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PubMed1997

Altered follicle stimulating hormone isoforms in female galactosaemia patients.

UNLABELLED: Many women affected with galactosaemia suffer from ovarian dysfunction and have elevated serum levels of follicle stimulating hormone (FSH). We have analysed FSH-glycoprotein isoforms from four galactosaemic and five healthy women. Besides the commonly found FSH species with a median isoelectric point (pI) of 4-5, the sera of the female galactosaemic patients contained qualitatively abnormal FSH isoforms with a pI close to neutral (6.4-7.0). The generally reduced galactosylation in patient samples was confirmed because sera of galactosaemic patients could incorporate 1.7 times more UDP-(14C)galactose than did healthy subjects. CONCLUSION: Our data indicate that the terminal disaccharides of FSH (a glycoprotein), galactose and sialic acid were partially deficient in three galactosaemic female patients with no galactose-1-phosphate uridyl transferase (GALT) activity in red cells. However, from a female patient with a residual GALT activity (a mild form of galactosaemia), no distinctive deficiency was observed. This again suggest an importance of GALT in retaining a correct FSH structure. Therefore the abundance of neutral FSH isoforms, which was described to have a higher binding affinity to its receptor and no capacity to activate cyclic adenosine mono-phosphate (cAMP), may cause a hormonal dysfunction in classical galactosaemia.

Adolescent↗
PubMed1997

Elevated plasma bile acids in hypergalactosaemic neonates: a diagnostic clue to portosystemic shunts.

UNLABELLED: To determine whether plasma levels of total bile acids may provide a useful index for hypergalactosaemia due to porto-systemic shunts, these levels were determined in hypergalactosaemic neonates. Increased levels were found in all cases with portohepatic venous or portocaval shunts. The levels of both total bile acids and galactose were normalized when the shunts disappeared on the echograms. Both bile acids and galactose are almost completely absorbed by the liver via the first portal blood passage. Portosystemic shunts contribute to elevated levels of bile acids and galactose. CONCLUSION: Increased plasma levels of total bile acids serve as a diagnostic clue to the presence of portosystemic shunts in neonates with hypergalactosaemia.

Arteriovenous Malformations↗
PubMed1997

Hypergalactosaemia in a newborn: self-limiting intrahepatic portosystemic venous shunt.

UNLABELLED: Hypergalactosaemia was found in 4 day-old boy during newborn screening. He had no enzyme deficiency but an intrahepatic vascular malformation permitting significant portosystemic venous shunting. The shunt caused hyperammonaemia, accentuated after meals, alimentary hyperglycaemia and hypergalactosaemia, and excess excretion of lactic, 3-hydroxy butyric and other organic acids in urine. Portal venous flow was unimpaired. The vascular anomaly regressed during the first 7 months of life. At this age, full tolerance to lactose-containing cows milk formula was evidenced by the normalization of pre- and postprandial blood glucose, ammonia and galactose, and closure of the shunt was confirmed by ultrasonography. This is one of the few observations of congenital intrahepatic venous shunt regressing spontaneously during infancy. CONCLUSION: A congenital intrahepatic portosystemic venous shunt can cause hypergalactosaemia in the newborn and hyperammonaemia in the small infant. The malformation may resolve spontaneously obviating the need for intervention.

Arteriovenous Malformations↗
PubMed1998

Decreases in Raf-1 levels in galactosaemic lens epithelial cells are partially reversed by myo-inositol.

Changes in the amounts and localization of protein kinase C (PKC) isoforms occur in galactosaemic lens epithelial cells. A link between PKC changes and myo-inositol depletion has been suggested. Raf-1, a component of a Ras pathway, is a substrate for PKC. Raf-1 levels were measured in galactosaemic lens epithelial cells grown with or without myo-inositol. Raf-1 levels were measured by densitometric scanning of Western blots from cells grown with or without 40 mmol/l galactose or 40 mmol/l galactose plus 1.0 micromol/l myo-inositol for 1, 3, 5 or 7 days. Scans were compared to those for PKCalpha, an isoform of PKC and to 14-3-3, a protein which binds to Raf-1. Cell growth was quantitated by thymidine incorporation. Raf-1 levels were decreased in bovine lens epithelial cells after 3, 5 or 7 days (33% of control) of growth in 40 mmol/l galactose. Addition of 1 micromol/l myo-inositol reversed this decrease at day 3, but not after 5 or 7 days of growth in 40 mmol/l galactose. PKCalpha and 14-3-3 levels were not affected by galactose. The decrease in Raf-1 was not a result of cell growth as measured by thymidine incorporation. These results suggest that Raf-1 levels are decreased during galactosaemia. This was only partially reversed by the addition of myoinositol.

Animals↗
PubMed1999

Molecular characterization of galactokinase deficiency in Japanese patients.

Galactokinase (GALK) deficiency is an autosomal recessive disorder, which causes cataract formation in children not maintained on a lactose-free diet. We characterized the human GALK gene by screening a Japanese genomic DNA phage library, and found that several nucleotides in the 5'-untranslated region and introns 1,2, and 5 in our GALK genomic analysis differed from published data. A 20-bp tandem repeat was found in three places in intron 5, which were considered insertion sequences. We identified five novel mutations in seven unrelated Japanese patients with GALK deficiency. There were three missense mutations and two deletions. All three missense mutations (R256W, T344M, and G349S) occurred at CpG dinucleotides, and the T344M and G349S mutations occurred in the conserved region. The three missense mutations led to a drastic reduction in GALK activity when individual mutant cDNAs were expressed in a mammalian cell system. These findings indicated that these missense mutations caused GALK deficiency. The two deletions, of 410delG and 509-510delGT, occurred at the nucleotide repeats GGGGGG and GTGTGT, respectively, and resulted in in-frame nonsense codons at amino acids 163 and 201. These mutations arose by slipped strand mispairing. All five mutations occurred at hot spots in the CpG dinucleotide for missense mutations and in short direct repeats for deletions. These five mutations in Japanese have not yet been identified in Caucasians. We speculate that the origin of GALK mutations in Japanese is different from that in Caucasians.

Adolescent↗
PubMed2005

Social outcome in treated individuals with inherited metabolic disorders: UK study.

Few data exist on the long-term social outcome of patients with inherited metabolic disorders, despite the fact that increasing numbers are surviving into adulthood. Here we report the findings of 329 patients aged from 11 to 70 years, of whom 172 had phenylketonuria, 38 had homocystinuria and 33 had galactosaemia. Twenty-eight per cent had no formal education qualifications, 59% were employed, but only 17% were in professional jobs (social classes I and II). The time of diagnosis and treatment had a significant impact on outcome in phenylketonuria, as did pyridoxine responsiveness or lack of it in homocystinuria. Effects on outcome in galactosaemia were not clear. Social integration is an important outcome of treatment of chronic disorders in childhood and warrants further study in this growing patient population.

Adolescent↗
PubMed2005

Body composition in children with galactosaemia.

Body composition in classical galactosaemia has not been studied. Patients with classical galactosaemia, an inherited disorder of galactose metabolism caused by deficiency of galactose-1-phosphate uridyltransferase (GALT, EC 2.7.7.10), might be at risk for an abnormal body composition because of intrinsic factors related to galactosaemia and/or diet-related factors. The aim of this study was to evaluate the body composition of children with classical galactosaemia. The studied population was a previously reported group of classical galactosaemia patients (13 male and 27 female, ages 3-17 years) with decreased height, weight, weight-for-height and insulin-like growth factor-I (IGF-I) Z-scores. Body composition data were obtained by dual-energy X-ray absorptiometry (DXA). In order to correct for height, fat mass (FM) and lean tissue mass (LTM) were divided by squared height. Mid-parental target height Z-scores were assessed and compared to actual height Z-scores. Linear and multiple regression analysis were done to investigate the relationship between body composition and IGF-I, dietary intake and growth data. We found decreased height Z-scores when compared to mid-parental target height Z-scores. Mean scores for FM and LTM (both adjusted for height) were decreased. LTM (adjusted for height) and height Z-score were correlated with IGF-I Z-score. FM (adjusted for height) was correlated with soy intake. No correlation was found between soy intake and IGF-I Z-score. In this limited group of patients, height is decreased and body composition is abnormal. The decreased levels of IGF-I and/or soy nutrition might play a role in these findings.

Absorptiometry, Photon↗
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

Mutational spectrum of classical galactosaemia in Spain and Portugal.

Classical galactosaemia is an autosomal recessive inherited metabolic disorder due to deficient galactose-1-phosphate uridyltransferase (GALT). Over 180 different base changes and disease-causing mutations have been reported in the GALT gene. Mutation p.Q188R was found to be the most common molecular defect among caucasian classical galactosaemia patients. We have characterized the spectrum of GALT mutations in a group of 51 Spanish families and 32 Portuguese families with this disease. p.Q188R is also the most prevalent mutation in the Spanish and Portuguese population, accounting for 50% and 57.8% of galactosaemic alleles, respectively. An additional 15 mutations were also identified in Spanish patients, four of which were novel: p.D28H, p.S181A, c.658dupG and c.377+53_1059+87del. In the Portuguese population, 11 different mutations were found, three of which were novel: p.R33H, p.P185S, and p.S192G. The differences observed between the genotypes identified in Portuguese and Spanish galactosaemic populations are notable. Only mutations p.Q188R, p.R148Q and c.820+13g>a were identified in both populations. In spite of the geographical proximity of Spain and Portugal, it seems that they have received genetic influences from different populations. The repeated migrations that occurred in the Iberian Peninsula throughout centuries may explain such variability.

Alleles↗
PubMed2006

Classical galactosaemia revisited.

Classical galactosaemia (McKusick 230400) is an: autosomal recessive disorder of galactose metabolism, caused by a deficiency of the enzyme galactose-1-phosphate uridyltransferase (GALT; EC 2.7.712). Most patients present in the neonatal period, after ingestion of galactose, with jaundice, hepatosplenomegaly, hepatocellular insufficiency, food intolerance, hypoglycaemia, renal tubular dysfunction, muscle hypotonia, sepsis and cataract. The gold standard for diagnosis of classical galactosaemia is measurement of GALT activity in erythrocytes. Gas-chromatographic determination of urinary sugars and sugar alcohols demonstrates elevated concentrations of galactose and galactitol. The only therapy for patients with classical galactosaemia is a galactose-restricted diet, and initially all galactose must be removed from the diet as soon as the diagnosis is suspected. After the neonatal period, a lactose-free diet is advised in most countries, without restriction of galactose-containing fruit and vegetables. In spite of the strict diet, long-term complications such as retarded mental development, verbal dyspraxia, motor abnormalities and hypergonadotrophic hypogonadism are frequently seen in patients with classical galactosaemia. It has been suggested that these complications may result from endogenous galactose synthesis or from abnormal galactosylation. Novel therapeutic strategies, aiming at the prevention of galactose 1-phosphate production, should be developed. In the meantime, the follow-up protocol for patients with GALT deficiency should focus on early detection, evaluation and, if possible, early intervention in problems of motor, speech and cognitive development.

Bone Density↗
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↗
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↗
PubMed2005

Suckling rat brain regional distribution of acetylcholinesterase activity in galactosaemia in vitro.

We aimed to evaluate the effect of in vitro galactosaemia on acetylcholinesterase (AChE) activity in different suckling rat brain regions. Various concentrations of galactose (Gal), galactose-1-phosphate (Gal-1-P) and/or galactitol (Galtol) were preincubated for 1 h with homogenates from frontal cortex, hippocampus and for 1-3 h with hypothalamus homogenates at 37( composite function)C. AChE activity was determined spectrophotometrically. Mixture A (Gal-1-P (2 mM), Galtol (2 mM), and Gal (4 mM) (=brain concentrations in classical galactosaemia)) or mixture B (Galtol (2 mM) and Gal (1 mM) (=brain concentrations in galactokinase deficiency galactosaemia)) inhibited by 18-20% (P < 0.01) AChE activity in frontal cortex or hippocampus homogenates. Gal-1-P (2-8 mM) reduced AChE activity by 20% (P < 0.01) on frontal cortex and hippocampus homogenates. Galtol (2-8 mM) resulted in an AChE inhibition (20-22% (P < 0.01)) in hippocampus, 2 mM of the substance had the same effect (20%, P < 0.01) on frontal cortex, whereas higher concentrations (4-8 mM) failed to decrease the enzyme activity anymore. Gal (1-8 mM) did not change AChE activity in the studied areas. Additionally, the hypothalamus enzyme activity was measured considerably high and remained unaltered in the presence of the above compounds. In conclusion, AChE activity was significantly higher in hypothalamus compared with those in frontal cortex and hippocampus. Frontal cortex and hippocampus AChE was significantly inhibited by Gal derivatives, whereas hypothalamus AChE activity remained unaltered possibly due to the histologically different innervation of this area.

Acetylcholinesterase↗