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PubMed1986

Feminization in a galactosemic girl in the presence of hypergonadotropic hypogonadism.

A galactosemic girl has been followed in our clinic since her 8th day of life when the diagnosis of transferase-deficiency galactosemia was made until her present age of 21 years. Although she presented with direct hyperbilirubinemia and severe liver dysfunction, her subsequent somatic and intellectual development under a strict galactose-free diet was normal. Liver function normalized. Her pubertal stage was Tanner B II and PH II at age 11.7 years and progressed normally to B V and PH V, but menarche did not occur. At age 16.8 years, low estradiol (51 pmol/L) and high gonadotropin levels (LH 44 U/L; FSH 43 U/L) were measured. Severely hypoplastic ovaries with a streak-like aspect were seen on laparoscopy. Sex chromatin was positive. Follow-up studies over the next 4 years confirmed elevated LH and FSH levels with an excessive response to stimulation with LHRH and persistently low estradiol levels (41 to 117 pmol/L). After an intravenous load of 200 mg DHEA-S, plasma estrone levels rose 1.8-fold and estradiol 11.4-fold above basal, demonstrating prompt conversion of androgens to estrogens. For over one year, the patient has been treated with the synthetic progestin norethisterone (15 mg per day for 10 days in a row every month) which has resulted in regular menstrual bleedings.

Adult↗
PubMed1983

A new mass screening method for determining UDP-galactose in blood.

We devised a new microfluorometric mass screening method for determining UDP-galactose by using only one blood disc of 3 mm in diameter. This method contains two coupling enzymes of UDP-galactose-4-epimerase and UDP-glucose dehydrogenase, and conversion of NAD to NADH. The assay ranges are 0 to 1 mM or 0 to 0.2 mM UDP-galactose in blood. UDP-galactose contents were determined in galactosemia of epimerase-, transferase- and kinase-deficiencies, and several cases with high or low Paigen's values.

Galactosemias↗
PubMed1987

Kidney morphology in experimental hyperglycemia.

To evaluate the role of hyperglycemia in the pathogenesis of diabetic nephropathy, the kidneys from dogs experimentally galactosemic for 5 yr have been compared with the kidneys from age-matched normal dogs and dogs with alloxan-induced diabetes for 5 yr. The width of glomerular capillary basement membrane and the quantity of plasma protein immunohistochemically demonstrable in the basement membrane were supranormal in the galactosemics, as they were in the diabetics. In contrast, kidney weight, mesangial volume, and the prevalence of obliterated glomeruli, glomerular exudates, and mesangial nodules in the galactosemic animals were comparable to those of normal animals and clearly were less than observed in the insulin-deficient diabetic animals. These galactosemic dogs are known to have developed a retinopathy morphologically indistinguishable from that of diabetic patients and dogs. Thus, galactosemia sufficient to produce diabetic-like lesions in the glomerular basement membrane and retina was found to be nevertheless insufficient to elicit several renal abnormalities that are typical of diabetes. The polyol concentration in erythrocytes was greater than normal in the galactosemics and the diabetics and was greatest in the galactosemics. The absence of mesangial expansion, glomerular obliteration, and nephromegaly in galactose-fed dogs raises the possibility that these abnormalities in diabetes are not a result of excessive polyol pathway activity.

Animals↗
PubMed1990

Na(+)-K(+)-ATPase and changes in ATP hydrolysis, monovalent cation affinity, and K+ occlusion in diabetic and galactosemic rats.

This study showed that steady-state kinetics of ATP hydrolysis by Na(+)-K(+)-ATPase are altered in the BB Wistar diabetic rat and experimental galactosemia. Four days after onset, this change was not evident if NaCNBH3 was omitted during enzyme preparations (indicating reversibility). Ninety days after onset, NaCNBH3 reduction was not necessary to see the change in ATP hydrolysis kinetics (indicating nonreversibility). The change in steady-state ATP hydrolysis was similar to that reported earlier for Na(+)-K(+)-ATPase of the lens epithelium and kidney medulla of diabetic individuals and for two in vitro glycosylation models. Our study also showed that the affinities of Na(+)-K(+)-ATPase for K+ are altered, and Na(+)-K(+)-ATPase-dependent K+ occlusion is inhibited in diabetic and galactosemic animals. Because K+ occlusion is required for efficient K+ transport, this finding supports previous in vitro studies that indicated that glycosylation inhibits pump-dependent K+ transport. Furthermore, our study suggested an irreversible impairment of Na(+)-K(+)-ATPase function in the diabetic BB Wistar rat as early as 15 days after onset, even when blood glucose was maintained at 6.7 mM by daily insulin injection.

Adenosine Triphosphate↗
PubMed1993

Aldose reductase inhibition fails to prevent retinopathy in diabetic and galactosemic dogs.

To investigate a possible role of excessive polyol production in the pathogenesis of diabetic retinopathy, 16 ALX-induced diabetic dogs and 20 experimentally galactosemic dogs were randomly assigned to 5 yr of treatment with either sorbinil, an aldose reductase inhibitor, or a placebo. The severity of hyperglycemia in sorbinil-treated and placebo groups was monitored throughout the 5-yr study by assay of glycosuria and nonenzymatically glycated plasma protein and HbA1 needed in an effort to avoid confounding possible group differences in hyperglycemia severity with possible drug effects. Inhibition of polyol production by sorbinil was monitored in erythrocytes throughout the study and also in retina and other tissue obtained at autopsy. Trypsin digests of retinal vessels were compared after 60 mo of diabetes and after 42 and 60 mo of galactosemia. In diabetic dogs, development of retinopathy was not significantly influenced by a sorbinil dose (20 mg.kg-1 x day-1) sufficient to prevent elevation of sorbitol levels in retina and other tissue. Likewise, in dogs made experimentally galactosemic for 42-60 mo, administration of sorbinil (60-80 mg.kg-1 x day-1) had no significant effect on the development of retinopathy notwithstanding prevention of 93-96% of the polyol elevation in retina and other tissue. Retinal capillary basement membrane was significantly thicker than normal in diabetic and in galactosemic dogs and was not significantly influenced by administration of sorbinil in either dog model. Thus, no evidence was found that the development of retinopathy is critically dependent on excessive polyol production or accumulation.

Aldehyde Reductase↗
PubMed1994

Comparison of retinal lesions in alloxan-diabetic rats and galactose-fed rats.

Galactose-fed rats develop a retinal microvascular disease, but retinopathy has not been found to develop reproducibly in diabetic rats. We sought to determine which retinal lesions can be reproducibly produced by long-term diabetes in rats, the extent to which the capillary lesions in diabetic rats and galactosemic rats are similar, and whether the retinopathy induced by 50% galactose can be reproduced satisfactorily by a lower concentration of galactose. Alloxan-diabetic rats and rats fed either a 50% galactose diet or a 30% galactose diet were killed after comparable durations of study (18 to 22 months). Rats fed 50% galactose showed greater than normal frequency of retinal pericyte ghosts and acellular capillaries, and thickening of capillary basement membranes by 18 months of galactosemia. Rats eating 30% galactose developed similar retinal lesions, and tended to be healthier than rats fed 50% galactose. Diabetes of 1 1/4 years or more likewise resulted in retinal pericyte ghosts, acellular capillaries and thickened capillary basement membrane. IRMAs and other vascular abnormalities were not reproducibly demonstrated at this duration of study, and saccular microaneurysms were not seen in any groups. In a number of diabetic rats, the severity of diabetes diminished spontaneously (after 1 to 1 1/2 years of insulin deficiency), thus making it essential that glycemia be systematically monitored. Both diabetic rats and experimentally galactosemic rats develop microvascular lesions that are consistent with at least the early stages of diabetic retinopathy, and these models should be useful to screen potential therapies for their ability to inhibit the development of retinopathy.

Alloxan↗
PubMed1985

Prevention of cataract development in severely galactosemic rats by the aldose reductase inhibitor, tolrestat.

With a fixed time period of galactose feeding, the rate of appearance of lenticular opacities depended on the severity of galactosemia, while with a fixed amount of galactose fed, the rate was time dependent. The capacity of tolrestat, a structurally novel inhibitor of aldose reductase (AR), to control cataract development was assessed in rats fed 30-50% galactose with the diet for 7 to 277 days. In rats fed 30% galactose for 31 days, the controlling effect of tolrestat was dose dependent, and no cataracts were detected at a dose of 35 mg/kg/day. In rats given tolrestat with the diet for 14 days, then rendered severely galactosemic with a diet containing 50% galactose, and subjected to continued treatment with tolrestat at a dose of 43 mg/kg/day, no changes were detected by slit-lamp microscopy after 207 days. The preventive effect was also dose dependent. In view of the established similarity in the pathogenesis of galactosemic and diabetic cataracts, the results obtained with tolrestat support its potential for controlling cataract development in diabetics.

Animals↗
PubMed1990

Cranial nerve dysfunction in conscious galactosemic rats as measured by the auditory-evoked brainstem response.

The purpose of this study was to extend our previous work with the auditory-evoked brainstem response and determine whether galactosemia would produce a functional neuropathy similar to that previously seen in streptozocin-induced diabetic rats. Sprague-Dawley male rats implanted with cortical electrodes received either normal chow (n = 17) or a 50% galactose diet (n = 17) for 5 weeks. Peak II latency of the auditory-evoked brainstem response, interpreted as a functional measure of the auditory nerve (VIII cranial) in rats, was significantly prolonged in galactose-fed rats relative to controls (P less than 0.05). These results demonstrate a functional deficit in the auditory nerves of galactosemic rats. The deficit in the auditory-evoked brainstem response of galactosemic rats is similar to our previous finding in streptozocin-induced diabetic rats.

Animals↗
PubMed1984

NIH conference. Aldose reductase and complications of diabetes.

Tissues of the eye affected by diabetes are the lens, cornea, and retina. The lens becomes cataractous through osmotic swelling of its cortical fibers. Sorbitol, formed in the presence of aldose reductase, accumulates in the lens during hyperglycemia. Dulcitol similarly accumulates in the presence of galactosemia. Cataractogenesis in both cases can be prevented by inhibitors of aldose reductase. The efficacy of synthetic inhibitors differs in various tissues and species, but they react with aldose reductase at a common structural site. The most promising inhibitor is sorbinil . Diabetic retinopathy is similarly related to sorbitol accumulation and may be prevented or reversed by inhibition of aldose reductase. Healing of corneal wounds in diabetes is facilitated by enzyme inhibition. Retinal vasculopathy of diabetes is due to selective loss of the intramural pericytes that normally form structural elements in the retinal capillary walls. The vulnerability of these cells is due to their aldose reductase content. Whether inhibition of aldose reductase will prevent retinopathy is being tested in a randomized trial conducted by the National Eye Institute.

Aldehyde Reductase↗
PubMed2001

Synthesis and evaluation of novel aldose reductase inhibitors: Effects on lens protein kinase Cgamma.

PURPOSE: To synthesize novel aldose reductase inhibitors (ARI) that will normalize losses in protein kinase Cgamma (PKCgamma) observed during diabetes and galactosemia. METHODS: ARI were synthesized as tricyclic pyrones 1-6 (HAR-1 through HAR-6) from 3-methyl-1H,7H-5a,6,8,9-tetrahydro-1-oxopyrano[4,3-b][1]benzopyran and (5aS,7S)-7-isopropenyl-3-methyl-1H,7H-5a,6,8,9-tetrahydro-1-oxopyrano[4,3-b][1]benzopyran and were tested by inhibition of aldose reductase enzyme activity in vitro and by inhibition of polyol formation in lens epithelial cells in culture. Identified compounds were further tested in galactosemic rat lens in vivo for (a) normalized PKCgamma levels by Western blot, (b) reduction of phosphorylation of the gap junction protein Cx46 by analyses of co-immunoprecipitated proteins, and (c) by normalization of gap junction activity as measured by dye transfer. RESULTS: HAR-1 (1H,7H-5a,6,8,9-tetrahydro-1-oxopyrano[4,3-b][1]benzopyran-3-acetic acid) was identified as an ARI with IC50 for aldose reductase inhibition at 2 nM. Polyol accumulation in lens epithelial cells was reduced by 80% at 10 microM. Rats fed 40% galactose for 9 days had an 80% reduction in PKCgamma levels which were normalized by HAR-1 at 100 mg/kg/day, fed orally. Phosphorylation of Cx46 was increased by 50% and this was normalized in HAR-1 treated rats (6 day treatment). Gap junction activity of galactosemic rats was reduced by 55% and this was normalized by HAR-1 in six day-treated rats. CONCLUSIONS: HAR-1 is a novel ARI which normalized losses of PKCgamma, changes in Cx46 phosphorylation, and gap junction activity.

Acetates↗
PubMedDate not supplied

[Abnormal antioxidant system in inborn errors of intermediary metabolism].

INTRODUCTION: Oxidative stress may be implied in the pathogenic mechanisms of inborn errors of intermediary metabolism (IEIM). OBJECTIVE: The evaluation of the antioxidant status in IEIM by the measurement of erythrocyte antioxidant enzyme activities, superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase and catalase. PATIENTS AND METHODS: 34 patients with IEIM: 1) eleven with organic acidurias on protein restricted diet; 2) nine without special diet; 3) five patients with aminoacidopathies on protein restriction; 4) three patients with galactosemia and six with aminoacidopathies on protein free diet. Erythrocyte antioxidant enzymes were measured by spectrometric procedures adapted to the Cobas Fara II analyser. RESULTS: SOD activity was significantly higher in groups 2 and 4 (p= 0.009, p= 0.001, respectively), and significantly lower in group 3 (p= 0.001) compared with age matched controls. SOD activity was significantly higher in the patients with IEIM on protein free diet (groups 2 and 4) compared with those on protein restricted diet (groups 1 and 3; p= 0.002) or with controls (p= 0.003). GPx activity was found significantly lower in group 1 patients (p= 0.004), and higher in group 2 (p= 0.029) compared with controls. CONCLUSIONS: 35% of the patients with IEIM had SOD activity above the control range, most of them with organic acidurias or homocystinuria, suggesting an induction of enzyme protein synthesis owing to an excess of free radical generation. The lower activities observed in patients on natural protein restriction may likely be due to a deficient bioavailability of antioxidant cofactors.

Amino Acid Metabolism, Inborn Errors↗
PubMed2002

Ethnic and gender patterns for the five congenital disorders in Texas from 1992 through 1998.

The Texas Department of Health's Newborn Screening Program screens for five inherited disorders: phenylketonuria (PKU), congenital adrenal hyperplasia (CAH), congenital hypothyroidism (CH), galactosemia (GAL), and sickle cell disease (SCD). The objective of this study was to determine the prevalence of these disorders and to describe ethnic and gender patterns in their distribution. Cases were identified from blood specimens collected at birth from live births in Texas from 1992 through 1998. During this time, the overall prevalence of these disorders per 10,000 live births was 0.70 for PKU, 0.21 for GAL, 4.18 for CH, 1.03 for CAH, and 3.92 for SCD. Ethnic and gender disparities were observed among PKU, CH, CAH, and SCD prevalence. Results suggest that unidentified mutations and environmental factors may exist that contribute to these patterns. This warrants further investigation to determine possible modifiable risk factors for populations with higher prevalence.

Adrenal Hyperplasia, Congenital↗
PubMedDate not supplied

[Bone alkaline phosphatase: characteristic and its clinical applications].

Bone alkaline phosphatase (BALP) is one of the most frequently used biochemical markers of bone formation. The presented paper describes the enzyme's specificity, physiological values during normal growth and development as well as its clinical applications in various diseases. The main interest concerns the ability of BALP to predict bone loss in primary (postmenopausal and senile osteoporosis) and secondary osteoporosis associated with metabolic diseases (galactosemia, cystic fibrosis, celiac disease), renal osteodystrophy, Paget disease and others. The determination of BALP activity seems to be also helpful in diagnosis of the diseases and in monitoring of antiresorptive therapy. Further studies on BALP are needed to elucidate whether this bone formation marker reflect the therapy outcome of individual patients with primary osseus tumours and metastases.

Age Factors↗
PubMed1975

[Results of a nine-year phenylketonuria (PKU) screening (author's transl)].

The percentage of children in Nordrhein-Westfalen who were tested for PKU free of charge and on a voluntary basis rose from 25.3% (1966) to 99.5% (1973). Among 1,431,999 newly born children, 262 children with suspected PKU were found, 225 of them diagnosed early and 37 late, 181 with "typical" and 81 with "atypical" PKU. Most of 102 children with late diagnosed PKU had an I.Q. of 80-50 or less, while in 95 children treated early, it was over 91 in 80% and below 90 in only 20%. There was a statistically highly significant difference in the I.Q. distribution between patients diagnosed early and those diagnosed late, while the mental development of phenylketonuria patients treated early was not different from that of a homogenous population group under the same conditions. After extending the test program in 1966, 1 maple syrup urine disease, 3 homocystinurias, 3 galactosemias and 1 galactokinase deficiency were found in addition to PKU.

Child↗
PubMed1991

Retinal polyol and myo-inositol in galactosemic dogs given an aldose-reductase inhibitor.

Galactitol and myo-inositol concentrations were measured in retinas, erythrocytes, and skeletal muscle of experimentally galactosemic dogs receiving a placebo or the aldose reductase inhibitor, sorbinil, for 5 yr. The concentration of galactitol was increased more than 30-fold in the retina and other tissues by galactosemia, and the increase was inhibited 90-96% in all tissues by sorbinil. The concentration of free myo-inositol was greater than normal in retinas of galactosemic dogs, and its concentration was not altered by the aldose-reductase inhibitor. The myo-inositol concentration likewise was greater than normal in the retinas of dogs that were diabetic for 2-4 months. The marked inhibition of polyol production and accumulation in the retina of sorbinil-treated galactosemic dogs was not associated with a comparable inhibition of retinopathy.

Aldehyde Reductase↗
PubMed1976

[Cataract due to galactokinase deficiency in a premature infant].

Report of a case of galactosemia due to galactokinase deficiency. The author recalls the clinical (opacity of the lens) and biological features (important galactosuria, gallactiloluria, normal aminoaciduria, minimal hyperglycemia following galactose load). Since symptoms of increased intracranial pressure were present in this case, as in another one previously described, the commonly accepted statement that cataract is the only lesion in galactokinase deficiency must be reconsidered.

Cataract↗
PubMedDate not supplied

[Identification of inborn errors of galactose metabolism in patients with cataracts].

133 patients with congenital or idiopathic cataracts were studied (94 patients had ages between 1 month and 14 years; 10 patients had ages between 16 and 50 years and 29 patients did not have an age registry) along with 18 patients with a clinical diagnosis of classic galactosemia. The activity of galactokinase (GALAK) and that of erythrocyte galactose-1-phosphate uridyl transferase (GALT) was measured. There were no individuals with a total deficiency of GALK or GALT. The cataract patients of ages between 1 monthly and 14 years, 3 (3.19%) and 4 (4.25%) showed GALK and GALT levels in the range corresponding to the respective heterozygotes. As compared with the expected incidence of heterozygotes in the general population (0.2% for GALK and 0.8% for GALT) we found a significant rise of individuals with low levels of enzymes for the metabolism of galactose. The possibility that heterozygote galactosemic states contribute a risk factor in the development of cataracts and its therapeutic implications are discussed.

Adolescent↗
PubMed1990

The effects of sorbinil, an aldose reductase inhibitor, on the corneal endothelium in galactosemic dogs.

Wide-field specular microscopy was used to examine the central corneal endothelium of age- and sex-matched beagle dogs fed for up to 32 months either normal control diets containing 30% nonnutrient filler (13 dogs) or diets containing 30% galactose with (13 dogs) or without (12 dogs) concomitant treatment with the aldose reductase inhibitor, sorbinil. Computerized morphometric analysis of the endothelial cells indicated that a significant decrease in cell density and increase in mean cell area occurred in untreated galactose-fed dogs after 32 months of feeding compared with the normal controls. However, no significant difference could be observed in similar galactose-fed dogs treated with sorbinil. No significant difference in the coefficient of variation of the area, or percent hexagonality of the endothelial cells, or the corneal thickness could be observed in any group. These findings demonstrated that endothelial abnormalities were present in the cornea of the galactose-fed dogs which were similar to those reported for diabetic dogs, rats, and patients and that these changes can be prevented by the concomitant administration of an aldose reductase inhibitor. These findings suggest a role for aldose reductase in the abnormalities noted in the corneal endothelium in diabetes and galactosemia.

Aldehyde Reductase↗