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Stanton Segal - One of the best experts on this subject based on the ideXlab platform.
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galactitol and galactonate accumulation in heart and skeletal muscle of mice with deficiency of Galactose 1 phosphate uridyltransferase
Molecular Genetics and Metabolism, 2004Co-Authors: Claire Yager, Cong Ning, Robert Reynolds, Nancy D Leslie, Stanton SegalAbstract:Abstract Under conditions of dietary Galactose loading, mice deficient in Galactose-1-Phosphate uridyltransferase (GALT) accumulate large amounts of galactitol and galactonate in heart and skeletal muscle. In contrast to liver, brain, and kidney, which form little galactitol when GALT-deficient animals (G/G) ingest a 40% Galactose diet, heart and skeletal muscle galactitol reaches 22.90±1.62 (M±SE) and 38.88±2.62μmol/g tissue, respectively, levels 40–100 times that of Galactose-1-Phosphate (Gal-1-P). Sixteen-day-old suckling G/G mice accumulate galactitol in heart and to a lesser extent, in skeletal muscle. Heart and skeletal muscle of G/G mice also form galactonate, with levels comparable to that of liver, which was presumed previously to be the only tissue capable of converting Galactose to galactonate under conditions of loading. The data suggest that heart and skeletal muscle play a role in disposition of Galactose when GALT activity is impaired, contributing a large share to urinary galactitol and galactonate excretion. The ability of heart and muscle to form galactonate may also contribute to the G/G mouse's ability to slowly oxidize Galactose to CO 2 , since the compound is an intermediate in an alternate route for Galactose disposition.
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galactitol and galactonate in red blood cells of Galactosemic patients
Molecular Genetics and Metabolism, 2003Co-Authors: Claire Yager, Robert Reynolds, Jie Chen, Stanton SegalAbstract:The red blood cell (RBC) concentration of galactitol and galactonate was measured in 27 patients with Galactose-1-Phosphate uridyltransferase (GALT) deficiency Galactosemia and 19 non-Galactosemic subjects by a newly devised isotope dilution gas chromatography/mass spectrometry (GC/MS) method. The method utilizing UL( 13 C)galactitol and UL( 13 C)galactonate was re- producible with excellent precision and recovery of 99%. The RBC galactitol in Galactosemic patients on Galactose-restricted diets averaged 5.98 � 1.2l M( MSD) with a range of 3.54-8.81lM. The mean in non-Galactosemic patients was 0.73 � 0.31lM with a range of 0.29-1.29lM. The mean of RBC galactonate in the same Galactosemic patients was 4.16 � 1.32l M( MSD) with a range of 0.68-6.47, while the mean in non-Galactosemic subjects was 1.94 � 0.96 (MSD) with a range of 0.69-3.84. In Galactosemic RBC the galactitol was higher than galactonate while this was reversed in non-Galactosemic cells. RBC Galactose-1-Phosphate (Gal-1-P) measured at the same time as galactitol and galactonate was 30 times the level of the other two metabolites. There was no rela- tionship between RBC Gal-1-P and galactitol or galactonate. The ability to measure all three Galactose metabolites in the same procedure offers the possibility of augmented monitoring of the Galactose metabolic status of patients. The measurement of RBC galactitol and galactonate presents a new means of characterizing Galactosemic patients and their levels monitored over time may provide new insight in the development of long-term complications observed in afflicted patients. 2003 Elsevier Inc. All rights reserved.
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identification of galactitol and galactonate in red blood cells by gas chromatography mass spectrometry
Clinica Chimica Acta, 2002Co-Authors: Jie Chen, Claire Yager, Robert Reynolds, Stanton SegalAbstract:Abstract Background : Because the products of alternate pathways of Galactose metabolism, galactitol and galactonate are important in Galactosemia, we sought to identify these compounds in red blood cells (RBC). Methods : RBC extracts were trimethylsilylated (TMS) and analyzed by gas chromatography/mass spectrometry (GC/MS). Results : The presence of both galactitol and galactonate was identified in RBC of 15 Galactosemic and 13 normal subjects by their mass spectra and chromatographic comparisons with both unlabeled and 13 C labeled standards. The levels in RBC of Galactosemics appear to be much higher than those of normal subjects. Conclusion : The determination of these compounds in RBC along with Galactose-1-Phosphate (gal-1-P) in the same procedure provides the potential for their use in better monitoring of diet therapy in Galactosemic patients.
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in vivo evidence of brain galactitol accumulation in an infant with Galactosemia and encephalopathy
The Journal of Pediatrics, 2001Co-Authors: Gerard T Berry, Alice T Mazur, Cong Ning, Jill V Hunter, Zhiyue J Wang, Steffi F Dreha, David G Brooks, R A Zimmerman, Stanton SegalAbstract:Abstract In a newborn infant with Galactose-1-Phosphate uridyltransferase deficiency and encephalopathy, brain magnetic resonance imaging revealed cytotoxic edema in white matter. Using in vivo proton magnetic resonance spectroscopy, we detected ~8 mmol galactitol per kilogram of brain tissue, an amount potentially relevant to the pathogenesis of brain edema. (J Pediatr 2001;138:260-2)
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plasma Galactose and galactitol concentration in patients with Galactose 1 phosphate uridyltransferase deficiency Galactosemia determination by gas chromatography mass spectrometry
Metabolism-clinical and Experimental, 2000Co-Authors: Cong Ning, Stanton SegalAbstract:Abstract The plasma concentration of Galactose and galactitol was measured in 27 patients with Galactose-1-Phosphate uridyltransferase (GALT) deficiency Galactosemia on a lactose-restricted diet, 17 infants on lactose-free formula, and 21 infants and children on a normal diet, by a newly devised isotope dilution gas chromatograph/mass spectrometry (GC/MS) method. The method was linear in the range of 0.1 to 10 μmol/L for Galactose and 1 to 20 μmol/L for galactitol with good reproducibility and a coefficient of variation less than 3%. The mean plasma Galactose in 15 patients who were homozygous for the most common Q188R mutation of the GALT gene was 2.72 ± 0.70 μmol/L (mean ± SE) with a range of 0.58 to 3.98 in specimens obtained at regular clinic visits. In 12 patients with other GALT mutations, it was 2.45 ± 0.75 μmol/L. The mean value in nonGalactosemic subjects on lactose-free formula was 0.52 ± 0.08 μmol/L, with a range of 0.12 to 1.25. The range in 21 normal subjects without diet restriction was 0.11 to 6.33 μmol/L, with a mean of 1.48 ± 0.32. The plasma galactitol level was 11.63 ± 0.46 and 10.85 ± 1.38 μmol/L in the 2 Galactosemic groups. There was no relationship between plasma Galactose and galactitol levels, with variable ratios of the two substances in the Galactosemic patients. Galactitol was not detectable in the plasma of normal subjects. The red blood cell Galactose-1-Phosphate level was also measured in the Galactosemic patients, and no relationship between plasma Galactose and red blood cell Galactose-1-Phosphate was found. The Galactose-1-Phosphate concentration was 28 to 54 times higher than the ambient Galactose. The low Galactose concentration in the plasma of Galactosemics on Galactose-restricted diets in relation to the higher plasma galactitol and red blood cell Galactose-1-Phosphate is a metabolic enigma. The ability to measure plasma Galactose accurately presents a new way of characterizing the Galactosemic patient and the levels monitored over time may provide insight into the development of long-term complications associated with the disorder. Copyright © 2000 by W.B. Saunders Company
Gerard T Berry - One of the best experts on this subject based on the ideXlab platform.
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Galactose 1 phosphate uridylyltransferase galt gene a novel positive regulator of the pi3k akt signaling pathway in mouse fibroblasts
Biochemical and Biophysical Research Communications, 2016Co-Authors: Bijina Balakrishnan, Manshu Tang, Wyman Chen, Xiaoping Huang, Didem Demirbas Cakici, Anwer Siddiqi, Gerard T BerryAbstract:Abstract The vital importance of the Leloir pathway of Galactose metabolism has been repeatedly demonstrated by various uni-/multicellular model organisms, as well human patients who have inherited deficiencies of the key GAL enzymes. Yet, other than the obvious links to the glycolytic pathway and glycan biosynthetic pathways, little is known about how this metabolic pathway interacts with the rest of the metabolic and signaling networks. In this study, we compared the growth and the expression levels of the key components of the PI3K/Akt growth signaling pathway in primary fibroblasts derived from normal and Galactose-1 phosphate uridylyltransferase (GalT)-deficient mice, the latter exhibited a subfertility phenotype in adult females and growth restriction in both sexes. The growth potential and the protein levels of the pAkt(Thr308), pAkt(Ser473), pan -Akt, pPdk1, and Hsp90 proteins were significantly reduced by 62.5%, 60.3%, 66%, 66%, and 50%, respectively in the GalT-deficient cells. Reduced expression of phosphorylated Akt proteins in the mutant cells led to diminished phosphorylation of Gsk-3β (−74%). Protein expression of BiP and pPten were 276% and 176% higher respectively in cells with GalT-deficiency. Of the 24 genes interrogated using QIAGEN RT 2 Profiler PCR Custom Arrays, the mRNA abundance of Akt1 , Pdpk1 , Hsp90aa1 and Pi3kca genes were significantly reduced at least 2.03-, 1.37-, 2.45-, and 1.78-fold respectively in mutant fibroblasts. Both serum-fasted normal and GalT-deficient cells responded to Igf-1-induced activation of Akt phosphorylation at +15 min, but the mutant cells have lower phosphorylation levels. The steady-state protein abundance of Igf-1 receptor was also significantly reduced in mutant cells. Our results thus demonstrated that GalT deficiency can effect down-regulation of the PI3K/Akt growth signaling pathway in mouse fibroblasts through distinct mechanisms targeting both gene and protein expression levels.
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in vivo evidence of brain galactitol accumulation in an infant with Galactosemia and encephalopathy
The Journal of Pediatrics, 2001Co-Authors: Gerard T Berry, Alice T Mazur, Cong Ning, Jill V Hunter, Zhiyue J Wang, Steffi F Dreha, David G Brooks, R A Zimmerman, Stanton SegalAbstract:Abstract In a newborn infant with Galactose-1-Phosphate uridyltransferase deficiency and encephalopathy, brain magnetic resonance imaging revealed cytotoxic edema in white matter. Using in vivo proton magnetic resonance spectroscopy, we detected ~8 mmol galactitol per kilogram of brain tissue, an amount potentially relevant to the pathogenesis of brain edema. (J Pediatr 2001;138:260-2)
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urine and plasma galactitol in patients with Galactose 1 phosphate uridyltransferase deficiency Galactosemia
Metabolism-clinical and Experimental, 1999Co-Authors: Michael J Palmieri, Alice T Mazur, Gerard T Berry, Cong NingAbstract:Abstract Urinary excretion of galactitol was determined in 95 normals ( N N ), 67 Galactosemic ( G G ), and 39 compound heterozygotes for the Duarte and Galactosemia genotype ( D G ). Galactitol excretion is age-dependent in both normal individuals and patients with classic Galactosemia on lactose-restricted diets. In Galactosemic patients who are homozygous for the Q188R mutation, urinary galactitol levels were fivefold to 10-fold higher than those of normal subjects of comparable age. All but a few patients with classic Galactosemia with the Q188R mutation and another mutant G allele had urinary excretion comparable to the Q188R homozygous patients. African-American Galactosemic patients with the S135L mutation of the Galactose-1-Phosphate uridyltransferase (GALT) gene also excreted abnormal quantities of galactitol. Most subjects with a Duarte allele and a G allele excrete normal amounts of the sugar alcohol. There is a correlation between galactitol excretion and red blood cell (RBC) Galactose-1-Phosphate (gal-1-P). Plasma galactitol was also elevated in Galactosemic patients (3.4 to 23.2 μmol/L; undetectable in normal individuals). In contrast to the decrease in urinary galactitol with age, plasma levels remain in a narrow concentration range with no significant difference with age. Urine and plasma galactitol distinguish Galactosemic patients from normals. In addition, urinary galactitol excretion may be an important parameter for the assessment of steady-state Galactose metabolism in Galactosemia.
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elevation of erythrocyte redox potential linked to galactonate biosynthesis elimination by tolrestat
Metabolism-clinical and Experimental, 1998Co-Authors: Robert Reynolds, Suzanne Wehrli, Gerard T Berry, Michael J PalmieriAbstract:Alternate pathways of Galactose metabolism were explored in erythrocytes from normal subjects and patients with Galactose-1-Phosphate uridylyltransferase (GALT) deficiency incubated with Galactose. Micromolar quantities of galactonate accumulated in both normal and mutant cells linearly with time up to 5 hours and with concentrations of Galactose up to 25 mmol/L. Galactitol also was found at levels less than one third of the galactonate level, while Galactose-1-Phosphate concentrations comparable to those of galactonate were found in Galactosemic cells. Concomitant with the formation of these Galactose metabolites, the erythrocyte redox potential based on measurement of lactate and pyruvate increased fourfold in both cell types. This was due to a 60% to 72% decrease in pyruvate and a 24% to 26% increase in lactate. The oxidation of Galactose to galactonate, which is known to generate NADH, is the most likely explanation for the increase in the redox state. The aldose reductase inhibitor (ARI), Tolrestat (Wyeth Ayerst Research, Princeton, NJ), at 70 μmol/L inhibited the formation of both galactonate and galactitol in both cell types without affecting Galactose-1-Phosphate, and eliminated the increase in the redox potential as indicated by restoration of pyruvate and lactate levels to the levels obtained before exposure of the cells to Galactose. A functioning galactonate pathway is a route of Galactose disposal in patients with GALT deficiency, but by altering the cellular redox potential, it may also contribute to Galactose toxicity.
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the effect of dietary fruits and vegetables on urinary galactitol excretion in Galactose 1 phosphate uridyltransferase deficiency
Journal of Inherited Metabolic Disease, 1993Co-Authors: Gerard T Berry, Michael J Palmieri, Alice T Mazur, Robert Reynolds, P. B. Acosta, J. A. Henstenburg, K.c. Gross, Stanton SegalAbstract:Even on a lactose-restricted diet, urinary galactitol excretion and erythrocyte Galactose-1-Phosphate levels are persistently elevated in patients with Galactose-1-Phosphate uridyltransferase deficiency. In order to determine the contribution of Galactose in dietary fruits and vegetables to this phenomenon, (1) the content of Galactose in a lactose-free diet was directly measured when a galactosaemic patient's diet was specifically enriched in those fruits and vegetables which contain relatively large amounts of free Galactose and (2) galactitol excretion was determined during ingestion of this diet for 3 weeks and while on a synthetic diet for 1 week that provided <8 mg Galactose/day. For comparison the effect of a 3-week supplementation of 200 mg Galactose/day was determined. The measured intake in total foodstuffs matched the theoretical content of Galactose in the patient's diet based on amounts in fruits and vegetables alone, thus supporting the concept that fruits and vegetables are primarily responsible for Galactose intake in a lactose-free diet. All of the dietary manipulations, however, had relatively little effect on metabolite levels, suggesting that endogenous Galactose production is primarily responsible for the elevated levels of Galactose metabolites routinely detected in patients on lactose-restricted diets.
Claire Yager - One of the best experts on this subject based on the ideXlab platform.
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monitoring of biochemical status in children with duarte Galactosemia utility of Galactose galactitol galactonate and Galactose 1 phosphate
Clinical Chemistry, 2010Co-Authors: Can Ficicioglu, Christie Hussa, Nina Hattiangadi Thomas, Paul R. Gallagher, Claire YagerAbstract:BACKGROUND: Duarte Galactosemia (DG) is frequently detected in newborn-screening programs. DG patients do not manifest the symptoms of classic Galactosemia, but whether they require dietary Galactose restriction is controversial. We sought to assess the relationships of selected Galactose metabolites (plasma Galactose, plasma galactitol, erythrocyte (RBC) galactitol, RBC galactonate, and urine galactitol and galactonate) to RBC Galactose 1-Phosphate (Gal-1-P), dietary Galactose intake, and neurodevelopmental/clinical outcomes in DG children. METHODS: We studied 30 children 1-6 years of age who had DG Galactosemia and were on a regular diet. All participants underwent a physical and ophthalmologic examination and a neurodevelopmental assessment. RBC galactitol, RBC galactonate, RBC Gal-1-P, plasma Galactose, plasma galactonate, and urine galactitol and galactonate concentrations were measured. RESULTS: RBC galactitol and galactonate concentrations were about 2 and 6 times higher, respectively, than control values. Plasma Galactose and galactitol concentrations were also about twice the control values. The mean values for RBC Gal-1-P and urine galactitol were within the reference interval. We found a relationship between plasma and urine galactitol concentrations but no relationship between RBC Galactose metabolites and urine galactitol. There was a significant relationship between Galactose intake and RBC Galactose metabolites, especially RBC galactitol (P < 0.0005) and RBC galactonate (P < 0.0005). Galactose intake was not related to the urine galactitol, plasma Galactose, or plasma galactitol concentration. RBC galactitol, RBC galactonate, plasma Galactose, plasma galactitol, and urine galactonate concentrations showed no relationship with clinical or developmental outcomes. CONCLUSIONS: DG children on a regular diet have RBC Gal-1-P concentrations within the reference interval but increased concentrations of other Galactose metabolites, including RBC galactitol and RBC galactonate. These increased concentrations correlate with Galactose intake and neither cause any developmental or clinical pathology during early childhood nor oblige a lactose-restricted diet.
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galactitol and galactonate accumulation in heart and skeletal muscle of mice with deficiency of Galactose 1 phosphate uridyltransferase
Molecular Genetics and Metabolism, 2004Co-Authors: Claire Yager, Cong Ning, Robert Reynolds, Nancy D Leslie, Stanton SegalAbstract:Abstract Under conditions of dietary Galactose loading, mice deficient in Galactose-1-Phosphate uridyltransferase (GALT) accumulate large amounts of galactitol and galactonate in heart and skeletal muscle. In contrast to liver, brain, and kidney, which form little galactitol when GALT-deficient animals (G/G) ingest a 40% Galactose diet, heart and skeletal muscle galactitol reaches 22.90±1.62 (M±SE) and 38.88±2.62μmol/g tissue, respectively, levels 40–100 times that of Galactose-1-Phosphate (Gal-1-P). Sixteen-day-old suckling G/G mice accumulate galactitol in heart and to a lesser extent, in skeletal muscle. Heart and skeletal muscle of G/G mice also form galactonate, with levels comparable to that of liver, which was presumed previously to be the only tissue capable of converting Galactose to galactonate under conditions of loading. The data suggest that heart and skeletal muscle play a role in disposition of Galactose when GALT activity is impaired, contributing a large share to urinary galactitol and galactonate excretion. The ability of heart and muscle to form galactonate may also contribute to the G/G mouse's ability to slowly oxidize Galactose to CO 2 , since the compound is an intermediate in an alternate route for Galactose disposition.
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galactitol and galactonate in red blood cells of Galactosemic patients
Molecular Genetics and Metabolism, 2003Co-Authors: Claire Yager, Robert Reynolds, Jie Chen, Stanton SegalAbstract:The red blood cell (RBC) concentration of galactitol and galactonate was measured in 27 patients with Galactose-1-Phosphate uridyltransferase (GALT) deficiency Galactosemia and 19 non-Galactosemic subjects by a newly devised isotope dilution gas chromatography/mass spectrometry (GC/MS) method. The method utilizing UL( 13 C)galactitol and UL( 13 C)galactonate was re- producible with excellent precision and recovery of 99%. The RBC galactitol in Galactosemic patients on Galactose-restricted diets averaged 5.98 � 1.2l M( MSD) with a range of 3.54-8.81lM. The mean in non-Galactosemic patients was 0.73 � 0.31lM with a range of 0.29-1.29lM. The mean of RBC galactonate in the same Galactosemic patients was 4.16 � 1.32l M( MSD) with a range of 0.68-6.47, while the mean in non-Galactosemic subjects was 1.94 � 0.96 (MSD) with a range of 0.69-3.84. In Galactosemic RBC the galactitol was higher than galactonate while this was reversed in non-Galactosemic cells. RBC Galactose-1-Phosphate (Gal-1-P) measured at the same time as galactitol and galactonate was 30 times the level of the other two metabolites. There was no rela- tionship between RBC Gal-1-P and galactitol or galactonate. The ability to measure all three Galactose metabolites in the same procedure offers the possibility of augmented monitoring of the Galactose metabolic status of patients. The measurement of RBC galactitol and galactonate presents a new means of characterizing Galactosemic patients and their levels monitored over time may provide new insight in the development of long-term complications observed in afflicted patients. 2003 Elsevier Inc. All rights reserved.
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identification of galactitol and galactonate in red blood cells by gas chromatography mass spectrometry
Clinica Chimica Acta, 2002Co-Authors: Jie Chen, Claire Yager, Robert Reynolds, Stanton SegalAbstract:Abstract Background : Because the products of alternate pathways of Galactose metabolism, galactitol and galactonate are important in Galactosemia, we sought to identify these compounds in red blood cells (RBC). Methods : RBC extracts were trimethylsilylated (TMS) and analyzed by gas chromatography/mass spectrometry (GC/MS). Results : The presence of both galactitol and galactonate was identified in RBC of 15 Galactosemic and 13 normal subjects by their mass spectra and chromatographic comparisons with both unlabeled and 13 C labeled standards. The levels in RBC of Galactosemics appear to be much higher than those of normal subjects. Conclusion : The determination of these compounds in RBC along with Galactose-1-Phosphate (gal-1-P) in the same procedure provides the potential for their use in better monitoring of diet therapy in Galactosemic patients.
Robert Reynolds - One of the best experts on this subject based on the ideXlab platform.
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galactitol and galactonate accumulation in heart and skeletal muscle of mice with deficiency of Galactose 1 phosphate uridyltransferase
Molecular Genetics and Metabolism, 2004Co-Authors: Claire Yager, Cong Ning, Robert Reynolds, Nancy D Leslie, Stanton SegalAbstract:Abstract Under conditions of dietary Galactose loading, mice deficient in Galactose-1-Phosphate uridyltransferase (GALT) accumulate large amounts of galactitol and galactonate in heart and skeletal muscle. In contrast to liver, brain, and kidney, which form little galactitol when GALT-deficient animals (G/G) ingest a 40% Galactose diet, heart and skeletal muscle galactitol reaches 22.90±1.62 (M±SE) and 38.88±2.62μmol/g tissue, respectively, levels 40–100 times that of Galactose-1-Phosphate (Gal-1-P). Sixteen-day-old suckling G/G mice accumulate galactitol in heart and to a lesser extent, in skeletal muscle. Heart and skeletal muscle of G/G mice also form galactonate, with levels comparable to that of liver, which was presumed previously to be the only tissue capable of converting Galactose to galactonate under conditions of loading. The data suggest that heart and skeletal muscle play a role in disposition of Galactose when GALT activity is impaired, contributing a large share to urinary galactitol and galactonate excretion. The ability of heart and muscle to form galactonate may also contribute to the G/G mouse's ability to slowly oxidize Galactose to CO 2 , since the compound is an intermediate in an alternate route for Galactose disposition.
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galactitol and galactonate in red blood cells of Galactosemic patients
Molecular Genetics and Metabolism, 2003Co-Authors: Claire Yager, Robert Reynolds, Jie Chen, Stanton SegalAbstract:The red blood cell (RBC) concentration of galactitol and galactonate was measured in 27 patients with Galactose-1-Phosphate uridyltransferase (GALT) deficiency Galactosemia and 19 non-Galactosemic subjects by a newly devised isotope dilution gas chromatography/mass spectrometry (GC/MS) method. The method utilizing UL( 13 C)galactitol and UL( 13 C)galactonate was re- producible with excellent precision and recovery of 99%. The RBC galactitol in Galactosemic patients on Galactose-restricted diets averaged 5.98 � 1.2l M( MSD) with a range of 3.54-8.81lM. The mean in non-Galactosemic patients was 0.73 � 0.31lM with a range of 0.29-1.29lM. The mean of RBC galactonate in the same Galactosemic patients was 4.16 � 1.32l M( MSD) with a range of 0.68-6.47, while the mean in non-Galactosemic subjects was 1.94 � 0.96 (MSD) with a range of 0.69-3.84. In Galactosemic RBC the galactitol was higher than galactonate while this was reversed in non-Galactosemic cells. RBC Galactose-1-Phosphate (Gal-1-P) measured at the same time as galactitol and galactonate was 30 times the level of the other two metabolites. There was no rela- tionship between RBC Gal-1-P and galactitol or galactonate. The ability to measure all three Galactose metabolites in the same procedure offers the possibility of augmented monitoring of the Galactose metabolic status of patients. The measurement of RBC galactitol and galactonate presents a new means of characterizing Galactosemic patients and their levels monitored over time may provide new insight in the development of long-term complications observed in afflicted patients. 2003 Elsevier Inc. All rights reserved.
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identification of galactitol and galactonate in red blood cells by gas chromatography mass spectrometry
Clinica Chimica Acta, 2002Co-Authors: Jie Chen, Claire Yager, Robert Reynolds, Stanton SegalAbstract:Abstract Background : Because the products of alternate pathways of Galactose metabolism, galactitol and galactonate are important in Galactosemia, we sought to identify these compounds in red blood cells (RBC). Methods : RBC extracts were trimethylsilylated (TMS) and analyzed by gas chromatography/mass spectrometry (GC/MS). Results : The presence of both galactitol and galactonate was identified in RBC of 15 Galactosemic and 13 normal subjects by their mass spectra and chromatographic comparisons with both unlabeled and 13 C labeled standards. The levels in RBC of Galactosemics appear to be much higher than those of normal subjects. Conclusion : The determination of these compounds in RBC along with Galactose-1-Phosphate (gal-1-P) in the same procedure provides the potential for their use in better monitoring of diet therapy in Galactosemic patients.
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elevation of erythrocyte redox potential linked to galactonate biosynthesis elimination by tolrestat
Metabolism-clinical and Experimental, 1998Co-Authors: Robert Reynolds, Suzanne Wehrli, Gerard T Berry, Michael J PalmieriAbstract:Alternate pathways of Galactose metabolism were explored in erythrocytes from normal subjects and patients with Galactose-1-Phosphate uridylyltransferase (GALT) deficiency incubated with Galactose. Micromolar quantities of galactonate accumulated in both normal and mutant cells linearly with time up to 5 hours and with concentrations of Galactose up to 25 mmol/L. Galactitol also was found at levels less than one third of the galactonate level, while Galactose-1-Phosphate concentrations comparable to those of galactonate were found in Galactosemic cells. Concomitant with the formation of these Galactose metabolites, the erythrocyte redox potential based on measurement of lactate and pyruvate increased fourfold in both cell types. This was due to a 60% to 72% decrease in pyruvate and a 24% to 26% increase in lactate. The oxidation of Galactose to galactonate, which is known to generate NADH, is the most likely explanation for the increase in the redox state. The aldose reductase inhibitor (ARI), Tolrestat (Wyeth Ayerst Research, Princeton, NJ), at 70 μmol/L inhibited the formation of both galactonate and galactitol in both cell types without affecting Galactose-1-Phosphate, and eliminated the increase in the redox potential as indicated by restoration of pyruvate and lactate levels to the levels obtained before exposure of the cells to Galactose. A functioning galactonate pathway is a route of Galactose disposal in patients with GALT deficiency, but by altering the cellular redox potential, it may also contribute to Galactose toxicity.
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the effect of dietary fruits and vegetables on urinary galactitol excretion in Galactose 1 phosphate uridyltransferase deficiency
Journal of Inherited Metabolic Disease, 1993Co-Authors: Gerard T Berry, Michael J Palmieri, Alice T Mazur, Robert Reynolds, P. B. Acosta, J. A. Henstenburg, K.c. Gross, Stanton SegalAbstract:Even on a lactose-restricted diet, urinary galactitol excretion and erythrocyte Galactose-1-Phosphate levels are persistently elevated in patients with Galactose-1-Phosphate uridyltransferase deficiency. In order to determine the contribution of Galactose in dietary fruits and vegetables to this phenomenon, (1) the content of Galactose in a lactose-free diet was directly measured when a galactosaemic patient's diet was specifically enriched in those fruits and vegetables which contain relatively large amounts of free Galactose and (2) galactitol excretion was determined during ingestion of this diet for 3 weeks and while on a synthetic diet for 1 week that provided <8 mg Galactose/day. For comparison the effect of a 3-week supplementation of 200 mg Galactose/day was determined. The measured intake in total foodstuffs matched the theoretical content of Galactose in the patient's diet based on amounts in fruits and vegetables alone, thus supporting the concept that fruits and vegetables are primarily responsible for Galactose intake in a lactose-free diet. All of the dietary manipulations, however, had relatively little effect on metabolite levels, suggesting that endogenous Galactose production is primarily responsible for the elevated levels of Galactose metabolites routinely detected in patients on lactose-restricted diets.
Cong Ning - One of the best experts on this subject based on the ideXlab platform.
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galactitol and galactonate accumulation in heart and skeletal muscle of mice with deficiency of Galactose 1 phosphate uridyltransferase
Molecular Genetics and Metabolism, 2004Co-Authors: Claire Yager, Cong Ning, Robert Reynolds, Nancy D Leslie, Stanton SegalAbstract:Abstract Under conditions of dietary Galactose loading, mice deficient in Galactose-1-Phosphate uridyltransferase (GALT) accumulate large amounts of galactitol and galactonate in heart and skeletal muscle. In contrast to liver, brain, and kidney, which form little galactitol when GALT-deficient animals (G/G) ingest a 40% Galactose diet, heart and skeletal muscle galactitol reaches 22.90±1.62 (M±SE) and 38.88±2.62μmol/g tissue, respectively, levels 40–100 times that of Galactose-1-Phosphate (Gal-1-P). Sixteen-day-old suckling G/G mice accumulate galactitol in heart and to a lesser extent, in skeletal muscle. Heart and skeletal muscle of G/G mice also form galactonate, with levels comparable to that of liver, which was presumed previously to be the only tissue capable of converting Galactose to galactonate under conditions of loading. The data suggest that heart and skeletal muscle play a role in disposition of Galactose when GALT activity is impaired, contributing a large share to urinary galactitol and galactonate excretion. The ability of heart and muscle to form galactonate may also contribute to the G/G mouse's ability to slowly oxidize Galactose to CO 2 , since the compound is an intermediate in an alternate route for Galactose disposition.
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in vivo evidence of brain galactitol accumulation in an infant with Galactosemia and encephalopathy
The Journal of Pediatrics, 2001Co-Authors: Gerard T Berry, Alice T Mazur, Cong Ning, Jill V Hunter, Zhiyue J Wang, Steffi F Dreha, David G Brooks, R A Zimmerman, Stanton SegalAbstract:Abstract In a newborn infant with Galactose-1-Phosphate uridyltransferase deficiency and encephalopathy, brain magnetic resonance imaging revealed cytotoxic edema in white matter. Using in vivo proton magnetic resonance spectroscopy, we detected ~8 mmol galactitol per kilogram of brain tissue, an amount potentially relevant to the pathogenesis of brain edema. (J Pediatr 2001;138:260-2)
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plasma Galactose and galactitol concentration in patients with Galactose 1 phosphate uridyltransferase deficiency Galactosemia determination by gas chromatography mass spectrometry
Metabolism-clinical and Experimental, 2000Co-Authors: Cong Ning, Stanton SegalAbstract:Abstract The plasma concentration of Galactose and galactitol was measured in 27 patients with Galactose-1-Phosphate uridyltransferase (GALT) deficiency Galactosemia on a lactose-restricted diet, 17 infants on lactose-free formula, and 21 infants and children on a normal diet, by a newly devised isotope dilution gas chromatograph/mass spectrometry (GC/MS) method. The method was linear in the range of 0.1 to 10 μmol/L for Galactose and 1 to 20 μmol/L for galactitol with good reproducibility and a coefficient of variation less than 3%. The mean plasma Galactose in 15 patients who were homozygous for the most common Q188R mutation of the GALT gene was 2.72 ± 0.70 μmol/L (mean ± SE) with a range of 0.58 to 3.98 in specimens obtained at regular clinic visits. In 12 patients with other GALT mutations, it was 2.45 ± 0.75 μmol/L. The mean value in nonGalactosemic subjects on lactose-free formula was 0.52 ± 0.08 μmol/L, with a range of 0.12 to 1.25. The range in 21 normal subjects without diet restriction was 0.11 to 6.33 μmol/L, with a mean of 1.48 ± 0.32. The plasma galactitol level was 11.63 ± 0.46 and 10.85 ± 1.38 μmol/L in the 2 Galactosemic groups. There was no relationship between plasma Galactose and galactitol levels, with variable ratios of the two substances in the Galactosemic patients. Galactitol was not detectable in the plasma of normal subjects. The red blood cell Galactose-1-Phosphate level was also measured in the Galactosemic patients, and no relationship between plasma Galactose and red blood cell Galactose-1-Phosphate was found. The Galactose-1-Phosphate concentration was 28 to 54 times higher than the ambient Galactose. The low Galactose concentration in the plasma of Galactosemics on Galactose-restricted diets in relation to the higher plasma galactitol and red blood cell Galactose-1-Phosphate is a metabolic enigma. The ability to measure plasma Galactose accurately presents a new way of characterizing the Galactosemic patient and the levels monitored over time may provide insight into the development of long-term complications associated with the disorder. Copyright © 2000 by W.B. Saunders Company
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urine and plasma galactitol in patients with Galactose 1 phosphate uridyltransferase deficiency Galactosemia
Metabolism-clinical and Experimental, 1999Co-Authors: Michael J Palmieri, Alice T Mazur, Gerard T Berry, Cong NingAbstract:Abstract Urinary excretion of galactitol was determined in 95 normals ( N N ), 67 Galactosemic ( G G ), and 39 compound heterozygotes for the Duarte and Galactosemia genotype ( D G ). Galactitol excretion is age-dependent in both normal individuals and patients with classic Galactosemia on lactose-restricted diets. In Galactosemic patients who are homozygous for the Q188R mutation, urinary galactitol levels were fivefold to 10-fold higher than those of normal subjects of comparable age. All but a few patients with classic Galactosemia with the Q188R mutation and another mutant G allele had urinary excretion comparable to the Q188R homozygous patients. African-American Galactosemic patients with the S135L mutation of the Galactose-1-Phosphate uridyltransferase (GALT) gene also excreted abnormal quantities of galactitol. Most subjects with a Duarte allele and a G allele excrete normal amounts of the sugar alcohol. There is a correlation between galactitol excretion and red blood cell (RBC) Galactose-1-Phosphate (gal-1-P). Plasma galactitol was also elevated in Galactosemic patients (3.4 to 23.2 μmol/L; undetectable in normal individuals). In contrast to the decrease in urinary galactitol with age, plasma levels remain in a narrow concentration range with no significant difference with age. Urine and plasma galactitol distinguish Galactosemic patients from normals. In addition, urinary galactitol excretion may be an important parameter for the assessment of steady-state Galactose metabolism in Galactosemia.
