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Biomedical subjects

L Edström

Publications and source records attributed to L Edström.

At least 19 recordsLinked to original sources
PubMed2005

Sarcoplasmic body myopathy--a rare hereditary myopathy with characteristic inclusions.

OBJECTIVES: To characterise a Swedish family with a rare hereditary myopathy with unique sarcoplasmic inclusion bodies in the muscle biopsy. MATERIALS AND METHODS: Part of the pedigree was described in 1980. Nine new members of the included and the phenotype further characterised through clinical, neurophysiological and radiological investigations. RESULTS: Six of the nine subjects displayed clinical and/or laboratory evidence of myopathy with sarcoplasmic inclusions. CONCLUSIONS: Sarcoplasmic body myopathy is distinguished from other distal myopathies by a more malignant course and early involvement of thenar muscles and hand flexors. Five to ten years after onset the affected subjects develop distal, as well as proximal, weakness and atrophy and the majority require a wheelchair after ten to fifteen years of disease. The disorder is manifested through elevated creatine kinase levels and the presence of the pathognomonic sarcoplasmic inclusions prior to clinical signs and symptoms.

Adult↗
PubMed2004

Changes in diaphragm structure following prolonged mechanical ventilation in piglets.

BACKGROUND: Prolonged mechanical ventilation and inactivity negatively affect muscle function. The mechanisms for this dysfunction are unclear and clinical studies of respiratory muscle are difficult to carry out. An animal model simulating the critical care environment was used to investigate the effects of 5 days' mechanical ventilation and diaphragm inactivity on diaphragm muscle morphology. METHODS: Twelve 2-4-month-old piglets weighing 23-30 kg were studied. Seven animals received controlled mechanical ventilation and sedation such that spontaneous breathing efforts were inhibited over 5 days. Five control animals were ventilated for only 4-6 h following surgical preparation. Diaphragm biopsies were obtained from the left costal region at the end of all experiments. RESULTS: Morphometric, morphologic, electron microscopic and enzyme histochemical examination of costal diaphragm biopsies was carried out. Contractile properties were studied over 5 days and the results have been previously reported. Cross-sectional area of alI fiber types was increased compared with controls. The proportion of type IIb/x fibers increased following inactivity (P < 0,05) and the proportion of type I and IIa fibers tended to decrease although not significantly. Focal areas of diaphragm fiber regeneration were found without signs of inflammation. Increased appearance of cytoplasmic vacuoles consisting of lipid accumulation was noted in type I fibers. Several study animals developed focal areas with weak myofibrillar ATPase activity and disrupted fiber organization. There were areas of myofibrillary destruction and loss of sarcomeric pattern, without evidence of selective thick filament loss or a change in the myosin to actin ratio. CONCLUSION: Five days' mechanical ventilation with sedation and complete diaphragm inactivity resulted in changes in muscle fiber structure. A causal relationship can not be concluded but the acute changes in fiber type distribution and structure suggest that previously reported diaphragm contractile impairment occurs at the level of muscle fibers.

Animals↗
PubMed2001

Huntington disease phenocopy is a familial prion disease.

Huntington disease (HD) is a common autosomal dominant neurodegenerative disease with early adult-onset motor abnormalities and dementia. Many studies of HD show that huntingtin (CAG)n repeat-expansion length is a sensitive and specific marker for HD. However, there are a significant number of examples of HD in the absence of a huntingtin (CAG)n expansion, suggesting that mutations in other genes can provoke HD-like disorders. The identification of genes responsible for these "phenocopies" may greatly improve the reliability of genetic screens for HD and may provide further insight into neurodegenerative disease. We have examined an HD phenocopy pedigree with linkage to chromosome 20p12 for mutations in the prion protein (PrP) gene (PRNP). This reveals that affected individuals are heterozygous for a 192-nucleotide (nt) insertion within the PrP coding region, which encodes an expanded PrP with eight extra octapeptide repeats. This reveals that this HD phenocopy is, in fact, a familial prion disease and that PrP repeat-expansion mutations can provoke an HD "genocopy." PrP repeat expansions are well characterized and provoke early-onset, slowly progressive atypical prion diseases with an autosomal dominant pattern of inheritance and a remarkable range of clinical features, many of which overlap with those of HD. This observation raises the possibility that an unknown number of HD phenocopies are, in fact, familial prion diseases and argues that clinicians should consider screening for PrP mutations in individuals with HD-like diseases in which the characteristic HD (CAG)n repeat expansions are absent.

Amino Acid Sequence↗
PubMed2001

Properly formed but improperly localized synaptic specializations in the absence of laminin alpha4.

Precise apposition of pre- to postsynaptic specializations is required for optimal function of chemical synapses, but little is known about how it is achieved. At the skeletal neuromuscular junction, active zones (transmitter release sites) in the nerve terminal lie directly opposite junctional folds in the postsynaptic membrane. Few active zones or junctional folds form in mice lacking the laminin beta2 chain, which is normally concentrated in the synaptic cleft. beta2 and the broadly expressed gamma1 chain form heterotrimers with alpha chains, three of which, alpha2, alpha4 and alpha5, are present in the synaptic cleft. Thus, alpha2beta2gamma1, alpha4beta2gamma1 and alpha5beta2gamma1 heterotrimers are all lost in beta2 mutants. In mice lacking laminin alpha4, active zones and junctional folds form in normal numbers, but are not precisely apposed to each other. Thus, formation and localization of synaptic specializations are regulated separately, and alpha4beta2gamma1 (called laminin-9) is critical in the latter process.

Animals↗
PubMed2000

Acute quadriplegia and loss of muscle myosin in patients treated with nondepolarizing neuromuscular blocking agents and corticosteroids: mechanisms at the cellular and molecular levels.

OBJECTIVE: Long-term treatment with nondepolarizing neuromuscular blocking agents and corticosteroids in the intensive care unit is not benign, and an increasing number of patients with acute quadriplegic myopathy have been reported with increased use of these drugs. The purpose of this study was to investigate the mechanisms underlying acute quadriplegic myopathy. DESIGN: Percutaneous muscle biopsy samples were obtained, and electrophysiologic examinations were performed during the acute phase and during recovery in patients with acute quadriplegic myopathy. Regulation of muscle contraction and myofibrillar protein synthesis was studied using cell physiologic techniques, ultrasensitive electrophoresis, in situ hybridization, and histopathologic techniques. SETTING: All patients were seen in the intensive care unit of different university hospitals. PATIENTS: All patients were critically ill with sepsis. They had been given massive doses of corticosteroids in combination with variable doses of neuromuscular blocking agents. All patients developed paralysis of spinal nerve-innervated muscles. On the other hand, cranial nerve-innervated muscle and sensory and cognitive functions were well maintained after discontinuation of treatment with neuromuscular blocking agents. INTERVENTION: Muscle biopsy samples were obtained and electrophysiologic examinations were performed in all patients. MEASUREMENTS AND MAIN RESULTS: The major observations in patients with acute quadriplegic myopathy were, as follows: a) a general decrease in myofibrillar protein content; b) specific but highly variable partial or complete loss of myosin and myosin-associated proteins; c) very low thick-filament/thin-filament protein ratios; d) absence of myosin messenger RNA; and e) a dramatically impaired muscle cell force-generating capacity in the acute phase of acute quadriplegic myopathy. During clinical improvement, normal expression of myosin messenger RNAs, reexpression of thick-filament proteins, and increased specific tension were observed. CONCLUSIONS: Acute quadriplegic myopathy is associated with a specific decrease in thick-filament proteins related to an altered transcription rate. Although the decreased content of thick-filament proteins is important for prolonged muscle weakness, it is not the primary cause of muscle paralysis in the acute stage, during which impaired muscle membrane excitability probably plays a more significant role. Several factors contribute to this condition, but the action of corticosteroids seems to be the predominant one, along with potentiation by neuromuscular blocking agents, immobilization, and probably also concurrent sepsis.

Acute Disease↗
PubMed1999

Genetic linkage of Welander distal myopathy to chromosome 2p13.

Welander distal myopathy (WDM) is an autosomal dominant myopathy with late-adult onset characterized by slow progression of distal muscle weakness. The disorder is considered a model disease for hereditary distal myopathies and is almost only seen in Sweden and some parts of Finland. A genomewide screening has been performed in initially two Swedish families with 400 highly polymorphic microsatellite markers. We report here that the disease is linked to chromosome 2p13. Seven additional nonrelated families have subsequently been mapped to the same area where a maximum two-point LOD score of 17.97 was obtained with the marker D2S2113 at 0.0 recombination fraction. The region has been restricted by recombinations and the finding of a common shared haplotype through all analyzed families. This restricts the gene locus region to 2.4 cM. These findings provide evidence for the involvement of a single locus for WDM. The WDM region overlaps with the linkage region for Miyoshi myopathy and limb-girdle muscular dystrophy 2B. The dysferlin gene responsible for these disorders is considered a primary candidate gene for WDM.

Chromosomes, Human, Pair 2↗
PubMed1999

Levels of transforming growth factor alpha (TGF-alpha) in human cerebrospinal fluid.

In this study, we investigated cerebrospinal fluid of patients with various neurological symptoms for the presence of transforming growth factor alpha (TGF-alpha). 41 samples of cerebrospinal fluid were collected by lumbar puncture performed routinely due to the clinical suspicion of neurological disease from 22 females (age 15-80 years, median 42 years) and from 19 males (age 18-82 years, median 48 years). A highly sensitive and specific radioimmunoassay was used to determine the concentration of TGF-alpha in the samples. The detection limit of the assay was about 200 pg TGF-alpha. There was no cross-reactivity to human EGF. We showed CSF indeed does contain TGFalpha. As TGF-alpha was detected in all 41 samples investigated, this growth factor appears to be a constant component of CSF. The mean concentration was 5.5 ng TGF-alpha (S.D. +/- 2.7 pg/ml, range 1.1 to 13.9 pg/ml). There was no significant correlation between TGF-alpha concentration in CSF and age (r = -0.006) and there was no significant difference between females (mean 5.8+/-3.10 pg/ml) and males (mean 5.2+/-1.96 pg/ml). No diagnosis was over represented in patients with TGF-alpha concentrations above or below 1 S.D. off the mean. However, highest concentrations of TGF-alpha were found in the group of patients with peripheral neurological sensory dysfunctions and polyneuropathy. We conclude that TGF-alpha is not only a constant component of human cerebrospinal fluid in adults but could also be significantly involved in the pathophysiology of various neurological diseases. The earlier hypothesis that TGF-alpha could mainly have a role in brain development needs hence to be re-evaluated.

Adolescent↗
PubMed1999

A second locus for autosomal dominant myopathy with proximal muscle weakness and early respiratory muscle involvement: a likely chromosomal locus on 2q21.

We recently mapped a locus for a new variant of autosomal dominant myopathy (Swedish families) with proximal muscle weakness, early respiratory muscle involvement, and unique muscle biopsy findings to chromosomal region 2q24-31. In this study, a French family with a similar clinical phenotype and pathology (muscle biopsy) was investigated to see whether the disease gene associated with the myopathy is mapped to the same region as the one in the Swedish families; however, chromosomal region 2q24-q31 was completely excluded. In order to localise the disease gene for the French family, a genome-wide scan was performed using polymorphic microsatellite markers. A maximum two-point lod score of 2.11 (the highest lod score that can be achieved in this family) was obtained for the markers in the region between D2S1272 and D2S1260, spanning 4 cM. This result suggests that the gene responsible for the French form is likely to be located on chromosome 2q21.

Chromosome Mapping↗
PubMed1999

Autosomal dominant myopathy with proximal weakness and early respiratory muscle involvement maps to chromosome 2q.

Two Swedish families with autosomal dominant myopathy, who also had proximal weakness, early respiratory failure, and characteristic cytoplasmic bodies in the affected muscle biopsies, were screened for linkage by means of the human genome screening set (Cooperative Human Linkage Center Human Screening Set/Weber version 6). Most chromosome regions were completely excluded by linkage analysis (LOD score <-2). Linkage to the chromosomal region 2q24-q31 was established. A maximum combined two-point LOD score of 4.87 at a recombination fraction of 0 was obtained with marker D2S1245. Haplotype analysis indicated that the gene responsible for the disease is likely to be located in the 17-cM region between markers D2S2384 and D2S364. The affected individuals from these two families share an identical haplotype, which suggests a common origin.

Chromosomes, Human, Pair 2↗
PubMed1999

Simultaneous analysis of expression of the three myotonic dystrophy locus genes in adult skeletal muscle samples: the CTG expansion correlates inversely with DMPK and 59 expression levels, but not DMAHP levels.

The causative mutation in the majority of cases of myotonic dystrophy has been shown to be the expansion of a CTG trinucleotide repeat, but the mechanism(s) by which this repeat leads to the very complex symptomatology in this disorder remains controversial. We have developed a highly sensitive and quantifiable assay, based on competitive RT-PCR, to test the hypothesis that the expansion disrupts the expression of the genes in its immediate vicinity, DMPK, 59 and DMAHP. In order to avoid cell culture-induced artifacts we performed these experiments using adult skeletal muscle biopsy samples and analysed total cytoplasmic poly(A)+mRNA levels for each gene simultaneously, as this is more physiologically relevant than allele-specific levels. There was considerable overlap between the expression levels of the three genes in myotonic dystrophy patient samples and samples from control individuals. However, in the myotonic dystrophy samples we detected a strong inverse correlation between the repeat size and the levels of expression of DMPK and 59. This is the first report of a possible effect of the CTG expansion on gene 59. Our results indicate that whilst a simple dosage model of gene expression in the presence of the mutation is unlikely to be sufficient in itself to explain the complex molecular pathology in this disease, the repeat expansion may be a significant modifier of the expression of these two genes.

Adult↗
PubMed1998

Welander hereditary distal myopathy, a molecular genetic comparison to hereditary myopathies with inclusion bodies.

Welander distal myopathy (WDM) is an autosomal dominant disorder with late onset predominantly affecting distal extensor muscles of the hands and the feet. The disorder is considered as the most common of the distal myopathies but is almost only seen in Sweden and some parts of Finland. The finding of rimmed vacuoles in muscle biopsies from patients with moderate and severe symptoms constitutes one similarity with hereditary inclusion body myopathy (HIBM) sparing the quadriceps as described by Argov and Yarom [Argov Z, Yarom R. J Neurol Sci 1984;64:33-43]. The question has been raised whether some of the different forms of distal myopathy might be allelic. In previous reports the gene defects for HIBM and autosomal recessive hereditary distal myopathy with rimmed vacuoles (DMRV) have been mapped to chromosome 9pl-q1. The Finnish tibial muscular dystrophy (TMD) that displays similar histopathological findings has recently been linked to chromosome 2q. We have investigated the regions of interest with dispersed microsatellite markers in four well-described pedigrees, and this study now excludes the regions on chromosome 9pl-q1 and 2q from linkage to WDM both by haplotype analysis and linkage analysis with the MLINK program. WDM, showing morphological similarities with HIBM, is clearly separated from the disorders mapped to chromosomes 9 and 2 on clinical and genetical grounds.

Adult↗
PubMed1998

Welander distal myopathy--an overview.

Welander distal myopathy has an autosomal dominant inheritance and a late onset. The onset of symptoms is in the hands and gradually distal muscles of the lower extremities are involved. The most-affected muscles are the long extensors of the hands and feet. CK-values are normal or slightly elevated. There is never any cardiac involvement in Welander distal myopathy. Neurophysiological findings are of both myopathic and neuropathic character. Histopathological findings in muscle biopsies are mainly of myopathic type and include rimmed vacuoles which correspond to autophagic vacuoles on the ultrastructural level. Tubulo-filamentous inclusions with a diameter of 16-21 nm, i.e. of the same type as found in patients with Inclusion Body Myositis, are found in the sarcoplasm and in myofibre nuclei. A neurogenic component in Welander distal myopathy has been suggested, on the grounds of a sensory dysfunction, neuropathic findings on neurophysiology and muscle biopsy and a decrease of A-delta nerve fibres on sural nerve biopsy. Genetic analysis has excluded linkage to other defined distal myopathies and hereditary Inclusion Body Myopathy loci.

Adult↗
PubMed1998

A Huntington disease-like neurodegenerative disorder maps to chromosome 20p.

Huntington disease (HD) is an autosomal dominant neurodegenerative disorder characterized by motor disturbance, cognitive loss, and psychiatric manifestations. The disease is associated with a CAG trinucleotide-repeat expansion in the Huntington gene (IT15) on chromosome 4p16.3. One family with a history of HD was referred to us initially for predictive testing using linkage analysis. However, the chromosome 4p region was completely excluded by polymorphic markers, and later no CAG-repeat expansion in the HD gene was detected. To map the disease trait segregating in this family, whole-genome screening with highly polymorphic dinucleotide-, trinucleotide-, and tetranucleotide-repeat DNA markers was performed. A positive LOD score of 3.01 was obtained for the marker D20S482 on chromosome 20p, by two-point LOD-score analysis with the MLINK program. Haplotype analysis indicated that the gene responsible for the disease is likely located in a 2.7-cM region between the markers D20S193 and D20S895. Candidate genes from the mapping region were screened for mutations.

Adult↗
PubMed1998

Chromosome mapping of Rett syndrome: a likely candidate region on the telomere of Xq.

Rett syndrome (RS) is a disease of neurological development. First reported 30 years ago in 1966, its biological and genetic basis remains obscure. RS is commonly thought of as an X linked dominant disorder lethal to hemizygous males. The few familial cases would arise through mosaicism or because of occasional females failing to manifest the disorder through skewed X inactivation in relevant cell types. We have one family where the mother and daughter are affected with RS, and which can be explained according to this hypothesis. If the alternative proposal of Thomas (1996) is correct, that the lack of males affected by such disorders is the result of a high male to female ratio of germline mutations rather than of gestational lethality, then the RS gene should be located on the grandpaternal chromosome. Genomic screening with markers covering the whole X chromosome has been performed. Studies using multiple informative markers indicate that the RS locus is likely to be located close to one of the X chromosome telomeres. Further investigations in eight additional families suggest the most likely region for the RS gene to be is the distal part of Xq (Xq28).

Chromosome Mapping↗
PubMed1997

Tenascin-C expression correlates with macrophage invasion in Duchenne muscular dystrophy and in myositis.

Tenascin-C (TN-C) is an extracellular matrix protein expressed during development in several tissues, but restricted to only a few areas in normal adult tissues. By immunizing mice with human fetal myoblasts we generated a monoclonal antibody to TN-C and mapped the epitope to the aminoterminal end containing EGF-like repeats. Using this antibody we detected by immunohistochemistry TN-C in the epimysium and perimysium of human fetal muscles, as well as in nonfibrillar deposits in myoblast cultures. In situ hybridization did not reveal any signal within human fetal muscle groups, suggesting that non-muscle cells synthesize the majority of the tenascin that localizes in and around human fetal muscle. Immunohistochemical analysis of muscle biopsies from Duchenne/Becker muscular dystrophy and myositis patients revealed that TN-C is expressed in skeletal muscle. Although the patterns of TN-C immunoreactivity were quite different in the two disease entities, the endomysial TN-C reactivity in both DMD/BMD and in myositis invariably correlated with the presence of macrophages.

Antibodies, Monoclonal↗
PubMed1997

Variation of CTG-repeat number of the DMPK gene in muscle tissue.

Myotonic dystrophy (DM) is associated with an unstable expansion of CTG repeats located in the 3' untranslated region of a protein kinase-encoding gene (DMPK) on chromosome 19 (19q13.3). The CTG repeat number varies between 5 and 37 in lymphocytes of normal individuals, whereas DM patients may have expansions from 50 to several thousand copies. Although the CTG expansions related to myotonic dystrophy (DM) are usually larger in muscle compared to peripheral blood, the variation in repeat number in non-dystrophic muscle is not known. In order to investigate if there is a variation, the CTG-repeat number was determined in percutaneous muscle biopsies obtained from 86 individuals without any muscle disorder or with a neuromuscular disorder without any clinical or histopathological signs of DM. The number of CTG repeats varied between 5 and 28, this being within the normal range reported for peripheral blood. A major sharp peak at n = 5 (27%) and a broader peak at n = 8-17 (56%) with peak values at n = 12 and 14 (11 and 14%, respectively) were observed. Alleles with 19 or more repeats amounted to 17% with a small peak at n = 20 and 21 (6 and 4%, respectively). It is concluded that the normal variation of CTG-repeat number in skeletal muscle is within the range found in peripheral blood, although there is a slight shift in the overall frequency distribution towards alleles with CTG repeat numbers in the higher range.

Alleles↗
PubMed1997

Welander distal myopathy is not linked to other defined distal myopathy gene loci.

Welander distal myopathy is an autosomal dominant disorder with late onset that affects extensor muscles of the hands and the feet. The disorder is considered as the most prevalent of the distal myopathies and is almost only seen in Sweden and in some parts of Finland. On clinical, morphological and genetical grounds the disorder is clearly separated from other distal myopathies. We have performed linkage analysis with the MLINK program in a total of six families with microsatellite markers dispersed throughout the genome and report exclusion for the localisation of the gene of 64% of the human genome. These studies have clearly separated Welander distal myopathy from previously mapped forms of distal myopathy such as the Miyoshi myopathy by excluding linkage to chromosome 2. The region on 14q that has been suggested to house the gene of the distal myopathy described by Laing et al. (Am J Hum Genet 1995;56:422-7), has as well been excluded by several markers.

Adult↗