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Biomedical subjects

E Conzelmann

Publications and source records attributed to E Conzelmann.

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

Low arylsulphatase A activity and choreoathetotic syndrome in three siblings: differentiation of pseudodeficiency from metachromatic leukodystrophy.

We report on a family with a sibship of three children for whom the diagnosis of "an unusual form of metachromatic leukodystrophy (MLD)" had been suggested earlier. The patients had choreiform movements and dystonic posturing accompanied by dysarthria since childhood. The availability of the polymerase chain reaction enabled us to show that the three siblings have a pseudodeficiency genotype (ASAp/ASAp). There was no abnormal sulphatiduria, and we propose that the neurological disease and low arylsulphatase A activity are unrelated to one another in this family. A diagnosis of MLD carries very serious implications, and we recommend that gene amplification by polymerase chain reaction and hybridization with allele-specific oligonucleotide probes should be used to corroborate the diagnosis, especially when there is no abnormal sulphatiduria and when metachromatic material cannot be demonstrated in a sural nerve biopsy.

Adolescent↗
PubMed1991

Biochemical basis of late-onset neurolipidoses.

The occurrence and the tremendous phenotypic variability of late-onset neurolipidosis variants are explained on the basis of a simple kinetic model that describes the correlation between residual activity of a deficient lysosomal enzyme and the degradation rate of its substrate in the lysosome.

Adult↗
PubMed1989

Pseudodeficiency of arylsulfatase A: a common genetic polymorphism with possible disease implications.

At the locus for arylsulfatase A (ASA) at least four to five alleles exist: besides the normal ASA+ and at least two to three deficiency alleles (ASA-), a pseudodeficiency allele, ASAp, is known. On SDS-PAGE the ASAp enzyme migrates slightly faster than ASA+. Treatment of extracts from cells with ASA+/ASA+, ASAp/ASAp, or ASA+/ASAp genotypes with endoglycosidase F leads to the same deglycosylated subunit pattern. Presumably the degree of glycosylation is lower in ASAp than in ASA+. In a large-scale screening project we determined a gene frequency of 7.3% for ASAp. Thus, the ASA locus is polymorphic. In seven families, ASAp showed a codominant mode of inheritance with ASA+. Homozygosity for ASAp has no obvious clinical consequences. In subjects with the compound genotype ASA-/ASAp, the residual enzyme activity may fall below a critical threshold, so that the substrate can no longer be hydrolyzed sufficiently. Since these compounds are not so rare (estimated frequency 0.073%), this mechanism could be of importance in neuropsychiatric disorders with late onset.

Alleles↗
PubMed1989

Adult-onset metachromatic leucodystrophy presenting without psychiatric symptoms.

A 24-year-old man presented with a spastic and ataxic condition resembling chronic-progressive multiple sclerosis. Radiological examination revealed symmetrical diffuse paraventricular demyelination. Electrophysiological findings suggested additional involvement of the brain stem and the peripheral nervous system. The diagnosis of adult-onset metachromatic leucodystrophy was confirmed by biochemical and ultrastructural examination. In contrast to almost all adult cases reported so far, psychiatric symptoms were not present.

Adult↗
PubMed1988

Probable metachromatic leukodystrophy/pseudodeficiency compound heterozygote at the arylsulfatase A locus with neurological and psychiatric symptomatology.

Metachromatic leukodystrophy (MLD) is an autosomal recessive progressive demyelination disorder caused by the deficiency of arylsulfatase A (ASA). However, there exist individuals with low ASA activity without clinical symptoms. This state is described as ASA pseudodeficiency (PD). A number of patients with low ASA activity and various neuropsychiatric symptoms have been observed. It is controversial to what extent low ASA activity predisposes for neurological and/or psychiatric symptomatology. Therefore, persons with low ASA activity who were collected from a large-scale screening among neuropsychiatric patients and healthy controls are presently being extensively evaluated using biochemical, genetic, and clinical methods. Here we present a female patient, who had been first hospitalized with the diagnosis encephalomyelitis disseminata. Her ASA activity determined in fibroblast extracts is intermediate between adult MLD and PD. Sulfatide degradation in cultured fibroblasts is diminished. The subunit pattern obtained after SDS-polyacrylamide gel electrophoresis and immunoblotting was determined in the index patient and 2 sibs. It is compatible with a compound genotype ASA-/ASAp in the index case. It appears probable that in this patient low ASA activity leads to the accumulation of sulfatide and either causes the appearance of neuropsychiatric symptoms or at least contributes to the demyelination process.

Adult↗
PubMed1987

Assay for cerebroside sulfate (sulfatide) sulfatase in cultured skin fibroblasts with the natural activator protein.

A simple procedure was developed to assay the ability of arylsulfatase A in extracts of cultured skin fibroblasts to degrade the natural substrate, sulfatide, in the presence of the physiological activator protein but without detergents. Inhibitory substances were removed by dialysis and by batch-wise ion-exchange chromatography. The enzyme recoveries during purification were monitored with a newly developed method that employs the chromogenic substrate 4-nitrocatecholsulfate at an incubation temperature of 4 degrees C. The residual sulfatidase activities determined with this procedure in fibroblasts from patients with various forms of MLD correlated well with the severity of the disease.

Cells, Cultured↗
PubMed1987

A simple chromogenic assay for arylsulfatase A.

Arylsulfatase A hydrolyzes the artificial chromogenic substrate 4-nitrocatechol-sulfate at 0 degree C at a rate of 24% of that at 37 degrees C whereas arylsulfatase B is almost inactive at 0 degree C. Based on this observation, a simple assay was developed which permits the accurate determination of low residual arylsulfatase A activities in cultured skin fibroblasts of infantile, juvenile and adult MLD patients and pseudodeficient individuals. In cultured skin fibroblasts, the following residual activities were found with this assay system: late-infantile patients, 0.0%, one juvenile patient, 1.0%, adult patients, 4.4-14% of normal average. healthy pseudodeficient probands ranged between 18% and 32%.

Catechols↗
PubMed1987

Identity of the activator proteins for the enzymatic hydrolysis of sulfatide, ganglioside GM1, and globotriaosylceramide.

The activator protein for the enzymatic hydrolysis of sulfatide, ganglioside GM1, and globotriaosylceramide was purified from human kidney, brain, and urine. As far as they could be assayed, these three activities cochromatographed during all steps, indicating that they are due to the same protein. This result was corroborated by immunochemical comparison of individually purified activator preparations. In contrast, the activator for ganglioside GM2 hydrolysis could clearly be separated from the other activities. Kinetic data were determined for the interaction of the sulfatide activator with the different glycolipids and hydrolases.

Brain Chemistry↗
PubMed1986

The influence of low arylsulfatase A activity on neuropsychiatric morbidity: a large-scale screening in patients.

A total of 1728 patients consecutively admitted to a neuropsychiatric hospital and 379 chronically ill inpatients were examined for activity of arylsulphatase A (ASA) in leucocytes. A further 519 healthy individuals served as controls. We did not find evidence for the involvement of low ASA activity in chronic patients. The consecutive admissions showed a slight preponderance in the lower ASA activity classes. This activity range covers persons heterozygous for ASA deficiency alleles. The data are compatible with the hypothesis that carriers of low ASA activity alleles are at a slightly higher risk for neuropsychiatric disorders.

Alleles↗
PubMed1985

Incorporation and metabolism of ganglioside GM2 in skin fibroblasts from normal and GM2 gangliosidosis subjects.

Ganglioside GM2, 3H-labeled in the sphingoid base, was added to the culture medium of normal and GM2 gangliosidosis fibroblasts. Ganglioside was found to adsorb rapidly to the cell surface, most of it could however be removed by trypsination. The trypsin-resistant incorporation was about 10 nmol/mg cell protein, after 48 h. The rates of adsorption and incorporation depended strongly on the concentration of fetal calf serum in the medium, higher serum concentrations being inhibitory. After various incubation times, the lipids were extracted, separated by thin-layer chromatography and visualized by fluorography. In normal cells a variety of degradation products as well as sphingomyelin was found whereas in GM2 gangliosidosis cells, only trace amounts of such products (mainly GA2) were found. In contrast, the higher gangliosides GM1 and GD1a were formed in comparable amounts (2.2-3.6% of total radioactivity after 92 h) in normal and pathologic cell lines. Supplementation of cells from GM2 gangliosidosis, variant AB, with purified GM2-activator protein restored ganglioside GM2 degradation to almost normal rates but had no effect on its glycosylation to gangliosides GM1 and GD1a. From these results we conclude that the synthesis of higher gangliosides from incorporated GM2 can occur by direct glycosylation and not only via lysosomal degradation and resynthesis from [3H]sphinganine-containing degradation products. Preliminary studies with subcellular fractionation after various times of [3H]ganglioside incorporation indicated biphasic kinetics for the net transport of membrane-inserted ganglioside to lysosomes, compatible with the notion that a portion of the glycolipids can also escape from secondary lysosomes and migrate to Golgi compartment or cell surface.

Animals↗
PubMed1985

Prenatal diagnosis of GM2 gangliosidosis with high residual hexosaminidase A activity (variant B1; pseudo AB variant).

A case of infantile GM2 gangliosidosis with high residual beta-hexosaminidase A activity toward the synthetic substrate 4-methylumbelliferyl-2-acetamido-2-deoxy-beta-D-glucopyranoside was diagnosed prenatally. Extracts from cultured amniotic fluid cells of the fetus had a hexosaminidase A activity of 27% of total hexosaminidase but were almost completely unable to degrade [3H]ganglioside GM2 (less than 0.5% of control values) when assayed in the presence of the natural activator protein. These results were confirmed by analyses of fetal muscle fibroblasts, liver, and brain. All tissues examined showed a profound deficiency of ganglioside GM2 galactosaminidase despite hexosaminidase A levels in the heterozygote range. In brain tissue, ganglioside GM2 content was elevated more than 4-fold. Hydrolysis of p-nitrophenyl glucosaminide-6-sulfate, a substrate specific for hexosaminidases A and S, by tissue extracts was also markedly reduced but the residual activities found (5% in liver, 12% in fibroblasts, and 16% in brain) were much higher than those with the physiological lipid substrate, ganglioside GM2.

Amniocentesis↗
PubMed1985

Hereditary heat-labile hexosaminidase B: a variant whose homozygotes synthesize a functional HEX A.

Homozygosity for a mutant allele at the beta-chain locus of hexosaminidase (HEX), resulting in a variant of heat-labile HEX B, is reported for the first time in two healthy children. HEX activity in their sera, leukocytes, and cultured skin fibroblasts is severely deficient when measured on the synthetic substrate 4-MU-GLcNAc. However, their cultured skin fibroblasts synthesize and process both alpha and beta chains of HEX, and their lymphoid cells hydrolyze normally the natural ganglioside GM2. This mutation is, therefore, different from at least one of the beta-chain mutations found in previously published families with heat-labile HEX B.

Cells, Cultured↗