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A Oldfors

Publications and source records attributed to A Oldfors.

At least 91 records · Page 5Linked to original sources
PubMed1992

Segregation and manifestations of the mtDNA tRNA(Lys) A-->G(8344) mutation of myoclonus epilepsy and ragged-red fibers (MERRF) syndrome.

We have studied the segregation and manifestations of the tRNA(Lys) A-->G(8344) mutation of mtDNA. Three unrelated patients with myoclonus epilepsy and ragged-red fibers (MERRF) syndrome were investigated, along with 30 of their maternal relatives. Mutated mtDNA was not always found in the offspring of women carrying the tRNA(Lys) mutation. Four women had 10%-33% of mutated mtDNA in lymphocytes, and no mutated mtDNA was found in 7 of their 14 investigated children. The presence of mutated mtDNA was excluded at a level of 3:1,000. Five women had a proportion of 43%-73% mutated mtDNA in lymphocytes, and mutated mtDNA was found in all their 12 investigated children. This suggests that the risk for transmission of mutated mtDNA to the offspring increases if high levels are present in the mother and that, above a threshold level of 35%-40%, it is very likely that transmission will occur to all children. The three patients with MERRF syndrome had, in muscle, both 94%-96% mutated mtDNA and biochemical and histochemical evidence of a respiratory-chain dysfunction. Four relatives had a proportion of 61%-92% mutated mtDNA in muscle, and biochemical measurements showed a normal respiratory-chain function in muscle in all cases. These findings suggest that > 92% of mtDNA with the tRNA(Lys) mutation in muscle is required to cause a respiratory-chain dysfunction that can be detected by biochemical methods. There was a positive correlation between the levels of mtDNA with the tRNA(Lys) mutation in lymphocytes and the levels in muscle, in all nine investigated cases. The levels of mutated mtDNA were higher in muscle than in lymphocytes in all cases. In two of the patients with MERRF syndrome, muscle specimens were obtained at different times. In both cases, biochemical measurements revealed a deteriorating respiratory-chain function, and in one case a progressive increase in the amount of cytochrome c oxidase-deficient muscle fibers was found.

Adult↗
PubMed1992

Lack of transmission of deleted mtDNA from a woman with Kearns-Sayre syndrome to her child.

We have investigated the daughter of a woman with Kearns-Sayre syndrome. The woman had a high percentage of deleted mtDNA in muscle, but no deleted mtDNA was detected in fibroblasts, bone marrow, and peripheral blood cells by Southern blot analysis. With PCR, analytical sensitivity was significantly increased, and deleted mtDNA was detected in all examined tissues from this patient. The patient had healthy parents and nine healthy siblings. No deleted mtDNA was detected in blood from the mother of the patient. The patient had an uneventful pregnancy and delivered at term. Deleted mtDNA could not be detected in placenta by Southern blot analysis. With PCR, deleted mtDNA was detected in the majority of placental specimens. This finding may, however, be due to contamination with maternal DNA. The patient's daughter was healthy at age 5 mo, and morphologic examination of muscle was normal. No transmission of deleted mtDNA to the daughter could be detected by Southern blot and PCR analysis of peripheral blood cells, bone marrow, fibroblasts, and muscle. The presence of deleted mtDNA was excluded at a fractional level of less than 1:100,000 in all examined tissues from the daughter.

Adolescent↗
PubMed1991

Leber's hereditary optic neuropathy and complex I deficiency in muscle.

We investigated a family with Leber's hereditary optic neuropathy in which affected individuals were homoplasmic for the point mutation of the NADH-dehydrogenase 4 gene of mitochondrial DNA, described by Wallace and colleagues in 1988. The proband had bilateral optic atrophy, tremor, dystonia, and sharply defined lesions in the putamen on magnetic resonance images. Optic atrophy was found in another 3 of 13 investigated relatives on the maternal side. Additional neurological signs were found but only in patients with optic neuropathy. The morphological appearance and the respiratory chain function of muscle tissue were investigated in the proband, his mother, and 3 siblings. Polarographic measurements revealed complex I deficiency in the 5 investigated subjects. Morphological changes of mitochondria were found in 4 of these subjects. There was no decrease in complex I activity measured as NADH ferricyanide reductase or rotenone-sensitive NADH cytochrome c reductase activities. In other cases with complex I deficiency, good agreement between polarographic and spectrophotometric measurements was found. This study showed that there is decreased activity of complex I of the respiratory chain in muscle and that cerebral striatal lesions occur in Leber's hereditary optic neuropathy with the NADH-dehydrogenase 4 gene point mutation.

Adolescent↗
PubMed1991

Skeletal muscle regeneration in young rats is dependent on growth hormone.

Skeletal muscle fibres have a well known ability to regenerate after different kinds of injury. This study was undertaken to establish if regenerating skeletal muscle is dependent on growth hormone (GH) in the same manner as normal, growing skeletal muscle in young rats. Muscle regeneration was achieved by injection of notexin into the soleus muscle. Initial necrosis, which included all muscle fibres, was followed by a rapid and uniform regeneration throughout the muscle. Cell proliferation was estimated by scintillation counting and autoradiography of incorporated [3H]thymidine, injected intravenously 1 h before killing, 7 or 27 days after the initiation of regeneration. GH deficiency was accomplished by hypophysectomy 4 days before the [3H]thymidine injection. Cell proliferation was diminished in both regenerating and normal muscle of the hypophysectomized rats compared to control and GH-substituted rats. After 7 days of regeneration the reduction of cell proliferation seen in hypophysectomized rats was less pronounced in the regenerating than in the normal muscle. These findings demonstrate that GH plays an important role for muscle regeneration in young rats, although other substances appear to be of greater importance during the early stages of regeneration.

Animals↗
PubMed1991

Inclusion body myositis and Welander distal myopathy: a clinical, neurophysiological and morphological comparison.

Five patients with inclusion body myositis (IBM), an acquired inflammatory myopathy, and five patients with Welander hereditary distal myopathy (WDM) were compared clinically and with neurophysiological and morphological techniques. Both diseases have a late insidious onset, but the course of IBM is more severe. IBM mainly affects proximal muscles in the lower extremities, while distal muscle groups are involved in both upper and lower extremities. In WDM there is always a strict distal muscle involvement. The neurophysiological characteristics of the two conditions include both myopathic and neurogenic components. In both diseases there were rimmed vacuoles in muscle fibres and at the ultrastructural level cytoplasmic 15-18 nm filamentous inclusions. Although the histopathology of muscle in IBM and WDM has some common features, inflammatory infiltrates were never found in WDM. Such infiltrates seem to be an important clue to the correct diagnosis of IBM.

Aged↗
PubMed1991

Mitochondrial encephalomyopathies in childhood. I. Biochemical and morphologic investigations.

During a 4-year period (1984 to 1988), 50 children referred with manifestations of central nervous system or neuromuscular disease combined with hyperlactatemia were subjected to investigations that aimed to identify and characterize children with mitochondrial disorders. Biochemical and morphologic investigations of quadriceps muscle biopsy tissue were done, including oximetric and spectrophotometric analysis of the respiratory chain function, enzyme histochemistry, electron microscopy, and analysis of mitochondrial DNA. A diagnosis of mitochondrial disease was based on the presence of at least two of five criteria: (1) abnormal results of oximetry, (2) abnormal results of spectrophotometry, (3) enzyme histochemical evidence of cytochrome x oxidase deficiency, (4) deletions or point mutations of mitochondrial DNA, and (5) abundant ultrastructurally abnormal mitochondria. With the combined biochemical and morphologic investigation, 20 of the children were found to have mitochondrial disorders. In an additional 10 children a mitochondrial disorder was neither excluded nor verified. Mitochondrial disorders are thus an important cause of central nervous system and neuromuscular disease in children with hyperlactatemia.

Biopsy↗
PubMed1991

Mitochondrial encephalomyopathies in childhood. II. Clinical manifestations and syndromes.

During a 4-year period 1984 to 1988, 20 children referred with manifestations of central nervous system or neuromuscular disease combined with hyperlactatemia were found to have a mitochondrial disease. Each diagnosis was based on the results of thorough biochemical and morphologic investigations. The patients were separated into one series with mainly encephalopathy (n = 14) and another with mainly myopathy (n = 6). The patients with encephalopathy had the following syndromes: Kearns-Sayre (n = 2), MERRF (myoclonus epilepsy and ragged red fibers; n = 2), MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes; n = 3), Alpers (n = 3), Leigh (n = 1), and other variants (n = 3). In patients with myopathy, three had hypertrophic nonobstructive cardiomyopathy. Ultrastructural abnormalities of mitochondria were the most common morphologic changes in the muscle biopsies. Complex I deficiency was most common in the patients with encephalopathy. All of the patients with myopathy had complex IV deficiency. Mutations of mitochondrial DNA were found in six patients with encephalopathy. We conclude that identification of defects at the DNA level and determination of the phenotypic expression with clinical, morphologic, and biochemical methods are fundamental for future rational classification of mitochondrial disorders.

Adolescent↗
PubMed1991

A freeze-fracture study of the perineurium in normal and protein-deprived rats.

Observations have been made using the freeze-fracture replication technique on the perineurium of normal and protein-deprived rats in which its permeability barrier function is known to be deficient. The perineurial cells of young normal rats possessed belt-like tight junctions (zonulae occludentes) at the borders and maculae occludentes at sites remote from their borders. In older rats, the zonulae occludentes were more prominent and the maculae occludentes relatively less frequent. No abnormalities were detected in the tight junctions of young rats with early induction of protein deficiency but this may have been related to sampling problems. In older severely protein-deficient animals, although many of the tight junctions were normal, some were abnormal and contained focal regions of dispersed strands. The density of caveolae in the surface membrane of the perineurial cells of older rats with severe protein deficiency was significantly greater than in the control animals. This provides support for the view that the pinocytotic-like vesicles of perineurial cells are involved in transport of substances across the cells. The increased numbers of caveolae in the protein deficient rats may reflect increased transcellular traffic. There were considerable differences in the density of P-face IMPs between the different perineurial lamellae, but the results did not allow a decision to be made as to whether there was a polarization of the cells between their endoneurial and epineurial aspects. No differences were detected in the density of P-face IMPs between the young control and protein-deprived rats. In the perineurium of the older rats with protein deficiency, IMP density was significantly greater in the E face than in the controls but not different in the P face. The delay in the development of enzymatic activity in the perineurium of protein-deficient rats that has been demonstrated histochemically is therefore not paralleled by a reduction in IMPs.

Animals↗
PubMed1990

Neuropathology in Kearns-Sayre syndrome.

The neuropathological changes found at autopsy in a case of Kearns-Sayre syndrome are described. We have previously analyzed the respiratory chain function in isolated muscle mitochondria and also described a large deletion of muscle mitochondrial DNA (mtDNA) in this case. The neuropathological examination revealed prominent neuronal degeneration and gliosis of the basal ganglia and there were bilateral areas of softening and total loss of nerve cells in the lenticular nuclei. The pallidum and caudate nucleus disclosed accumulation of iron-containing pigment. The white matter in the cerebrum, brain stem and cerebellum showed widespread and focally accentuated spongy change due to splitting of myelin lamellae. It is suggested that deficiency of respiratory chain enzymes due to the mtDNA deletion is of pathogenetic importance in the development of the described changes.

Adult↗
PubMed1990

Inclusion body myositis: peripheral nerve involvement. Combined morphological and electrophysiological studies on peripheral nerves.

The occurrence of neuropathy in 5 cases of inclusion body myositis (IBM) was studied. The intramuscular nerve branches showed variable ultrastructural changes in all cases. The observed changes were loss of axons, wallerian degeneration and axon terminal atrophy. EMG with concentric needles showed myopathic motor unit potentials in all cases. A reduced interference pattern due to loss of motor units was found in all cases. All but one patient showed fibrillation potentials in several muscle groups. Motor nerve conduction velocities and F-wave latencies were pathological in two of the cases, in which there were motor unit potentials with increased amplitude and duration as evidence of reinnervation. Sural nerve biopsy in one of these cases revealed slight neuropathy of the axonal type. These findings support the concept of peripheral nerve involvement in many cases of IBM.

Action Potentials↗
PubMed1990

X-linked myotubular myopathy: a linkage study.

Two families with the congenital X-linked infantile form of myotubular myopathy have been investigated by linkage analysis using markers from the X-chromosome. Linkage was found at the locus Xq28 (with DXS52). The analysis gave a peak lod score of 2.41 at the recombination fraction zero. Free recombinations (theta = 0.50) were seen using the markers DXS84, DXS14 and DXS146 from the p arm of the X-chromosome. Since the disorder is very rare, it is important to add cumulative linkage data from the few families that do exist.

Female↗
PubMed1990

Effects of growth hormone on muscle regeneration and IGF-I concentration in old rats.

A study was made of regeneration of skeletal muscle in young adult and old rats and of the effects of administration of growth hormone to old rats. Regeneration was achieved by subjecting the right extensor digitorum longus muscle to ischaemic necrosis. The level of insulin-like growth factor I in serum was markedly decreased in old rats of 27 months of age compared with young adult rats aged 6 months. Daily injections of 4 IE recombinant human growth hormone during the 10 weeks of regeneration increased the level of insulin like growth factor I to almost the same levels as in rats aged 6 months. The body weight increased by 13% in the old rats treated with recombinant human growth hormone, while the weight of the untreated old rats was constant. The regenerating right and the normal left extensor digitorum longus muscles were studied 10 weeks after the ischaemic necrosis. The absolute and relative weights of regenerating muscle were decreased in 27-month-old rats compared with the rats aged 6 months. No significant difference between normal old rats and old rats treated with recombinant human growth hormone was observed either in muscle weight or in maximum contraction force. The results show that old rats have reduced levels of circulating insulin-like growth factor I. Administration of recombinant human growth hormone raises the level of insulin-like growth factor I to that of young adult rats, and causes an increased body weight. Muscle regeneration after ischaemic necrosis is impaired in old rats apparently by the formation of large amounts of connective tissue. Supplementation with growth hormone does not reverse this impairment.

Aging↗
PubMed1990

Progressive increase of the mutated mitochondrial DNA fraction in Kearns-Sayre syndrome.

We have performed morphologic and biochemical studies in three pediatric cases of Kearns-Sayre syndrome. All cases had heteroplasmy with a high percentage of mitochondrial DNA (mtDNA) with deletion in muscle. The deletions were mapped to the same region of mtDNA but were of different sizes. The same type of deletion could also be detected in fibroblasts from all cases but the percentage was considerably lower. In two cases, an increase with time of the mutated mtDNA fraction in muscle was found and this increase paralleled the progression of the disease. Oximetric evaluation of respiratory-chain function in isolated muscle mitochondria showed a complex I deficiency in one case and was normal in the two other cases. Comparison of the fractional concentration of mtDNA with deletion in muscle and isolated mitochondria showed that the isolated mitochondria were not representative of the mitochondrial population in muscle. Mitochondria with high percentage of mtDNA with deletion were selectively lost. The finding of different mitochondrial populations is in good agreement with the morphology. One case spontaneously recovered from an infantile sideroblastic anemia before the development of Kearns-Sayre syndrome. The anemia was of the same type as that in Pearson's syndrome, a mitochondrial disorder with high amounts of mtDNA with deletion in blood cells. These findings indicate that the phenotype of a mtDNA deletion disorder can change with time and is governed by the fractional concentration of mtDNA with deletion in different tissues.

Adolescent↗
PubMed1989

Autofluorescence emission spectra of neuronal lipopigment in mucopolysaccharidosis (Sanfilippo's syndrome).

Characteristics of intraneuronal lipopigment in two siblings with Sanfilippo's syndrome are reported. A lipopigment emission spectrum probably reflects its composition and the (uncorrected) autofluorescence emission spectra results are compared with spectra from non-diseased tissue and from previously reported childhood-onset neuronal ceroidlipofuscinoses (ceroidoses), adult-onset ceroidosis (Kufs' disease) and animal ceroidoses. Values derived from the emission spectra from Sanfilippo's syndrome could be distinguished from those obtained from equivalent regions of non-diseased brains and were within the range of abnormal values previously reported from accumulations of pigment in various types of neuronal ceroidosis. Some abnormal lipopigment in Sanfilippo tissue was indistinguishable from some lipopigment in childhood-onset ceroidosis and in Kufs' disease. These results indicate that the intraneuronal lipopigment which accumulates to an abnormal extent in Sanfilippo's syndrome should not be termed "lipofuscin", which is a normal cerebral constituent, but "ceroid" to denote lipopigment with abnormal characteristics.

Adult↗
PubMed1989

Cytochrome c oxidase deficiency in infancy.

Five children with early onset of muscle weakness, lactic acidosis and deficient cytochrome c oxidase staining in the muscle biopsy were studied. By oximetric assay of the respiratory chain of isolated mitochondria, cytochrome c oxidase deficiency was confirmed in four of the cases, while one case showed only a slight decrease of cytochrome c oxidase activity but considerably reduced activity when assayed spectrophotometrically. The muscle biopsies exhibited mitochondrial structural abnormalities and lipid storage in the four cases with oximetrically confirmed cytochrome c oxidase deficiency, while the biopsy of the case with markedly reduced activity of cytochrome c oxidase only in the enzyme-histochemical and spectrophotometrical assays had normal morphology. The light microscopical staining of cytochrome c oxidase in the four cases with oximetrically confirmed deficiency showed deficient staining of the enzyme in all extrafusal fibres in three cases but one of the cases had normal enzyme-histochemical activity of cytochrome c oxidase in about 25% of the fibres. In two cases muscle spindles were included in the biopsy. The intrafusal fibres showed normal enzyme-histochemical activity of cytochrome c oxidase. Ultrastructural examination of the enzyme distribution in two of the cases revealed great heterogeneity of the mitochondria. The structurally abnormal mitochondria were usually deficient of enzyme activity. The mitochondria of endothelial cells appeared to have normal activity. Immunohistochemical staining with polyclonal antibodies to cytochrome c oxidase revealed presence of immunoreactive material corresponding to the localisation of mitochondria in all cases.(ABSTRACT TRUNCATED AT 250 WORDS)

Biopsy↗
PubMed1989

Muscle regeneration. The effect of hypophysectomy on cell proliferation and expression of insulin-like growth factor-I.

Against the background of the importance of growth hormone (GH) for normal muscle growth, a study was performed to investigate whether lack of GH after hypophysectomy affects the cell proliferation and the local production of insulin-like growth factor-I (IGF-I) in the early stages of muscle regeneration in adult rats. The level of IGF-I in the serum of hypophysectomised rats was reduced to about 30% of that of controls. The incorporation of [methyl-3H]thymidine into the regenerating muscle showed a peak 6 days after the operation and then gradually declined to the end of the period of study 30 days after initiation of regeneration by ischemic necrosis. The DNA content rose to a maximum level after 6-8 days, and remained high after 30 days. There was no major difference in the incorporation of [3H]thymidine in regenerating muscle of hypophysectomised and control rats, but the DNA concentration in the regenerating muscles of hypophysectomised rats was significantly reduced after 30 days. There was a corresponding reduction in the number of nuclei per muscle fibre, indicating that hypophysectomy has a small effect on the cell proliferation during the early stages of muscle regeneration. Immunohistochemical demonstration of IGF-I in the regenerating muscle revealed the transient presence of immunoreactive material in satellite cells and myotubes after 6 to 8 days of regeneration but no immunoreactivity after 30 days. No obvious difference was observed between hypophysectomised and control rats, indicating that the endogenous production of IGF-I in regenerating skeletal muscle can occur independently of GH.

Animals↗