Clinical spectrum of mitochondrial DNA mutation at base pair 8344.
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DNA Mutational Analysis↗
Biomedical subjects
G Karpati
Publications and source records attributed to G Karpati.
The pathogenesis of dermatomyositis.
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Complement Membrane Attack Complex↗
Familial inclusion body myositis among Kurdish-Iranian Jews.
We report two cases of adult-onset, slowly progressive limb-girdle muscle weakness with a remarkable sparing of quadriceps muscles that developed in patients from different families of Iranian-Kurdish-Jewish origin. Each patient had a similarly affected sibling. The findings by means of muscle biopsies showed abnormalities typical of inclusion body myositis, including abundant lined vacuoles and characteristic cytoplasmic inclusions of 15- to 18-nm filaments. Remarkably, many vacuolated muscle fibers showed immunoreactivity to neural cell adhesion molecule, a fetal muscle antigen. The common origin of these patients from an isolated ethnic group with frequent consanguinity and the familial incidence is indicative of a genetic causation or predisposition, probably with an autosomal recessive inheritance. This familial myopathy is one of several clinical syndromes that share the typical pathological findings of inclusion body myositis. The pathogenic relationship between these different familial forms and the more common sporadic form of inclusion body myositis is not known.
Adult↗
In vivo magnetic resonance spectroscopy of brain and muscle in a type of mitochondrial encephalomyopathy (MERRF).
Phosphorus magnetic resonance spectroscopy allows noninvasive measurement of the intracellular phosphate-containing metabolites and intracellular pH in localized volumes of human muscle and brain in vivo. This technique was used to study 8 patients with a mitochondrial cytopathy (myoclonus epilepsy with ragged red fibers). Phosphorus magnetic resonance spectroscopy of resting gastrocnemius muscle demonstrated significantly increased relative intracellular inorganic phosphate concentrations (p less than 0.0005) and decreased phosphocreatine to inorganic phosphate concentration ratios (p less than 0.01) in the patients, although only 3 had myopathic signs or symptoms. We propose, therefore, that phosphorus magnetic resonance spectroscopy of resting skeletal muscle is a useful clinical test in evaluation of progressive myoclonus epilepsy. In contrast to results from muscle, however, the relative phosphate metabolite concentrations and intracellular pH in central volumes of the brains of these patients were normal, despite evidence from our previous positron emission tomography studies suggesting that there is diffuse impairment of cerebral oxidative metabolism.
Brain↗
Mitochondrial dysfunction in multiple symmetrical lipomatosis.
Multiple symmetrical lipomatosis is a striking clinical finding associated with a variety of peripheral and central nervous system abnormalities. We describe 4 unrelated patients with evidence of mitochondrial dysfunction in skeletal muscle. Multiple symmetrical lipomatosis is an additional, albeit unusual, manifestation of the expanding clinical spectrum of mitochondrial diseases.
Adult↗
Glucocorticoids and immunosuppressants do not change the prevalence of necrosis and regeneration in mdx skeletal muscles.
Therapeutic doses of methylprednisolone, azathioprine, cyclosporin A, and cyclophosphamide administered to mdx mice between 15 and 45 days of age failed to significantly influence the time course and prevalence of necrosis and regeneration or serum creatine kinase activity. This finding contrasts with previously reported findings of beneficial effects of glucocorticoids in Duchenne muscular dystrophy (DMD). This may indicate that, mechanisms upon which beneficial effects of glucocorticoids depend in DMD, do not operate (sufficiently) in mdx mice.
Animals↗
Dystrophin is tightly associated with the sarcolemma of mammalian skeletal muscle fibers.
Sarcolemmal vesicles with right-side-out configuration were prepared from normal fresh human and rabbit skeletal muscle bundles by incubation in 140 mM KCl solution containing collagenase. The vesicles were used to examine the association of dystrophin, the protein product of the Duchenne muscular dystrophy gene, with the sarcolemma. Western blot analysis, indirect immunofluorescence, and immunoperoxidase staining using specific antibodies raised against the N-terminal and the C-terminal domains show that dystrophin remains associated with the membrane of sarcolemmal vesicles. Indirect immunofluorescence microscopy using permeabilized and unpermeabilized vesicles indicated that both the N-terminus and the C-terminus of dystrophin are localized to the cytoplasmic surface of the sarcolemma. These results suggest that dystrophin has much stronger attachment to the surface membrane than it has to the internal domain of skeletal muscle fibers. Sarcolemmal vesicles thus represent a new system for studying the function of dystrophin and the molecular basis of its association with the sarcolemma.
Amino Acid Sequence↗
Major alteration of the pathological phenotype in gamma irradiated mdx soleus muscles.
Two thousand rads of gamma irradiation delivered to the lower legs of ten day old normal and x-chromosome linked muscular dystrophy (mdx) mice caused significant inhibition of tibial bone and soleus muscle fiber growth. In the irradiated mdx solei, there was a major loss of muscle fibers, lack of central nucleation, and some endomysial fibrosis. These features were caused by a failure of regeneration of muscle fibers due to impaired proliferative capacity of satellite cells. Gamma irradiation transforms the late pathological phenotype of mdx muscles, so that in one major aspect (muscle fiber loss) they resemble muscles in Duchenne muscular dystrophy. However, extensive endomysial fibrosis which is another characteristic feature of Duchenne muscular dystrophy did not develop. This experimental model could be useful for the functional investigation of possible beneficial effects of therapeutic interventions in mdx dystrophy.
Animals↗
In vivo muscle magnetic resonance spectroscopy in the clinical investigation of mitochondrial disease.
We have investigated the sensitivity and specificity of a rapid phosphorus magnetic resonance spectroscopy (MRS) protocol for detecting metabolic abnormalities in vivo in skeletal muscle of patients with mitochondrial disease. We examined 17 patients with mitochondrial myopathies. Sixteen had only mild or minimal myopathic signs and symptoms. Phosphorus magnetic resonance spectra from the resting gastrocnemius muscles showed an abnormal intracellular energy state (marked by an increased intracellular inorganic phosphate concentration) in 14/17. In 3/17, this was associated with a decreased phosphocreatine concentration. We also studied 20 patients with other diseases of muscle (inflammatory myopathies, metabolic myopathies, muscular dystrophies, and myasthenia gravis) that can present with similar clinical features. Spectra showed increased intracellular inorganic phosphate concentrations in 6/20. All of these muscle diseases were associated with evidence of muscle fiber necrosis. Abnormalities in the muscle energy state in these cases may be due to secondary mitochondrial dysfunction. Except for cases of polymyositis and dermatomyositis, these 6 other myopathies could be readily distinguished from the mitochondrial myopathies on the basis of the clinical examination and blood tests. We conclude that phosphorus MRS of resting muscle is practical in a clinical setting and has a useful sensitivity and specificity for mitochondrial myopathies when used in conjunction with standard noninvasive tests.
Adenosine Triphosphate↗
Inhibition of myosatellite cell proliferation by gamma irradiation does not prevent the age-related increase of the number of dystrophin-positive fibers in soleus muscles of mdx female heterozygote mice.
In skeletal muscles of young mdx female heterozygote mice, there is a mosaic of dystrophin-positive and dystrophin-negative fiber segments. In older animals, there is a marked decline in the number of dystrophin-negative fiber segments. This phenomenon might be due to a fusion of dystrophin-competent satellite cells into the originally dystrophin-negative fiber segments during growth. To study this possibility, soleus muscles of 10-day-old mdx female heterozygotes were gamma irradiated (2000 rads) to inhibit subsequent myosatellite cell proliferation and fusion. In the irradiated soleus muscles of animals at 60 days, the relative amount of dystrophin measured by quantitative immunoblots was not significantly different from that of the contralateral nonirradiated muscles. The prevalence of dystrophin-negative fibers in the 60-day-old irradiated solei was not higher than in the nonirradiated contralateral muscles, implying that dystrophin-competent satellite cell fusion was not a significant factor in the observed conversion. A longitudinal expansion of the cytoplasmic domain of the original dystrophin-competent myonuclei during growth could explain the observed conversion phenomenon.
Aging↗
Correlative multidisciplinary approach to the study of mitochondrial encephalomyopathies.
Mitochondrial encephalomyopathies can be caused by defects in the mitochondrial respiratory complexes. The clinical phenotypes are quite protean but in many instances a characteristic or suggestive clinical presentation permits a tentative bedside diagnosis. The diagnosis can be verified by laboratory investigations. The major laboratory hallmarks of mitochondrial encephalomyopathies include: ragged red fibers on muscle biopsy, a specific defect or deficiency in a mitochondrial respiratory enzyme complex, mtDNA abnormalities, reduced anaerobic threshold by bicycle ergometry, impaired cellular energy state by MRS and characteristic brain imaging abnormalities. Monitoring of some of these parameters along with the clinical phenotype will aid in the evaluation of therapeutic trials.
Brain Diseases↗
Deletion mutants are functionally dominant over wild-type mitochondrial genomes in skeletal muscle fiber segments in mitochondrial disease.
We mapped the distribution and expression of wild-type and deleted mitochondrial DNA (mtDNA) molecules in skeletal muscle fibers of patients with mitochondrial disease. We show that ragged red fiber segments, which are characteristic histological features of these myopathies, represent focal accumulations of mitochondria containing predominantly deleted mtDNAs and that the mutant genomes are absent or extremely rare in normal fiber segments. This suggests that the mtDNA mutations play a direct role in focal mitochondrial accumulation. Although levels of wild-type mtDNAs and mRNAs in ragged red fiber segments are near normal, mitochondrial function, as revealed by cytochrome oxidase cytochemistry, is severely impaired. This suggests that the presence of mutant mtDNAs interferes with the expression of coexisting wild-type mtDNAs in these segments at a posttranscriptional level.
Base Sequence↗
Dystrophin is localized to the plasma membrane of human skeletal muscle fibers by electron-microscopic cytochemical study.
Electron-microscopic immunoperoxidase technique revealed plasmalemmal localization of dystrophin in microscopically normal human skeletal muscle fibers obtained from nine routine diagnostic muscle biopsies. There was no evidence of periodicity of the immunoreactive product nor was there any evidence of immunostaining in any organelle besides the plasma membrane. Dystrophin appears to be a cytoskeletal protein associated with the plasmalemma. Its function is presumed to be the maintenance of the mechanical stability of the surface membrane so that it can withstand the normal contraction-induced stresses without disruption.
Biopsy↗
Immunological aspects of histoincompatible myoblast transfer into non-tolerant hosts.
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Animals↗
The principles and practice of myoblast transfer.
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Animals↗
Dystrophin-deficient mdx muscle fibers are preferentially vulnerable to necrosis induced by experimental lengthening contractions.
Lengthening contractions were induced in the right anterior tibialis muscles (ATM) of anaesthetized normal and mdx (dystrophic) mice by supramaximal, nonfatiguing stimulation of the sciatic nerve for 180 min. In the left ATM of the same animals identical stimulation caused shortening contractions because of a prestimulation Achilles tenotomy. The prevalence of recently necrotic fibers was determined in all stimulated ATM by demonstrating the presence of IgG in the necrotic fibers using immunoperoxidase staining of cryostat sections. The results were compared to unstimulated normal and mdx ATM. A significantly higher rate of necrosis was demonstrated after lengthening contractions in the mdx ATM than normal ATM. Unstimulated normal and mdx ATM have either no or extremely infrequent necrotic fibers. We suggest that the enhanced vulnerability of mdx muscle fibers to lengthening contractions is related to the deficiency of dystrophin, which renders the sarcolemma more susceptible to suffer focal breaks. A similar situation may occur in Duchenne muscular dystrophy.
Animals↗
Age-related conversion of dystrophin-negative to -positive fiber segments of skeletal but not cardiac muscle fibers in heterozygote mdx mice.
Immunoreactive dystrophin was examined in muscle fibers of quadriceps, extraocular muscles and cardiac ventricular muscles of female heterozygote mdx mice at 10, 35 and 60 days of age, with microscopic immunoperoxidase method and by immunoblots. In quadriceps muscle fibers there was a marked gradual diminution of the dystrophin-negative fiber segments between age 10 and 60 days. We suggest that this was partly due to a spontaneous fusion of dystrophin-competent satellite cells into the dystrophin-negative fiber segments and partly to an expansion of the cytoplasmic domain of dystrophin expression related to the original myonuclei. In cardiac muscle that lacks satellite cells, there was persistence of a large number of dystrophin-negative fiber segments even at age 60 days and probably beyond. The findings of this study have implications for the detection of heterozygote female carriers of Duchenne muscular dystrophy (DMD) and for the possible therapy of DMD muscles by myoblast transfer.
Aging↗
Congenital inflammatory myopathy.
We present 3 patients with congenital inflammatory myopathy and summarize the literature. CNS involvement (microcephaly/intellectual delay) may or may not be present. Serum creatine kinase activity is elevated, the EMG is myopathic, and the muscle biopsy reveals inflammatory infiltrates, muscle fiber damage, and class I major histocompatibility complex products in muscle sarcolemma. Possible etiologies include intrauterine viral infection or an autoimmune process. Treatment with steroids may result in some motor improvement but has no effect on the CNS involvement. Despite a common time of presentation, these patients have a heterogeneous clinical profile, often suggesting a congenital muscular dystrophy syndrome.
Female↗