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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 in red blood cells of children with the duarte Galactosemia genotype
Molecular Genetics and Metabolism, 2005Co-Authors: Can Ficicioglu, Claire Yager, Stanton SegalAbstract:We measured galactitol, galactonate, and galactose-1-phosphate in the red blood cell (RBC) to elucidate the biochemical phenotype of infants with a Duarte/Galactosemia (D/G) genotype by isotope dilution GC/MS. The RBC galactonate, galactitol and Gal-1-P were quantified in 14 D/G newborns on a lactose containing formula or breast milk, eight D/G newborns on a galactose-free formula, and 18 D/G children between 1 and 2 years of age that were on a regular diet. The results were compared with those of non-galactosemic subjects of comparable age. In the D/G newborns on regular formula/breast milk, the levels of RBC galactitol, galactonate, and Gal-1-P were significantly higher than those of D/G newborns on diet treatment and non-galactosemic newborns. There was no difference in the levels of RBC galactitol, galactonate, and Gal-1-P between D/G newborns on a lactose-restricted diet and the control group. There appears to be two different responses to dietary galactose intake in D/G children. The first group of D/G children placed on a regular diet after a year of lactose restriction had higher RBC galactitol, galactonate levels than those of non-galactosemic children. The mean level of RBC galactonate was higher and the mean value of RBC galactitol was as high as that of galactosemic (G/G) patients on diet treatment. The second group of D/G children on a regular diet had normal levels of RBC galactitol and galactonate. The levels of RBC Gal-1-P were normal in both groups of D/G patients. The alternative pathway products may reflect galactose intake better than RBC Gal-1-P in D/G children.
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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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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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Apparent Galactose Appearance Rate in Human Galactosemia Based on Plasma [13C]Galactose Isotopic Enrichment
Molecular Genetics and Metabolism, 2000Co-Authors: Cong Ning, P. Thomas Fenn, Ian A. Blair, Gerard T Berry, Stanton SegalAbstract:Abstract Determination of endogenous galactose formation in galactosemic subjects provides important information in understanding the etiology of the long-term complications. To accomplish this task a sensitive method for measurement of isotopic enrichment of plasma galactose was developed. The aldononitrile pentaacetate derivative of galactose was utilized for gas chromatography/mass spectrometry analysis. Using a phenyl-methylsilicone capillary column, adequate separation of galactose from glucose was obtained by temperature programming of the chromatography. The specific fragmentation pattern of m/z 212, 225, 314 from d-[ 12 C]galactose and m/z 213, 226, 315 from l-[ 13 C]galactose was used for the galactose enrichment measurement by atom percent excess (APE). There was good correlation between expected enrichment and determined APEs at galactose concentrations of 1, 2, and 5 μmol/L with a coefficient of variation ranging from 0.22 to 7.17%. The method provides an accurate estimation of plasma [ 13 C]galactose enrichment from which the galactose production rate can be calculated. The steady-state plasma l-[ 13 C]galactose isotopic enrichment of three individuals with Galactosemia, two males ages 33 and 13, and one female age 9, during constant infusion of l-[ 13 C]galactose was 55, 41, and 55%, allowing the estimation of the apparent galactose appearance rate of 0.62, 1.09, and 0.82 mg/kg/h, respectively. The reanalysis of three previous studies by the present method found that APE values determined by the method then employed, butylboronate acetate derivatization, were systemically lower than those determined with aldononitrile pentaacetate derivatization, making for an overestimation of the apparent galactose appearance rate. The small plasma sample volumes needed make it feasible to perform these studies in infants and young children with Galactosemia.
Gerard T Berry - One of the best experts on this subject based on the ideXlab platform.
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transient developmental delays in infants with duarte 2 variant Galactosemia
Molecular Genetics and Metabolism, 2021Co-Authors: Susan E Waisbren, Cynthia S. Gubbels, Catherine Tran, Didem Demirbas, Margaret Hsiao, Vikram Daesety, Gerard T BerryAbstract:Duarte Galactosemia is not classic Galactosemia, but rather an example of biochemical variant Galactosemia that results in approximately 25% residual activity of galactose-1-phosphate uridylyltransferase (GALT) enzyme. In contrast, classic Galactosemia is associated with complete or near complete absence of GALT activity. While infants with classic Galactosemia are placed on galactose-restricted diets to prevent the acute and long-term manifestations of their metabolic disorder, while individuals with Duarte variant Galactosemia (Duarte-2 Galactosemia) do not require diet therapy. The long-term complications that are seen in classic Galactosemia such as cerebellar ataxia, and hypergonadotropic hypogonadism do not occur in Duarte-2 Galactosemia. While Duarte Galactosemia does not appear to be a metabolic disease, it may have an impact on early neurodevelopmental outcomes. This study examined developmental outcomes and the need for special services in individuals with Duarte-2 Galactosemia in comparison to individuals with classic Galactosemia. We performed a medical record review of individuals with GALT deficiency who were evaluated at Boston Children's Hospital and enrolled in our study of outcomes in Galactosemia. This included 95 participants, 21 with Duarte-2 Galactosemia and 73 with classic Galactosemia. Duarte-2 participants had developmental test scores within the average range. However, 42% of subjects with Duarte-2 Galactosemia had participated in early intervention and/or special education and 32% received speech therapy. Their pattern of strengths and weaknesses in cognitive/language/motor domains was similar to that noted in participants with classic Galactosemia, albeit to a milder degree. The data indicate that in children with Duarte-2 variant Galactosemia, the cognitive/language and motor skills were within normal limits with their cognitive/language skills developing earlier than their motor skills during their first year of life. A history of diet treatment was not related to the use of special services. These results suggest that Duarte-2 Galactosemia increases the risk for early mild developmental delays irrespective of treatment history, which resolves over time, and highlights the need to further assess neurodevelopment in early infancy, in Duarte-2 Galactosemia. As Duarte-2 Galactosemia is not a bona fide biochemical genetic disease, we hypothesize that elements in the genomic space that include the GALT gene are responsible for a transient delay in language-related motor skills during early infancy.
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identification of neuronal structures and pathways corresponding to clinical functioning in Galactosemia
Journal of Inherited Metabolic Disease, 2020Co-Authors: Gerard T Berry, Susan E Waisbren, Banu Ahtam, Vera Anastasoaie, Matthew Brown, Stephanie Petrides, Onur AfacanAbstract:Classic Galactosemia (OMIM# 230400) is an autosomal recessive disorder due to galactose-1-phosphate uridyltransferase deficiency. Newborn screening and prompt treatment with a galactose-free diet prevent the severe consequences of Galactosemia, but clinical outcomes remain suboptimal. Five men and five women with classic Galactosemia (mean age = 27.2 ± 5.47 years) received comprehensive neurological and neuropsychological evaluations, electroencephalogram (EEG) and magnetic resonance imaging (MRI). MRI data from nine healthy controls (mean age = 30.22 ± 3.52 years) were used for comparison measures. Galactosemia subjects experienced impaired memory, language processing, visual-motor skills, and increased anxiety. Neurological examinations revealed tremor and dysarthria in six subjects. In addition, there was ataxia in three subjects and six subjects had abnormal gait. Mean full scale IQ was 80.4 ± 17.3. EEG evaluations revealed right-sided abnormalities in five subjects and bilateral abnormalities in one subject. Compared to age- and gender-matched controls, subjects with Galactosemia had reduced volume in left cerebellum white matter, bilateral putamen, and left superior temporal sulcus. Galactosemia patients also had lower fractional anisotropy and higher radial diffusivity values in the dorsal and ventral language networks compared to the controls. Furthermore, there were significant correlations between neuropsychological test results and the T1 volume and diffusivity scalars. Our findings help to identify anatomic correlates to motor control, learning and memory, and language in subjects with Galactosemia. The results from this preliminary assessment may provide insights into the pathophysiology of this inborn error of metabolism.
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pathophysiology and targets for treatment in hereditary Galactosemia a systematic review of animal and cellular models
Journal of Inherited Metabolic Disease, 2020Co-Authors: Minela Haskovic, Gerard T Berry, Ana I. Coelho, Jorgen Bierau, Jo Vanoevelen, Laura K M Steinbusch, Luc J I Zimmermann, Eduardo Villamormartinez, Estela M RubiogozalboAbstract:Since the first description of Galactosemia in 1908 and despite decades of research, the pathophysiology is complex and not yet fully elucidated. Galactosemia is an inborn error of carbohydrate metabolism caused by deficient activity of any of the galactose metabolising enzymes. The current standard of care, a galactose-restricted diet, fails to prevent long-term complications. Studies in cellular and animal models in the past decades have led to an enormous progress and advancement of knowledge. Summarising current evidence in the pathophysiology underlying hereditary Galactosemia may contribute to the identification of treatment targets for alternative therapies that may successfully prevent long-term complications. A systematic review of cellular and animal studies reporting on disease complications (clinical signs and/or biochemical findings) and/or treatment targets in hereditary Galactosemia was performed. PubMed/MEDLINE, EMBASE, and Web of Science were searched, 46 original articles were included. Results revealed that Gal-1-P is not the sole pathophysiological agent responsible for the phenotype observed in Galactosemia. Other currently described contributing factors include accumulation of galactose metabolites, uridine diphosphate (UDP)-hexose alterations and subsequent impaired glycosylation, endoplasmic reticulum (ER) stress, altered signalling pathways, and oxidative stress. galactokinase (GALK) inhibitors, UDP-glucose pyrophosphorylase (UGP) up-regulation, uridine supplementation, ER stress reducers, antioxidants and pharmacological chaperones have been studied, showing rescue of biochemical and/or clinical symptoms in Galactosemia. Promising co-adjuvant therapies include antioxidant therapy and UGP up-regulation. This systematic review provides an overview of the scattered information resulting from animal and cellular studies performed in the past decades, summarising the complex pathophysiological mechanisms underlying hereditary Galactosemia and providing insights on potential treatment targets.
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classic Galactosemia and clinical variant Galactosemia
2014Co-Authors: Gerard T BerryAbstract:Clinical characteristics The term "Galactosemia" refers to disorders of galactose metabolism that include classic Galactosemia, clinical variant Galactosemia, and biochemical variant Galactosemia (not covered in this chapter). This GeneReview focuses on: Classic Galactosemia, which can result in life-threatening complications including feeding problems, failure to thrive, hepatocellular damage, bleeding, and E coli sepsis in untreated infants. If a lactose-restricted diet is provided during the first ten days of life, the neonatal signs usually quickly resolve and the complications of liver failure, sepsis, and neonatal death are prevented; however, despite adequate treatment from an early age, children with classic Galactosemia remain at increased risk for developmental delays, speech problems (termed childhood apraxia of speech and dysarthria), and abnormalities of motor function. Almost all females with classic Galactosemia manifest hypergonadatropic hypogonadism or premature ovarian insufficiency (POI). Clinical variant Galactosemia, which can result in life-threatening complications including feeding problems, failure to thrive, hepatocellular damage including cirrhosis, and bleeding in untreated infants. This is exemplified by the disease that occurs in African Americans and native Africans in South Africa. Persons with clinical variant Galactosemia may be missed with newborn screening as the hyperGalactosemia is not as marked as in classic Galactosemia and breath testing is normal. If a lactose-restricted diet is provided during the first ten days of life, the severe acute neonatal complications are usually prevented. African Americans with clinical variant Galactosemia and adequate early treatment do not appear to be at risk for long-term complications, including POI. Diagnosis/testing The diagnosis of classic Galactosemia and clinical variant Galactosemia is established by detection of elevated erythrocyte galactose-1-phosphate concentration, reduced erythrocyte galactose-1-phosphate uridylyltranserase (GALT) enzyme activity, and/or biallelic pathogenic variants in GALT. In classic Galactosemia, erythrocyte galactose-1-phosphate is usually >10 mg/dL and erythrocyte GALT enzyme activity is absent or barely detectable. In clinical variant Galactosemia, erythrocyte GALT enzyme activity is close to or above 1% of control values but probably never >10%-15%. However, in African Americans with clinical variant Galactosemia, the erythrocyte GALT enzyme activity may be absent or barely detectable but is often much higher in liver and in intestinal tissue (e.g., 10% of control values). Virtually 100% of infants with classic Galactosemia or clinical variant Galactosemia can be detected in newborn screening programs that include testing for Galactosemia in their panel. However, infants with clinical variant Galactosemia may be missed if the program only measures blood total galactose level and not erythrocyte GALT enzyme activity. Management Treatment of manifestations: Standard of care in any newborn who is "screen-positive" for Galactosemia is immediate dietary intervention while diagnostic testing is under way. Once a diagnosis is confirmed, restriction of galactose intake is continued and all milk products are replaced with lactose-free formulas (e.g., Isomil® or Prosobee®) containing non-galactose carbohydrates; dietary restrictions on all lactose-containing foods and other dairy products should continue throughout life, although management of the diet becomes less important after infancy and early childhood. In rare instances, cataract surgery may be needed in the first year of life. Childhood apraxia of speech and dysarthria require expert speech therapy. Developmental assessment at age one year by a psychologist and/or developmental pediatrician is recommended in order to formulate a treatment plan with the speech therapist and treating physician. For school-age children, an individual education plan and/or professional help with learning skills and special classrooms as needed. Hormone replacement therapy as needed for delayed pubertal development and/or primary or secondary amenorrhea. Stimulation with follicle-stimulating hormone may be useful in producing ovulation in some women. Prevention of secondary complications: Recommended calcium, vitamin D, and vitamin K intake to help prevent decreased bone mineralization; standard treatment for gastrointestinal dysfunction. Surveillance: Biochemical genetics clinic visits every three months for the first year of life or as needed depending on the nature of the potential acute complications; every six months during the second year of life; yearly thereafter. Routine monitoring for: the accumulation of toxic analytes (e.g., erythrocyte galactose-1-phosphate and urinary galactitol); cataracts; speech and development; movement disorder; POI; nutritional deficiency; and osteoporosis. Agents/circumstances to avoid: Breast milk, proprietary infant formulas containing lactose, cow's milk, dairy products, and casein or whey-containing foods; medications with lactose and galactose. Evaluation of relatives at risk: To allow for earliest possible diagnosis and treatment of at-risk sibs: Perform prenatal diagnosis when the GALT pathogenic variants in the family are known; or If prenatal testing has not been performed, test the newborn for either the family-specific GALT pathogenic variants or erythrocyte GALT enzyme activity. Pregnancy management: Women with classic Galactosemia should maintain a lactose-restricted diet during pregnancy. Genetic counseling Classic Galactosemia and clinical variant Galactosemia are inherited in an autosomal recessive manner. Couples who have had one affected child have a 25% chance of having an affected child in each subsequent pregnancy. Molecular genetic carrier testing for at-risk sibs and prenatal testing for pregnancies at increased risk are an option if the GALT pathogenic variants in the family are known. If the GALT pathogenic variants in a family are not known, prenatal testing can rely on assay of GALT enzyme activity in cultured amniotic fluid cells.
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the male reproductive system in classic Galactosemia cryptorchidism and low semen volume
Journal of Inherited Metabolic Disease, 2013Co-Authors: Cynthia S. Gubbels, Gerard A.j. Dunselman, Estela M Rubiogozalbo, Corrine K Welt, John C M Dumoulin, Simon G F Robben, Catherine M Gordon, Gerard T BerryAbstract:Previous studies examining reproductive parameters in men with Galactosemia have inconsistently demonstrated abnormalities. We hypothesized that men with Galactosemia may demonstrate evidence of reproductive dysfunction. Pubertal history, physical examination, hormone levels and semen analyses were examined in 26 males with Galactosemia and compared to those in 46 controls. The prevalence of cryptorchidism was higher in men with Galactosemia than in the general population [11.6 % vs. 1.0 % (95%CI: 0.75–1.26; p < 0.001)]. Testosterone (461 ± 125 vs. 532 ± 133 ng%; p = 0.04), inhibin B (144 ± 66 vs. 183 ± 52 pg/mL; p = 0.002) and sperm concentration (46 ± 36 vs. 112 ± 75 × 106 spermatozoa/mL; p = 0.01) were lower and SHBG was higher (40.7 ± 21.5 vs 26.7 ± 14.6; p = 0.002) in men with Galactosemia compared to controls. Semen volume was below normal in seven out of 12 men with Galactosemia. Men with Galactosemia have a higher than expected prevalence of cryptorchidism and low semen volumes. The subtle decrease in testosterone and inhibin B levels and sperm count may indicate mild defects in Sertoli and Leydig cell function, but does not point towards severe infertility causing reproductive impairment. Follow-up studies are needed to further determine the clinical consequences of these abnormalities.
Cong Ning - One of the best experts on this subject based on the ideXlab platform.
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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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Apparent Galactose Appearance Rate in Human Galactosemia Based on Plasma [13C]Galactose Isotopic Enrichment
Molecular Genetics and Metabolism, 2000Co-Authors: Cong Ning, P. Thomas Fenn, Ian A. Blair, Gerard T Berry, Stanton SegalAbstract:Abstract Determination of endogenous galactose formation in galactosemic subjects provides important information in understanding the etiology of the long-term complications. To accomplish this task a sensitive method for measurement of isotopic enrichment of plasma galactose was developed. The aldononitrile pentaacetate derivative of galactose was utilized for gas chromatography/mass spectrometry analysis. Using a phenyl-methylsilicone capillary column, adequate separation of galactose from glucose was obtained by temperature programming of the chromatography. The specific fragmentation pattern of m/z 212, 225, 314 from d-[ 12 C]galactose and m/z 213, 226, 315 from l-[ 13 C]galactose was used for the galactose enrichment measurement by atom percent excess (APE). There was good correlation between expected enrichment and determined APEs at galactose concentrations of 1, 2, and 5 μmol/L with a coefficient of variation ranging from 0.22 to 7.17%. The method provides an accurate estimation of plasma [ 13 C]galactose enrichment from which the galactose production rate can be calculated. The steady-state plasma l-[ 13 C]galactose isotopic enrichment of three individuals with Galactosemia, two males ages 33 and 13, and one female age 9, during constant infusion of l-[ 13 C]galactose was 55, 41, and 55%, allowing the estimation of the apparent galactose appearance rate of 0.62, 1.09, and 0.82 mg/kg/h, respectively. The reanalysis of three previous studies by the present method found that APE values determined by the method then employed, butylboronate acetate derivatization, were systemically lower than those determined with aldononitrile pentaacetate derivatization, making for an overestimation of the apparent galactose appearance rate. The small plasma sample volumes needed make it feasible to perform these studies in infants and young children with Galactosemia.
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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: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 micromol/L for galactose and 1 to 20 micromol/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 micromol/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 micromol/L. The mean value in nongalactosemic subjects on lactose-free formula was 0.52 +/- 0.08 micromol/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 micromol/L, with a mean of 1.48 +/- 0.32. The plasma galactitol level was 11.63 +/- 0.46 and 10.85 +/- 1.38 micromol/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.
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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.
Judith L Fridovichkeil - One of the best experts on this subject based on the ideXlab platform.
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epimerase deficiency Galactosemia
2016Co-Authors: Judith L Fridovichkeil, Lora J H Bean, Richard J SchroerAbstract:Clinical characteristics Epimerase deficiency Galactosemia (GALE deficiency Galactosemia) is generally considered a continuum comprising several forms: Generalized. Enzyme activity is profoundly decreased in all tissues tested. Peripheral. Enzyme activity is deficient in red blood cells (RBC) and circulating white blood cells, but normal or near normal in all other tissues. Intermediate. Enzyme activity is deficient in red blood cells and circulating white blood cells and less than 50% of normal levels in other cells tested. Infants with generalized epimerase deficiency Galactosemia develop clinical findings on a regular milk diet (which contains lactose, a disaccharide of galactose and glucose); manifestations include hypotonia, poor feeding, vomiting, weight loss, jaundice, hepatomegaly, liver dysfunction, aminoaciduria, and cataracts. Prompt removal of galactose/lactose from their diet resolves or prevents these acute symptoms. Longer-term features that may be seen in those with generalized epimerase deficiency include short stature, developmental delay, sensorineural hearing loss, and skeletal anomalies. In contrast, neonates with the peripheral or intermediate form generally remain clinically well even on a regular milk diet and are usually only identified by biochemical testing, often in newborn screening programs. Diagnosis/testing The diagnosis of epimerase deficiency Galactosemia is established in a proband with impaired GALE activity in RBC or other cells and/or biallelic pathogenic variants in GALE identified on molecular genetic testing. The degree of GALE enzyme activity impairment in RBC does not distinguish between the clinically severe generalized and the milder intermediate or peripheral forms of epimerase deficiency; further enzymatic testing in other cell types such as stimulated leukocytes or EBV-transformed lymphoblasts is required to make that distinction. Management Treatment of manifestations: The common acute and potentially lethal symptoms of generalized epimerase deficiency Galactosemia are prevented or corrected by a galactose/lactose-restricted diet. Note: Affected individuals may require trace environmental sources of galactose: infants should be fed a formula (e.g., soy formula) that contains trace levels of galactose or lactose. Continued dietary restriction of dairy products in older children is recommended. In contrast, infants with peripheral epimerase deficiency Galactosemia are believed to remain asymptomatic regardless of diet; infants with intermediate epimerase deficiency Galactosemia may benefit in the long term from early dietary galactose/lactose restriction, but this remains unclear. Standard treatment for developmental delay, skeletal anomalies, poor weight gain / failure to thrive, mature cataracts, and sensorineural hearing loss. Prevention of primary manifestations: In generalized epimerase deficiency Galactosemia, restriction of dietary galactose/lactose appears to correct or prevent the common acute signs and symptoms of the disorder (hepatic dysfunction, renal dysfunction, and mild cataracts), but not the developmental delay or learning impairment observed in some affected individuals. Because of the difficulty in distinguishing peripheral and intermediate forms of epimerase deficiency Galactosemia, dietary restriction of galactose/lactose is recommended for all infants with GALE deficiency, relaxing the restriction, as warranted, once a more accurate diagnosis has been confirmed. Surveillance: Hemolysate gal-1P (galactose-1-phosphate) or urinary galactitol is monitored, especially if the diet is to be normalized. Acceptable levels of RBC gal-1P are not known, but are estimated to be Agents/circumstances to avoid: Dietary galactose/lactose in persons with generalized epimerase deficiency Galactosemia, certainly as infants and perhaps for life. Evaluation of relatives at risk: Each at-risk newborn sib should be treated with dietary restriction of galactose from birth while awaiting results of diagnostic testing for epimerase deficiency Galactosemia; either molecular genetic testing (if the pathogenic variants in the family are known) or measurement of GALE enzyme activity in RBC (if the pathogenic variants in the family are not known) can be performed. Genetic counseling Epimerase deficiency Galactosemia is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a GALE pathogenic variant, each full sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible if the pathogenic variants in the family are known.
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newborn screening for Galactosemia in the united states looking back looking around and looking ahead
JIMD Reports, 2014Co-Authors: Brook M Pyhtila, Kelly A Shaw, Samantha E Neumann, Judith L FridovichkeilAbstract:It has been 50 years since the first newborn screening (NBS) test for Galactosemia was conducted in Oregon, and almost 10 years since the last US state added Galactosemia to their NBS panel. During that time an estimated >2,500 babies with classic Galactosemia have been identified by NBS. Most of these infants were spared the trauma of acute disease by early diagnosis and intervention, and many are alive today because of NBS. Newborn screening for Galactosemia is a success story, but not yet a story with a completely happy ending. NBS, follow-up testing, and intervention for Galactosemia continue to present challenges that highlight gaps in our knowledge. Here we compare Galactosemia screening and follow-up data from 39 NBS programs gathered from the states directly or from public sources. On some matters the programs agreed: for example, those providing relevant data all identify classic Galactosemia in close to 1/50,000 newborns and recommend immediate and lifelong dietary restriction of galactose for those infants. On other matters the programs disagree. For example, Duarte Galactosemia (DG) detection rates vary dramatically among states, largely reflecting differences in screening approach. For infants diagnosed with DG, >80% of the programs surveyed recommend complete or partial dietary galactose restriction for the first year of life, or give mixed recommendations; <20% recommend no intervention. This disparity presents an ongoing dilemma for families and healthcare providers that could and should be resolved.
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modifiers of ovarian function in girls and women with classic Galactosemia
The Journal of Clinical Endocrinology and Metabolism, 2013Co-Authors: Jessica B Spencer, Tyler J. Gleason, Michael P Epstein, Jennifer R Badik, Emily L Ryan, Alaine K Broadaway, Judith L FridovichkeilAbstract:Context: Classic Galactosemia is a potentially lethal genetic disorder resulting from profound impairment of galactose-1P uridylyltransferase (GALT). More than 80% of girls and women with classic Galactosemia experience primary or premature ovarian insufficiency despite neonatal diagnosis and rigorous lifelong dietary galactose restriction. Objective: The goal of this study was to test the relationship between markers of ovarian reserve, cryptic residual GALT activity, and spontaneous pubertal development in girls with classic Galactosemia. Design and Setting: This was a cross-sectional study with some longitudinal follow-up in a university research environment. Patients: Patients included girls and women with classic Galactosemia and unaffected controls, <1 month to 30 years old. Main Outcome Measures: We evaluated plasma anti-Mullerian hormone (AMH) and FSH levels, antral follicle counts ascertained by ultrasound, and ovarian function as indicated by spontaneous vs assisted menarche. Results: More than ...
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oxidative stress contributes to outcome severity in a drosophila melanogaster model of classic Galactosemia
Disease Models & Mechanisms, 2012Co-Authors: Patricia Jumbolucioni, Marquise L Hopson, Darwin Hang, Yongliang Liang, Dean P Jones, Judith L FridovichkeilAbstract:Classic Galactosemia is a genetic disorder that results from profound loss of galactose-1P-uridylyltransferase (GALT). Affected infants experience a rapid escalation of potentially lethal acute symptoms following exposure to milk. Dietary restriction of galactose prevents or resolves the acute sequelae; however, many patients experience profound long-term complications. Despite decades of research, the mechanisms that underlie pathophysiology in classic Galactosemia remain unclear. Recently, we developed a Drosophila melanogaster model of classic Galactosemia and demonstrated that, like patients, GALT-null Drosophila succumb in development if exposed to galactose but live if maintained on a galactose-restricted diet. Prior models of experimental Galactosemia have implicated a possible association between galactose exposure and oxidative stress. Here we describe application of our fly genetic model of Galactosemia to the question of whether oxidative stress contributes to the acute galactose sensitivity of GALT-null animals. Our first approach tested the impact of pro- and antioxidant food supplements on the survival of GALT-null and control larvae. We observed a clear pattern: the oxidants paraquat and DMSO each had a negative impact on the survival of mutant but not control animals exposed to galactose, and the antioxidants vitamin C and α-mangostin each had the opposite effect. Biochemical markers also confirmed that galactose and paraquat synergistically increased oxidative stress on all cohorts tested but, interestingly, the mutant animals showed a decreased response relative to controls. Finally, we tested the expression levels of two transcripts responsive to oxidative stress, GSTD6 and GSTE7, in mutant and control larvae exposed to galactose and found that both genes were induced, one by more than 40-fold. Combined, these results implicate oxidative stress and response as contributing factors in the acute galactose sensitivity of GALT-null Drosophila and, by extension, suggest that reactive oxygen species might also contribute to the acute pathophysiology in classic Galactosemia.
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biomarkers of ovarian function in girls and women with classic Galactosemia
Fertility and Sterility, 2009Co-Authors: Rebecca D Sanders, Jessica B Spencer, Michael P Epstein, Susan Pollak, Pratibhasri A Vardhana, Joyce W Lustbader, Judith L FridovichkeilAbstract:Objective To determine whether premature ovarian insufficiency (POI) associated with classic Galactosemia results from a true impairment of ovarian function or from aberrant FSH. Design Cross-sectional study. Setting University research laboratory. Patient(s) Study subjects included 35 girls and women with Galactosemia and 43 control girls and women between the ages of Intervention(s) Blood sampling and medical and reproductive histories were obtained. Main Outcome Measurement(s) We determined FSH and anti-Mullerian hormone (AMH) levels in subjects with and without classic Galactosemia. FSH bioactivity was measured in a subset of girls and women with and without Galactosemia who were not on hormone therapy. Result(s) FSH levels were significantly higher and AMH levels were significantly lower in our galactosemic cases relative to controls. FSH bioactivity did not significantly differ between cases and controls. Conclusion(s) Close to 90% of girls and women with classic Galactosemia have a profound absence of ovarian function, a deficit that is evident shortly after birth, if not before. These patients have no evidence of abnormally functioning FSH. AMH levels can be assessed before menarche or after initiation of hormone therapy and may supplement FSH as a useful blood biomarker of ovarian function for patients with classic Galactosemia.
Louis J Elsas - One of the best experts on this subject based on the ideXlab platform.
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introduction to the maastricht workshop lessons from the past and new directions in Galactosemia
Journal of Inherited Metabolic Disease, 2011Co-Authors: Gerard T Berry, Louis J ElsasAbstract:Hereditary Galactosemia is an autosomal recessive genetic disorder of carbohydrate metabolism (OMIM 230400; Fridovich-Keil andWalter 2008; Elsas 2010; Berry and Walter 2011). The mutated gene encodes a protein, galactose1-phosphate uridyltransferase (GALT, EC 2.7.7.12), that catalyzes the conversion of galactose-1-phosphate and UDPglucose to UDP-galactose and glucose-1-phosphate (Fig. 1). In the newborn period, a life-threatening disease with multiorgan involvement emerges, particularly in those infants ingesting lactose in breast milk and proprietary baby formulas containing the ingredients of cow’s milk (Berry and Walter 2011). The first observation of this nutritional toxicity state involving the neonate and breast milk was by von Reuss in 1908 (von Reuss 1908). In the next decade, Goppert documented the presence of excess galactose in the urine of a similarly affected infant (Goppert 1917). The first well characterized infant with hyperGalactosemia and galactosuria who responded to a lactose-restricted diet was described by Mason and Turner in 1935 (Mason and Turner 1935). This paper, describing an African-American infant with a variant form of Galactosemia, served to reveal marked hyperGalactosemia as an integral component of GALT deficiency. However, establishment of the abnormal biochemistry awaited the discovery of Schwarz in 1956 (Schwarz et al. 1956) that the substrate, galactose-1-phosphate, was elevated in erythrocytes from galactosemic patients exposed to galactose, and the demonstration later that year in the Kalkar laboratory that GALTenzyme activity was absent (Isselbacher et al. 1956). This rare Mendelian disorder with a world-wide frequency of 1/40,000 to 1/60,000 newborn infants entered the modern era of molecular biology when Reichardt and Berg cloned a GALT cDNA from a human liver library (Reichardt and Berg 1988), and its correct cDNA sequence enabled cloning and delineation of the structure of the GALT gene (Flach et al. 1990; Leslie et al. 1992). Soon thereafter, many causative gene mutations were identified producing a heterogeneous array of impaired pGALT function (Elsas and Lai 1998; Tyfield 2000; Calderon et al. 2007). It was clear in the decades following the landmark Mason and Turner paper that restriction of galactose intake in the affected newborn infant would usually permit survival and allow the following early infantile complications to remit, resolve or disappear: poor growth, poor feeding, emesis, jaundice, liver enlargement and dysfunction that includes hyperbilirubinemia, transaminasemia, hypofibrinoginemia with bleeding diathesis, cataracts, encephalopathy, including lethargy, irritability and hypotonia, hyperchloremic metabolic acidosis, albuminuria, generalized aminoaciduria and anemia. Yet, between 1970 and 1990, there was a growing awareness that there were “clouds over Galactosemia” (Anonymous 1982; Holton and Leonard 1994), that patients were not faring as well as physicians had expected (Komrower and Lee 1970; Lee 1972; Fishler et al. 1972, 1980; Komrower 1982; Waisbren et al. 1983; Gitzelmann and Steinmann 1984), especially given the fact that lactose restriction largely eliminates death from E. coli sepsis (Levy et al. 1977). And, this was all the more poignant, as infants Communicated by: Estela Rubio
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verbal dyspraxia and Galactosemia
Pediatric Research, 2003Co-Authors: Amy L Webb, Mary Jane Kennedy, Rani H. Singh, Louis J ElsasAbstract:Classical Galactosemia is an autosomal recessive disorder resulting from deficient galactose-1-phosphateuridyl transferase (GALT) activity. Verbal dyspraxia is an unusual outcome in Galactosemia. Here we validated a simplified breath test of total body galactose oxidation against genotype and evaluated five potential biochemical risk indicators for verbal dyspraxia in Galactosemia: cumulative percentage dose (CUMPCD) of 13CO2 in breath, mean erythrocyte galactose-1-phosphate, highest erythrocyte galactose-1-phosphate, mean urinary galactitol, and erythrocyte GALT activity. Thirteen controls and 42 patients with Galactosemia took a 13C-galactose bolus, and the (CUMPCD) of 13CO2 in expired air was determined. Patients with 2.7 mg/dL, and mean urinary galactitol levels >135 mmol/mol creatinine were associated with dyspraxic outcome with odds ratios of 21, 13, and 5, respectively. We conclude that total body oxidation of galactose to CO2 in expired air reflects genotype and that this breath test is a sensitive predictor of verbal dyspraxia in patients with Galactosemia.
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verbal dyspraxia and Galactosemia
Pediatric Research, 2003Co-Authors: Amy L Webb, Mary Jane Kennedy, Rani H. Singh, Louis J ElsasAbstract:Classical Galactosemia is an autosomal recessive disorder resulting from deficient galactose-1-phosphateuridyl transferase (GALT) activity. Verbal dyspraxia is an unusual outcome in Galactosemia. Here we validated a simplified breath test of total body galactose oxidation against genotype and evaluated five potential biochemical risk indicators for verbal dyspraxia in Galactosemia: cumulative percentage dose (CUMPCD) of (13)CO(2) in breath, mean erythrocyte galactose-1-phosphate, highest erythrocyte galactose-1-phosphate, mean urinary galactitol, and erythrocyte GALT activity. Thirteen controls and 42 patients with Galactosemia took a (13)C-galactose bolus, and the (CUMPCD) of (13)CO(2) in expired air was determined. Patients with or =5% CUMPCD had milder mutant human GALT alleles. Twenty-four patients consented to formal speech evaluation; 15 (63%) had verbal dyspraxia. Dyspraxic patients had significantly lower CUMPCD values (2.84 +/- 5.76% versus 11.51 +/- 7.67%; p 2.7 mg/dL, and mean urinary galactitol levels >135 mmol/mol creatinine were associated with dyspraxic outcome with odds ratios of 21, 13, and 5, respectively. We conclude that total body oxidation of galactose to CO(2) in expired air reflects genotype and that this breath test is a sensitive predictor of verbal dyspraxia in patients with Galactosemia.
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the molecular biology of Galactosemia
Genetics in Medicine, 1998Co-Authors: Louis J Elsas, Kent LaiAbstract:Classic Galactosemia is an autosomal recessive disorder caused by the deficiency of galactose 1-phosphate uridyltransferase (GALT). Although the potentially lethal, neonatal hepatotoxic syndrome is prevented by newborn screening and galactose restriction, long-term outcome for older patients with Galactosemia remains problematic. After the cloning and sequencing of the GALT gene, more than 130 mutations in the GALT gene have been associated with GALT deficiency; this review relates them to function and clinical outcome. Two common mutations, Q188R and K285N, account for more than 70% of G alleles in the white population and are associated with classic Galactosemia and impaired GALT function. In the black population, S135L accounts for 62% of the alleles causing Galactosemia and is associated with good outcomes. A large 5 kb deletion in the GALT gene is found in Ashkenazim Jews. The Duarte Galactosemia variant is caused by N314D. Homozygosity for N314D reduces GALT activity to 50%. When either E203K or a 1721C-->T transition (Los Angeles variant) are present in cis with N314D, GALT activity reverts to normal. In this review, we discuss the structural biology of these mutations as they affect both the GALT enzyme and patient outcome.
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a prevalent mutation for Galactosemia among black americans
The Journal of Pediatrics, 1996Co-Authors: Kent Lai, Rani H. Singh, Sharon D Langley, P P Dembure, Lawrence N Hjelm, Louis J ElsasAbstract:Abstract OBJECTIVE: To define the mutation causing Galactosemia in patients of black American origin who have no galactose-1-phosphate uridyltransferase (GALT) activity in erythrocytes but good clinical outcome. METHODS: We discovered a mutation caused by a C→T transition at base-pair 1158 of the GALT gene that results in a serine-to-leucine substitution at codon 135 (S135L). We developed a method with which to screen populations for its prevalence. We compared galactose-1-phosphate uridyltransferase among erythrocytes, leukocytes, and transformed lymphoblasts, as well as total body oxidation of D-[ 13 C]-galactose to 13 CO 2 among three genotypes for GALT (S135L/S135L, Q188R/Q188R, and Normal/Normal). RESULTS: We found a 48% prevalence of the S135L mutation among 17 black American patients with classic Galactosemia and a 1% prevalence in a population of 50 black Americans without Galactosemia. The S135L mutation was not found in 84 white patients with G/G Galactosemia nor in 87 white control subjects without Galactosemia. We found normal whole body oxidation of D-[ 13 C]-galactose by the patient homozygous for S135L and various degrees of enzyme impairment among different tissues. CONCLUSIONS: The S135L mutation in the GALT gene is a prevalent cause of Galactosemia among black patients. Because GALT activity varies in different tissues of patients homozygous for S135L, they may have a better clinical outcome than patients who are homozygous for Q188R when both are treated from infancy. (J PEDIATR 1996;128:89-95)
