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PubMed2005

Dietary galactose inhibits GDF-9 mediated follicular development in the rat ovary.

Clinical evidence suggests an association between galactosemia and premature ovarian failure, but the mechanism is still not fully understood. Growth differentiation factor-9 (GDF-9) is thought to be an obligatory growth factor during the gonadotropin-independent phase of folliculogenesis. The objective of this study was to examine the effects of galactose on initiation of folliculogenesis in the peripubertal interval and the connection between galactose toxicity and GDF-9 expression in the ovary. After immature Long-Evans rats (n = 10) were fed a diet consisting of 20% galactose for 19 days, whole body, ovary and uterine weights were measured. Serum estradiol and progesterone concentrations were measured by radioimmunoassay. Ovarian follicles were counted by morphometric analysis and GDF-9 expression was investigated by immunohistochemistry and immunoblot assay. Galactose treatment did not affect the onset of puberty as marked by the time of vaginal opening. The galactose diet significantly decreased the number of healthy growing follicles. The results of immunoblot assay showed that both bands corresponding to propeptide and mature forms of GDF-9 decreased with the galactose diet about 90 and 70%, respectively. The results of immunohistochemical staining showed that the GDF-9 positive follicle number and the ratio of GDF-9 positive to GDF negative (primordial/non-growing) follicles significantly decreased with this high galactose diet. The present study suggests that a high galactose diet inhibits follicular development, possibly through down-regulation of GDF-9 in the rat ovary, implying that GDF-9 may be involved in galactose-related ovarian toxicity.

Animals↗
PubMed2004

The rate of de novo galactose synthesis in patients with galactose-1-phosphate uridyltransferase deficiency.

Using both a continuous infusion of isotopically labeled [1-13C]galactose with a steady-state analysis and a single injection kinetic approach, we have calculated the apparent galactose appearance rate (GAR) in patients with galactose-1-phosphate uridyltransferase deficiency and control subjects. With the steady-state protocol, the GAR in 18 patients less than 18 years of age was 1.34+/-0.53 mg/kg/h (mean+/-SD) and was significantly greater than the mean of 0.56+/-0.01 mg/kg/h (p=0.004) in five patients above 18 years of age. Patients who were given a priming dose of [1-13C]galactose had a reduced GAR compared to those without a priming dose, 0.73+/-0.05 (n=9) vs 1.46+/-0.62 (n=14)mg/kg/h (p=0.005). The GAR in controls was lower than in patients ranging from 0.58 to 0.68 mg/kg/h in children and 0.07-0.09 mg/kg/h in adults. In the single bolus studies the plasma [13C]galactose enrichment decreased in a biexponential pattern suggesting at least a two-compartment system. The calculated GAR in three adult patients was similar to that found in them by the continuous infusion technique. The GAR in patients suggests the source of galactose for the continued elevation of galactose metabolites as well as the basis for the long-term complications in galactosemia despite restricted dietary galactose intake.

Adolescent↗
PubMed2001

Overview of common inherited metabolic diseases in a Southern Chinese population of Hong Kong.

BACKGROUND: The Joint metabolic clinic at the Prince of Wales Hospital was established in January 1997 to provide a comprehensive multi-disciplinary care to patients with inherited metabolic diseases (IMDs). Patients are referred from both within and outside our hospital. Until July, 2000, more than 40 patients and families with 20 different biochemical diagnoses attend the clinic for regular follow up. A pattern of more common IMDs among Hong Kong Chinese emerged from our case registry. In order to advance the understanding of Chinese metabolic diseases, we examined the molecular basis of those diseases with unique features in Chinese or were locally prevalent. Mutations were found in patients with primary carnitine deficiency, ornithine transcarbamylase deficiency, X-linked adrenoleukodystrophy, glutaric aciduria type I, and galactosemia. We also analyzed the mutations in multiple carboxylase deficiency and Niemann-pick type C on four families. CONCLUSIONS: Although IMDs are a significant cause of mortality and morbidity among pediatric patients, with a better understanding of the molecular genetics of these diseases, prenatal diagnosis of these common IMDs will be facilitated, which is currently the most effective way of controlling IMDs.

Fatty Acids↗
PubMed2000

Influence of tolrestat on the defective leukocyte-endothelial interaction in experimental diabetes.

One of the most devastating secondary complications of diabetes is the blunted inflammatory response that becomes evident even in the very early stages of poorly controlled diabetes mellitus. While the etiology of this diminished response is not clearly understood, it has been linked to a decrease in the respiratory burst of neutrophils, as well as a decrease in microvessel response to inflammatory mediators and defective leukocyte-endothelial interactions. Using video microscopy to visualize vessels of the internal spermatic fascia, we have characterized leukocyte-endothelial interactions in alloxan-induced diabetic and in galactosemic rats by quantitating the number of leukocytes rolling along the venular endothelium and the number of leukocytes sticking to the vascular wall after topical application of zymosan-activated plasma or leukotriene B(4) (1 ng/ml), as well as after the application of a local irritant stimulus (carrageenan, 100 microg). We observed that while 33 days of alloxan-induced diabetes or 7 days of galactosemia had no effect on total or differential leukocyte counts and on the wall shear rate, both treatments significantly (P<0.001) reduced the number of leukocytes rolling along the venular endothelium by about 70% and the number of adhered leukocytes in postcapillary venules by 60%. These effects were not observed in diabetic and galactosemic animals treated with an aldose reductase inhibitor. The results suggest that impaired leukocyte-endothelial cell interactions are a consequence of an enhanced flux through the polyol pathway.

Aldehyde Reductase↗
PubMed1995

Family history as a predictor of early menopause.

OBJECTIVE: To determine the relative importance of family history as a predictor of early menopause. DESIGN: Case-control study. From a population-based survey of 10,606 women between 45 and 54 years of age, we selected 344 cases with early menopause (average age 42.2 years) and 344 age-matched controls who were still menstruating or who had a menopause after age 46 years. Subjects were interviewed about their medical and family history and blood was drawn for identification of women who were carriers for the classic or Duarte variant of galactosemia, a potential hereditary factor for early menopause. Logistic regression analysis was used to estimate the risk of an early menopause in women with and without a family history of early menopause. RESULTS: Overall 129 (37.5%) of the early menopause cases reported a family history of menopause before age 46 years in a mother, sister, aunt, or grandmother compared to 31 (9.0%) of controls yielding an odds ratio (OR) of 6.1 (95% confidence interval [CI] of 3.9 to 9.4) after adjustment for smoking history, education, parity, and body mass index. Risk for early menopause associated with family history of same was greatest: for family history in a sister, OR = 9.1 (95% CI 3.1 to 26.5); multiple relatives, OR = 12.4 (95% CI 4.4 to 34.2); and cases menopausal before age 40 years, OR = 8.4 (95% CI 2.5 to 31.2). Cases with a family history of early menopause were not more likely to have errors of galactose metabolism compared with cases without a family history or to all controls, nor did they possess Turner's stigmata such as short stature, but they were less likely to have brothers in their sibships. CONCLUSIONS: Although preferential recall of family history by women with early menopause could contribute to the association between family history and early menopause observed in this study, a genetic factor is also plausible including partial deletions of the X chromosome compatible with the deficiency of male siblings in cases with family history of early menopause.

Adult↗
PubMed2001

Potential of capillary electrophoresis, tandem mass spectrometry and coupled capillary electrophoresis-tandem mass spectrometry as diagnostic tools.

Urine and blood samples from patients with known metabolic disorders have been analyzed by CE, MS-MS and CE-MS-MS. For the identification of defects in acylcarnitine metabolism, blood spots on filter paper were analyzed using an MS-MS "neonatal screening" approach. Direct CE-MS-MS analysis was used for the analysis of urine samples from patients with different metabolic disorders, including galactosemia, neuroblastoma, Zellweger syndrome, propionic acidemia and alcaptonuria. The sensitivity of the CE-MS-MS method was increased by use of multiple reaction monitoring.

Electrophoresis, Capillary↗
PubMed2000

Sickle-cell disease not identified by newborn screening because of prior transfusion.

Erythrocyte transfusion can impair detection of sickle-cell disease, galactosemia, or biotinidase deficiency with newborn screening. We report on 4 infants with SCD in whom delayed diagnosis was associated with neonatal transfusion. In 2 cases, the initial newborn screening showed no hemoglobin S. In no case was the recommended screening >/=120 days from the last transfusion obtained. Two children had significant SCD-related morbidity before diagnosis.

Anemia, Neonatal↗
PubMed1993

Uridine diphosphoglucose content of human erythrocytes: assessment by conversion to uridine diphosphoglucuronate.

To settle the ongoing controversy regarding differential uridine diphosphoglucose (UDPG) and uridine diphosphogalactose (UDPGal) content of erythrocytes, which may be important in evaluating the metabolic abnormality in patients with galactosemia, we derived a combined enzymatic-high-performance liquid chromatography (HPLC) assay. Uridine diphosphoglucuronate (UDPGA), the unique product of UDPG dehydrogenase activity, was separated and quantified by HPLC in extracts of human erythrocytes. The quantity of UDPGA produced in cell filtrates incubated with the enzyme corresponds to the amount of UDPG directly determined by HPLC. The amount of UDPGA produced was independent of the enzyme purity or activity used. On the other hand, the amounts of UDPG estimated by fluorometric measurement of the production of reduced nicotinamide adenine dinucleotide varied with the enzyme purity and activity. The combined enzymatic-HPLC method confirms the direct determinations of UDPG content of normal erythrocytes. The results indicate that, under appropriate conditions, the fluorometric-based assay will give accurate estimates of UDPG, but the direct HPLC method yields consistent and correct UDPG and UDPGal determinations.

Chromatography, High Pressure Liquid↗
PubMed1994

Delta 4-3-oxosteroid 5 beta-reductase deficiency causing neonatal liver failure and hemochromatosis.

Neonatal liver failure was evaluated in two infants. Neither infant had evidence of congenital infection, galactosemia, alpha 1-antitrypsin deficiency, tyrosinemia, Zellweger syndrome, or hemophagocytic lymphohistiocytosis. Abnormal levels of iron were detected in the minor salivary glands of the first infant and in the explanted liver of the second. Analyses of urinary bile salts by fast-atom bombardment ionization mass spectrometry and gas chromatography-mass spectrometry revealed a paucity of primary bile acids and a predominance of 7 alpha-hydroxy-3-oxo-4-cholenoic and 7 alpha,12 alpha-dihydroxy-3-oxo-4-cholenoic acids. These findings are consistent with delta 4-3-oxosteroid 5 beta-reductase deficiency, a primary genetic defect in bile acid synthesis. Postmortem evaluation of the first infant revealed significant iron deposition in the liver, pancreas, thyroid, adrenal glands, myocardium, stomach, and submucosal glands of the respiratory tract. In both infants examination of the liver revealed extensive loss of hepatic parenchyma. These cases expand the clinical spectrum of bile acid metabolism defects to include neonatal liver failure with associated hemochromatosis.

Bile Acids and Salts↗
PubMed1997

Black children deficient in galactose 1-phosphate uridyltransferase: correlation of activity and immunoreactive protein in erythrocytes and leukocytes.

A recent study found a high prevalence of a missense mutation (S135L) in the gene for galactose 1-phosphate uridyltransferase (GALT) in black children with galactosemia (J Pediatr 1996; 128:89-95). In the present study, GALT activity and GALT protein content were measured in erythrocytes and leukocytes of eight black and seven white galactosemic (GALT-deficient) children, for correlation with the presence of the S135L and Q188R (highly prevalent in white galactosemic children) missense mutations. The S135L mutation was found in 9 of 16 alleles of black children but not in white children; the Q188R mutation was found in 10 of 14 alleles examined in white galactosemic children and in 4 of 16 alleles in black galactosemic children. The GALT activity was near zero in the erythrocytes of white and black galactosemic children (0.26 +/- 0.28 vs 0.33 +/- 0.25 mumol/hr per gram of hemoglobin, respectively; p = 0.61) (normal 17 to 26 mumol/hr per gram), and no correlation of erythrocyte activity with genotype was observed. The GALT activity was higher in the leukocytes of black galactosemic children compared with white children (5 +/- 6 vs 1 +/- 2 mumol/hr per gram, respectively) (normal 172 to 374 mumol/hr per gram), but the difference was not statistically significant (p = 0.11). Analysis by genotype revealed that the two S135L homozygotes had much more leukocyte activity (9 and 17 mumol/hr per gram) than Q188R homozygotes or than all non-S135L allelic genotypes. Compound heterozygotes (S135L/G) had intermediate activity. The GALT protein was not detectable by Western blot in the erythrocytes of either white or black galactosemic children, as determined by antibodies specific for both C- and N-terminal sequences. The GALT protein was undetectable in the leukocytes of white galactosemic children, but leukocytes from black galactosemic children with the S135L mutation contained reduced but readily detectable GALT protein. Erythrocyte galactose 1-phosphate levels were significantly lower in galactosemic children with an S135L mutant allele (1.1 +/- 0.2 gm/dl) compared with children who had other mutations (3.1 +/- 0.9 mg/dl; p = 0.0001). The correlation of protein content data with activity levels in the blood cells suggests that the S135L missense mutation affects the stability of GALT protein to produce a deficiency state.

Adolescent↗
PubMed1989

Laboratory detection of metabolic disease.

This article describes the clinical signs, abnormal chemistry, histopathology, and biochemical tests that assist in the diagnosis of many inherited metabolic diseases. Small molecule diseases (for example, amino acid disorders, organic acidurias, and galactosemia) may present with acute illness and lead to unexplained death. Diagnosis of the specific enzyme defect may permit treatment by dietary changes or vitamin supplementation. Large molecule diseases are degenerative disorders due to storage of glycogen, glycoproteins, or mucopolysaccharides. Table 7 presents a compendium of laboratory investigations one should consider using when abnormalities are found in multiple organ systems. The investigation of a child with a mucopolysaccharidosis is used as an example of the use of this table. Investigating pediatricians should realize that many laboratory tests involved in the diagnosis of metabolic disease required special collection and handling by the laboratory.

Amino Acid Metabolism, Inborn Errors↗
PubMed1995

Consumption of a high-galactose diet induces diabetic-like changes in the inner ear.

Diabetes mellitus is a disease that affects multiple organ systems. In our laboratory it has been shown that there is a significant loss of outer hair cells in genetically diabetic rats. Galactosemia can also produce diabetic-like changes. This study was performed to demonstrate whether these changes also occur in the cochlea. Three groups of Sprague-Dawley rats were used and fed either a control diet, a 50% galactose diet, or a 50% galactose diet with the addition of an aldose reductase inhibitor. After 6 months the animals were killed, and the cochleas were removed, fixed, and stained. Diabetes-induced damage was assessed by counting the hair cells and calculating the neuroganglion cell density. The histopathologic changes induced by galactose were manifested as outer hair cell loss and a decrease in neuroganglion cell density. Control animals had the least amount of hair cell loss and the greatest neuroganglion cell density of all three groups. Galactose-only animals demonstrated the most pronounced changes in both hair cell loss and neuroganglion cell degeneration; however, only changes of neuroganglion cell density in the basal turn were significant. The addition of an aldose reductase inhibitor provided inconclusive results in both hair cell determination and neuroganglion cell density; however, generally the inhibitor partially prevented the damage produced by galactose. These results suggest that a high-galactose diet can induce diabetic-like changes in the cochlea.

Aldehyde Reductase↗
PubMed1998

Availability of specific sugars for glycoconjugate biosynthesis: a need for further investigations in man.

We review the metabolism of specific sugars used for protein glycosylation, focusing on the fate of exogenously provided sugars. Theoretically, all glycoprotein sugars can derive from glucose, but previous studies show that other exogenous sugars can be incorporated into glycoproteins. From data obtained in congenital galactosemia, exogenous galactose may be important for correct glycosylation. Contrary to galactose, the metabolism of other sugars seems to depend on insulin regulation: stimulation of their endogenous production in diabetic subjects might participate in some diabetic complications, precluding the need for an exogenous supply. The metabolic fate of these sugars is different according to the administration route and exogenous supply may be important either in enteral nutrition or in some clinical situations as has been suggested for sialic acid in the newborn. Data in man are too sparse to reach firm conclusions, implying a need for further investigations. Our preliminary results in animals and man demonstrate that stable isotope methodology allows one to trace glycoprotein sugar metabolism in nutritionally relevant conditions with accuracy and sensitivity, using doses of specific sugars well below toxic levels.

Animals↗
PubMed2001

Screening for inborn errors of metabolism using gas chromatography-mass spectrometry.

Screening of newborns for inborn errors of metabolism (IEM) in China is both a challenging and undeveloped area for gynecologists and pediatricians. Since 1999, the Capital Institute of Pediatrics has been studied as regards screening for IEM using advanced gas chromatography-mass spectrometry (GC-MS) method in collaboration with the Matsumoto Institute of Life Science (MILS), Japan, and has successfully diagnosed 51 cases of IEM in a total of 393 patients. Galactosemia, phenylketonuria and methylmalonic acidemia were the most frequent disorders among 51 cases of IEM. Treatment by suitable drugs and/or diet therapy was very effective in the most cases.

Gas Chromatography-Mass Spectrometry↗
PubMed1997

Nutritional considerations and management of the child with liver disease.

Nutritional management of the infant and child with liver disease is highly dependent upon the type of liver disease. Acute liver disease, such as that secondary to viral hepatitis, requires no specific nutritional therapy with the exception that branched-chain amino acid supplements may be indicated in the management of hepatic encephalopathy. Nutritional management of the child with chronic liver disease depends upon whether or not cholestasis is present, since in that condition, large amounts of fat-soluble vitamin supplements and medium-chain triglycerides are usually required for optimum growth. However, anicteric cirrhotic liver disease also presents nutritional challenges because of hypermetabolism, enteropathy, and increased protein oxidation. Certain inborn errors of metabolism that result in liver disease (including galactosemia, hepatorenal tyrosinemia, hereditary fructose intolerance, and Wilson's disease) have specific nutritional requirements. And, finally, the advent of pediatric liver transplantation has placed new emphasis on the importance of optimum nutritional management of the child with chronic liver disease, since improvement of nutritional status in the pretransplant period maximizes success of the transplant. This review will focus on the pathogenesis of malnutrition in childhood liver disease and will provide recommendations for nutritional assessment and monitoring as well as nutritional management of cholestatic liver disease, anicteric cirrhotic liver disease, and the inborn errors of metabolism enumerated above. Specific recommendations for nutritional management of the child awaiting liver transplantation will be provided.

Child↗
PubMedDate not supplied

Aldose reductase and the development of renal disease in diabetic dogs.

Effects of 5 years administration of an aldose reductase inhibitor (Sorbinil) on renal structure and albumin excretion were evaluated in diabetic dogs. Glycemia, estimated by frequent measurements of HbA1, glycated plasma proteins and glucosuria, was kept comparable between the placebo- and Sorbinil-treated diabetic groups. Kidney structure was evaluated using morphometric techniques by light and electron microscopy, and excretion of immunoreactive albumin was measured yearly. Placebo-treated diabetic dogs developed nephromegaly, glomerular enlargement, increased mesangial volume, and basement membrane thickening during the 5 years of study, and by the fifth year, excreted greater than normal quantities of albumin. Sorbinil treatment prevented sorbitol accumulation in erythrocytes and tended to have a similar effect in renal cortex, but had no beneficial effect on renal structure or albuminuria. Experimental galactosemia, another model of polyol over-production, failed to produce nephromegaly, glomerular enlargement, or mesangial expansion in dogs even after 5 years of galactose-feeding. The results suggest that polyol over-production and/or accumulation per se are not sufficient to account for the nephromegaly, glomerular enlargement, or increased mesangial volume observed in diabetic dogs.

Albuminuria↗
PubMedDate not supplied

Neutrophils in galactose-fed dogs: suppressed apoptosis and increased adhesion to retinal capillary endothelial cells.

Dogs fed a diet containing 30% galactose develop diabetes-like retinal capillary changes. As retinal capillary occlusion is commonly observed in diabetic retinopathy, neutrophil apoptosis and the interaction of neutrophils with retinal capillary endothelial cells were investigated. Neutrophils were isolated with Ficoll-Hypaque centrifugation from dogs fed a 30% galactose diet and dogs fed a normal, control diet containing 30% non-nutrient filler. Apoptosis of neutrophils was microscopically examined after incubation at 37 degrees C for 3 hours with either 100 U/mL tumor necrosis factor alpha (TNF-alpha), 2 microg/mL cycloheximide or 50 ng/mL phorbol 12-myristate 13-acetate (PMA). Neutrophil adhesion to dog retinal capillary endothelial cells was examined by counting the cells attached to the surface of endothelial cells after the incubation in the presence of either 100 U/mL TNF-alpha or 5 microg/mL lipopolysaccharides (LPS) at 37 degrees C for 3 hours. With all three stimulants TNF-alpha, cycloheximide and PMA, the rate of apoptosis was significantly lower for neutrophils isolated from galactose-fed dogs compared to control dogs fed a normal diet. Preincubation of neutrophils from control dogs in medium containing 30% galactose for 3 hours did not affect the rate of apoptosis. Neutrophil adhesion to retinal capillary endothelial cells induced by incubation in the presence of either 100 U/mL TNF-alpha or 5 microg/ml LPS was significantly higher with neutrophils isolated from galactose-fed dogs than those from control dogs. The data indicate that long-term galactose feeding is essential with development of various neutrophil dysfunctions. These neutrophil changes may contribute to the development of retinal microangiopathy associated with diabetes and galactosemia.

Animals↗
PubMed2002

[Ovarian genes].

The number of ovarian follicles decreases during genital life by apoptosis, which accelerates from 40 until the menopause. Several findings plead in favour of a genetic control of these events. Ovarian insufficiency can occur by three mechanisms: reduction in the primary follicles reserve (ataxia-telangiectasy), follicular maturation blocking (modification of the genes GDF-9 and GDF-9B, null mutation of FSH receptor gene, auto-immune polyglandular disease, PBE syndrome), or apoptosis acceleration (chemotherapy, smoking, galactosemia, Turner's syndrome). However, the aetiology of premature ovarian insufficiencies in woman remains unknown in more than 90% of the cases. Genetic studies on the family cases should make it possible to identify new genes involved in ovarian control.

Animals↗