Alternate metabolic pathway in galactosemia. Observations in patient with galactosemia.
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Adolescent↗
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Screening for galactosemia. Studies of the gene frequencies for galactosemia and the Duarte variant.
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Black or African American↗
[Recent studies on galactosemia and fructosemia. Congenital monosaccharide intolerance (galactosemia-fructosemia)].
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Carbohydrate Metabolism, Inborn Errors↗
[Significance of the Weidemann test in the diagnosis of galactosemia and in galactosemia screening].
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Galactosemias↗
Living with classical galactosemia: health-related quality of life consequences.
OBJECTIVE: Classical galactosemia (McKusick 230400) is an autosomal recessive disorder of galactose metabolism caused by a deficiency of galactose-1-phosphate uridyltransferase (EC 2.7.712). Treatment, consisting of a severe restriction of dietary galactose, is life saving, but most patients develop abnormalities despite this diet. The aim of this study was to study the influence of galactosemia on the patients' health-related quality of life (HRQoL), on educational levels, and on the specific galactosemia-related concerns of these families. METHODS: Age-specific HRQoL questionnaires, a classical galactosemia-specific questionnaire designed by the authors, and a list of questions regarding educational attainment were handed out or sent to all 75 members of the Dutch Galactosemia Society and their families. RESULTS: Sixty-three (84%) patients with classical galactosemia from 58 families returned the questionnaire. Concerning HRQoL, significant differences between patients aged 1 to 5 and healthy children were found on the domains of abdominal complaints and communication. Patients aged 8 to 15 years differed from their healthy peers on the domain of cognitive function. Mothers of patients aged 6 to 15 reported a significantly lower HRQoL on the domains of motor and cognitive function. Patients 16 years and older had significant lower scores on the domains of cognitive and social function. The percentage of patients who attend special schools is significantly higher than in the general population, and the educational attainment is significantly lower in patients with classical galactosemia. CONCLUSIONS: This is the first study to describe the HRQoL of patients with classical galactosemia using well-developed and validated instruments in different age groups. The results of the present study indicate that having galactosemia negatively influences the HRQoL. Early and regular evaluation and support of possible cognitive problems should be a major part of the protocol for the follow-up of patients with classical galactosemia.
Adolescent↗
Abnormalities of retinal metabolism in diabetes or galactosemia: ATPases and glutathione.
PURPOSE: Experimental galactosemia and diabetes are known to result in diabetic-like retinopathy in animals, but the mechanism by which the retinopathy develops remains unclear. Defects of retinal metabolism that are common to galactosemia and diabetes are closely associated with the development of retinopathy and might play a role in the pathogenesis of the retinal disease. METHODS: Effects of experimental galactosemia on retinal calcium-activated ATPase [(Ca,Mg)-ATPase], sodium-potassium ATPase [(Na,K)-ATPase], glutathione, ATP, and pertinent ions have been compared with the effects of experimental diabetes in rat and dog models of diabetic retinopathy. RESULTS: Activities of (Ca,Mg)-ATPase and (Na,K)-ATPase were decreased as a result of either experimental galactosemia or diabetes in both the dog and the rat, and the decreases were accompanied by a diminution of reduced glutathione (GSH) in the retina. Ouabain-insensitive ATPase activity in the retina was not significantly reduced by diabetes or galactosemia, suggesting that the observed defects in (Ca,Mg)-ATPase and (Na,K)-ATPase activities were specific. The decrease of retinal GSH levels was associated with an elevated concentration of oxidized glutathione in diabetes but not in galactosemia. Retinal ATP and ion concentrations remained unaffected by experimental galactosemia or diabetes. CONCLUSIONS: Comparison of two etiologically dissimilar models of diabetic retinopathy (diabetes and galactosemia) has revealed abnormalities of retinal metabolism that are shared by the two models. Further comparisons of retinal metabolism between these two models should reveal additional sequelae of hyperglycemia that are associated with, and that might play a role in, the development of diabetic retinopathy.
Adenosine Triphosphate↗
Molecular heterogeneity of classical and Duarte galactosemia: mutation analysis by denaturing gradient gel electrophoresis.
Classical galactosemia is caused by one common missense mutation (Q188R) and by several rare mutations in the galactose-1-phosphate uridyltransferase (GALT) gene. The most common variant of GALT, the Duarte variant, occurs as two types, Duarte-1 (D-1) and Duarte-2 (D-2), both of which carry the sequence change N314D. D-1 increases, whereas D-2 decreases GALT activity. To study the molecular genetics of classical and Duarte galactosemia, we analyzed the GALT mutations in 30 families with classical galactosemia, in 10 families with the D-2 variant and in 3 individuals carrying the D-1 allele by denaturing gradient gel electrophoresis (DGGE). DGGE detected 59 of the 60 classical galactosemia alleles. Q188R accounted for 60%, K285N accounted for 28% of these alleles. Eight novel candidate galactosemia mutations were found. On all D-2 alleles N314D occurred in cis with two intronic sequence changes, on the D-1 alleles in cis with a neutral mutation in exon 7. We conclude that the mutations causing galactosemia are highly heterogeneous and that K285N is a second common galactosemia mutation in our population.
Adult↗
Mutations at the galactose-1-p-uridyltransferase gene in infants with a positive galactosemia newborn screening test.
Newborn screening for galactosemia yields a high number of false-positive results. Confirmatory DNA testing for unknown galactosemia mutations on the initial positive sample using novel techniques of mutation detection tenders itself to reduce the recall rate. The potential benefits of confirmatory DNA testing, however, could be offset by the detection of a high percentage of galactosemia carriers, Duarte/galactosemia compound heterozygotes, and infants with benign sequence changes in the galactose-1-phosphate uridyltransferase (GALT) gene among infants with a positive biochemical screening test. Our aim was to determine the frequency and allelic distribution of all sequence changes in the GALT gene in 110 newborns with a positive total galactose screening test among 43,688 Austrian newborns screened consecutively. We found that only 20 of the 110 probands carried at least one known or novel candidate galactosemia mutation (one galactosemia homozygote, 7 Duarte/galactosemia compounds, 12 carriers) as judged by denaturing gradient gel electrophoresis and cleavage fragment length polymorphism analysis. Four novel galactosemia candidate mutations (Q9H, A46fsdelCAGCT, M129T, L342I) were identified. Sixty-seven probands had no detectable sequence changes and 23 carried only the benign Duarte or Los Angeles variant alleles or silent mutations. We conclude that a rapid and automatable confirmation test for unknown GALT mutations, e.g. on a high-density oligonucleotide array basis, has the potential to lower the recall rate of galactosemia screening in our population by about five-fold from 0.25 to 0.046%. Further research, however, will be required before the development of such a test can be advocated.
Austria↗
A prevalent mutation for galactosemia among black Americans.
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-(13C)-galactose to 13CO2 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-(13C)-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.
Base Sequence↗
Analysis of common mutations in the galactose-1-phosphate uridyl transferase gene: new assays to increase the sensitivity and specificity of newborn screening for galactosemia.
Classical galactosemia is a genetic disease caused by mutations in the galactose-1-phosphate uridyl transferase (GALT) gene. Prospective newborn screening for galactosemia is routine and utilizes the universally collected newborn dried blood specimen on filter paper. Screening for galactosemia is achieved through analysis of total galactose (galactose and galactose-1-phosphate) and/or determining the activity of the GALT enzyme. While this approach is effective, environmental factors and the high frequency of the Duarte D2 mutation (N314D) does lead to false positive results. Using DNA derived from the original newborn dried blood specimen and Light Cycler technology a panel of five assays able to detect the four most frequently encountered classical galactosemia alleles (Q188R, S135L, K285N, and L195P) and the N314D Duarte variant mutation are described. The five assays are performed simultaneously using common conditions. Including DNA preparation, set-up, amplification, and analysis the genotype data for all five loci is obtained in less than 2 hours. The assays are easily interpreted and amenable to high-throughput newborn screening. Mutational analysis is useful to reduce false positive results, differentiate D/G mixed heterozygotes from classical galactosemia, and to clearly identify a very high percentage of those affected by classical galactosemia.
Base Sequence↗
Neonatal screening for galactosemia by quantitative analysis of hexose monophosphates using tandem mass spectrometry: a retrospective study.
BACKGROUND: Classic galactosemia (OMIM 230400) is an inherited disorder in the metabolism of galactose caused by deficiency of the enzyme galactose 1-phosphate uridyl transferase (EC 2.7.7.12). Galactosemia leads to accumulation of galactose and galactose 1-phosphate (gal-1-P) in blood and tissues and, if untreated, produces neonatal death or severe mental retardation, cirrhosis of the liver, and cataracts. Hence, the disorder is included in many neonatal screening programs. METHODS: We retrospectively analyzed filter-paper blood samples obtained 4-8 days postpartum for routine neonatal screening from 12 galactosemia patients and 2055 random controls. Total hexose monophosphates (HMPs) were used as a marker of gal-1-P and were assayed by negative-ion mode electrospray tandem mass spectrometry (tandem MS) with settings biased toward gal-1-P detection. The predominant precursor/product ion pair m/z 259/79 was used to quantify total HMPs by external standardization. RESULTS: Linear calibration curves were obtained in the range 0-8 mmol/L gal-1-P. The detection limit was 0.1 mmol/L HMP, and total CVs ranged from 13% at the detection limit to <8% at >1 mmol/L HMP. The method was in agreement with an alkaline phosphatase-galactose dehydrogenase method. All samples from galactosemia patients contained increased HMP concentrations (range for patients, 2.6-5.2 mmol/L; range for reference group, <0.10-0.94 mmol/L). The diagnostic sensitivity and specificity were 100% at a cutoff of 1.2 mmol/L HMP. A Duarte/classic galactosemia compound heterozygous sample could be discriminated clearly from both patient and reference samples. CONCLUSION: Quantitative analysis of HMPs by tandem MS can be used in laboratory investigations of galactosemia.
Alkaline Phosphatase↗
Usefulness of per-rectal portal scintigraphy with Tc-99m pertechnetate for galactosemia in infants.
Galactosemia discovered by newborn screening is rarely caused by enzyme deficiency. It has recently been reported that among patients without enzyme deficiency portosystemic shunting may be a cause of galactosemia in some patients. We did per-rectal portal scintigraphy in patients with such galactosemia detected during screening of newborns to examine the usefulness of this method for the diagnosis of portosystemic shunts via the inferior mesenteric vein. The subjects were eight neonates with galactosemia without enzyme deficiency detected during screening. A solution containing technetium-99m pertechnetate was instilled into the rectum, and serial scintigrams were taken while radioactivity curves for the liver and heart were recorded sequentially. The per-rectal portal shunt index was determined by calculating the ratio for counts of the liver to counts for the heart integrated for 24 seconds immediately after the appearance of the liver time-activity curve. A portosystemic shunt was detected in both of the patients with a shunt index of 30% or more, but not in the six patients with a shunt index less than 30%. The blood galactose levels of these six patients later entered the reference range. This method is noninvasive and there is little exposure to the radionuclide. It seemed to be useful for the diagnosis of portosystemic shunt in newborns with galactosemia without enzyme deficiency.
Child, Preschool↗
Radiochemical assay of minute quantities of galactose-1-phosphate uridyltransferase activity in erythrocytes and leukocytes of galactosemia patients.
A sensitive radioisotopic method has been developed which can detect galactose-1-phosphate uridyltransferase (GALT) activity as low as 0.1% of normal control values in both erythrocytes and leukocytes. This assay utilizes carbon-14 labeled galactose-1-phosphate with high specific activity and requires removal of endogenous galactose-1-phosphate (Gal-1-P) and uridine diphosphate glucose (UDPGlc) through dialysis. Optimal exogenous UDPGlc concentration has been determined with a fixed concentration of Gal-1-P in the incubation. The rate of product, uridine diphosphate galactose (UDPGal), formation is monitored at three different times. Among 423 patients with galactosemia studied by this method, 363 patients exhibited no detectable GALT activity in their erythrocytes and 60 patients were found to have detectable erythrocyte GALT activity ranging from 0.02 to 5.0 units normal values: > 20 units). The former group of patients was designated as classic galactosemia (GG) and the latter group as galactosemia variant (GV). Leucocytes from ten patients belonging to the GG group also showed complete absence of GALT activity while leukocytes from two patients belonging to the GV group showed GALT activity at levels comparable with those found in their erythrocytes. Because there is extensive biochemical heterogeneity among galactosemia patients, we recommend that an assay with increase sensitivity be carried out on blood samples from galactosemia patients so that clinical, biochemical and molecular correlations made by different groups of investigators can be compared.
Carbon Radioisotopes↗
Vitreous hemorrhage as an ophthalmic complication of galactosemia.
A major complication of galactosemia is cataracts. This is usually considered to be the sole ophthalmic feature of this disorder. However, we have encountered vitreous hemorrhage, a very rare ophthalmic finding, in five neonates with galactosemia and have found four probable additional cases in the literature. All of these infants had severe neonatal manifestations of galactosemia and were discovered to have vitreous hemorrhage by ophthalmologic examination initiated by the observation of clouding of the eye or on a routine basis. The infants lost most or all vision from the affected eye. Retinal abnormalities were present in the involved eyes of the five neonates of whom we have direct knowledge. Thus we believe that retinal hemorrhage is the most likely source of the vitreous hemorrhage and that the coagulopathy associated with neonatal disease in galactosemia leads to vitreous hemorrhage. Prompt recognition and therapy for the coagulopathy would likely prevent vitreous hemorrhage in galactosemia.
Female↗
Molecular basis of galactosemia: mutations and polymorphisms in the gene encoding human galactose-1-phosphate uridylyltransferase.
We describe the molecular characterization of two mutations responsible for galactosemia, an inherited disorder of galatose metabolism that causes jaundice, cataracts, and mental retardation in humans. The coding region of galactose-1-phosphate uridylyltransferase (GALT; UDPglucose:alpha-D-galactose-1-phosphate uridylyltransferase, EC 2.7.7.12) was amplified by the polymerase chain reaction from total cDNA of a classic galactosemic individual and was characterized by direct sequencing of the products. Two missense mutations were identified: (i) replacement of valine-44 by methionine and (ii) replacement of methionine-142 by lysine. These mutations led to a drastic reduction in GALT activity when individual mutant cDNAs were overexpressed in a mammalian cell system, although full-length protein is synthesized in this assay. The two galactosemia mutations account for 3 of the 15 galactosemia alleles analyzed. These results suggest that galactosemia is caused by a variety of mutations, which might be responsible for the observed clinical heterogeneity of this disorder. We also present the molecular characterization of two GALT polymorphisms: (i) replacement of leucine-62 by methionine and (ii) replacement of asparagine-314 by aspartate. It appears that galactosemia mutations tend to occur in regions that are highly conserved throughout evolution while the polymorphisms change variable residues.
Amino Acid Sequence↗
The molecular biology of galactosemia.
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.
Ethnicity↗
Verbal dyspraxia and galactosemia.
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 <5% CUMPCD had mutant alleles that severely impaired human GALT enzyme catalysis. 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 < 0.008) and significantly higher mean erythrocyte galactose-1-phosphate (3.38 +/- 0.922 mg/dL versus 1.92 +/- 1.28 mg/dL; p = 0.019) and mean urinary galactitol concentrations (192.4 +/- 75.8 mmol/mol creatinine versus 122.0 +/- 56.4; p = 0.048) than patients with normal speech. CUMPCD values <5%, mean erythrocyte galactose-1-phosphate levels >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.
Adult↗
Abnormalities of retinal metabolism in diabetes or experimental galactosemia: V. Relationship between protein kinase C and ATPases.
In the retinas of diabetic animals, protein kinase C (PKC) activity is elevated, and Na+-K+-ATPase and calcium ATPase activities are subnormal. These abnormalities are also present in another model of diabetic retinopathy, experimental galactosemia. We have investigated the relationship between hyperglycemia-induced abnormalities of PKC and ATPases using a selective inhibitor of beta isoform of PKC (LY333531). Diabetes or experimental galactosemia of 2 months' duration resulted in > 50% elevation of PKC activity in the retina, and administration of LY333531 prevented the elevation. In retinas of the same rats, the LY333531 prevented hyperglycemia-induced decreases of both Na+-K+-ATPase and calcium ATPase activities. Retinal microvessels, the main site of lesions in diabetic retinopathy, likewise showed elevated activity of PKC and inhibition of ATPases in diabetes and in experimental galactosemia, and administration of LY333531 to diabetic animals prevented these abnormalities. PKC activity in sciatic nerves, in contrast, became subnormal in diabetes and experimental galactosemia, and LY333531 had no effect on PKC activity in the sciatic nerve. PKC activity in the cerebral cortex was not affected by diabetes or experimental galactosemia. The results suggest that diabetes-induced reductions in Na+-K+-ATPase and calcium ATPase in the retina are mediated in large part by PKC-beta. The availability of an agent that can normalize the hyperglycemia-induced increase in PKC activity in the retina should facilitate investigation of the role of PKC in the development of diabetic retinopathy.
Animals↗