The carbohydrate-deficient glycoprotein syndrome. A new inherited multisystemic disease with severe nervous system involvement.
Explore the source record for details and available documents.
Adolescent↗
Biomedical subjects
H Stibler
Publications and source records attributed to H Stibler.
Carbohydrate-deficient transferrin in serum: a new marker of potentially harmful alcohol consumption reviewed.
During the last 16 years an increasing number of studies have indicated a new diagnostic marker of alcohol abuse, unrelated to any of the conventional markers of alcoholism. This marker, now called carbohydrate-deficient transferrin, consists mainly of one or two isoforms of transferrin that are deficient in their terminal trisaccharides. Such isoforms have so far been detected by methods based on charge, i.e., isoelectric focusing, chromatofocusing, and anion-exchange chromatography of various designs combined with immunological detection techniques. This transferrin abnormality measures an accumulated effect of alcohol consumption, appearing after regular intake of 50-80 g of ethanol/day for at least one week and normalizing slowly during abstinence (half-life = about 15 days). To summarize all studies to date, approximately 2500 individuals have been examined, with a total clinical sensitivity of 82% and a specificity of 97%. False-positive results have only occasionally been reported: in a few patients with severe liver disease, usually primary biliary cirrhosis and chronic active hepatitis; in patients with genetic D variants of transferrin; and in patients with (and some carriers of) a recently identified inborn error of glycoprotein metabolism. The mechanism behind the transferrin abnormality is unknown but an acetaldehyde-mediated inhibition of glycosyl transfer has been suggested. Carbohydrate-deficient transferrin may thus offer a new possibility of diagnosing alcohol-related disorders. Its measurement is little affected by other conditions and, contrary to conventional markers of alcohol abuse, is apparently largely independent of concomitant liver disease.
Alcoholism↗
Glycoprotein glycosyltransferase activities in serum in alcohol-abusing patients and healthy controls.
The activities of glycoprotein sialyl-, galactosyl- and N-acetylglucosaminyl-transferase in serum were examined in 14 alcoholic patients with a median BAC of 65 mmol/l and in 14 healthy age- and sex-matched controls. The median alcohol intake of the patients was 250 g/day for 1-3 weeks. All had elevated levels of carbohydrate-deficient transferrin in serum and normal or near normal liver function tests. The activities of galactosyl- and N-acetylglucosaminyl-transferase at subsaturated substrate concentration were significantly reduced in the patients. Vmax for all three enzymes was 35-55% lower in the patients than in the controls. Ethanol up to 500 mmol/l had no effect on these enzymes in serum. Acetaldehyde up to 200 mumol/l produced a significant dose-dependent inhibition of all three glycosyltransferases ranging from 19 to 44% at 200 mumol/l. Pyridoxal-5'-phosphate had a similar inhibitory effect on all enzyme activities suggesting the presence of lysine in the substrate or acceptor sites, or in the glycoprotein acceptors. The latter finding provides a possible molecular basis for acetaldehyde to modify glycosyl transfer. The results indicate that in man, alcohol abuse is connected with reduced activities of several glycosyltransferases in serum, which may reflect an important mechanism behind the carbohydrate deficiencies in secretory as well as membrane-bound glyconjugates in alcoholic patients.
Acetaldehyde↗
A modified method for the assay of carbohydrate-deficient transferrin (CDT) in serum.
CDT has been shown to be a good marker of regular high alcohol intake. It has been measured principally by isoelectric focusing or pH-based anion exchange chromatography. The present assay was developed to improve the technical stability of the latter method. It is based on anion exchange of serum using ionic strength instead of pH followed by a transferrin in RIA of isotransferrins with pI > 5.7. Two hundred and fifty-one individuals were examined. With the exception of a new inborn error of glycoprotein metabolism, the sensitivity for alcohol abuse was 94% and the specificity was 98%. The values correlated with the total amount of alcohol recently consumed and normalized with a mean t1/2 of 15 days.
Adult↗
Carbohydrate deficient serum transferrin in a new systemic hereditary syndrome.
Four patients with a new, inherited, complex developmental deficiency syndrome were studied. The syndrome affects the central and peripheral nervous system, and also the retina, liver, bone, adipose tissue, and genital organs. Abnormalities of glycoproteins, glycopeptide hormones, and lipids have been found in serum from these patients, the most pronounced being increased cathodal forms of transferrin. Isoforms of serum transferrin were therefore analysed qualitatively and quantitatively by isoelectric focusing and isocratic anion exchange chromatography, and the carbohydrate composition was determined in transferrin isolated by immune affinity chromatography. All the patients had about tenfold raised serum concentrations of isotransferrins with higher isoelectric points than normal. Similar findings, though less pronounced, were made in all the fathers and in one of the mothers. Half the transferrin in the patients was constantly present in two principal abnormal cathodal forms in approximately equal amounts. Carbohydrate determinations in purified transferrin showed quantitatively similar deficiencies of sialic acid, galactose, and N-acetylglucosamine, the mannose content being normal. The results suggest that either two or all of the normally four terminal trisaccharides in transferrin may be missing. A defect in the synthesis or catabolism, or both, of this trisaccharide, which is common to many secretory glyco-conjugates, is likely. Apart from providing a quantitative diagnostic method, the present findings may serve as a basis for further studies of the metabolic deficiency in this syndrome.
Biomarkers↗
The physical state of the erythrocyte membrane in myotonic dystrophy.
The molecular pathology of myotonic dystrophy is believed to be expressed at the plasma membrane level. Previous assessments of membrane fluidity, a marker of the biochemical state of the membrane, have yielded conflicting results. In this study, erythrocyte membrane fluidity was reevaluated using highly sensitive fluorescence probe techniques. Steady-state anisotropy was measured with diphenylhexatriene (DPH), trimethylaminophenyl-hexatriene (TMA-DPH) and phenylhexatrienylphenylpropionic acid, probing different regions of the membrane. In the patients, significantly increased steady-state anisotropy was obtained with DPH, probing the hydrophobic core of the membrane, while slightly reduced anisotropy was found with TMA-DPH. The dynamic properties of the membrane lipids were further examined by means of time-resolved measurements with DPH. The excited state decay kinetics could best be described by a bi-exponential decay model. A large redistribution of the probe populations and a reduction of the average order parameter were found in the patients indicating a less ordered or more fluid lipid matrix. These perturbations might be induced by a protein abnormality and altered protein-lipid interaction within the erythrocyte membrane.
Adolescent↗
Transferrin microheterogeneity in rats treated chronically with ethanol.
The microheterogeneity of rat serum transferrin was analyzed by isoelectric focusing and immunofixation from Wistar rats chronically treated with ethanol either by inhalation (4 weeks) or by a liquid diet (6 weeks) and from pair-fed controls. In spite of the length of ethanol exposure, a daily ethanol intake of 13-18 g/kg b.wt. and BAC levels of 1.0-4.1 g/l, no transferrin abnormality similar to that found in human alcoholics was observed. It is apparent that these two common animal models for chronic high ethanol consumption are not suitable for experimental studies of ethanol-associated effects on transferrin.
Animals↗
Alcohol abuse increases the lipid structural order in human erythrocyte membranes. A steady-state and time-resolved anisotropy study.
The effect of ethanol abuse on the lipid ordering of the human erythrocyte membranes was studied by steady-state and time-resolved fluorescence anisotropy measurements of DPH and its polar analogue TMA-DPH, which probe different membrane regions. Steady-state anisotropy values with DPH as a probe were slightly but significantly increased (+3%) in erythrocyte membranes from alcoholic patients. A resistance to the ethanol fluidizing effect was evidenced in these membranes with DPH and TMA-DPH. No difference in the probe lifetimes was detected between the control and the alcoholic subjects. In the alcoholic patients as compared to the healthy controls, the residual anisotropy for DPH was significantly increased (+7%) corresponding to an increase in the orientational order parameter of 4%; a decrease of the apparent correlation time value was also observed. Nevertheless, no differences between the two erythrocyte populations were observed with TMA-DPH.
Adult↗
Transferrin phenotype and level of carbohydrate-deficient transferrin in healthy individuals.
Elevated concentrations of carbohydrate-deficient components of transferrin (CDT) in serum may be used as a sensitive and specific marker of regular, high alcohol consumption. When determined by a new, simplified assay, CDT values are nearly normally distributed in low- or non-alcohol-consuming control populations. The importance of transferrin phenotype for this normal variation was analyzed in 100 healthy, European men and women with no or negligible alcohol intake. No significant relation was found between phenotype and CDT value in this population. The three rare B-variants found had low CDT levels, and one subject, examined outside the study, with a rare D-variant indicated that D-variants may result in false-positive CDT values. Moreover, women tended to have somewhat higher values than men, in whom CDT levels were weakly correlated with age. Other as yet undefined biological factors are clearly responsible for the major part of the normal variation of CDT values in nonalcoholic individuals.
Adolescent↗
Sialyltransferase activity in erythrocyte membranes and serum in patients with myotonic dystrophy.
Sialyltransferase activity was measured in erythrocyte membranes and in serum in patients with myotonic dystrophy and in matched healthy controls. The reason for assaying this enzyme was to study a possible mechanism behind a previously reported deficiency of glycoprotein-bound sialic acid in the erythrocyte membrane in patients with this disease. No significant differences in sialyltransferase activity with endogenous or different exogenous glycoprotein acceptors were found.
Adolescent↗
An apparent homozygous X-linked disorder with carbohydrate-deficient serum glycoproteins.
Explore the source record for details and available documents.
Carbohydrates↗
Carbohydrate-deficient transferrin in serum in patients with liver diseases.
Carbohydrate-deficient transferrin (CDT) in serum was analyzed by isocratic microanion exchange chromatography at pH 5.65 followed by a transferrin radioimmunoassay in 102 patients with biopsy-verified liver diseases. CDT values were normal in all of the 87 nonalcohol-abusing patients irrespective of type or degree of liver disease. Thirteen of the 15 alcoholic patients (87%) with current abuse showed elevated CDT values while in abstaining alcoholics with remaining liver disease the values were normal. No correlations were found between CDT level and volume density of liver fibrosis or steatosis or values of a number of clinicochemical liver tests. The only significant correlation demonstrated was between CDT concentration and the level of present daily alcohol consumption in the alcoholic patients. These results indicate that CDT can be used as a marker of present but not previous alcohol abuse, even in patients with various liver diseases.
Adolescent↗
Alterations of erythrocyte membrane organization in alcoholics.
Studies of fluorescence polarization of DPH have shown that erythrocyte membrane "fluidity" and fluidization by ethanol are significantly reduced in alcoholics. By using probes of the polar part of the membrane, ANS and TMA-DPH, in addition to DPH, it was shown in the present study that disturbances also exist in the polar region of the membrane which probably are related to changes in surface glycoconjugates. Furthermore, the acute fluidizing effect of ethanol was correlated with the capacity of the membrane to bind ethanol, which in turn appeared to be linked to the glycans. Chronic ethanol abuse thus causes complex disturbances of membrane organization at different levels of the membrane.
Adult↗
Glycoprotein sialyl- and galactosyl transferase activities in erythrocyte membranes in alcoholic patients and healthy controls.
In investigating possible mechanisms underlying carbohydrate deficiencies in serum transferrin and erythrocyte membranes in alcoholics, a total of 27 alcoholic patients and 27 healthy controls were examined for the activities of sialytransferase in serum and erythrocyte membranes and galactosyltransferase in erythrocyte membranes. The enzymes were assayed with endogenous and different exogenous glycoprotein acceptors and with [14C] CMP-sialic acid and [14C] UDP-galactose as substrates. No decrease in enzyme activities were found in alcoholic patients compared to controls, indicating that chronic ethanol abuse does not exert any direct inhibitory effect on these glycosyltransferases in isolated erythrocyte membranes or on sialytransferase in serum. Further studies of the effect of ethanol on the metabolism of complex carbohydrates are clearly necessary.
Adult↗
Micro anion exchange chromatography of carbohydrate-deficient transferrin in serum in relation to alcohol consumption (Swedish Patent 8400587-5).
A new simplified and rapid method for detection and quantitation of "carbohydrate-deficient transferrin" in serum is described. The method is based on isocratic anion exchange chromatography of isotransferrins in disposable microcolumns followed by a double antibody transferrin radioimmune assay. This technique, which separates all transferrin components isoelectric above pH 5.65, showed a very good reproducibility and accuracy with a coefficient of variation between 5 and 9%. 77 alcoholic patients could be clearly separated from 80 healthy "normal consumers" and 33 total abstainers with a specificity of 100% and a sensitivity of 91%. The values were significantly correlated to the amount of alcohol consumed during the latest month, and declined in abstaining alcoholics with a mean biological half-life of 17 days. Elevated levels occasionally appeared in healthy individuals after daily consumption of 60 g of ethanol during a 10-day period. In a sample of 187 patients with nonalcohol-related conditions only 2% false-positive values were found. This method is suggested as a potential tool for detecting and monitoring alcohol abuse.
Adolescent↗
Abnormal erythrocyte survival in patients with myotonic dystrophy.
In four of six patients with myotonic dystrophy whom we studied 51Cr labeled erythrocytes were found to have a biphasic survival kinetic. After in initial significantly more rapid disappearance than in controls, about 80% of the labeled cells reappeared in circulation, and were thereafter eliminated at a significantly faster rate than normal. This type of biphasic survival pattern may partly be related to reduced sialic acid concentration of the erythrocyte membrane in patients with this disease.
Erythrocyte Aging↗
The effects of ethanol exposure during the brain growth spurt in rats.
The purpose of this study was to determine whether micromorphological changes occur at a low level of ethanol exposure previously shown by us to induce alterations in synaptosomal biochemistry. The results suggest that 4 g ethanol per kg body weight daily throughout the brain growth spurt causes no significant structural changes in the cerebellum, lobule IX, at the light and electron microscopic levels. Although ethanol- and isocaloric sucrose-treated groups did not differ from each other in cumulative percent body weight gain throughout the treatment period, both groups differed significantly in this parameter from isocaloric milk-treated and "handled" control groups. On the day following completion of the treatment period, brain weight in the ethanol-treated group was significantly less than that of all other groups. Further, the results indicate that isocaloric sucrose "pair feeding" is contraindicated in postnatal studies and that nutritional status is better controlled by daily gavage of neonates than by other methods currently used in ethanol studies in postnatal animals.
Animals↗
Carbohydrate composition of erythrocyte membranes and glycosidase activities in serum in patients with myotonic dystrophy, limb-girdle dystrophy and congenital myotonia.
A number of abnormalities in cell membrane function, including cells other than muscle cells, have been described in patients with inherited muscular diseases such as myotonic dystrophy and congenital myotonia. The basic molecular defects are, however, still unknown. The complex carbohydrates of membrane-bound glycoconjugates are of vital importance for the normal performance of the cell membrane. In this study the concentrations of the three major carbohydrates (sialic acid, galactose and hexosamines) of the erythrocyte membrane were therefore determined in patients with myotonic dystrophy, limb-girdle dystrophy and congenital myotonia. The activities of relevant glycosidases in serum were also assayed. In each of the three diseases pertinent changes of the carbohydrate pattern were found. In patients with myotonic dystrophy the sialic acid and in patients with limb-girdle dystrophy the hexosamine concentration was significantly reduced (P less than 0.0005). The sialic acid, galactose and hexosamine concentrations were all significantly increased in patients with congenital myotonia. No increase of the neuraminidase (sialidase) activity was found in sera from patients with myotonic dystrophy. In patients with limb-girdle dystrophy, the activities of serum hexosaminidases were normal. These results support the contention that certain inherited muscular diseases may represent generalized membrane disorders, and suggests that disturbances of membrane-bound glycoproteins and/or glycolipids might be of importance in the pathogenesis of some of these disorders.
Acetylglucosaminidase↗