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PubMed1990

Galactose disorders: an overview.

There are three separate disorders of galactose metabolism of clinical importance. Galactokinase deficiency mainly causes cataracts which regress without complications providing a galactose-free diet is started early enough. UDPgalactose-4-epimerase deficiency seems extremely rare. A common feature of the two reported cases is nerve deafness. Galactose-1-phosphate uridyl transferase deficiency poses the greatest problems because of the poor long-term outcome in spite of a galactose-restricted diet, and with no clear indications of how and when the underlying damage occurs. Recent evidence of low erythrocyte and tissue UDPgal levels, associated with ovarian dysfunction, may indicate impaired galactoside synthesis. Administration of uridine corrects the UDPgal depletion and trials in which it is added to the galactose-restricted diet have begun.

Animals↗
PubMed1990

Culture of galactosaemic fibroblasts in the presence of galactose: effect of inosine.

Fibroblasts from three galactosaemics had no galactose-1-phosphate uridyltransferase (GALT) activity. These fibroblasts cells were cultured in different media supplemented with dialysed fetal calf serum. Galactosaemic and control cell strains stopped growing in hexose-free medium. In glucose-free medium containing galactose, galatosaemic cells, in contrast to control cells, stopped growing after two days and died. In the same medium supplemented with inosine, they exhibited the same growth pattern as the control cell strains although in the presence of high concentrations of galactose-1-phosphate (Gal-1-P). These findings indicated that the glucose-free medium containing galactose supplemented with dialysed fetal calf serum and inosine, as a ribose donor, was appropriate for further in vitro investigations of galactose metabolism in galactosaemic cells.

Cell Division↗
PubMed1996

Three missense mutations in the galactose-1-phosphate uridyltransferase gene of three families with mild galactosaemia.

UNLABELLED: Classical galactosaemia caused by deficiency of galactose-1-phosphate uridyltransferase (GALT) is characterized by acute symptoms of hepatocellular dysfunction, sepsis, cataracts and failure to thrive. Galactose limitation reverses these complications immediately, however, most of these children have a long-term complication of verbal dyspraxia mental retardation and ovarian failure. The GALT gene was cloned and several mutations including the common Q188R have been reported. In this study the coding region of GALT was amplified by polymerase chain reaction from genomic DNA of classical galactosaemic individuals and characterized by direct sequencing of the products. Three missense mutations were identified in three patients with a mild galactosaemic variant: (1) replacement of threonine-138 by methionine (T138M); (2) replacement of arginine by tryptophan (R259W); and (3) replacement of threonine by alanine (T350A). All three galactosaemic individuals, one girl and two boys, have varying degrees of residual GALT activity in RBC and their galactose-1-phosphate levels decreased much faster than in other galactosaemic patients. These missense mutations occur in regions that are not highly conserved domains. CONCLUSION: The study of the molecular basis related to the phenotype variation may indeed help to prognosticate the outcome of patients with classical galactosaemia.

Amino Acid Sequence↗
PubMed1986

Oral intake of glucose plus galactose and erythrocyte galactose-1-phosphate. A nutritional evaluation of hydrolyzed lactose.

This study deals with the metabolic effects of hydrolyzed lactose: After an overnight fast 5 healthy adult volunteers consumed a glucose-galactose mixture equivalent to 61.4 g of lactose (or 125 g of a dried skim milk powder with hydrolyzed lactose). The postprandial rise of erythrocyte galactose-1-phosphate (gal-1-P) never exceeded 22.3 mumol per liter packed red blood cells. This amounts to no more than 22% of the levels known from galactosemic children to be safe, concerning ocular, neural or hepatic damage. We conclude that the consumption of the hydrolyzed lactose does not cause a risk for consumer's health as judged from this galactose metabolite. A considerably higher risk, however, may accompany the consumption of galactose alone which causes around 17-fold higher plasma galactose levels and around 8-fold higher erythrocyte gal-1-P concentrations for more extended time periods.

Adult↗
PubMed1993

Long-term outcome in 134 patients with galactosaemia.

In a retrospective study 134 galactosaemic patients, born between 1955 and 1989 in the Federal Republic of Germany were traced and their long-term outcome evaluated. We investigated 83 galactosaemic patients (78 homozygotes, 5 compound heterozygotes) by clinical, psychometric and laboratory testing; 31 patients were evaluated by medical history, the remaining 20 patients had died due to sequelae of the underlying disease. In 48 out of 78 classical galactosaemia patients galactose-free therapy had been started before the 15th day, in 19 between days 15 and 56 and in 11 patients after the 56th day. Physical findings revealed that puberty was delayed in 1 out of 18 males and 6 out of 11 females. Neurological abnormalities included ataxia (n = 6), intention tremor (n = 11) and microcephaly (n = 10). Speech abnormalities were found in 43 out of 66 patients over 3 years of age and disturbance of visual perception and/or arithmetic deficits in 29. Intelligence declined with age, i.e., a DQ or IQ less than 85 was found in 4 out of 34 patients less than 6 years of age (12%), in 10 out of 18 between 7 and 12 years (56%) and in 20 out of 24 older than 12 years (83%). Metabolite patterns (RBC galactose-1-phosphate and UDP-galactose, plasma and urinary galactitol) did not correlate with DQ or IQ. Dietary compliance was good in almost all patients. Compound heterozygotes (n = 5) had normal mental and growth development and all laboratory parameters were in the normal range.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1995

In vivo study of brain metabolism in galactosemia by 1H and 31P magnetic resonance spectroscopy.

In order to further evaluate different hypotheses concerning brain metabolism in galactosemia, six adult patients aged 18-29 years with classical galactosemia under dietary treatment underwent localized 1H and 31P magnetic resonance spectroscopy (MRS) in addition to conventional T1- and T2-weighted MRI. Galactose-1-phosphate levels in erythrocytes were 1.1-3.7 mg/dl, plasma concentrations of galactitol ranged from 8.4-14.2 mumol/l. Imaging revealed abnormal peripheral myelination in five and enlargement of lateral ventricles in two patients. Brain galactitol in parieto-occipital white matter was below detectability of 1H MRS leading to the assumption that brain concentrations of the free metabolite was well below 1 mmol/kg. Signal intensities of free myo-inositol, which was postulated to be indicative of changes in the second messenger pathway, were within the normal range. MRS data revealed a normal energy status of the brain. In summary 1H and 31P MRS indicated normal metabolite concentrations as compared to healthy controls.

Adolescent↗
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

Leguminosae in the diet: the raffinose-stachyose question.

Adhering to a galactose-free diet by strictly avoiding dairy products and known hidden sources of galac-tose does not completely normalize galactose-1-phosphate (gal-1-P) in erythrocytes from patients with galactosemia. Major neurological complications, even in the best treated patients, are threatening a good clinical outcome and dictate a continuous search for leaks in the dietary regimen. Raffinose and stachyose, present in important amounts in various vegetables, contain alpha-1,4 linked galactose which is cleaved only by bacterial alpha-galactosidases, presumably in the lower part of the gut. In order to test the hypothesis whether galactose released from raffinose and stachyose could be a source of absorbed galactose and a cause of elevated gal-1-P six patients with galactosemia (aged 6-24 years), underwent a raffinose- and stachyose-poor dietary regimen for 2 weeks. Before, after, and during the test period, the daily intake of stachyose and raffinose as well of protein, carbohydrate, fat and minerals was calculated from food protocols obtained from the patients. Plasma galactose and erythrocyte gal-1-P were measured at the end of the three test phases. Stachyose and raffinose intake was reduced to 5%-10% during the experimental diet, which was well tolerated, except for constipation in some patients. In five of the six patients gal-1-P in erythrocytes was somewhat lower (statistically not significant) during the test phase than during regular diet while plasma galactose remained unchanged. Galactose released from raffinose and stachyose may be absorbed and contribute to elevated gal-1-P values in erythrocytes of galactosemic patients.

Adult↗
PubMed1983

Further observations in a case of uridine diphosphate galactose-4-epimerase deficiency with a severe clinical presentation.

The red-cell concentrations of galactose-1-phosphate and uridine diphosphate galactose have been studied in relation to dietary galactose in a case of uridine diphosphate galactose-4-epimerase deficiency (McKusick 23035). Uridine diphosphate galactose accumulates rapidly in response to very small amounts of galactose but the concentration of galactose-1-phosphate increases proportionately to galactose intake. The significance of the observation is discussed with respect to the pathogenesis and treatment of the disease.

Biotransformation↗
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↗
PubMed2005

Galactosaemia: early treatment with an elemental formula.

Classical galactosaemia is caused by deficient galactose-1-phosphate uridyl transferase activity, and is treated by dietary galactose restriction. Despite dietary treatment, long-term outcomes have not been uniformly favourable. Late complications may include speech abnormalities, ataxia, cognitive impairment, growth delay, bone alterations and ovarian failure. We report an infant whose erythrocyte galactose 1-phosphate (gal-1-P) levels remained well above the treatment range on a low-galactose (soy) formula. Once she was begun on an elemental formula (galactose-free), gal-1-P levels decreased rapidly to within the treatment range. Urine galactitol levels decreased on the elemental formula but were within published treatment ranges despite treatment changes. These did not correlate with the gal-1-P levels. This case suggests further study be considered to determine whether a truly galactose-free diet in infancy could alter the long-term prognosis of classical galactosaemia.

Erythrocytes↗
PubMed2006

Pregnancy and lactation in a woman with classical galactosaemia heterozygous for p.Q188R and p.R333W.

A 31-year old patient who is compound heterozygous for the two galactose-1-phosphate uridyltransferase mutations p.Q188R and p.R333W delivered two healthy boys after uneventful spontaneous pregnancies. The patient chose to breast-feed her first baby and her galactose metabolites in blood and urine were monitored closely. A temporary increase in her galactose-1-phosphate (gal-1-P) levels with a maximum of 0.30 mmol/L on day 2 after delivery was observed. Galactose-1-phosphate was normalized 10 days after delivery. At the time of weaning, 8 months after delivery, her menses returned and she had normal sex steroid levels. She became pregnant again 2 months later. The second baby was also breast-fed. This time an increase in her gal-1-P values could be seen for 3 weeks with a maximum gal-1-P level of of 0.25 mmol/L at day 7. Only minor changes in her urine galactitol values were noted during the study period but the values stayed in the range of treated galactosaemia patients. We thus report that breast-feeding has been possible with only small adverse effects on the levels of galactose metabolites in a patient with classical galactosaemia.

Adult↗
PubMed2006

Two familial cases of high blood galactose of unknown aetiology.

We report two male siblings presenting as newborns with increased blood galactose, urinary excretion of galactitol, and normal galactose 1-phosphate on a breast milk diet. A lactose-free diet led to normalization of all metabolites, while reintroduction of galactose in the diet resulted in an accumulation of metabolites. Potential causes of galactosaemia include: (1) activities of three enzymes of galactose metabolism: galactokinase (GALK), galactose-1-phosphate uridyltransferase (GALT), and uridine diphosphate galactose 4'-epimerase (GALE), (2) portosystemic shunting, (3) Fanconi-Bickel syndrome, (4) tyrosinaemia. Each was excluded with appropriate tests. These two familial cases may represent a novel autosomal or X-linked recessive disorder of galactose metabolism, possibly due to a novel defect in the transport of galactose across the plasma membrane.

Carbohydrate Metabolism, Inborn Errors↗
PubMed2006

Carbohydrate ligands of human C-reactive protein: binding of neoglycoproteins containing galactose-6-phosphate and galactose-terminated disaccharide.

Binding of carbohydrate ligand by human C-reactive protein (CRP), in both native form and structurally deviated form (neoCRP or mCRP), was investigated using galactose-6-phosphate (Gal6P)- and Galbeta3GalNAc-containing bovine serum albumin (BSA) derivatives. To this end, we synthesized glycosides of Gal6P and Galbeta3GalNAc that can potentially generate a terminal aldehyde group. omega-Aldehydo glycosides were then conjugated to BSA via reductive amination. Using these neoglycoproteins, we showed that: (1) Gal6P-BSA and Galbeta3GalNAc-BSA bound to both forms of CRP, the former with or without calcium and the latter only in the absence of calcium; (2) phosphate-containing ligands can be bound with or without calcium, but the binding is much stronger in the presence of calcium than in the absence, underscoring the importance of direct coordination of phosphate to two calcium ions observed in the X-ray structure of phosphorylcholine (PC)-CRP complex; (3) cross-inhibition studies further corroborated the hypothesis that binding sites of PC and sugar are contiguous; (4) while PC-BSA bound to the native CRP over a wide pH range of 4.5 to 9, all the carbohydrate ligands and protamine-BSA (poly-cation-based ligand) exhibited optimal binding at around pH 6 to 6.5; and (5) ligand-binding conformation of mCRP appears to be more fragile than that of the native CRP in the acidic media (pH < 6).

Binding Sites↗
PubMed2005

Suckling rat brain regional distribution of Na+,K+-atpase activity in the in vitro galactosaemia: the effect of L-cysteine and glutathione.

Inhibition of Na+,K+-ATPase activity causes edema and cell death in central nervous system. We determined the in vitro effects of galactose-l-phosphate (Gal-1-P), galactitol (Galtol) and galactose (Gal) (mix A = classical galactosaemia) or Galtol and Gal (mix B = galactokinase deficiency galactosaemia), on Na+,K+-ATPase activity in suckling rat brain frontal cortex, hippocampus or hypothalamus homogenates. Gal-1-P or Galtol alone at different concentrations, significantly inhibited Na+,K+-ATPase whereas Gal activated the enzyme in all investigated brain regions. Both mix A and mix B inactivated the enzyme by 20-30% (p < 0.001) in all studied areas. L-Cysteine (Cys) and glutathione (GSH) supplementation in mix B not only reversed the enzyme inhibition but also resulted in an activation of 50-60%, (p < 0.001) in all brain areas. Their presence in mix A also activated the inhibited Na+,K+-ATPase in hippocampus and hypothalamus to a lower degree, whereas Cys reversed the frontal cortex enzyme activity to control value only. These findings indicate that oxidation of the enzyme critical groups may be involved in galactosaemia, producing inhibitory effect. This phenomenon is reversed by antioxidants Cys and GSH, implying that free radicals may be implicated in the observed enzyme inactivation.

Animals↗