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Biomedical subjects

J E Månsson

Publications and source records attributed to J E Månsson.

At least 19 recordsLinked to original sources
PubMed2002

Free sialic acid storage (Salla) disease in Sweden.

UNLABELLED: The first 23 patients diagnosed with Salla disease in Sweden are presented. A high incidence of the "Finnish" R39C mutation, together with genealogical data, indicates that a large proportion of the mutations are of Finnish origin. All patients had pathologically high levels of free sialic acid in urine and in fibroblasts. The clinical picture confirms what has already been reported from Finland, with early psychomotor retardation, ataxia and speech problems. One-third of the patients had epilepsy. CONCLUSIONS: Salla disease is more common in Sweden than supposed. A large proportion of the mutated alleles seem to be of Finnish origin. The clinical picture is the same as that reported from Finland.

Female↗
PubMed2001

Distal infantile neuroaxonal dystrophy--a new familial variant with perineuronal argyrophilic bodies.

We report on two sisters with an infantile onset of dyskinetic movements, tonic spasms, seizures and apneic spells. The condition deteriorated to a hypotonic "burnt out" stage by the age of 3 years in the older sister and to a stable dyskinetic condition by the age of 2.5 years in the younger one. A skin biopsy from the older sister revealed myelinated nerve fibers crowded with neurofilaments. The extensive investigation for neurometabolic disorder, magnetic resonance imaging of the brain, and ophthalmological and neurophysiological examinations were not especially revealing. The older sister died at the age of 3 years. The autopsy revealed no apparent loss of nerve cells in the brain and no sign of storage disease. However, silver-stained coarse granules, immunopositive for neurofilament polypeptide, were found around nerve cell bodies in the cortex and in the basal ganglia. Electron microscopy revealed perineuronal membrane-bound profiles filled with filaments. Silver-stained axonal torpedoes were found in the cerebellum, but there were no spheroids. The substantia nigra, the locus ceruleus and the nucleus basalis of Meynert showed extensive perineuronal and perivascular swelling. Homovanillic acid was severely reduced, while 5-hydroxyindoleacetic acid and hydroxymethylphenyl glycol were normal in the cerebrospinal fluid of the severely affected, autopsied case. The two cases are considered to represent a new form of infantile neuroaxonal dystrophy, characterized by the degeneration of perineuronal terminals in the cerebral cortex and in the basal ganglia, as well as by axonal degeneration in the cerebellum and peripheral nerves.

Brain↗
PubMed2001

Cerebrospinal fluid markers in children with cerebral white matter abnormalities.

Disorders of the cerebral white matter in children constitute a heterogeneous group and the diagnostic work is often complicated. Clinical and radiological characteristics can provide diagnostic clues but there is a need for further diagnostic methods. This study focused on assessing neurochemical "markers" in the cerebrospinal fluid considered to reflect damage to white matter components such as myelin and glial cells as well as neurones with their axons and synapses. The aim was to evaluate whether they contributed to the elucidation of pathogenic processes and the direction of further diagnostic efforts. Seventeen of the 26 cases had increased levels of the glial cell marker ganglioside GD3, indicating gliosis, or of the CNS myelin marker sulfatide, indicating myelin disturbance. As signs of disturbed maturation or sustenance, the nerve cell markers GD1 b, GT1 b and total gangliosides were reduced, as was the synapse marker GD1a. Increased 5-HIAA indicated increased serotonergic turnover. Children with an increased level of the axonal marker Tau protein had a progressive disease whereas GD1a was reduced in the progressive group (n = 11). In contrast, GD3 and HVA were increased in the non-progressive group (n = 15). The chemical profiles were found to be useful, in combination with clinical and radiological findings, when investigating children with white matter abnormalities.

Adolescent↗
PubMed2001

Depletion of rafts in late endocytic membranes is controlled by NPC1-dependent recycling of cholesterol to the plasma membrane.

In mammalian cells, cholesterol is thought to associate with sphingolipids to form lateral membrane domains termed rafts. Increasing evidence suggests that rafts regulate protein interactions, for example, during signalling, intracellular transport and host-pathogen interactions. Rafts are present in cholesterol-sphingolipid-enriched membranes, including early and recycling endosomes, but whether rafts are found in late endocytic organelles has not been analyzed. In this study, we analyzed the association of cholesterol and late endosomal proteins with low-density detergent-resistant membranes (DRMs) in normal cells and in cells with lysosomal cholesterol-sphingolipid accumulation. In normal cells, the majority of [(3)H]cholesterol released from [(3)H]cholesterol ester-LDL associated with detergent-soluble membranes, was rapidly transported to the plasma membrane and became increasingly insoluble with time. In Niemann-Pick C1 (NPC1) protein-deficient lipidosis cells, the association of LDL-cholesterol with DRMs was enhanced and its transport to the plasma membrane was inhibited. In addition, the NPC1 protein was normally recovered in detergent-soluble membranes and its association with DRMs was enhanced by lysosomal cholesterol loading. Moreover, lysosomal cholesterol deposition was kinetically paralleled by the sequestration of sphingolipids and formation of multilamellar bodies in late endocytic organelles. These results suggest that late endocytic organelles are normally raft-poor and that endocytosed LDL-cholesterol is efficiently recycled to the plasma membrane in an NPC1-dependent process. The cholesterol-sphingolipid accumulation characteristic to NPC disease, and potentially to other sphingolipidoses, causes an overcrowding of rafts forming lamellar bodies in the degradative compartments.

Androstenes↗
PubMed2000

The spectrum of SLC17A5-gene mutations resulting in free sialic acid-storage diseases indicates some genotype-phenotype correlation.

Lysosomal free sialic acid-storage diseases include the allelic disorders Salla disease (SD) and infantile sialic acid-storage disease (ISSD). The defective gene, SLC17A5, coding for the lysosomal free sialic acid transporter was recently isolated by positional cloning. In the present study, we have identified a large number of mutations in SLC17A5 in patients presenting with either Salla disease or the ISSD phenotype. We also report for the first time the exon-intron boundaries of SLC17A5. All Finnish patients with SD (n=80) had a missense mutation changing a highly conserved arginine to cysteine (R39C); 91% of them were homozygotes for this old founder mutation. The compound-heterozygote patients, with the founder mutation in only one allele, presented with a more severe phenotype than did the homozygote patients. The same R39C mutation was also found both in most of the Swedish patients with SD and in a heterozygous form in five patients from central Europe who presented with an unusually severe (intermediate) SD phenotype. Ten different mutations, including deletions, insertions, and missense and nonsense mutations, were identified in patients with the most severe ISSD phenotype, most of whom were compound heterozygotes. Our results indicate some genotype-phenotype correlation in free sialic acid-storage diseases, suggesting that the phenotype associated with the homozygote R39C mutation is milder than that associated with other mutations.

Age of Onset↗
PubMed2000

CSF sulfatide distinguishes between normal pressure hydrocephalus and subcortical arteriosclerotic encephalopathy.

OBJECTIVES: To examine the CSF concentrations of molecules reflecting demyelination, neuronal and axonal degeneration, gliosis, monoaminergic neuronal function, and aminergic and peptidergic neurotransmission in a large series of patients with normal pressure hydrocephalus (NPH) or subcortical arteriosclerotic encephalopathy (SAE), to elucidate pathogenic, diagnostic, and prognostic features. METHODS: CSF concentrations of glycosphingolipid (sulfatide), proteins (neurofilament triplet protein (NFL), glial fibrillary acidic protein (GFAP)), neuropeptides (vasoactive intestinal peptide (VIP), 4-aminobutyric acid (GABA)), and monoamines (homovanillic acid (HVA), 5-hydroxy-indoleacetic acid (5-HIAA), 4-hydroxy-3-methoxyphenylglycol (HMPG)) were analysed in 43 patients with NPH and 19 patients with SAE. The diagnoses of NPH and SAE were based on strict criteria and patients with NPH were subsequently operated on. Twelve clinical variables, psychometric tests measuring perceptual speed, accuracy, learning, and memory and a psychiatric evaluation were performed in all patients and before and after a shunt operation in patients with NPH. RESULTS: The CSF sulfatide concentration was markedly increased in patients with SAE (mean 766, range 300-3800 nmol/l) compared with patients with NPH (mean 206, range 50-400 nmol/l) (p<0.001). 5-HIAA, GABA, and VIP in CSF were higher in patients with SAE than in patients with NPH. The patients with NPH with cerebrovascular aetiology had higher sulfatide concentrations and a poorer outcome after shunt surgery than patients with NPH with other aetiologies. CONCLUSIONS: The pathogenesis of the white matter changes in NPH and SAE is different and ischaemic white matter changes can be a part of the NPH state. The markedly increased CSF sulfatide concentrations in patients with SAE indicate ongoing demyelination as an important pathophysiological feature of SAE. The CSF sulfatide concentration distinguished between patients with SAE and those with NPH with a sensitivity of 74% and a specificity of 94%, making it an important diagnostic marker.

Adult↗
PubMed1999

In vitro production of cytokines is influenced by sulfatide and its precursor galactosylceramide.

Effects of sulfatide and its precursor galactosylceramide (gal-cer) on the kinetics of production of cytokines were studied. In human mononuclear leucocytes, gal-cer but not sulfatide induced significantly increased amounts of interleukin (IL)-1beta, IL-6 and tumor necrosis factor (TNF) mRNA. In phytohemagglutinin-stimulated cultures, gal-cer increased the levels of IL-1beta and IL-6 mRNA and secreted IL-1beta and IL-6, while sulfatide decreased the amounts of IL-6 mRNA and secreted IL-6. Gal-cer also increased TNF secretion. In lipopolysaccharide-stimulated cells, sulfatide but not gal-cer decreased the secretion of IL-1beta and IL-10, a potent suppressor of production of many cytokines. Thus, sulfatide and gal-cer affect cytokine production differently, most likely at the level of gene expression. This may have implications in diseases where inflammatory cytokines play a pathogenic role.

Adult↗
PubMed1999

Expression of the GM1-species, [NeuN]-GM1, in a case of human glioma.

Altered glycosylation is a common feature in tumors of various kind and particular interest has been focused on the expression of tumor-associated gangliosides. We have previously identified some human glioma-associated gangliosides and in this study yet another, not previously described, ganglioside has been isolated. The ganglioside was prepared from human glioma tissue taken at autopsy. The new ganglioside bound cholera-toxin B-subunit and its structure was confirmed by fast atom bombardment-mass spectrometry to be NeuN-GM1 (II3NeuNH2-GgOse4Cer). In the dissected tumor specimen, the concentration of NeuN-GM1 was 0.1 micromol/g wet weight and accounted for approximately 20% of the monosialoganglioside fraction. Normal human brain tissue specimens (n = 10) did not contain detectable (>0.5 nmol/g wet weight of tissue) amounts of NeuN-GM1, indicating that this ganglioside might be associated with human glioma. However, none of the 17 other tumour specimens reveal any detectable amounts of this ganglioside. In conclusion, NeuN GM1 is a glioma-associated ganglioside but its exceptional expression limits its relevance as a molecule involved in general tumor biology.

Brain↗
PubMed1998

Cerebrospinal fluid monoamines in Prader-Willi syndrome.

BACKGROUND: The behavioral phenotype of Prader-Willi syndrome (PWS) suggests hypothalamic dysfunction and altered neurotransmitter regulation. The purpose of this study was to examine whether there was any difference in the concentrations of monoamine metabolites in the cerebrospinal fluid (CSF) in PWS and non-PWS comparison cases. METHODS: The concentration of monoamine metabolites in CSF was determined in 13 children and adolescents with PWS diagnosed on clinical and genetic criteria. The concentrations were compared with those from 56 comparison cases in healthy and other contrast groups. RESULTS: The concentrations of dopamine and particularly serotonin metabolites were increased in the PWS group. The differences were most prominent for 5-hydroxyindoleacetic acid. The increased concentrations were found in all PWS cases independently of age, body mass index, and level of mental retardation. CONCLUSIONS: The findings implicate dysfunction of the serotonergic system and possibly also of the dopamine system in PWS individuals, and might help inform future psychopharmacologic studies.

Adolescent↗
PubMed1998

Is monoamine oxidase activity elevated in Prader-Willi syndrome?

The platelet contents of monoamine oxidase (MAO-B) were analyzed in 17 children and young adults with Prader-Willi syndrome and 18 non-PWS comparison cases. MAO-B activity was significantly higher in the former group, suggesting monoamine dysfunction in Prader-Willi syndrome.

Adolescent↗
PubMed1998

Animal models of lysosomal disease: an overview.

The relative rarity of human lysosomal disorders, extremely heterogeneous genetic background and ethical restrictions make well-controlled studies difficult with human patients. Genetically authentic animal models complement human patients with their ready availability, homogeneous genetic background and the relatively flexible experimental designs. Spontaneous animal models of human lysosomal disorders are rare, particularly among small laboratory animals. However, the homologous recombination and embryonic stem cell technology has so far enabled us to duplicate almost all known human sphingolipidoses, two mucopolysaccharidoses and aspartylgly-cosaminuria in mice and more disorders are expected in the near future. This technology also allows generation of mouse mutants that are not known or are highly unlikely to exist in humans, such as 'double-knockouts'. Studies of lysosomal disease have come to the half-way turning point of the marathon race from clincopathological descriptions, identification of affected compounds, enzymology, to the present gene-level inquiries. The animal models will play an important role in our long journey from nucleic acids back to biology. While the utility of these mouse models is obvious, species differences in the brain development and metabolic pathways must be always remembered if the ultimate goal of the study is application to human patients. After all, the mouse is not human.

Animals↗
PubMed1998

Generalized peroxisomal disorder in male twins: fatty acid composition of serum lipids and response to n-3 fatty acids.

Male, identical twins presented with hypotonia, hypoglycaemia, dysmorphic facies, feeding problems, discoloured stools, hepatomegaly, and nephrolithiasis. Elevated blood levels of very long-chain fatty acids and bile acids suggested a peroxisomal disorder. Plasmalogen biosynthesis in cultured fibroblasts was reduced. Morphologically distinct peroxisomes were undetectable in liver. Twin 1 suffered from nephrocalcinosis and severe infection, and died at 18 months of age. Twin 2 was blind and physically severely retarded with epilepsy, but survived up to the age of 5 years. Studies of the fatty acid composition of serum lipids showed barely detectable values of eicosapentaenoic (EPA) and docosahexaenoic acid (DHA). During long-term treatment with these n-3 fatty acids, started at age 10 months, the fatty acid profile of the serum lipids was improved or normalized. Since n-3 fatty acids are essential elements in normal development, notably of the nervous system, we suggest that treatment with EPA and DHA should be started as early as possible in general peroxisomal disorders.

Diseases in Twins↗
PubMed1997

Serotonergic, noradrenergic, and dopaminergic measures in suicide brains.

Concentrations of the three main monoamines (5-HT, NA, and DA), their metabolites (5-HIAA, DOPAC, and HVA), and the serotonin precursor 5-hydroxy-L-tryptophan were simultaneously measured in frontal cortex, gyrus cinguli, and hypothalamus from 23 controls and 18 suicide victims. Overall suicides did not show significant differences with respect to the control group in any of the measured compounds. Significant increases in noradrenaline and dopamine concentrations were noted in the carbon monoxide poisoning suicides, together with a significant increased hypothalamic dopamine in the drug overdose suicides. It is suggested that the suicidal behavior is not related to substantial changes in cortical and hypothalamic monoaminergic function; however, the reported results could be secondary to the rapid effect of hypoxia and of the acute self-administration of certain drugs in specific metabolic pathways.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1997

Increased activity of lysosomal glycohydrolases in glioma tissue and surrounding areas from human brain.

Increased metabolic activity represented by an increase in both anabolism and catabolism in tumours, including gliomas, is a well known phenomenon and utilised in positron emission tomography imaging of tumours. In this study lysosomal enzyme activities of some glycohydrolases were investigated in glioma tissue from human brain. Tumour tissue (ten cases) and brain tissue surrounding the tumour tissue (seven cases) from patients with a histopathological diagnosis of glioblastoma multiforme or anaplastic astrocytoma were analysed for activity of the lysosomal enzymes galactosylceramidase, glucosylceramidase, beta-galactosidase, beta-N-acetyl-glucosaminidase, beta-glucuronidase and acid phosphatase. All of the investigated lysosomal enzymes except galactosylceramidase showed increased activity compared with that in normal brain tissue. Moreover, despite sparsity of tumour cells the specimens taken from surrounding areas showed elevated activities of the same enzymes. The findings indicate an upregulation of the activity not only in tumour but also in normal cells of the surrounding area.

Adolescent↗
PubMed1997

Early-infantile galactosialidosis with multiple brain infarctions: morphological, neuropathological and neurochemical findings.

Post-mortem morphological, neuropathological and neurochemical findings are described in a girl, aged 14 months, with the early-infantile form of galactosialidosis. An elevation in non-lipid sialic acid was noted in both the grey and white matter of the brain, whereas the white matter displayed a clear reduction in all the major lipids. Multiple cortical-subcortical infarctions were found in the brain, most probably caused by compromised circulation due to endothelial luminal encroachment. Electron microscopy of cerebral blood vessels revealed major swelling of the endothelium due to prominent cytoplasmic vacuolisation. Multiple cytoplasmic vacuoles containing sparse granular or membranous matter were also seen in neurons and glial cells of the brain and spinal cord. Zebra bodies were found in the Purkinje cells, as well as in the spinal anterior horn cells. Prominent endothelial vacuolisation was noted in the liver and kidneys. The renal vascular encroachment was probably the cause of the arterial hypertension with elevated plasma renin activity in the present case. There were innumerable fine vacuoles in the renal epithelium and in the Kupffer cell of the liver, whereas coarser vacuoles were observed in the hepatocytes. The neuronal ultrastructural findings in the present case bear some resemblance to the few reported cases of late-infantile and adult cases of galactosialidosis. The prominent endothelial vacuolisation and focal cerebrovascular lesions, that have not previously been described in galactosialidosis, may be features specific to the rapidly progressive early-infantile form.

Brain↗
PubMed1997

Encephaloneuropathy with lysosomal zebra bodies and GM2 ganglioside storage.

An 11-year-old girl died of a neuronal storage disorder that clinically was characterized by failure to thrive and muscular hypotonia from birth, with the subsequent evolution of motor neuron disease, epilepsy, and dementia. A wide range of metabolic disorders, including all forms of GM2 gangliosidosis, could be excluded. Electron microscopy demonstrated neuronal zebra body inclusions, and immunohistochemistry demonstrated that GM2 ganglioside was a major constituent of the storage material. We suggest that the patient died of a lysosomal storage disease that is clinically and biochemically different from Tay-Sachs disease, Sandhoff disease, and other GM2 gangliosidoses described previously. This case also further demonstrates that significant accumulation of GM2 ganglioside, which is crucial for dendritic formation, may occur in neuronal storage diseases lacking known defects in ganglioside catabolism.

Child↗
PubMed1997

Increased levels of cholesterol esters in glioma tissue and surrounding areas of human brain.

The proliferation of glioma cells requires cholesterol, which could be provided by synthesis within the cells or by uptake of cholesterol esters in particles of Low Density Lipoprotein (LDL). Cholesterol esters and cholesterol were therefore analysed in human glioma tissue, its surrounding areas and serum from 40 patients. The analyses revealed an increased concentration of cholesterol esters up to 100 times (0.1-10 mumol/g) in both tumour-tissue and surrounding areas compared with control material (< 0.1 mumol/g). The analyses also demonstrated that cholesterol esters in tumour tissue eminated mainly from serum. The cholesterol concentrations were significantly lower in tumour tissue compared with surrounding areas as expected. These results indicate that tumour cell proliferation utilises serum derived cholesterol esters presumably carried by LDL particles.

Adolescent↗