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PubMed1987

Metabolic studies of a sustained galactose overload in rat.

In order to obtain an experimental model for studying inherited disorders of galactose metabolism in man, we administered to adult rats a diet supplemented with 50% of galactose during 38 days. The results showed clinical symptoms such as polyuria, polydipsia, growth retardation and bilateral cataract. The main biochemical features were an increase in the galactokinase and uridyltransferase activities in liver, an ubiquitous accumulation in tissues and a considerable urinary elimination of galactose and galactitol, a weak accumulation of galactose-1-phosphate in tissue and a hyperaminoaciduria. This work led us to quantify the respective importance of the major pathway and minor pathways of galactose in the rat after a galactose-rich diet.

Animals↗
PubMed1989

Effect of uridine on hepatic galactose-1-phosphate uridyltransferase.

Uridine sugar nucleotides are important intermediates in galactose metabolism and may play a role in the long-term galactose toxicity in human galactose-1-phosphate uridyltransferase deficiency galactosemia. Since administration of uridine, a precursor of uridine nucleotides, has been considered as a therapeutic measure, we have investigated the effects of this compound on the activity of rat hepatic transferase. Uridine has been found to be an inhibitor of the enzyme in in vitro studies and to cause an increase in galactose-1-phosphate in liver perfused with galactose which is consistent with physiologic inhibition of the enzyme. Uridine is a partial linear competitive inhibitor of UDPglucose and an uncompetitive inhibitor of galactose-1-phosphate. These findings suggest caution should be applied in giving the compound to subjects with genetically limited transferase activity because of the possibility of inhibiting the small amount of residual enzyme.

Aging↗
PubMed1984

Galactosemia: how does long-term treatment change the outcome?

In galactosemic subjects, treatment prevents liver and kidney failure, brain damage and cataracts, but total exclusion of galactose from the diet does not ensure the absence of all pathology. Early and well-treated children show satisfactory general health and growth, make reasonable though suboptimal intellectual progress, are prone to speech defects, and commonly experience visual perceptual difficulties and some social maladjustment. Two different metabolites are potentially toxic: galactitol is responsible for the cataracts while galactose-1-phosphate causes the rest of the pathology. As both metabolites are present in the fetus and in postnatal life, pathological changes may develop at any time in life, even when treatment is strict. Owing to UDP-galactose 4'-epimerase, man can generate galactose from glucose from early embryonic life on. Therefore, transferase-deficient individuals can form galactose-1-phosphate in the absence of exogenous galactose, a process for which UDP-glucose pyrophosphorylase is essential. Biosynthesis of galactose from glucose in well-treated galactosemics constitutes a mechanism of self-intoxication, not only in utero but also in adult life. The prognosis for some treated galactosemics may depend on their own ability to limit this process. Galactosemic girls, whether well-treated or not, run a considerable risk of developing ovarian dysfunction. Hypergonadotropinism has been diagnosed from 2 years of age to the third decade. Prenatal ovarian failure is not excluded but the observed facts suggest that ovarian failure is acquired after ovarian differentiation and initiation of folliculogenesis, at an individual rate and possibly through continuous self-intoxication with galactose-1-phosphate. Up to now, mild hypergonadotropinism has been documented in only 2 galactosemic males, but the male cohort of galactosemics studied for gonadal dysfunction is yet small.

Female↗
PubMed1986

A modified method for the estimation of galactose-1-phosphate.

The measurement of galactose-1-phosphate has been advocated for monitoring galactosaemia. A radioenzymatic method is described in which red-cell haemolysates are incubated with radiolabelled uridine diphospho-glucose and exogenous galactose-1-phosphate uridyl transferase. Labelled glucose-1-phosphate is formed in proportion to the amount of galactose-1-phosphate present and is separated from the labelled uridine diphospho-glucose by affinity chromatography. The method is reproducible and has a low limit of detection. This allows it to be carried out on 100 microL of packed red cells.

Boronic Acids↗
PubMed1984

Resistance of the male gonad to a high galactose diet.

Rats were fed a 50% galactose diet during pregnancy and nursing, and the testes were later examined and hormone levels determined in male offspring. Exposure to galactose for various periods during pregnancy, throughout the entire gestation, or postnatally to nursing mother until pups were 5 wk of age produced no significant differences from control testicular weight, seminiferous tubular diameter, or microscopic appearance of the testis when the offspring became adult (66 or 127 d). Serum luteinizing hormone, follicle stimulating hormone, and testosterone levels were determined 127 d postnatally and no significant differences from controls were observed in any of the treatment groups. Blood galactose-1-phosphate levels in animals receiving the 50% galactose diet were comparable to levels observed in human galactosemia. The resistance of the rat testis to a high galactose diet is consistent with the infrequency of testicular insufficiency in human galactosemia, and contrasts with the prenatal female gonadal sensitivity to galactose previously demonstrated in the rat and the high frequency of ovarian failure in human galactosemia.

Animals↗
PubMed1992

A study of galactose intolerance in human and rat liver in vivo by 31P magnetic resonance spectroscopy.

An oral load of 20 mg/kg galactose produces significant changes in the 31P magnetic resonance spectrum of the liver of a galactosemic patient. The peak at 5.2 ppm (which includes inorganic phosphate and galactose-1-phosphate) increased on two occasions to about twice its original size 60 min after galactose administration. An oral load of 10 mg/kg galactose given to a second patient produced no discernible changes at 30 min. We have also used an animal model of galactose intolerance, in which galactose metabolism in rats was blocked by the acute administration of ethanol. Studies in vivo and in vitro showed that the increase in the peak at 5.2 ppm was largely due to galactose-1-phosphate. We have shown in this preliminary study that small amounts of galactose can produce significant elevation of hepatic galactose-1-phosphate, which can be detected by 31P magnetic resonance spectroscopy.

Adenosine Triphosphate↗
PubMed2003

Verbal dyspraxia and galactosemia.

Classical galactosemia is an autosomal recessive disorder resulting from deficient galactose-1-phosphateuridyl transferase (GALT) activity. Verbal dyspraxia is an unusual outcome in galactosemia. Here we validated a simplified breath test of total body galactose oxidation against genotype and evaluated five potential biochemical risk indicators for verbal dyspraxia in galactosemia: cumulative percentage dose (CUMPCD) of (13)CO(2) in breath, mean erythrocyte galactose-1-phosphate, highest erythrocyte galactose-1-phosphate, mean urinary galactitol, and erythrocyte GALT activity. Thirteen controls and 42 patients with galactosemia took a (13)C-galactose bolus, and the (CUMPCD) of (13)CO(2) in expired air was determined. Patients with <5% CUMPCD had mutant alleles that severely impaired human GALT enzyme catalysis. Patients with > or =5% CUMPCD had milder mutant human GALT alleles. Twenty-four patients consented to formal speech evaluation; 15 (63%) had verbal dyspraxia. Dyspraxic patients had significantly lower CUMPCD values (2.84 +/- 5.76% versus 11.51 +/- 7.67%; p < 0.008) and significantly higher mean erythrocyte galactose-1-phosphate (3.38 +/- 0.922 mg/dL versus 1.92 +/- 1.28 mg/dL; p = 0.019) and mean urinary galactitol concentrations (192.4 +/- 75.8 mmol/mol creatinine versus 122.0 +/- 56.4; p = 0.048) than patients with normal speech. CUMPCD values <5%, mean erythrocyte galactose-1-phosphate levels >2.7 mg/dL, and mean urinary galactitol levels >135 mmol/mol creatinine were associated with dyspraxic outcome with odds ratios of 21, 13, and 5, respectively. We conclude that total body oxidation of galactose to CO(2) in expired air reflects genotype and that this breath test is a sensitive predictor of verbal dyspraxia in patients with galactosemia.

Adult↗
PubMedDate not supplied

The effect of galactose metabolic disorders on rat brain acetylcholinesterase activity.

To evaluate whether in classical galactosemia galactose (Gal), galactose-1-phosphate (Gal-1-P) and galactitol (Galtol) affect brain acetylcholinesterase (AChE) activity, various concentrations (1-16 mM) of these compounds were preincubated with brain homogenates of suckling rats as well as with pure eel Electroforus electricus AChE at 37 degrees C for 1 h. Initially, Galtol (up to 2.0 mM) increased (25%) AChE activity which decreased. thereafter, reaching the control value in high Galtol concentrations. Gal-1-P decreased gradually the enzyme activity reaching a plateau (38%), when incubated with 8-16 mM. However, when the usually found 2 mM of Galtol and 2 mM of Gal-1-P, concentrations in galactosemia were added in the incubation mixture simultaneously, brain AChE was stimulated (16%). Galtol or Gal-1-P modulated brain AChE as well as enzyme activity of E.electricus in the same way. Gal, Glucose (Glu) and glucose-1-phosphate (Glu-1-P) had no effect on AChE activity. It is suggested that Galtol as well as Gal-1-P can affect acetylcholine degradation acting directly on AChE molecule. Consequently the direct action of these substances on the enzyme might explain the brain cholinergic dysfunction in untreated galactosemia patients.

Acetylcholinesterase↗
PubMedDate not supplied

The effect of galactose metabolic disorders on rat brain Na+,K+-ATPase activity.

To evaluate the effect of galactose metabolic disorders on the brain Na+,K+-ATPase in suckling rats. Separate preincubations of various concentrations (1-16 mM) of the compounds galactose-1-phosphate (Gal-1-P) and galactitol (galtol) with whole brain homogenates at 37 degrees C for 1 h resulted in a dose dependent inhibition of the enzyme whereas the pure enzyme (from porcine cerebral cortex) was stimulated. Glucose-1-phosphate (Glu-1-P) or galactose (Gal) stimulated both rat brain Na+,K+-ATPase and pure enzyme. A mixture of Gal-1-P (2 mM), galtol (2 mM) and Gal (4 mM), concentrations commonly found in untreated patients with classical galactosemia, caused a 35% (p < 0.001) rat brain enzyme inhibition. Additionally, incubation of a mixture of galtol (2 mM) and Gal (1 mM), which is usually observed in galactokinase deficient patients, resulted in a 25% (p < 0.001) brain enzyme inactivation. It is suggested that: a) The indirect inhibition of the brain Na+,K+-ATPase by Gal-1-P should be due to the presence of the epimer Gal and phosphate and that the pure enzyme direct activation by Gal-1-P and Glu-1-P to the presence of phosphate only. b) The observed brain Na+,K+-ATPase inhibitions in the presence of toxic concentrations of Gal-1-P and/or galtol could modulate the neural excitability, the metabolic energy production and the catecholaminergic and serotoninergic system.

Animals↗
PubMed1982

Simultaneous quantitative estimation of galactose-1-phosphate and galactose in blood for the diagnosis of galactosemia.

A new microfluorometrical simultaneous assay method of galactose-1-phosphate and galactose in blood discs was devised by use of alkaline phosphatase and beta-galactose dehydrogenase. Our method statistically corresponded well with the Kirkman's method. It can detect 1 X 10(-10) mole of minimal concentration of galactose-1-phosphate and galactose in one blood disc paper (3 mm in diameter), and this means the sensitivity of assay of galactose-1-phosphate was 0.1 mg%. Assay range in our method was very broad (0-2 mM or 0-10 mM). The accuracy and reproducibility of galactose-1-phosphate assay were 3.4 +/- 0.1 mg%, 8.0 +/- 0.4 mg% or 15.1 +/- 0.6 mg%. Mean values of galactose-1-phosphate and galactose in blood on normal infants were 0.8 mg% and 0.3 mg%, respectively. We applied this method to mass screening of galactosemia and could accurately distinguish many positive and false positive cases detected by Paigen's and Beutler's methods. This method gave us an easy and accurate assay system for the diagnosis of uridyl transferase and galactokinase deficiencies.

Alkaline Phosphatase↗
PubMed2004

Quenching accumulation of toxic galactose-1-phosphate as a system to select disruption of protein-protein interactions in vivo.

The reverse two-hybrid system has been developed to readily identify molecules or mutations that can disrupt protein-protein interactions in vivo. This system is generally based on the interaction-dependent activation of a reporter gene, whose product inhibits the growth of the engineered yeast cell. Thus, disruption of the interaction between the hybrid proteins can be positively selected because, by reducing the expression of the negative marker gene, it allows cell growth. Although several counter-selectable marker genes are currently available, their application in the reverse two-hybrid system is generally confronted with technical and practical problems such as low selectivity and relatively complex experimental procedures. Thus, the characterization of more reliable and simple counter-selection assays for the reverse two-hybrid system continues to be of interest. We have developed a novel counter-selection assay based on the toxicity of intracellular galactose-1-phosphate, which accumulates upon expression of a galactokinase-encoding GAL1 reporter gene in the absence of transferase activity. Decreased GAL1 gene expression upon dissociation of interacting proteins causes reduction of intracellular galactose-1-phosphate concentrations, thus allowing cell growth under selective conditions.

Fungal Proteins↗
PubMed1977

Kinetics of ethanol inhibition of galactose elimination in perfused pig liver.

The effect of ethanol (5--25 mM) on the galactose elimination kinetics in the intact liver was studied in the isolated perfused pig liver, using the steady-state infusion technique. Ethanol reduced galactose-Vmax on average to 0.07 mmol/min kg liver in six experiments from 0.43 mmol/min kg obtained in control experiments without ethanol. Also Km was significantly reduced from 0.23 mmol/l plasma water to 0.03 mmol/l. Ethanol increased UDP-galactose ten-fold simultaneous with a rise in hepatic outflow ratio of lactate to pyruvate to about 300 from 10; this indicates that ethanol inhibits epimerase. In experiments with increasing galactose elimination rates, the concentration of galactose-1-P increased much less than the concentration of galactose, and the phosphorylation of galactose therefore seems to be rate-limiting. In vitro galactokinase is inhibited by galactose-1-P. In the present study ethanol increased galactose-1-P five to ten times, and the reduction of Vmax and Km by ethanol could be explained by uncompetitive inhibition by galactose-1-P with Ki about 0.1 mmol/l. Ethanol decreased UDP-glucose to about 40% and UTP to less than 5%, probably due to trapping as UDP-galactose. This may depress the forward transferase reaction, and therefore the other co-substrate galactose-1-P rises--and inhibits galactokinase.

Adenosine Diphosphate↗
PubMedDate not supplied

Ophthalmic findings in classical galactosemia--a screened population.

Classical galactosemia due to a deficiency of galactose-1-phosphate-uridyl transferase, is an autosomal recessive disorder of galactose metabolism with an incidence in Ireland of one in 30,000 births. It can result in cataract formation through the accumulation of galactitol within the lens. Seventeen children with transferase deficient galactosemia were studied. Early diagnosis followed by a galactose-free diet and tight biochemical control prevented cataract formation in 13 cases after a mean follow-up of 6.3 years. Cataracts did not regress in all patients commenced on diet by 6 weeks but early treatment prevented progression. The ophthalmologist may play an important role in the monitoring of patients with this disease as the recognition of new lens opacities by slit-lamp biomicroscopy may be the most sensitive initial index of inadequate biochemical control.

Adolescent↗
PubMed2001

Neonatal screening for galactosemia by quantitative analysis of hexose monophosphates using tandem mass spectrometry: a retrospective study.

BACKGROUND: Classic galactosemia (OMIM 230400) is an inherited disorder in the metabolism of galactose caused by deficiency of the enzyme galactose 1-phosphate uridyl transferase (EC 2.7.7.12). Galactosemia leads to accumulation of galactose and galactose 1-phosphate (gal-1-P) in blood and tissues and, if untreated, produces neonatal death or severe mental retardation, cirrhosis of the liver, and cataracts. Hence, the disorder is included in many neonatal screening programs. METHODS: We retrospectively analyzed filter-paper blood samples obtained 4-8 days postpartum for routine neonatal screening from 12 galactosemia patients and 2055 random controls. Total hexose monophosphates (HMPs) were used as a marker of gal-1-P and were assayed by negative-ion mode electrospray tandem mass spectrometry (tandem MS) with settings biased toward gal-1-P detection. The predominant precursor/product ion pair m/z 259/79 was used to quantify total HMPs by external standardization. RESULTS: Linear calibration curves were obtained in the range 0-8 mmol/L gal-1-P. The detection limit was 0.1 mmol/L HMP, and total CVs ranged from 13% at the detection limit to <8% at >1 mmol/L HMP. The method was in agreement with an alkaline phosphatase-galactose dehydrogenase method. All samples from galactosemia patients contained increased HMP concentrations (range for patients, 2.6-5.2 mmol/L; range for reference group, <0.10-0.94 mmol/L). The diagnostic sensitivity and specificity were 100% at a cutoff of 1.2 mmol/L HMP. A Duarte/classic galactosemia compound heterozygous sample could be discriminated clearly from both patient and reference samples. CONCLUSION: Quantitative analysis of HMPs by tandem MS can be used in laboratory investigations of galactosemia.

Alkaline Phosphatase↗
PubMed2002

Erythrocyte galactose 1-phosphate quantified by isotope-dilution gas chromatography-mass spectrometry.

BACKGROUND: Measurements of alpha-D-galactose 1-phosphate (Gal-1-P) in erythrocytes are used to monitor the adequacy of dietary therapy in the treatment of galactosemia. We have devised a gas chromatography-mass spectrometry (GC/MS) isotope-dilution method for quantification of Gal-1-P. METHODS: We prepared trimethylsilyl (TMS) derivatives and used alpha-D-[2-(13)C]Gal-1-P as the internal standard for GC/MS. Results obtained with this method were compared with those determined by the established enzymatic method for samples from 23 healthy individuals (11 children and 12 adults), 9 suspected patients with galactosemia, 12 galactosemic patients on diet therapy, and 2 newly diagnosed toxic neonates. RESULTS: The method was linear up to 2.5 mmol/L with a lower limit of detection of 2.1 nmol (0.55 mg/L). Intra- and interassay imprecision (CVs) was 2.2-8.8%. In the 23 healthy individuals, values ranged from nondetectable to 9.2 micromol/L (2.4 mg/L of packed erythrocytes). Galactosemic patients on diet therapy had values of 10.9-45 mg/L of packed erythrocytes, whereas the newly identified patients had values of 166 and 373 mg/L. CONCLUSIONS: The GC/MS method is precise and useful over the wide range of concentrations needed to assess the galactose burden in patients with galactosemia.

Adult↗