level of Vmax rather than of Km. Studies using UDP-N-acetylgalactosamine as a competitor of UDPgalactose further demonstrate that the Km values for these two substrates vary by less than a factor of 3 for both the wild-type and mutant proteins. Finally, we have explored the impact of the V94M substitution on susceptibility of yeast expressing human GALE to galactose toxicity, including changes in the levels of galactose 1-phosphate (gal-1-P) accumulated in these cells at different times following exposure to galactose. We have observed an inverse correlation between the level of GALE activity expressed in a given culture and the degree of galactose toxicity observed. We have further observed an inverse correlation between the level of GALE activity expressed in a culture and the concentration of gal-1-P accumulated in the cells. These data support the hypothesis that elevated levels of gal-1-P may underlie the observed toxicity. They further raise the intriguing possibility that yeast may provide a valuable model not only for assessing the impact of given patient mutations on hGALE function, but also for exploring the metabolic imbalance resulting from impaired activity of GALE in living cells.

Amino Acid Substitution↗
PubMed1999

Attenuation of sugar cataract by ethyl pyruvate.

Studies describe an attenuation of sugar cataract formation by topical administration of ethyl pyruvate. Cataract formation was induced by feeding young rats a 30% galactose diet. Mature cataracts appeared in about thirty days. Instillation of the eye drops containing 5% ethyl pyruvate decelerated the process significantly. Biochemically, the effect was reflected by lowering in the contents of dulcitol and glycated proteins. The ATP levels were also higher in comparison to the placebo treated group. The effects are hence attributable to the effect of pyruvate in inhibiting dulcitol synthesis and protein glycation, in addition to its antioxidant properties and metabolic support. The use of esterified pyruvate instead of the unesterified pyruvate was preferred because of its greater penetration through the cornea and consequently a higher concentration attained in the aqueous humor.

Adenosine Triphosphate↗
PubMed2001

Oxidation of galactose by galactose-1-phosphate uridyltransferase-deficient lymphoblasts.

The ability of EB virus-transformed lymphoblasts with undetectable galactose-1-phosphate uridyltransferase (GALT) from 15 galactosaemic patients to oxidize [1-(14)C]galactose to 14CO2 was compared to that of cells from 7 normal subjects. The oxidation of galactose but not of glucose was markedly diminished by cells from Q188R homozygous galactosaemic patients but was not absent. After 2.5 h these cells liberated 14CO2 at nearly 3% and at 5 h up to 9% of normal. Cells from patients homozygous for the S135L mutation produced much larger amounts of 14CO2 (15-17% of normal) and were distinguishable from the Q188R homozygous cells. A cell line with a homozygous deletion of the GALT gene oxidized galactose at 7% of the normal rate, suggesting that pathways(s) other than GALT exist in these cells as well as Q188R homozygous cells for oxidation of galactose to CO2. Concentration dependence studies are consistent with the presence of a pathway that is unsaturable or has a very high Km The ability of 10(7) lymphoblasts with the S135L genotype to oxidize more than 7% of the sugar to 14CO2 in 5 h suggests the presence of residual GALT despite the inability to detect the activity by enzymatic analysis.

Adolescent↗
PubMed2002

Type II citrullinaemia (citrin deficiency) in a neonate with hypergalactosaemia detected by mass screening.

Type II citrullinaemia (CTLN2) is an adult- or late childhood-onset liver disease characterized by a liver-specific defect in argininosuccinate synthetase protein. The enzyme abnormality is caused by deficiency of the protein citrin, which is encoded by the SLC25A 13 gene. Until now, however, few cases with SLC25A13 mutations have been reported in children with liver disease. We describe an infant who presented with neonatal hepatitis in association with hypergalactosaemia detected by neonatal mass screening. DNA analysis of SLC25A13 revealed that the patient was homozygous for a IVS11+1G>A mutation. This case suggests that SLC25A13 mutant should be suspected in neonatal patients with hypergalactosaemia of unknown cause.

Citrullinemia↗
PubMed2002

Pyruvate modulates antioxidant status of cultured human lens epithelial cells under hypergalactosemic conditions.

Lens epithelial cells are the metabolic unit of the lens and antioxidant enzymes are mainly concentrated here. The purpose of this study was to maintain human lens epithelial cells (HLEC) in culture and examine the status of antioxidant enzymes (glutathione peroxidase (GSHPx), catalase (CAT), glutathione-S-transferase (GST)), lipid peroxidation product malondialdehyde (MDA) and glutathione (GSH) levels in these cells under normal as well as hypergalactosemic (30 mM galactose) conditions. Further, effect of pyruvate, a physiological antioxidant has also been evaluated on these parameters. For conducting experiments, anterior capsule specimens obtained from fresh cadaver eyes from eye bank were cultured in Dulbecco's Modified Eagle's Medium (DMEM) supplemented with 20% fetal calf serum. Upon confluency, the cells were subcultured in three separate flasks containing DMEM alone (normal group), DMEM + 30 mM D-galactose (control group), DMEM + 30 mM D-galactose + 5 mM pyruvate (test group) and incubated for 24 or 72 h. These cells were observed under the phase contrast microscope for any morphological changes and harvested for the estimation of various antioxidant parameters. Our results show significant weakened antioxidant defense in HLEC when incubated in the presence of galactose as compared to normal. Addition of pyruvate significantly modulated levels of GSH, MDA, GSHPx, CAT and GST.

Antioxidants↗
PubMed2002

Newborn screening compared to clinical identification of biochemical genetic disorders.

A group of 28 patients with inherited metabolic disease (homocystinuria galactosaemia, maple syrup urine disease and biotinidase deficiency) diagnosed by screening were compared with a group of 17 similar patients identified clinically. The rate of hospitalization was similar for the two groups. The patients diagnosed clinically showed a higher incidence of mental retardation and their parents experienced greater stress and found greater difficulty in meeting their child's needs.

Adolescent↗