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PubMedDate not supplied

Nitric oxide synthases modulate progenitor and resident endothelial cell behavior in galactosemia.

We used knockout animals of either inducible nitric oxide synthase (iNOS(/)) or endothelial NOS (eNOS(/)) to characterize the role of NOS in galactosemia, a model of diabetic retinopathy. NADH oxidase and nitrotyrosine were used as biomarkers of oxidative stress and vascular dysfunction. These animals were engrafted with hematopoietic stem cells (HSC) expressing green fluorescence protein (gfp(+)) to characterize the contribution of HSC and endothelial progenitor cells to neovascularization. Increased NADH oxidase activity and superoxide generation occurred in all galactose-fed mice. eNOS(/) mice demonstrated increased iNOS immunoreactivity in their retinal vasculature. Nitrotyrosine levels were low at baseline in the wild-type (WT) mice, eNOS(/) and iNOS(/) mice, and the galactose-fed iNOS mice and increased following galactose feeding in eNOS(/) and WT. Galactose-fed WT.gfp and iNOS(/).gfp chimeric animals had areas of perfused new vessels composed of gfp(+) cells. In contrast, galactose-fed eNOS(/).gfp mice produced copious, unbranched, nonperfused tubes. Thus, nitric oxide modulates HSC behavior and vascular phenotype in the retina. Although there is increased NADH oxidase and superoxide in galactosemic mice of all isoforms, iNOS is the source of nitric oxide responsible for peroxynitrite and nitrotyrosine formation that leads to the pathology observed in galactosemic mice.

Animal Feed↗
PubMed1998

Defective galactosylation of serum transferrin in galactosemia.

The glycosylation of serum transferrin from galactosemic patients with a deficiency of galactose-1-phosphate uridyl transferase (EC 2. 7.7 12) is abnormal but becomes normal after treatment with a galactose-free diet. To understand the structural and biochemical basis of the abnormal glycosylation, transferrin was purified from the serum of untreated and treated galactosemic patients and normal controls and the N-linked glycans analyzed by HPLC. The glycans from normal transferrin consisted predominantly (86%) of the disialylated biantennary complex type. The glycans from untreated galactosemic patients were more heterogeneous and contained four major truncated glycans in addition to a smaller amount (13%) of the disialylated biantennary complex type. The truncated glycans were deficient in galactose and sialic acid and their structures were consistent with a decrease in galactosyltransferase activity in hepatocytes, the probable cells of origin of the transferrin. This is postulated to be due to direct inhibition of the galactosyltransferase activity by the accumulated galactose-1-phosphate or to an effect on the formation of UDP-galactose, the donor substrate in the reaction. After treatment the proportion of the truncated glycans decreased and the proportion of the disialylated biantennary complex type increased, returning almost but never completely to normal, even after prolonged treatment in some cases. There was no clear relationship between the length of treatment and the normalization of glycosylation and the level of galactose-1-phosphate in red blood cells, the usual parameter for monitoring the treatment of galactosemics. It is suggested that the persistence of abnormally glycosylated proteins may contribute to the long-term complications in galactosemia.

Carbohydrate Sequence↗
PubMed2003

Comorbidity of schizophrenia and galactosemia: effective clozapine treatment with weight gain.

Weight gain with atypical antipsychotics such as clozapine has been hypothesized to have a multifactorial genesis. Beside changes in neurotransmitter systems caused by antipsychotic-induced receptor blockade, hormonal changes and other neuroleptic side-effects (sedation, reduced activity, reduced basal metabolic rate, dry mouth) are also discussed. Our unique case report of a patient with comorbid galactosemia and schizophrenia is an interesting example of weight gain being a positive side-effect of clozapine, not necessarily associated with increased appetite and higher caloric intake.

Adult↗
PubMed1978

An unusual form of galactosemia: studies on erythrocytes and hair roots.

An unusual form of galactosemia is described in a 7-month-old boy, characterized by a late onset of the clinical symptoms. A high apparent residual activity of erythrocyte galactose-1-phosphate uridyl transferase (GT) was measured with the spectrophotometric UDP-Glucose consumption test(+/-25% of normal). The residual activity in erythrocyte lysates, determined when the patient was 7, 16 and 22 months old, significantly decreased upon storage and after preincubation with NAD-ase. The radiochemical measurement of GT activity demonstrated a severe deficiency: only a level of +/-1% of normal activity was observed, and no effects of storage or NAD-ase could be demonstrated. GT and galactokinase (GK) activities were measured radiochemically in lysates from hair roots obtained from the human scalp, and it was found that the GT/GK activity ratio is a useful index for the detection of heterozygotes. Erythrocyte and hair root lysates from the heterozygous parents of the patient displayed GT/GK ratios which were intermediate between mutant and normal. Because they offer a simple and fast way to obtain biopsy material, hair roots might become of increasing importance for carrier detection studies.

Adult↗
PubMed1981

Hemoglobin A1 in galactosemia, a possible role in monitoring dietary compliance.

The finding of elevated HbA1 levels in two galactosemic infants of 24.1% and 23.8% (normal 6.3-8.2%) led to an assessment of the effects of dietary management in galactose-1-phosphate uridyl transferase deficiency and galactokinase deficiency. Exclusion of dietary galactose and lactose in the two propositi resulted in a reduction of HbA1 levels to normal in one and towards normal in the other. HbA1 was measured in twelve treated subjects with transferase deficiency, seven carriers, and one child te uridyl transferase deficiency and galactokinase deficiency. Exclusion of dietary galactose and lactose in the two propositi resulted in a reduction of HbA1 levels to normal in one and towards normal in the other. HbA1 was measured in twelve treated subjects with transferase deficiency, seven carriers, and one child te uridyl transferase deficiency and galactokinase deficiency. Exclusion of dietary galactose and lactose in the two propositi resulted in a reduction of HbA1 levels to normal in one and towards normal in the other. HbA1 was measured in twelve treated subjects with transferase deficiency, seven carriers, and one child with galactokinase deficiency. Five transferase deficient children had elevated HbA1 levels, and four of these agreed to a six week strict dietary exclusion of galactose and lactose. This trial resulted in a fall in HbA1 levels in all subjects (mean 12.6% to mean 9.2%). These results suggest HbA1 levels may be of value in assessing and ensuring dietary compliance in galactosemia.

Adolescent↗
PubMed1979

Galactosemia: alterations in sulfate metabolism secondary to galactose-1-phosphate uridyltransferase deficiency.

Cultures of nonmutant as well as galactokinase-deficient fibroblasts incorporate 20 percent more [35S]sulfate when galactose is substituted for glucose in the medium; galactose-1-phosphate uridyltransferase-deficient cells incorporate 65.5 percent less. In addition to incorporating less [35S]sulfate, the uridyltransferase-deficient cells showed significant accumulation of intracellular galactose-1-phosphate within 4 hours after galactose exposure. Under the same conditions, no difference in [3H]uridine incorporation was observed. This metabolic alteration, occurring in response to galactose exposure, may be related to the pathophysiology of classical galactosemia.

Cells, Cultured↗
PubMed1980

A new variant of galactosemia: galactose-1-phosphate uridylytransferase sensitive to product inhibition by glucose 1-phosphate.

In the erythrocytes of a patient with the clinical symptoms of galactosemia, a galactose-1-phosphate uridylyltransferase with abnormal kinetics was observed. Under standard assay conditions, the uridylyltransferase activity was almost normal initially and became completely inactivated within 30 min. The abnormal kinetics could be ascribed to a product inhibition by glucose 1-phosphate. The inhibition was produced by a variety of sugar phosphates, the most potent of which proved to be glucose 1-phosphate, mannose 1-phosphate, and fructose 6-phosphate. The variant galactose-1-phosphate uridylyltransferase was further characterized by a lowered affinity towards galactose 1-phosphate, non-Michaelis-Menten kinetics towards UDP-glucose, an increased thermal stability, and complete inactivity upon Cellogel electrophoresis.

Child, Preschool↗
PubMed1981

A new method of blood galactose estimation for mass screening of galactosemia.

A new method for quantitative determination of galactose in blood by fluorescence of NADH was described. The assay system consisted of beta-galactose dehydrogenase, NAD, buffer and a denatured blood disc (3 mm diameter), and the reaction was carried out for 1 hr at 37 degrees C. Denaturation of hemoglobin was accomplished by exposing the blood disc to a vapor of formic acid in an air-tight container; this procedure completely eliminated false positive cases of galactosemia. This method can be applied in a wide range of galactose concentration from low (0 mg%) to high levels (200-1,000 mg%) with the accuracy of 8.0 +/- 0.3 mg% from a coefficient of variation of 3.5%. Semi-quantitative assay was also possible by using a spot test like Beutler's method. The galactose content in one disc paper (3 mm diameter) of blood containing 5 mg% galactose is approximately 0.1 micrograms. The newly developed method is satisfactorily applicable in neonatal mass screening and clinical cases.

False Positive Reactions↗
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↗
PubMed1984

Experimental galactosemia produces diabetic-like retinopathy.

Six normal dogs were made galactosemic by feeding a 30% D-galactose diet, and were followed up to 5 yr. For comparison, 10 normal dogs and 10 alloxan-diabetic dogs were concurrently fed the diet less the galactose supplement. Retinopathy occurred in each of four dogs glactosemic 3 or more yr, and was absent at lesser durations of galactosemia, and from normal dogs not given the galactose supplement. The retinopathy was marked by saccular capillary aneurysms, hemorrhages, nonperfused or acellular vessels, tortuous hypertrophic capillaries, loss of capillary pericytes, and other lesions typical of diabetic patients and alloxan-diabetic dogs. In galactose-fed dogs, blood galactose varied between 0 (fasted) and 250 mg/dl (postprandial), and glycosylated hemoglobin levels became supranormal. In contrast to diabetic dogs, blood levels of glucose, free fatty acids, and branched-chain amino acids were not elevated in the galactosemic dogs, and their serum insulin seemed normal. The results suggest that the level of blood hexose is itself an important determinant of retinopathy.

Amino Acids, Branched-Chain↗
PubMed1993

Reduced renal accumulation and toxicity of cisplatin in experimental galactosemia.

The kidneys of streptozotocin (STZ)-diabetic rats are resistant to certain toxic effects of the antineoplastic drug cisplatin. The mechanism is unknown. This study used the galactosemic rat model to test the hypothesis that the apparent diabetes-induced protection is due to changes in the kidney secondary to chronically elevated hexose concentrations. Galactosemic rats are normoinsulinemic and are free from many of the multiple biochemical abnormalities seen in STZ diabetics. The experiments compared renal cortical platinum (Pt) and blood urea nitrogen (BUN) levels after intraperitoneal injection of 5 mg/kg of cisplatin in galactosemic, STZ-diabetic, and age-matched nondiabetic Sprague-Dawley rats. Nephrotoxicity was defined as a BUN concentration ratio (after to before cisplatin) > 2.5. The results demonstrate that the kidneys of both galactosemic and STZ-diabetic rats became resistant to cisplatin-induced elevation of BUN and, further, that the development of the protection was related to the duration of the diabetic state. Although the protective effect developed more slowly in the galactosemic rats, the attenuation of the rise in BUN was ultimately comparable to that seen in STZ diabetics. Renal cortex [Pt] after cisplatin injection was significantly lower in galactosemics and STZ diabetics compared with age-matched nondiabetics, with the order nondiabetics > galactosemics > STZ diabetics. It was noted, however, that renal Pt accumulation was maximally depressed within 4 weeks of experimental diabetes, whereas the BUN ratio continued to decline with increasing duration of both galactosemia and STZ diabetes. Thus, reduced renal Pt accumulation cannot by itself explain the progressive attenuation of the toxicity. The results support the hypothesis and suggest that the galactosemic rat will be a useful model for mechanistic study of diabetes-induced protection from cisplatin nephrotoxicity.

Animals↗
PubMed1975

[Pathobiochemistry of galactosemia and usefulness of the Gt system in expert opinions (author's transl)].

We investigated the genetic polymorphism of galactose-1-phosphate-uridyl-transferase (Gt) of 525 blood samples from Southern Germany. The gene frequencies of Gt1 are 0.9581 and of Gt2 0.0623. Comparing the gene frequencies of galactosemia (0.006), GtD (0.06), Gt1 (0.9581) and Gt2 (0.0623), we see that the gene frequencies of GtD and Gt2 are nearly identical. In expert opinions that Gt is a system of insufficient information.

Electrophoresis, Agar Gel↗
PubMed1975

[Higher nervous activity in rats with symptoms of hereditary galactosemia].

The patterns of behaviour and neural processes in rats with symptoms of hereditary galactosemia were investigated. Certain impairment of neural processes, particularly of the internal inhibition process in galactosemic rats was established. This is evidenced by low conditioning rate and lower level of responding in 2-way shuttle-box avoidance achieved by galactosemic rats in comparison with galactose-resistant rat substrain. Significant changes in motor activity and emotionality level in the course of repeated open-field testings were not found in galactosemic rats. The pecularities of the active avoidance acquisition, an analysis of the capacity to the retention of acquired task demonstrated an impaired mechanism of long-term memory storage in galactosemic animals.

Animals↗
PubMedDate not supplied

[Screening for congenital hypothyroidism, phenylketonuria, galactosemia and biotinidase deficiency in a sample of mentally retarded patients in the city of Havana].

INTRODUCTION: Congenital hypothyroidism (CH), phenylketonuria (PKU), galactosemia (GAL) and biotinidase deficiency (BD) are innate errors in metabolism that share varying degrees of mental retardation (MR) as a common characteristic. AIMS. The aim of our study was to screen individuals with MR of unknown origin for CH, PKU, GAL and BD. PATIENTS AND METHODS: Venous blood samples were collected on SS 903 specimen collection paper from 55 individuals with MR of unspecific origin born within the period 1977 1997. CH diagnosis was performed through determination of total thyroxine (T4) and thyroid stimulating hormone (TSH), using the UMELISA T4 and neonatal TSH reagent kits, respectively, and the detection of PKU, GAL and BD was conducted by determining phenylalanine (Phe), total galactose (Gal) and biotinidase enzyme activity (Biot) using UMTEST PKU, GAL and BIOTINIDASA. RESULTS: The mean values obtained for the analytes that were evaluated were: 0.8 mUI of TSH/L of total blood (EEM: 0.2), 113.1 nmol of T4/L of serum (EEM: 5.4), 67.7 mol of Phe/L of total blood (EEM: 0.1), 0.1 mmol of Gal/L of total blood (EEM: 0.01), and Biot activity was normal in all cases. CONCLUSIONS: This study enabled us to determine the T4, TSH, Phe and Gal levels in a sample from the Cuban population with MR of unknown causation. In addition, slightly higher levels of T4 were found in children who had hyperkinesis

Amidohydrolases↗
PubMed1992

[Long-term results in children with classical galactosemia].

Galactosemia due to uridyl-transferase deficiency was detected in 47 patients between 1/1/1967 and 31/12/1988. The condition took a fulminant course in 31 patients and 10 infants in this group died between the 6th and the 18th day of life. The determination of uridyl-transferase in 36 patients confirmed the diagnosis. Exchange blood transfusion was undertaken in 25 infants because of hyperbilirubinemia, septicemia or neurological symptoms. 5 of the 31 children had a cataract. In most cases the lactose-free diet was commenced in the 2nd week of life. 27 patients were followed up with respect to somatic and intellectual development. Gonadal function was investigated in 5 patients; hypergonadotropic hypogonadism was found in the 4 girls.

Adult↗
PubMedDate not supplied

[Galactosemia and galactitolemia--ignored pathologies?].

The regular or common appearance of galactose into the sangvin medium because of the great consumption of galactose for the common subjects and especially for the alcoholics, and the temperate consumption for the persons having enzymatic deficiencies into their metabolism for lactose and galactose, too; they both might become dangerous. It is discussed about the methods that must be taken early to forestalling the appearance of the cataract and other complicated affection of galactosemia and galactitolemia.

Cataract↗
PubMed2005

Galactosemia in Thai patient at Phramongkutklao Hospital: a case report.

Galactosemia is a rare autosomal recessive disorder of galactose metabolism, which occurs as a consequence of a deficiency of one of these three enzymes: galactokinase, galactose-1-phosphate uridyltransferase, and uridine diphosphate galactose-4-epimerase, leading to elevated level of galactose and its metabolites in blood. The presented case was a 2-month-old, Thai female infant with persistent cholestatic jaundice, bilateral posterior subcapsular cataracts, and hepatomegaly. Laboratory investigations showed slightly elevated serum aminotransferase, and increased urinary excretion of galactose, galactitol and galactonate (by urine gas chromatography/mass spectrometry). These findings indicated an error in galactose metabolism. Soy-based formula was introduced to the patient. Clinical and laboratory results were improved after a few months of treatment. Genetic counseling was provided to the family for 25% of recurrence risk. Prenatal diagnosis is not established in Thailand.

Female↗
PubMed1979

[Galactosemia].

This paper is a review of inborn errors in galactose metabolism with special attention being paid to practical aspects of this problem. The authors presented the history of experimental research on galactose metabolism in human body, patomechanisms of biochemical abnormalities and clinical course of the disease as well as the review of genetic papers regarding polymarphism of galactose-1-phosphate uridyl transferase, galactosemic variants in human population and the possibilities of early diagnosis and treatment of galactosemia.

Alleles↗