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Biomedical subjects

S W Eber

Publications and source records attributed to S W Eber.

At least 37 records · Page 2Linked to original sources
PubMed1991

Triosephosphate isomerase deficiency: haemolytic anaemia, myopathy with altered mitochondria and mental retardation due to a new variant with accelerated enzyme catabolism and diminished specific activity.

A new triosephosphate isomerase (TPI) variant is described in an 8-year-old Turkish girl suffering from chronic haemolytic anaemia, myopathy and developmental retardation since early infancy. The enzyme activity profile revealed a generalized deficiency in erythrocytes, granulocytes, mononuclear blood cells, skeletal muscle tissue and cerebrospinal fluid. The concentration of enzyme substrate dihydroxyacetone phosphate was distinctly elevated. Biochemical examination showed accelerated enzyme deamidation, the first step in the normal catabolism of TPI during aging of the erythrocyte. The specific activity of the variant TPI, determined by antibody titration, was reduced to 61% of normal. Its heat stability was markedly decreased. Muscle biopsy and neuropsychological testing further clarified the pathogenesis of the disorder. A prevalent alteration of mitochondria similar to that seen in mitochondrial myopathy and an elevated amount of intracellular glycogen were found. The patient's retarded intellectual development was mainly due to impaired visual perception and sensory-motor co-ordination in addition to a lack of syllogistic reasoning. The findings indicate that the low TPI activity leads to a metabolic block of the glycolytic pathway and hence to a generalized impairment of cellular energy supply.

Anemia, Hemolytic↗
PubMed1991

Saethre-Chotzen syndrome (ACS III) in four generations.

The acrocephalosyndactylies (ACS) are a group of inherited disorders characterized by premature fusion of cranial sutures in association with abnormalities of the hands and feet. Based on their clinical features, different types of ACS have been described. We here report on a family with 9 individuals affected with ACS III (Saethre-Chotzen syndrome), 5 of them severely. Clinical features of the patients are presented with regard to differential diagnostic delineations.

Acrocephalosyndactylia↗
PubMed1990

Myopathy with altered mitochondria due to a triosephosphate isomerase (TPI) deficiency.

Morphological changes are shown in the muscle biopsy specimens of an 8-year-old girl who suffered from a triosephosphate isomerase (TPI) deficiency, resulting in a chronic, nonspherocytic, hemolytic anemia, mental retardation and neuromuscular impairment. The newly introduced enzyme histochemical reaction for TPI demonstrated a total lack of histochemically detectable enzyme activity, whereas biochemical analysis of muscle tissue revealed less than 10% of the normal enzyme activity. Electron microscopy showed a degenerative myopathy with an increase in the amount of intracellular glycogen. Additionally, mitochondrial changes within the muscle fibers were observed to be similar to those in mitochondrial myopathies. The disturbed balance between glycerin-aldehyde phosphate and dihydroxyacetone phosphate, due to the deficiency of the TPI enzyme, is interpreted as the biochemical background of an impaired electron transport across the mitochondrial membrane, resulting in the coexistence of an impaired glycolytic pathway and an impaired mitochondrial metabolism of muscle cells.

Carbohydrate Epimerases↗
PubMed1990

Variable clinical severity of hereditary spherocytosis: relation to erythrocytic spectrin concentration, osmotic fragility, and autohemolysis.

To determine whether stratifying hereditary spherocytosis by degree of severity could provide guidelines regarding which patients would benefit from splenectomy, we evaluated the clinical characteristics of 80 patients (63 children) and 27 healthy relatives. In addition to routine hematologic determinations, osmotic fragility, autohemolysis, erythrocyte spectrin content, and erythrocyte membrane lipid phosphorus were measured and correlated with the disease severity. Four categories were identified: (1) spherocytosis as a trait in symptom-free relatives of patients with recessively inherited disease; (2) mild and (3) moderate spherocytosis, largely observed in patients with dominantly inherited disease; and (4) severe spherocytosis, observed in only two patients, who were characterized by recessive inheritance and transfusion dependence. By the identification of carriers, a recessive mode of inheritance could be demonstrated in 20% of the families with spherocytosis. The erythrocyte spectrin concentration was normal in carriers and patients with mild spherocytosis, and was significantly reduced in the moderate and severe states of the disease. This difference was not accounted for by reduced membrane area of the cells, as measured by the phospholipid concentration per cell. We conclude that patients with mild spherocytosis usually do not require splenectomy during childhood and adolescence; patients with moderate or severe disease should have splenectomy. Patients with severe spherocytosis have a partial response to splenectomy but a considerable degree of increased hemolysis persists. Most patients with less than 80% of normal spectrin content require splenectomy.

Adolescent↗
PubMed1990

Combination of congenital nonspherocytic haemolytic anaemia and impairment of granulocyte function in severe glucosephosphate isomerase deficiency. A new variant enzyme designated GPI Calden.

In two siblings, children of non-consanguineous parents, glucosephosphate isomerase (GPI) deficiency was found to be the cause of recurrent haemolytic crises. Characterization of the variant enzyme found in both individuals revealed low specific activity in erythrocytes and leucocytes, increased electrophoretic mobility and pronounced thermolability. Evaluation of the electrophoretic data allows the conclusions that these siblings are compound heterozygous carriers of GPI deficiency. The new variant was designated GPI Calden. Further investigations revealed that isolated granulocytes of both siblings show marked reduction of bactericidal activity and decreased production of superoxide anion. With rare exceptions, deficiency of this enzyme was supposed to cause congenital nonspherocytic haemolytic anaemia only. Here we report on two siblings presenting with the characteristic haemolytic anaemia and a significant decrease in granulocyte function, both presumably as the result of GPI deficiency. Our data indicate that impairment of granulocyte function might be a more general feature of severe GPI deficiency than formerly noted.

Anemia, Hemolytic, Congenital↗
PubMed1989

Structural basis for the high activation energy of spectrin self-association.

The association of spectrin hetero-dimer (alpha beta) to the tetramer (alpha 2 beta 2, which predominates in the cell) is marked by an exceptionally high activation energy, so that the reaction does not proceed measurably in the cold. We have tested the hypothesis that this is due to intra-dimer association between the alpha- and beta-chain ends, which must be broken before tetramers can form. Two mutant univalent spectrins with association defects at the alpha and beta ends, respectively, and incapable therefore of intra-dimer bonding, were found to associate rapidly with one another at 4 degrees C. The bimolecular rate constant is greater than for the association of normal dimers by 6 orders of magnitude.

Elliptocytosis, Hereditary↗
PubMed1989

G6PD Avenches and G6PD Moosburg: biochemical and erythrocyte membrane characterization.

Two new G6PD variants with severe enzyme deficiency in Switzerland (G6PD Avenches, G6PD I) and in Germany (G6PD Moosburg, G6PD II) are described. One patient had suffered from severe postpartal hyperbilirubinemia, the other one presented with chronic hemolysis and remittent hyperbilirubinemia. Both variants showed diminished electrophoretic mobility, both variants were heat labile. The Michaelis-Menten constants KM for glucose-6-phosphate and for NADP+ were normal. 2-Desoxy-glucose-6-phosphate was utilized by G6PD I in a higher and by G6PD II at a lower rate than by the normal enzyme. Desamino-NADP+ and galactose-6-phosphate were utilized by both variants at a normal rate. The electrophoretic separation of membrane proteins of G6PD II showed both in the presence and in the absence of 6-mercaptoethanol no difference concerning the formation of membrane protein aggregates between patient and normal control.

Adolescent↗
PubMed1989

Hereditary stomatocytosis: consistent association with an integral membrane protein deficiency.

We studied the RBC membrane proteins of four patients, including a mother and daughter, with hereditary stomatocytosis. One- and two-dimensional gel electrophoresis revealed that a 28 kDa integral protein, present in normal RBC membranes, was absent in all four patients. This abnormality, reported once previously (Lande et al, 1982), appears to be a characteristic feature of hereditary stomatocytosis, and may be related to the underlying permeability defect in this disorder.

Adult↗
PubMed1989

[Molecular pathology of the erythrocyte membrane. Erythrocyte membrane defects as a cause of congenital hemolytic anemia].

Recently numerous defects of erythrocyte membrane proteins have been described in hereditary hemolytic anemias. An exact biochemical characterization of some different types of hereditary spherocytosis, hereditary elliptocytosis, hereditary pyropoikilocytosis and the hemolytic anemias with increased cation permeability (hereditary stomatocytosis) is possible after analysis of membrane proteins with SDS-polyacrylamide gel electrophoresis, quantitative determination of spectrin, the relation of dimeric to tetrameric spectrin, and partial tryptic digestion of the spectrins. The known clinical heterogeneity of the mentioned disorders is now partially explained by the different biochemical defects of the erythrocyte membrane. In classical hereditary spherocytosis a close relationship between erythrocyte spectrin content and clinical severity has been found. The clinical manifestation in hereditary elliptocytosis and hereditary pyropoikilocytosis mainly depends on the functional disturbance of variant spectrins, especially their ability to form tetramers, i.e. their ability for self-association of the spectrin chains. In the hydrocytic form of stomatocytosis a deficiency of the integral protein band 7.2b has been documented. Besides the analysis of erythrocyte membrane proteins the classical methods used in the study of congenital hemolytic anemias cannot be missed. Signs of increased hemolysis, erythrocyte morphology, osmotic fragility, autohemolysis, heat and mechanical stability of the erythrocyte membrane, intracellular cation concentration and studies of other family members, are indispensable prerequisites for classification, prognosis, and indication of therapeutic efforts, especially splenectomy.

Anemia, Hemolytic, Congenital↗
PubMed1988

Glucuronyl transferase deficiency and mild hereditary spherocytosis: effect of splenectomy.

In a 6-year-old girl an association of hereditary spherocytosis and a defect in hepatic bilirubin metabolism has been found. The patient suffered from mild compensated haemolytic anaemia and excessive hyperbilirubinaemia (maximum concentration 581 mumol/l), the serum activity of liver enzymes was slightly increased. Examination of the erythrocyte membrane proteins revealed a deficiency of the major membrane skeletal protein, spectrin (about 75% of normal) which is probably the basic genetic defect of hereditary spherocytosis. Examination of the patient's family revealed a recessive mode of inheritance. The concentration of bilirubin conjugates in the patient's serum was decreased due to a reduced UDP-glucuronyl transferase activity found in homogenates of liver tissue. Histological liver examination showed an intrahepatic cholestasis, which is a secondary and reversible alteration resulting from severe hyperbilirubinaemia. After splenectomy, normalization of the increased haemolysis and hepatic dysfunction was observed. The excessive hyperbilirubinaemia can be explained by the association of an increased bilirubin load due to haemolytic anaemia and the diminished hepatic conjugation of bilirubin.

Anemia, Hemolytic↗
PubMed1988

Interactions of spectrin in hereditary elliptocytes containing truncated spectrin beta-chains.

An abnormal spectrin, in which one subunit is truncated, has been detected in a large German family. The inheritance is autosomal dominant. The affected members of the family suffer in widely varying degree from a microcytic hemolytic anemia. The red cell morphology varies correspondingly from smooth elliptocytes to predominantly poikilocytes. The abnormal spectrin makes up approximately 30% of the total and is almost entirely present as the dimer. The truncated chain is not phosphorylated by the endogenous cAMP-independent kinase, and it has been identified as a chain of beta-type, using monoclonal antibodies. Because a univalent terminal spectrin alpha-chain fragment will bind to normal dimers with an association constant lower by only a factor of two than that for the self-association of the dimers, it would be expected that the mutant dimers (alpha beta') would readily enter into an association with normal (alpha beta) dimers to give alpha 2 beta beta' tetramers (though not with each other). In dilute solution this is indeed observed, and the diminution in tetramer concentration when 30% of normal spectrin is replaced by alpha beta' dimers, amounts to only a small proportion. Moreover, in the membrane skeleton, if there is pairwise apposition of dimer units, only 9% of pairings will be between units that cannot associate. We have shown that the failure of alpha beta' dimers to enter into heterologous associations in situ is not due to the elimination of the ankyrin binding site near the truncated end of the beta-chain: this site is fully functional, as judged by rebinding to spectrin-depleted vesicles. When the spectrin is extracted from the membrane in the cold, the material released initially consists almost entirely of alpha beta' dimers; when the spectrin of normal membranes is partly dissociated to dimers in situ by warming at low ionic strength, extraction in the cold then leads similarly to much more rapid release of the dimer than of the tetramer. The similar rates of liberation of normal and abnormal dimer make it unlikely that the interaction of the latter with the membrane is in any way defective. When mixtures of alpha beta and alpha beta' dimers are bound to spectrin-depleted inside-out membrane vesicles from normal cells and tetramers are allowed to form by equilibration at 30 degrees C, the proportion of the abnormal species appearing in the tetramer is much lower than would be expected on a statistical basis. The relation of the self-association equilibrium on the membrane to that of spectrin in dilute solution is analyzed.

Elliptocytosis, Hereditary↗
PubMed1988

[Aplastic crises in hereditary spherocytosis].

Parvovirus B19-infections are diagnosed with increasing frequency. In addition to erythema infectiosum they cause a temporary red cell aplasia of 5-10 days duration, in patients with hemolytic anemia an aplastic crisis as demonstrated in 5 patients with hereditary spherocytosis. In every case an acute infection by parvovirus B19 could be diagnosed. Hemoglobin concentrations dropped to 4.0-6.2 g/dl, reticulocytes were diminished to 0-25,000/microliters. In every case there followed a complete recovery of erythropoiesis after 2-3 days.

Acute Disease↗
PubMed1987

Neuropathology of Seckel syndrome in fetal stage with evidence of intrauterine developmental retardation.

Marked intrauterine developmental retardation in a fetal case of Seckel syndrome was morphologically defined in the 29th week of gestation by comparing with a large number of length-matched and age-matched controls. Telencephalic micrencephaly with reduced neuroblast production, retarded functional differentiation of the pituitary gland, and generalized hypotrophy with craniofacial stigmata were observed.

Abnormalities, Multiple↗
PubMed1986

Clinical symptoms and biochemical properties of three new glucosephosphate isomerase variants.

Glucosephosphate isomerase deficiency as the cause of macrocytic congenital nonspherocytic hemolytic anemia is described in three unrelated families. The biochemical properties of the variant glucosephosphate isomerases indicate that the patients have new variants, designated as GPI Kiel, GPI Hamburg, and GPI Homburg. The severity of the clinical symptoms depended on the amount of residual GPI activity and the biochemical properties of the variant enzyme. Thus the patient with GPI Kiel (34% residual activity) whose variant GPI was slightly unstable showed a mild chronic hemolytic anemia. The patient with GPI Homburg (7% residual activity) whose variant enzyme was stable and had a reduced specific activity, suffered from severe congenital hemolytic anemia and neuromuscular symptoms. Due to the special properties of GPI Homburg, we assume that both the hematological and neuromuscular symptoms of the patient with GPI Homburg are caused by his GPI deficiency. The twins with GPI Hamburg (27% residual activity) had a distinctly unstable variant enzyme and had suffered from hemolytic crises since birth. Only GPI Homburg showed an altered electrophoretic mobility and an increased affinity for fructose-6-phosphate. The other two variants had normal values.

Adolescent↗
PubMed1986

[Corrective craniofacial surgery in the acrocephalosyndactylia syndrome (Saethre-Chotzen syndrome)].

The possibility of plastic surgery in acrocephalosyndactylia syndrome during infancy is shown. Due to her main signs and symptoms and the mode of inheritance the patient suffered from an acrocephalosyndactylia syndrome type III (Saethre-Chotzen). Craniofacial surgery with frontal craniotomy, turn of frontal bone and frontal orbital advancement were performed at the age of eight months, using bone plates developed by Luhr. The reconstruction gave an aesthetically satisfactory result, and further development was normal. The condition for a good result is the cooperation between plastic surgeons, neurosurgeons, anaesthesiologists and paediatricians in specialised centres.

Acrocephalosyndactylia↗
PubMed1986

[Angelman syndrome].

An eight-year-old boy with Angelman-(Happy Puppet-)Syndrome is described. Nearly all typical symptoms of the syndrome, especially severe psychomotoric retardation with spontaneous outbursts of laughing and protrusions of the tongue, athetoid movements, typical electroencephalogram and microcephaly, could be found in our patient. The incidence of the Angelman-syndrome may be underestimated.

Abnormalities, Multiple↗
PubMed1985

Glucose-6-phosphate dehydrogenase (G6PD) Iserlohn and G6PD Regensburg: two new severe enzyme defects in German families.

Two new inheritable variants of glucose-6-phosphate dehydrogenase have been found in two unrelated German families. Patients with one variant (G6PD Iserlohn, also referred to as G6PD I) suffered from intermittent hemolytic crises caused by fava beans; patients with the other variant (G6PD Regensburg, G6PD II) disclosed chronic nonspherocytic hemolytic anemia aggravated by drug treatment. Due to their unusual biochemical characteristics, the new variants were designated G6PD Iserlohn and G6PD Regensburg. Both variants showed a reduction of enzyme activity to about 6% of the normal in erythrocytes, normal electrophoretic mobility, increased affinity for glucose-6-phosphate, a reduced affinity for NADP and a pH optimum in the neutral region (7.0 and 7.5). G6PD Iserlohn had a decreased affinity for the inhibitor NADPH; G6PD Regensburg had a normal inhibitor constant. Deamino NADP was utilized at an increased rate by G6PD Regensburg. G6PD Iserlohn was thermostable, G6PD Regensburg mildly instable. G6PD activity in leukocytes was normal in G6PD Iserlohn and reduced to the same degree as in erythrocytets in G6PD Regensburg. The cause of the decreased activity of G6PD Iserlohn appears to be in vivo instability; in G6PD Regensburg further mechanisms might include reduced specific activity or reduced synthesis of the variant enzyme.

Anemia, Hemolytic↗