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[Hereditary galactosemia in rats: biochemical mechanisms of the disease].

A W/SSM rat strain with symptoms of inherited galactosemia (cataracts, hepatosplenomegaly, aminoaciduria) was previously developed by selection and inbreeding of Wistar rats highly susceptible to the galactosemic effect of galactose. Decreased activity of galactose-I-phosphate uridyl transferase (Gal-I-PUT) in liver and erythrocytes is the salient biochemical feature of the strain. The crossing experiments have shown that the decrease in Gal-I-PUT activity was not required for the expression of main galactosemia symptoms. The experiments excluded low galactokinase activity and high susceptibility of glucose-6-phosphate dehydrogenase and phosphoglucomutase to galactose-I-phosphate as probable reasons of galactosemia. It was shown that increased transport of 14C-galactose to the erythrocytes was characteristic of galactosemic rat strain. The intracellular accumulation of galactose concerned with its increased transport was assumed as a major reason for the development of galactosemia symptoms in W/SSM rats. Genetic analysis has shown that lens lesions in galactosemic rats were controlled by one dominant gene. It is suggested that this gene is responsible for the enhances transport of galactose into the rat cells and its accumulation in toxic concentrations. The main galactosemic symptoms including cataracts result obviously rom the pleiotropic effect of this gene; the decreased activity of Gal-I-PUT may be a consequence of its epistatic effect.

Animals↗
PubMed1984

Curious neurologic sequelae in galactosemia.

Two siblings with classic transferase deficiency galactosemia that was detected at birth have been treated with lactose restriction since the neonatal period. Both patients developed a unique and progressive neurologic syndrome of mental retardation, tremor, and ataxia. Careful review of the family history and medical records, the absence of metabolic disturbances other than those related to galactosemia, and the aggregate physical findings and neurodiagnostic studies ruled out other neurologic disorders in these siblings. It is therefore proposed that these patients represent a subgroup of transferase-deficient galactosemic patients, who develop characteristic neurologic sequelae with conventional dietary management. The existence of this subgroup should be considered in evaluations of therapeutic responses in cohorts of patients with galactosemia. Further, galactosemia should be included in the differential diagnosis of tremor and ataxia in the setting of mental retardation.

Adolescent↗
PubMed1982

[Biochemical mechanisms of the development of hereditary galactosemia in W/SSM strain rats].

The W/SSM rat strain with symptoms of inherited galactosemia (cataracts, hepatosplenomegaly, aminoaciduria etc.) was previously developed by selection and inbreeding of Wistar rats highly susceptible to the galactosemic effect of galactose. The decreased activity of galactose-1-phosphate uridyl transferase (Gal-1-PUT) in liver and erythrocytes is the salient biochemical feature of the strain. The crossing experiments have shown that the decrease in Gal-1-PUT activity is not a prerequisite for the expression of main galactosemia symptoms. The experiments excluded the low galactokinase activity and high susceptibility of glucoso-6-phosphate dehydrogenase and phosphoglucomutase to galactose-1-phosphate as probable causes of galactosemia. It was shown that the increased transport of 14C-galactose to erythrocytes is characteristic of the galactosemic rat strain. The intracellular accumulation of galactose concerned with its increased transport was assumed to be a major reason of the development of galactosemia symptoms in W/SSM rats. Genetic analysis has shown that lens lesions in galactosemic rats are controlled by one dominant gene. It is suggested that this gene is responsible for the enhanced transport of galactose into the rat cells and its accumulation in toxic concentrations. The main galactosemic symptoms, including cataracts, result obviously from the pleiotropic effect of this gene, while the decreased activity of Gal-1-PUT may be a consequence of its epistatic effect.

Animals↗
PubMed1994

A common mutation associated with the Duarte galactosemia allele.

The human cDNA and gene for galactose-1-phosphate uridyl transferase (GALT) have been cloned and sequenced. A prevalent mutation (Q188R) is known to cause classic galactosemia (G/G). G/G galactosemia has an incidence of 1/38,886 in 1,396,766 Georgia live-born infants, but a more common variant of galactosemia, Duarte, has an unknown incidence. The proposed Duarte biochemical phenotypes of GALT are as follows: D/N, D/D, and D/G, which have approximately 75%, 50%, and 25% of normal GALT activity respectively. In addition, the D allele has isoforms of its enzyme that have more acidic pI than normal. Here we systematically determine (a) the prevalence of an A-to-G transition at base pair 2744 of exon 10 in the GALT gene, transition that produces a codon change converting asparagine to aspartic acid at position 314 (N314D), and (b) the association of this mutation with the Duarte biochemical phenotype. The 2744G nucleotide change adds an AvaII (SinI) cut site, which was identified in PCR-amplified DNA. In 111 biochemically unphenotyped controls with no history of galactosemia, 13 N314D alleles were identified (prevalence 5.9%). In a prospective study, 40 D alleles were biochemically phenotyped, and 40 N314D alleles were found. By contrast, in 36 individuals known not to have the Duarte biochemical phenotype, no N314D alleles were found. We conclude that the N314D mutation is a common allele that probably causes the Duarte GALT biochemical phenotype and occurs in a predominantly Caucasian, nongalactosemic population, with a prevalence of 5.9%.

Alleles↗
PubMed1996

[Galactosemia: a problem still unsolved].

Classical galactosemia is an inherited metabolic disease that results from galactose-1-phosphate uridyltransferase deficiency. Untreated galactosemia has various manifestations, including central nervous system damage, hepatic failure, cataract. Galactose-restricted dietary treatment, the only therapy used in galactosemia, brings considerable improvement, especially in the neonatal period. However, in the most galactosemic patients this treatment does not prevent development of late-onset complications; mental retardation, ovarian failure and neurologic disturbances. This article presents a review of contemporary hypotheses on possible factors influencing the outcome in galactosemia, especially in regard to late-onset complications.

Galactosemias↗
PubMed2000

Mutation analysis of the GALT gene in Czech and Slovak galactosemia populations: identification of six novel mutations, including a stop codon mutation (X380R).

A study of the galactose-1-phosphate uridyltransferase (GALT) gene from 37 unrelated galactosemia families is reported here. A total of 16 sequence variations in eleven mutated alleles was found. The two most common molecular defects were the mutations Q188R (46.0%) and K285N (25.7%). Six novel mutations in the GALT gene, X380R, Y209S, E340K, L74fsdelCT, Q169K and L256/P257delGCC, were detected. Three mutations, V151A, L195P and R204X that were previously described in other populations, were also found. The mutation X380R, which breaks the stop codon of the GALT gene, causes elongation of the GALT enzyme's protein chain. A deletion of four nucleotides in the 5' promoter region, in a position 116 - 119 nucleotides upstream from the initiate codon (5'UTR-119delGTCA), was revealed in Duarte (D2) alleles, in addition to N314D, IVS4nt-27g-->c, IVS5nt+62g-->a, and IVS5nt-24g-->a. An unusual molecular genotype was observed on 2 types of classical galactosemia alleles, with six variations from the normal nucleotide sequence presented in cis (mutation V151A or E340K plus five Duarte (D2) characteristic variations). In summary, galactosemia is a heterogeneous disorder at the molecular level, and mutation N314D, appears to be an ancient genetic variant of the GALT gene. Hum Mutat 15:206, 2000.

Amino Acid Substitution↗
PubMed1992

Genetic basis of galactosemia.

Classic galactosemia is an inborn error of galactose metabolism and results from deficiency of the ubiquitously expressed enzyme galactose-1-phosphate uridyltransferase (GALT). Nine missense mutations, three splicing mutations, three GALT protein polymorphisms, and one silent nucleotide substitution have been identified to date. Most of the disease-causing mutations are rare among patients. The most common mutation, Q188R, has a frequency of only one-fourth in the patient population examined. Three classes of disease-causing mutations have been reported: CRM+ missense mutations (the most common class), CRM- missense mutations, and splicing mutations. Thus, galactosemia is heterogeneous at the molecular level, which is noteworthy in light of the well-documented clinical variability observed in this disorder. It has also been shown that eight of nine galactosemia missense mutations occur in evolutionarily well-conserved domains, suggesting that they affect functionally and/or structurally important residues. In contrast, all protein polymorphisms alter variable amino acids which presumably are not important for the enzyme's function.

Amino Acid Sequence↗
PubMed1995

Molecular characterization of galactosemia (type 1) mutations in Japanese.

We characterized two novel mutations of the galactose-1-phosphate uridyltransferase (GALT) gene in two Japanese patients with GALT deficiency and identified N314D and R333W mutations, previously found in Caucasians. One novel missense mutation was an G-to-A transition in exon 8, resulting in the substitution of arginine by histidine at the codon 231 (R231H). GALT activity of the R231H mutant construct was reduced to 15% of normal controls in a COS cell expression system. The other was a splicing mutation, an A-to-G transition at the 38th nucleotide in exon 3 (318A-->G), resulting in a 38-bp deletion in the GALT cDNA by activating a cryptic splice acceptor site. In seven Japanese families (14 alleles for classic form and one allele for Duarte variant) with GALT deficiency, the R231H and 318A-->G mutations were found only on both alleles of the proband. The N314D and R333W mutations were found on one allele each. The Q188R was prevalent in the United States but not in Japanese patients. The N314D mutation was associated with the Duarte variant in Japanese persons, as well as in the United States. We speculate that classic galactosemia mutations appear to differ between Japanese and Caucasian patients. Our limited data set on galactosemia mutations in Japanese suggests that the N314D GALT mutation encoding the Duarte variant arose before Asian and Caucasian people diverged and that classic galactosemia mutations arose and/or accumulated after the divergence of Asian and Caucasian populations.

Amino Acid Sequence↗
PubMed1998

Human UDP-galactose 4' epimerase (GALE) gene and identification of five missense mutations in patients with epimerase-deficiency galactosemia.

The galactosemias are a series of three inborn errors of metabolism caused by deficiency of any one of the three human galactose-metabolic enzymes: galactokinase (GALK), galactose-1-phosphate uridyl transferase (GALT), and UDP-galactose 4' epimerase (GALE). We report here the characterization of the entire coding sequence of the GALE gene and screening for mutations in epimerase-deficient individuals. The human GALE gene is about 4 kb in size and is divided into 11 exons on chromosome band 1p36. We have identified five mutations in the GALE gene of epimerase-deficient galactosemia patients. The patients were either homozygotes or compound heterozygotes for mutations. These results confirm that epimerase-deficiency galactosemia is the result of missense mutations in the GALE gene and indicate that the disease is characterized by extensive allelic heterogeneity.

Base Sequence↗
PubMed1995

Linkage disequilibrium between a SacI restriction fragment length polymorphism and two galactosemia mutations.

We have identified a novel SacI restriction fragment length polymorphism (RFLP) in the human galactose-1-phosphate uridyl transferase (GALT) gene. This RFLP can be readily typed by the polymerase chain reaction (PCR). The polymorphic allele is found on about 11% of normal chromosomes and is in linkage disequilibrium with the two most common mutations identified in GALT thus far: Q188R and N314D. Q188R is found exclusively on chromosomes with the SacI restriction site, whereas N314D is found only on chromosomes lacking this site. This suggests that these two mutations arose independently in evolution on different chromosomal backgrounds. Galactosemia patients without the Q188R mutation have a frequency of the SacI polymorphism similar to normal controls suggesting that several different galactosemia mutations must be present in them. The SacI RFLP may also be useful in the prenatal diagnosis of galactosemia.

DNA Mutational Analysis↗
PubMed1995

Newborn mass screening for galactosemia.

Methods for mass screening of newborns for galactosemia have been available since 1964. Although galactosemia is rare, many countries have included screening for galactosemia in their national screening programs, yet other countries deny the necessity for screening. Despite the early appearance of clinical symptoms, newborns may be reliably diagnosed in time only through mass screening.

Galactosemias↗
PubMed1998

Simultaneous occurrence of various mutations and polymorphisms in cis and in trans of the galactose-1-phosphate uridyltransferase gene in a Turkish family with classical galactosemia.

Classical galactosemia, characterized clinically by acute hepatic dysfunction, sepsis, cataract, and failure to thrive, is caused by deficiency of galactose-1-phosphate uridyltransferase (GALT). Galactose restriction normalizes these acute symptoms; however, long-term complications such as intellectual deficits and ovarian failure are conspicuous in the majority of patients. Here we report two Turkish siblings with classical galactosemia. The clinical course of the two children differed markedly: only the older girl suffered from severe acute symptoms during the neonatal period, and she developed greater mental retardation than her younger affected brother. The functional activity of GALT was virtually absent in each affected children. The mother and two healthy siblings exhibited approximately 50% normal GALT activity and the father approximately 25%. Molecular analysis revealed that these two galactosemic siblings were homozygous for a stop codon mutation of E340X in GALT exon 10. Moreover, two additional mutations, a neutral polymorphism L218L and N314D, which are typical for the Duarte-I variant, were found in the same GALT allele. The two healthy siblings and the parents were heterozygous for these combinations of mutations. In addition, the father's second GALT allele revealed three intron mutations at nucleotide position 1105 (G-->C), 1323 (G-->A) and 1391 (G-->A) and the N314D mutation, which correspond to the mutations of Duarte-2 variant. Our findings indicate that in classical galactosemia several distinct mutations can be present in one allele (in cis) of the GALT gene. Therefore it seems to be necessary to examine all introns and exons of the GALT gene in galactosemic patients who do not carry the Q188R mutation or another frequent mutation in the GALT gene.

Adolescent↗
PubMed1976

Biokinetics of galactose in the homozygotes and heterozygotes of both forms of galactosemia.

41 heterozygoes and 4 homozygotes with a deficiency of galactose 1-phosphate uridyl transferase and also 3 heterozygotes and 1 homozygous patient with galactokinase deficiency were subjected to intravenous galactose loading tests with a dose of 350 mg/kg body weight in order to answer the question whether it is possible to detect the heterozygotes of both types of galactosemia by this method. For comparison, 38 healthy children and adolescents, 24 children with epidemic hepatitis and 4 children with cirrhosis of the liver, which was verified by histology, were included in the study. The elimination half-life (and also the other pharmacokinetic parameters as inaugurated by Dost) was the same for all the heterozygotes for both types of galactosemia almost without exception, and for the healthy cs, children in the acute stages of hepatitis and patients with cirrhosis of the liver was prolonged 2 to 5 times the normal. In patients with hepatitis, however, the elimination half-life was normal before the transaminases. Accordingly, the galactose clearance was decreased to half and one-fourth of the normal. Hence, heterozygotes with galactosemia cannot be detected with galactose loading tests.

Adolescent↗
PubMed1983

Prenatal diagnosis of galactosemia and properties of galactose-1-phosphate uridyltransferase in erythrocytes of galactosemic variants as well as in human fetal and adult organs.

The kinetic characteristics and isoelectrofocusing patterns of uridyltransferase and the concentrations of galactose-1-phosphate in hemolysates were investigated in a family with compound variants of Duarte and classical galactosemia. There were no significant differences in Km values between the genotypes. However, the isoelectrofocusing study with thin-layer polyacrylamide gels (PAGIF) as well as with agarose gels (AGIF) showed a distinctive difference. The enzyme from the Duarte variant resolved into at least two more activity bands at pH between 5.2 and 5.4. The accumulation of galactose-1-phosphate was observed only in homozygotes for classical galactosemia. Compound heterozygotes (G-D) without any clinical manifestations did not show an accumulation of galactose-1-phosphate. The isoelectrofocusing study of the enzyme in human tissues revealed their activity resolving into multiple bands, 6-8 bands at pH 5.50-6.00 and 1-3 bands at pH 4.9-5.2. No significant differences were found in the patterns between fetal and adult liver except that the intensity of the anodic bands (pH 4.9-5.2) was weaker in fetal tissues. Prenatal diagnosis of classical galactosemia was performed in nine families by measuring the enzyme activity in cultivated amniotic fluid cells. Absence of the enzyme activity in amniotic fluid cells was found in two cases, and in four cases the heterozygosity was diagnosed by a relative low enzyme activity, 30-50% of the activity in control cells cultured in parallel.

Amniotic Fluid↗
PubMed1988

The development of electroretinogram abnormalities and the possible role of polyol pathway activity in diabetic hyperglycemia and galactosemia.

This study examined the induction of electroretinogram abnormalities in hyperglycemia and the possible role of increased polyol pathway activity in the development of these changes. Both diabetic hyperglycemia and galactosemia caused the prolongation of peak latencies and in some cases a reduction in the amplitudes of oscillatory potentials on the b-wave. Diabetic hyperglycemia-associated abnormalities were prevented and normalized by insulin or ADN-138, an aldose reductase inhibitor. Galactosemia-induced abnormalities were inhibited by ADN-138, and were reversed either by ADN-138 treatment or by withdrawal of galactose from the diet. Polyol accumulation was prevented by insulin or ADN-138, and the elevated polyol level was reversed by insulin, ADN-138, or withdrawal of galactose in diabetic hyperglycemia and/or galactosemia. These results suggest that the increased polyol pathway activity in the hyperglycemia may be involved in the development of electroretinogram abnormalities similar to those in human diabetes; therefore, ADN-138 could be a useful drug for therapy of retinopathy in the early diabetic stage.

Animals↗
PubMed1991

Characterization of a novel biochemical abnormality in galactosemia: deficiency of glycolipids containing galactose or N-acetylgalactosamine and accumulation of precursors in brain and lymphocytes.

Classic galactosemia, an inborn error of human galactose metabolism, is characterized by a deficiency of the enzyme galactose-1-phosphate uridyltransferase (GALT). The current model for the pathophysiology of this disease ascribes most of its symptoms to the toxicity of intracellular galactose-1-phosphate (Gal-1-P), one of the substrates of GALT which accumulates in the untreated disease state. Recently, a reduction in the intracellular concentration of UDP-Gal (uridine diphosphogalactose), one of the products of GALT, has been described in treated galactosemic patients. We investigated whether galactosemic patients might also have reduced amounts of those macromolecules that depend on UDP-Gal for their biosynthesis. We report a reduction in glycolipids that contain either galactose or its derivative N-acetylgalactosamine and an accumulation of the precursors to these compounds in the brain of a neonate with galactosemia. We also found an imbalance in glycolipids in galactosemic lymphoblasts. This novel biochemical abnormality observed in galactosemic patients is not addressed by dietary galactose-restriction therapy and could explain some of the chronic neurologic and other complications of galactosemia.

Acetylgalactosamine↗
PubMed2004

Short-term exogenous galactose supplementation does not influence rate of appearance of galactose in patients with classical galactosemia.

INTRODUCTION: Recently, evidence has been presented that adult patients with classical galactosemia have higher than expected galactose tolerance. This may be caused by a decrease of endogenous galactose production with ageing. Alternatively, suppression of endogenous galactose production by exogenous galactose might be implicated. The aim of this study was to determine if the rate of appearance of galactose is suppressed by exogenous galactose. MATERIALS AND METHODS: Two adult patients with classical galactosemia and three healthy control subjects were given a primed continuous infusion of D-[1-13C]galactose to determine the rate of appearance of galactose (GAR, expressed as micromol/kg/h) before and during additional galactose supplementation. After initial assessment of GAR (GAR1), GAR was determined during doubled (GAR2) or quadrupled (GAR4) galactose infusion. RESULTS: GAR1 was 2.48 and 2.44 in patients 1 and 2, and 0.46, 0.34, and 0.39 in control subjects 1, 2, and 3, respectively. GAR(2) was 2.43 and 2.13 in patients 1 and 2, and 0.57, 0.38, and 0.47 in control subjects 1, 2, and 3, respectively. In patient 1 the experiment was repeated during quadrupled galactose infusion. Here GAR1 was 3.01 and GAR4 was 3.26. CONCLUSIONS: No significant differences between GAR before and during additional galactose infusion were found in patients and in control subjects. GAR1 was significantly higher in patients than in control subjects. We conclude that the rate of appearance of galactose is not influenced by exogenous galactose, at least under short-term conditions, in patients with classical galactosemia and in control subjects.

Adult↗
PubMed1989

Hyperglycemia and development of glomerular pathology: diabetes compared with galactosemia.

Dogs were randomly assigned to experimental galactosemia or diabetes, or to a normal untreated group, and diabetic animals were then randomly assigned to either poor or good glycemic control. At five years duration, kidneys from the animals were compared by quantitative stereology. Glomerulopathy appeared in the poor control diabetes group, and the thickness of glomerular capillary basement membrane, the glomerular tuft volume, and the fraction of glomerulus occupied by mesangium were each significantly greater than normal. The capillary filtering surface area per glomerulus was supranormal also, but nonetheless was subnormal relative to glomerular volume. The development of glomerulopathy was significantly inhibited in dogs assigned to good glycemic control. In galactosemic animals, the basement membrane thickness was greater than normal, but the glomerular volume, fractional and absolute volumes of mesangium, and capillary filtering surface area remained normal. The polyol concentration in renal cortex seemed elevated by galactosemia no less than by diabetes, and was highest in galactosemia. The galactosemic animals are known to have developed a retinopathy morphologically comparable to that of diabetic patients and diabetic dogs. Thus, sequelae of hyperglycemia sufficient to produce glomerular basement membrane thickening and retinopathy proved not necessarily sufficient to produce the mesangial expansion and glomerular hypertrophy typical of diabetes.

Animals↗