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PubMed1995

Galactose-1-phosphate in the pathophysiology of galactosemia.

In galactosemia, galactose-1-phosphate (gal-1-P) is not properly metabolized and accumulates in the fetus and after birth in various tissues when lactose or galactose is ingested. Well-treated galactosemics retain a low level of red cell gal-1-P which increases after breaks of diet. The ester is an indicator of the biogenesis of galactose from glucose and has been considered a pathogenic agent by inhibiting enzymes such as glucose-6-phosphatase, glucose-6-phosphate dehydrogenase, phosphoglucomutase, and glycogen phosphorylase, but the evidence remains presumptive. A futile cycle of galactose phosphorylation and dephosphorylation, and the sequestration of phosphorus in gal-1-P are also suspected to play a role in the pathogenesis of galactosemia.

Galactose↗
PubMed1995

Galactitol in galactosemia.

Urinary galactose and galactitol excretion in controls is age-dependent with the highest concentrations at a younger age. Untreated patients with classical galactosemia excreted highly elevated amounts of galactitol (8000-69,000 mmol/mol creatinine; controls 3-81) which did not correlate with galactose excretion. After treatment, galactose excretion returned to normal in all patients whereas galactitol excretion (45-900 mmol/mol creatinine) remained above the age-matched control range. The excretion of galactitol (96-170 mmol/mol creatinine) in untreated compound heterozygotes was much lower although still above the age-matched control levels, and it returned to normal after treatment. In untreated classical galactosemia patients the galactitol in plasma (120-500 mumol/l) was markedly elevated (controls 0.08-0.86 mumol/l); under treatment, the galactitol concentrations (4.7-20 mumol/l) remained above the control range in all. There was no correlation with age nor with galactose-1-phosphate and UDP-galactose levels. Two untreated compound heterozygotes had elevated plasma galactitol (6.0 and 63 mumol/l) which, when treated, returned to normal.

Age Factors↗
PubMedDate not supplied

Pregnancy-exaggerated galactosemia and congenital cataracts.

One child in a family and two children in another family had galactosemia and congenital cataract. Two of them had total soft cataracts while in one, cataract was less soft. In addition, they had mild lactosuria. The mothers of the affected children had significant lactosuria and mild galactosuria without cataracts. Fathers did not have galactosuria or lactosuria. Clinically unaffected siblings in one family had mild galactosuria and lactosuria. Pregnancy-exaggerated galactosemia was suspected in these two mothers who gave birth to children with congenital cataract. As an extension of this work, 5001 pregnant women were screened for galactose in urine just before the delivery of babies. Mild galactosuria was present in 54 (1.08%). Three children had congenital cataract and one had changes in posterior pole and cornea. Restriction of lactose by reducing intake of milk and milk products during pregnancy by mothers with galactosuria is recommended to avoid the birth of children with congenital cataract.

Adult↗
PubMed2001

Galactosemia: deletion in the 5' upstream region of the GALT gene reduces promoter efficiency.

Galactosemia is a metabolic disorder caused by a defect in the galactose-1-phosphate uridyltransferase (GALT) enzyme. In previous studies, we have shown that the presence of a deletion in the 5' upstream (promoter) region of the GALT gene is associated with the Duarte (D2) allele. In the present study, by using a promoter fusion assay we provide direct evidence that a GTCA deletion located in position -119/-116 of the GALT gene (considered in relation to the translational start site) decreases transcription of a reporter gene to about 55% compared with a normal "healthy" promoter transfected into human hepatocyte HepG2 cells. This result coincides well with previously published biochemical data showing 50% GALT-gene activity in Duarte (D2) galactosemia patients. By transfecting the same promoters (normal and deleted) into mouse NIH/3T3 cells, we show that the GTCA motif in the promoter region of the GALT gene was conserved throughout evolution. We conclude that the -119/-116delGTCA promoter mutation is a crucial factor in reduction of Duarte allele enzyme activity.

3T3 Cells↗
PubMed2001

Large-scale molecular screening for galactosemia alleles in a pan-ethnic population.

DNA samples from 4,796 subjects from diverse ethnic groups were screened for five frequently encountered galactose-1-phosphate uridyl transferase (GALT) mutations: S135L (cDNA nt 404C-->T, as numbered from the initiator ATG codon, with A=1); Q188R (cDNA nt 563A-->G); K285 N (cDNA nt 855G-->T); the Duarte variant, N314D (cDNA nt 940A-->G); and the Los Angeles variant, which contains L218L (cDNA nt 652C-->T) and N314D. Among Whites, the gene frequency of the Q188R mutation was 0.29%, and that of the K285 N mutation was 0.062%. Only one S135L mutation was encountered among 505 African-Americans (gene frequency 0.10%). The pan-ethnic gene frequencies of the Duarte and the Los Angeles variants were 5.1% and 2.7%, respectively. Both of these frequencies were significantly less among African-Americans and Asians than among Whites and Hispanics. Native Americans revealed a higher incidence of the both variants. Based upon the gene frequency of the Q188R mutation in the White population, the birth incidence of classic galactosemia is estimated at one patient per 47,000 in the White population. This prevalence would be increased by inbreeding. It agrees well with the results from newborn screening programs and is only minimally higher than that reported in most studies, suggesting that most, if not all, infants with the galactosemia genotype are born and survive sufficiently long to be screened.

Alleles↗
PubMed1977

Prenatal diagnosis of galactosemia.

Prenatal diagnosis of disorders of galactose metabolism was done in one instance in a family with a known galactokinase deficiency and in six cases in five families at risk for galactosemia. The galactokinase activity in cultured amniotic cells was found to be normal, and the diagnosis was confirmed postnatally. In the six pregnancies at risk for galactosemia, four were considered to be unaffected and two to be affected. Of the latter, one was carried to term, and the erythrocyte transferase activity of the baby was shown to be absent. The other pregnancy was terminated, and examination of fetal tissues by biochemical studies confirmed the diagnosis. This experience substantiates the concept that prenatal diagnosis of disorders of galactose metabolism is feasible.

Amniotic Fluid↗
PubMed1990

Non-tryptophan fluorescence and high molecular weight protein formation in lens crystallins of rats with chronic galactosemia: prevention by the aldose reductase inhibitor sorbinil.

Crystallin-bound non-tryptophan fluorescence and protein cross-linking were studied in chronic galactosemia. Fluorescence (excitation/emission--370/440 nm) was significantly higher in galactosemic rats compared to controls (P less than 0.001). Accumulation of fluorescence was significantly reduced both in water soluble (P less than 0.001) and insoluble (P less than 0.005) lens fractions in galactosemic rats receiving the aldose reductase inhibitor sorbinil. High performance liquid chromatography of water soluble lens crystallins showed an increase in the content of high molecular weight proteins and the fluorescence associated with it. Sorbinil partly prevented the formation of such fluorescent high molecular weight proteins. Under reducing conditions, sodium dodecyl sulfate polyacrylamide gel electrophoresis of water soluble proteins revealed a distinct high molecular weight protein of 60 kDa in galactosemia. Sorbinil treatment completely abolished the formation of this protein. Western blotting using rabbit antiserum to bovine alpha-, beta- and gamma-crystallins revealed the presence of gamma, but not alpha- and beta-crystallins in the 60-kDa protein. Formation of this protein may result from trimerization of gamma-crystallins or from an association of gamma-crystallin with a non-crystallin cytosolic protein or mixed protein cross-linking of gamma-crystallins with membrane protein(s). The present study shows that polyol pathway in cataractogenesis also extends to protein cross-linking and formation of fluorescent compounds, the nature of which remains to be elucidated.

Aldehyde Reductase↗
PubMed1992

Minimizing false positive diagnoses in newborn screening for galactosemia.

Heat and humidity, rather than summertime heat alone, cause extensive loss of galactose-1-phosphate uridyltransferase activity in mailed blood spots and seem to account for false positive diagnoses of galactosemia. The spots are partially protected from the effects of atmospheric humidity if they are allowed to dry and then are sealed in a plastic freezer bag before being exposed to higher humidity. Conversely, extensive loss of transferase activity occurs if the samples are sealed in the bags before the spots are dry. The fluorescence from transferase activity can be monitored with greater sensitivity fluorometrically than visually. A simultaneous fluorometric determination of phosphoglucomutase activity reveals whether decreased transferase activity represents sample deterioration or galactosemia. Mg2+ and a sulfhydryl agent, such as dithiothreitol, are needed for activity of phosphoglucomutase, an enzyme in the sequence leading to the fluorescent substance (NADPH). They must be added in certain modifications of the assay.

Dithiothreitol↗
PubMedDate not supplied

Neurologic complications in galactosemia.

Two siblings, a 27-year-old man and his 24-year-old sister were diagnosed with classic transferase deficiency galactosemia at birth and were treated with strict lactose restriction. Despite well-documented dietary management, both siblings are mentally retarded and manifest a progressive neurologic condition characterized by hypotonia, hyperreflexia, dysarthria, ataxia, and a postural and kinetic tremor. Magnetic resonance imaging revealed moderate cortical atrophy, a complete lack of normal myelination, and multifocal areas of increased signal in the periventricular white matter on T2-weighting. These patients suggest that even with early diagnosis and treatment, individuals with galactosemia may have significant neurologic morbidity with abnormalities of white matter development. This finding raises the possibility of biochemical heterogeneity within the classic transferase deficiency group, as well as the possibility of a lack of available galactose metabolites necessary for glycolipid synthesis causing a disruption of normal myelin development.

Adult↗
PubMed2004

Bone metabolism in galactosemia.

Classical galactosemia is an autosomal recessively inherited disorder of galactose metabolism. Treatment consists of life-long dietary restriction of galactose. Despite treatment, long-term complications occur such as a decreased bone mineral density (BMD). A decreased BMD might be the result of either dietary deficiencies secondary to the galactose-restricted diet or unknown intrinsic factors. In this study, 40 children with classical galactosemia (13 males and 27 females, aged 3-17 years) on dietary treatment were included to gain insight in the bone metabolism of galactosemics. We found weight and height Z scores significantly decreased in galactosemics. Mean areal BMD Z scores of lumbar spine and of femoral neck as measured by Dual energy X-ray Absorptiometry (DXA) were -0.6 (P < 0.001) and -0.3 (P = 0.066), respectively. Mean volumetric BMD of the femoral neck was significant lower in galactosemics (P < 0.001). The recommended dietary allowances (RDA) for calcium, magnesium, zinc, vitamin D, and protein were met in all patients. Mean serum levels of calcium, phosphate, magnesium, zinc, 1,25-dihydroxy vitamin D (1,25OHD), parathormone (PTH), 17-beta estradiol, bone alkaline phosphatase (BAP), and under-carboxylated osteocalcin (ucOC) were normal. Serum levels of IGF-1 Z score, carboxylated osteocalcin (cOC), N-terminal telopeptide (NTX), and C-terminal telopeptide (CTX) were significantly lower in galactosemics than in control subjects. The different bone markers were strongly correlated. The low levels of IGF-1 Z score, formation marker cOC, and resorption markers NTX and CTX suggest a decreased bone metabolism in galactosemics.

Adolescent↗
PubMed2005

An updated review of the long-term neurological effects of galactosemia.

Classical galactosemia is an autosomal recessive condition in which there is near total absence of the activity of galactose-1-phosphate uridyltransferase. Patients with this condition have substantial motor, cognitive, and psychiatric impairments despite dietary treatment. A characteristic pattern of biochemical abnormalities is observed in patients with this disorder. Galactose-1-phosphate, the substrate of galactose-1-phosphate uridyltransferase, accumulates within cells, and surplus galactose is reduced to galactitol or oxidized to galactonate. Using sophisticated mass spectrometry, these compounds as well as free galactose can be measured in plasma and in urine. It is clear that initiation of dietary restriction of galactose in the newborn period produces reversal of hepatic, renal, brain, and immune dysfunction, along with reduction of the accumulated galactose metabolites. However, the neurologist should be aware that chronic and progressive neurologic impairments occur even in patients spared these neonatal symptoms. The purpose of this review is to summarize current information about neurologic complications of galactosemia and what is known, and still unknown, about its pathophysiology.

Cognition Disorders↗
PubMed2005

Functional characterization of the K257R and G319E-hGALE alleles found in patients with ostensibly peripheral epimerase deficiency galactosemia.

Epimerase deficiency galactosemia is an autosomal recessive condition resulting from the impairment of UDP-galactose 4'-epimerase (hGALE). Although a small number of clinically severe patients have been reported who exhibit "generalized" GALE deficiency, the vast majority exhibit an apparently benign "peripheral" form of the disorder in which enzyme impairment is restricted to the circulating red and white blood cells. Previously, preliminary data were reported suggesting that GALE deficiency is 10-fold more common among African-Americans than among non-African-Americans, and that two missense mutations, K257R and G319E, are found in at least some of these patients. We report here functional studies of these alleles involving expression of the substituted human enzymes in a null-background strain of yeast. Although under normal assay conditions both substituted proteins demonstrate enzyme activities indistinguishable from the wild-type, one (G319E) demonstrates mild impairment under conditions of substrate limitation. No impairments are evident under conditions of cofactor (NAD) limitation. These results are consistent with the apparently benign status of peripheral epimerase deficiency galactosemia, but leave open the question of why patients with these substitutions demonstrate GALE deficiency in their red blood cells. While the possibility remains that K257R and G319E may cause tissue-specific impairments not recapitulated in vitro or in yeast, an equally if not more plausible explanation suggested by interspecies sequence alignments is that both substitutions may be polymorphisms that exist in linkage disequilibrium with other, as yet unidentified causal mutations.

Alleles↗
PubMed2006

Untreated classical galactosemia patient with mild phenotype.

Despite life-long galactose restriction, long-term complications generally occur in classical galactosemia. We report an adult male with classical galactosemia (Q188R homozygosity, severely reduced erythrocyte galactose-1-phosphate uridyltransferase activity) who has a surprisingly mild phenotype despite genotype and enzyme activity associated with severe phenotype. Moreover he has a normal galactose intake from the age of 3 years. This case is probably an example of the important role of yet unknown susceptibility and or modifier genes.

Adult↗
PubMed2003

Capillary electrophoresis with laser-induced fluorescence detection for laboratory diagnosis of galactosemia.

Galactosemia, a metabolic disorder associated with the intolerance to dietary galactose due to an inherited enzymatic deficiency, is indicated by heightened levels of galactose in urine (galactosuria). In this report, capillary electrophoresis (CE) with laser-induced fluorescence detection was evaluated for its ability to screen urinary carbohydrates, particularly galactose. Neonatal urine samples with normal and abnormal levels of galactose were analyzed with galactose concentrations quantitated relative to urinary creatinine concentrations to account for variable urinary dilution. Analysis of nine samples by CE in a single-blind manner defined four as negative (normal) and five as positive for galactosuria with galactose levels as high as 146.8 +/- 5.9 mM. Galactosuria was correlated with clinical galactosemia diagnoses for four of the positive samples, while the remaining positive was associated with a patient diagnosed with Hurler's syndrome.

Electrophoresis, Capillary↗
PubMed1982

Galactose intolerance in individuals with double heterozygosity for Duarte variant and galactosemia.

The most frequent cause for an abnormal result during screening of newborn infants for galactosemia is double heterozygosity for Duarte variant and galactosemia, in which galactose-1-phosphate uridyl transferase activity is reduced to approximately 17% of normal. Thirty-nine oral galactose tolerance tests were performed in 27 infants and children with this condition. In comparison to age-matched controls, all children with this genetic variant reached much higher levels of blood galactose and galactose-1-phosphate following oral galactose challenge. The integrated plasma galactose response increased with the age of the child, whereas integrated erythrocyte galactose-1-phosphate responses were elevated to the same degree at all ages. Although all children appeared clinically normal, the marked abnormalities in the ability to dispose of ingested galactose raise questions concerning appropriate dietary recommendations for such children.

Blood Glucose↗
PubMed1997

Abnormalities of retinal metabolism in diabetes or experimental galactosemia. IV. Antioxidant defense system.

Activities of enzymes that protect the retina from reactive oxygen species were investigated in experimentally diabetic rats and experimentally galactosemic rats, two animal models known to develop vascular lesions consistent with diabetic retinopathy. Diabetes or experimental galactosemia of 2 months duration significantly decreased the activities of glutathione reductase and glutathione peroxidase in the retina while having no effect on the glutathione synthesizing enzymes glutathione synthetase and gamma-glutamyl cysteine synthetase. Activities of two other important antioxidant defense enzymes-superoxide dismutase (SOD) and catalase-also were decreased (by more than 25%) in retinas of diabetic rats and galactosemic rats. Administration of supplemental antioxidants, vitamins C and E, for the 2 months prevented the diabetes-induced impairment of antioxidant defense system in the retina. In experimentally galactosemic rats, the supplemental antioxidants were not as effective: SOD activity was normalized, but the enzymes of the glutathione redox cycle were only partly restored, and the subnormal catalase activity was unaffected. Diabetes or experimental galactosemia results in significant impairment of the antioxidant defense system in the retina, and exogenous antioxidant supplementation can help alleviate the subnormal activities of antioxidant defense enzymes.

Animals↗
PubMed1999

Abnormalities of retinal metabolism in diabetes or experimental galactosemia. VI. Comparison of retinal and cerebral cortex metabolism, and effects of antioxidant therapy.

Metabolic abnormalities observed in retina and in cerebral cortex were compared in diabetic rats and experimentally galactosemic rats. Diabetes or experimental galactosemia of 2 months duration significantly increased oxidative stress in retina, as shown by elevation of retinal thiobarbituric acid reactive substances (TBARS) and subnormal activities of antioxidant defense enzymes, but had no such effect in the cerebral cortex. Activities of sodium potassium adenosine triphosphatase [(Na,K)-ATPase] and calcium ATPase became subnormal in retina as well as in cerebral cortex. In contrast, protein kinase C (PKC) activity was elevated in retina but not in cerebral cortex in the same hyperglycemic rats. Dietary supplementation with an antioxidant mixture (containing ascorbic acid, Trolox, alpha-tocopherol acetate, N-acetyl cysteine, beta-carotene, and selenium) prevented the diabetes-induced and galactosemia-induced elevation of retinal oxidative stress, the elevation of retinal PKC activity and the decrease of retinal ATPases. In cerebral cortex, administration of the antioxidant diet also prevented the diabetes-induced decreases in (Na,K)-ATPase and calcium ATPases, but had no effect on TBARS and activities of PKC and antioxidant-defense enzymes. The results indicate that retina and cerebral cortex differ distinctly in their response to elevation of tissue hexose, and that cerebral cortex is more resistant than retina to diabetes-induced oxidative stress. The greater resistance to oxidative stress in cerebral cortex, as compared to retina, is consistent with the resistance of cerebral cortex to microvascular disease in diabetes, and with a hypothesis that oxidative stress contributes to microvascular disease in diabetes. Dietary supplementation with these antioxidants offers a means to inhibit multiple hyperglycemia-induced retinal metabolic abnormalities.

Animals↗
PubMed2001

A PCR-based method for detecting known mutations in the human UDP galactose-4'-epimerase gene associated with epimerase-deficiency galactosemia.

Epimerase-deficiency galactosemia results from impairment of the human enzyme UDP galactose-4'-epimerase (GALE). We report a rapid, internally controlled PCR-based method for detection of nine naturally occurring point mutations in human GALE associated with epimerase deficiency. These mutations were derived from patients whose clinical presentations ranged from mild to severe; all but one of these mutations have been reported previously. The tests described here work well on both cDNA and genomic samples and require no specialized equipment beyond a thermal cycler and an agarose gel electrophoresis system. Finally, although these tests in no way replace the need for biochemical diagnosis in epimerase-deficiency galactosemia, they do provide the possibility of additional molecular information to support a biochemical diagnosis and facilitate the possibility of more accurate carrier testing, should that option be desired.

Base Sequence↗