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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↗
PubMed2002

The P28T mutation in the GALK1 gene accounts for galactokinase deficiency in Roma (Gypsy) patients across Europe.

Galactokinase deficiency is an inborn error of metabolism that, if untreated, results in the development of cataracts in the first weeks of life. The disorder is rare worldwide, but has a high incidence among the Roma (Gypsies). In 1999, we reported the founder Romani mutation, P28T, identified in affected families from Bulgaria. Subsequent studies have detected the same mutation in Romani patients from different European countries. The screening of 803 unrelated control individuals of Romani ethnicity from Bulgaria, Hungary, and Spain has shown an overall carrier rate of 1:47 and an expected incidence of affected births about 1:10,000. Using disease haplotype analysis, the age of the P28T mutation was estimated at 750 y, preceding the splits of the proto-Roma into the numerous populations resident in Europe today. The findings suggest that the mutation has spread with the early diaspora of the Roma throughout Europe. Superimposed on this old distribution pattern is the new migration wave of the last decade, with large numbers of Roma moving to Western Europe as a result of the economic changes in the East and the wars in former Yugoslavia. The changing demographic pattern of Romani minorities can be expected to lead to a homogenization of the incidence of "private" Romani disorders and founder mutations. The P28T mutation is thus likely to account for a high proportion of galactokinase deficiency cases across Europe. Mutation-based pilot newborn screening programs would provide current incidence figures and help to design long-term prevention of infantile cataracts due to galactokinase deficiency.

Amino Acid Substitution↗
PubMed1989

Late onset of distinct neurologic syndromes in galactosemic siblings.

We discuss siblings with galactose-1-phosphate uridyl transferase deficiency who developed neurologic complications after the age of 30. One has partial complex seizures and the other has generalized seizures, progressive ataxia, and apraxia. As more galactosemic children survive into adulthood, more neurologic complications may become more prevalent.

Adult↗
PubMed1994

Synthesis and aldose reductase inhibitory activity of 2-substituted 6-fluoro-2,3-dihydrospiro[4H-1-benzopyran-4,4'-imidazolidine]-2',5'-dio nes.

Optically active and racemic 2-substituted 6-fluoro-2,3-dihydrospiro[4H-1- benzopyran-4,4'-imidazolidine]-2',5'-diones were synthesized stereoselectively from (+)-, (-)-, and (+/-)-6-fluoro-3, 4-dihydro-4-oxo-2H-1-benzopyran-2-carboxylic acid [(+)-1, (-)-1, and (+/-)-1], respectively, for evaluation as new aldose reductase inhibitors. Among these compounds, the 2S,4S compounds were found to be more potent inhibitors of aldose reductase in vitro and in vivo than the corresponding 2R,4R enantiomers. The chloromethyl compound [(+)-5] showed highly potent activities in inhibiting cataract formation in the lenses and polyol accumulation in the sciatic nerve of rats.

Aldehyde Reductase↗
PubMed1998

Application of hepatic tolerance tests to the functional reserve assessment in rat models of fatty liver.

The present study was designed to define whether maximal removal rate of indocyanine green (ICG Rmax), plasma cyclic 3',5'-adenosine monophosphate (cAMP) response to exogenous glucagon (peak to basal ratio of cAMP level: P/B cAMP) and plasma half-life of galactose (t1/2 galactose) can measure the hepatic functional reserve of fatty liver prepared in rats fed choline-deficient (9 weeks), 2% cholesterol (2 weeks) or 0.25% DL-ethionine (2 weeks) diet. Although changes in cholesterol and phospholipid values in serum during feeding periods differed among the models, histopathologic examinations in the liver of almost all animals revealed intermediate to severe fatty liver with or without fibrosis at each termination. ICG Rmax and P/B cAMP were significantly decreased in rats fed choline-deficient or DL-ethionine diet, implying reductions in hepatic functional mass and disturbances in hepatic cAMP production. Meanwhile, t1/2 galactose showed no change in any of the models, suggesting that glucose metabolisms in the models used may be preserved. These findings demonstrate that ICG Rmax and P/B cAMP can apply to measurement of hepatic surviving reserve of fatty liver with fibrosis.

Animals↗
PubMed2005

Research for newborn screening: developing a national framework.

Newborn metabolic screening represents the largest application of genetic testing in medicine. As new technologies are developed, the number of conditions amenable to newborn screening (NBS) will continue to expand. Despite the scope of these programs, the evidence base for a number of NBS applications remains relatively weak. This article briefly reviews the evidence base for several conditions. The article then develops a proposal for a structured sequence of research protocols to evaluate potential applications for NBS before their formal implementation in public health programs. Such a framework for research will require collaboration between states and the federal government, a collaboration that is emerging through recent federal legislation and funding.

Anemia, Sickle Cell↗
PubMed1987

Permeability changes in blood-retinal barrier of galactosemic rats are prevented by aldose reductase inhibitors.

Permeability-surface-area products (PA) for sucrose at the blood-retinal barrier (BRB) were determined with quantitative in vivo techniques and compared in control rats, rats fed a 50% galactosemic diet, and rats fed a diet containing both galactose and the aldose reductase inhibitor sorbinil. The mean PA +/- SE for controls was 0.656 x 10(-5) +/- 0.13 ml.g-1.s-1 and increased by approximately 500% in galactose-fed animals to 3.13 x 10(-5) +/- 0.32 ml.g-1.s-1. Animals fed both galactose and sorbinil showed no significant difference from control animals (P greater than .05), with a PA of 0.91 x 10(-5) +/- 0.22 ml.g-1.s-1. No breach in the BRB to horseradish peroxidase was detected in any of the groups. These results demonstrate an increased permeability at the BRB to small molecules in galactosemic rats that is prevented by an aldose reductase inhibitor. This suggests that the retinal capillary basement membrane thickening seen in galactosemic rats is associated with an increased permeability of the BRB and that aldose reductase is implicated in its pathogenesis.

Aldehyde Reductase↗
PubMed1989

Prevention of nerve edema and increased blood-nerve barrier permeability-surface area product in galactosemic rats by aldose reductase or thromboxane synthetase inhibitors.

Nerve water content and the permeability-surface area product (PA) to [3H]-or [14C]sucrose at the blood-nerve barrier were determined in unanesthetized control rats fed a normal diet and in rats fed galactose with or without an aldose reductase inhibitor (Statil or AL 1576) or a thromboxane synthetase inhibitor (CGS 12970). Nerve water content was determined by taking the difference between dry and wet weights of whole tibial nerves. PA was determined by an intravenous bolus injection of radiotracer with multiple-time-point graphic and quantitative autoradiographic methods. The mean nerve water content in galactosemic rats was 15% higher than in control rats after 7-11 mo on the diet. Statil and AL 1576 prevented nerve edema, but CGS 12970 was only partially effective in preventing an increase in nerve water content in galactose-fed rats. In galactosemic rats, the mean PA to sucrose at the blood-nerve barrier, calculated from nerve dry weight, was twofold higher than in control rats. Treatment with Statil, AL 1576, or CGS 12970 prevented increased PA. Our results suggest that nerve edema and increased blood-nerve barrier PA are secondary to polyol production and can be prevented by inhibiting aldose reductase.

Aldehyde Reductase↗
PubMed1994

Characterization of the mechanism for the chronic activation of diacylglycerol-protein kinase C pathway in diabetes and hypergalactosemia.

Similar vascular pathological conditions are observed in diabetic animals and those with diet-induced hypergalactosemia. Both diabetes and hypergalactosemia are believed to cause vascular dysfunction via a common biochemical mechanism. In this study, we have found that both diabetes and hypergalactosemia in the short term (2-4 months) can increase total diacylglycerol (DAG) levels by 52 +/- 9 and 74 +/- 13% in the retina and aorta, respectively, of diabetic dogs, and by 94 +/- 9 and 78 +/- 11% in the retina and aorta, respectively, in dogs with hypergalactosemia as compared with normal control animals (P < 0.01). The elevation of DAG levels was maintained for 5 years in the aortas of diabetic and hypergalactosemic dogs. To characterize the mechanism of the DAG increases, we have determined that total DAG levels were significantly increased in cultured macro- and microvascular cells exposed to elevated glucose (22 mM) and galactose (16.5 mM) levels. These increased levels were not prevented by sorbinil, an aldose reductase inhibitor. One of the sources of the increased DAG levels was probably derived from de novo synthesis from both hexoses as determined by radiolabeling studies. Intracellularly, the DAG elevation activated protein kinase C (PKC) activity with increases of 58 +/- 12% (P < 0.05) and 66 +/- 8% (P < 0.01) in the membrane fraction of cultured aortic smooth muscle cells exposed to elevated glucose and galactose levels, respectively. These findings have clearly demonstrated a possible common biochemical mechanism by which hyperglycemia and hypergalactosemia can chronically activate the DAG-PKC pathway in the vasculature and could be a possible explanation for the development of diabetic vascular complications.

Animals↗
PubMed1996

Galactosemic neuropathy in transgenic mice for human aldose reductase.

We studied the functional consequences of an enhanced polyol pathway activity, elicited with galactose feeding, on the peripheral nerve of transgenic mice expressing human aldose reductase. Nontransgenic littermate mice were used as controls. With a quantitative immunoassay, the expression level of human aldose reductase in the sciatic nerve was 791 +/- 44 ng/mg protein (mean +/- SE), about 25% of that in human sural nerve. When the transgenic mice were fed food containing 30% galactose, significant levels of galactitol accumulated in the sciatic nerve. Galactose feeding of nontransgenic littermate mice led to a 10-fold lower accumulation of galactitol. Galactose feeding for 16 weeks caused a significant and progressive decrease in motor nerve conduction velocity in transgenic mice to 80% of the level of galactose-fed littermate mice, which was not significantly different from that of galactose-free littermate mice. A morphometric analysis of sciatic nerve detected > 10% reduction of mean myelinated fiber size but no alterations of myelinated fiber density in galactose-fed transgenic mice compared with other groups. The functional and structural changes that develop in galactose-fed transgenic mice are similar to those previously reported in diabetic animals. The results of these studies suggest that transgenic mice expressing human aldose reductase may be a useful model not only for defining the role of the polyol pathway in diabetic neuropathy but also for identifying and characterizing effective inhibitors specific for human aldose reductase.

Aldehyde Reductase↗