An A-to-G transition at nucleotide pair 11084 in the ND4 gene may be an mtDNA polymorphism.
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Adenine↗
Biomedical subjects
I Nonaka
Publications and source records attributed to I Nonaka.
Mild deficiency of dystrophin-associated proteins in Becker muscular dystrophy patients having in-frame deletions in the rod domain of dystrophin.
The dystrophin-glycoprotein complex spans the sarcolemma to provide a linkage between the subsarcolemmal cytoskeleton and the extracellular matrix in skeletal muscle. In Duchenne muscular dystrophy (DMD), the absence of dystrophin leads to a drastic reduction in all of the dystrophin-associated proteins in the sarcolemma, thus causing the disruption of the dystrophin-glycoprotein complex and the loss of the linkage to the extracellular matrix. The resulting sarcolemmal instability is presumed to render muscle fibers susceptible to necrosis. In the present study, we investigated the status of the dystrophin-associated proteins in the skeletal muscle from patients with Becker muscular dystrophy (BMD), a milder allelic form of DMD. BMD patients having in-frame deletions in the rod domain of dystrophin showed a mild to moderate reduction in all of the dystrophin-associated proteins in the sarcolemma, but this reduction was not as severe as that in DMD patients. The reduction of the immunostaining for the dystrophin-associated proteins showed a good correlation with that for dystrophin in both intensity and distribution. Our results indicate that (1) the abnormality of the sarcolemmal glycoprotein complex, which is similar to but milder than that in DMD patients, also exists in these BMD patients and (2) the rod domain of dystrophin is not crucial for the interaction with the dystrophin-associated proteins.
Adolescent↗
[A case of rigid spine syndrome--histological findings of muscles].
A 10-year-old boy with rigid spine syndrome was reported. He had mild weakness in the limb, and moderate weakness in the neck flexor and extensor muscles since early childhood. Because of limited flexion of the spine, he could not bend down. CT of the muscles revealed increased low density in the erector spine muscle, predominantly at the lumbar level. In the biopsy specimens obtained from the left biceps brachii and erector spine muscles, there was a variation in fiber size with scattered necrotic and regenerating fibers, and fibrosis, predominantly in the latter. Except for scattered fibers with rimmed vacuoles, the overall histopathological features were similar to those seen in progressive muscular dystrophies, suggesting that the dystrophic process is one of the major pathomechanisms for rigid spine syndrome.
Child↗
[The significance of cytoplasmic body in neuromuscular diseases].
To know the significance of cytoplasmic body (CB), the incidence and histochemical characteristics of the body were examined on muscle biopsied specimens from patients with various neuromuscular diseases. The CB was identified in a variety of neuromuscular diseases including metabolic disorders, muscular dystrophies, and neurogenic atrophies. The incidence varied from biopsy to biopsy comprising up to 93% of muscle fibers. The CB was numerous in type II glycogen storage (Pompe) disease, mitochondrial myopathies, especially in ragged-red fibers, inflammatory myopathies, myotonic dystrophy, and small denervating and degenerating fibers. Since the CB was present mostly in areas with increased acid phosphatase activity, it is thought to be a secondarily induced product from focal myofibrillar degeneration.
Humans↗
[A patient with lysosomal glycogen storage disease with normal acid maltase].
A 13-year-old boy with mental retardation developed idiopathic cardiomyopathy and glycogen storage myopathy, but with normal lysosomal enzyme activities, consistent with a syndrome of lysosomal glycogen storage disease with normal acid maltase coined by Danon et al (1981). He was in good health except for WPW syndrome diagnosed at 7 years of age. He had heart murmur with abnormal ECG, elevated serum GOT, GPT, LDH, CK and aldolase levels. An echocardiogram showed obstructive hypertrophic cardiomyopathy. Lysosomal enzyme activities including acid alpha-glucosidase in fibroblasts were within normal limits. In the biopsied biceps brachii muscle, there was a mild variation in fiber size. An approximately 10 percent of myofibers had tiny vacuoles which contained periodic acid Schiff positive granules and were slightly high in acid phosphatase activity. The vacuoles were encircled by membranes with high neuron specific enolase (NSE) and acethylcholin-esterase (AchE) activities. On electron microscopy, numerous autophagic vacuoles scavenging glycogen granules were recognized as seen in acid maltase deficiency. Because the vacuolar membranes were high in NSE and AchE activities, lysosomal membrane formation from the cell membrane may be defective. When one has a patient with mild to moderate mental retardation, idiopathic hypertrophic cardiomyopathy and high serum CK level, muscle biopsy must be performed to rule out the present disorder.
Adolescent↗
Characterization of a macrophage lineage cell colony-stimulating factor produced by thymic myoid cells.
Thymic myoid cells produced macrophage lineage cell stimulatory factors. Activities were separated into two factors on DEAE-Sepharose CL-6B chromatography: one eluted at lower concentrations of NaCl and the other at higher concentrations of NaCl. The latter fraction was purified to homogeneity with an apparent molecular weight of 100,000. This factor stimulated the growth of macrophage-lineage cells from the bone marrow, but not that of granulocytes, megakaryocytes or erythroblasts. The 100,000 MW factor was able to induce Ia antigens on proliferating bone marrow cells. These results suggest that myoid cell-derived 100,000 MW factor plays significant roles in the generation of Ia-positive macrophage lineage cells which are important for T-cell development in the thymus.
Animals↗
MELAS mutation in mtDNA binding site for transcription termination factor causes defects in protein synthesis and in respiration but no change in levels of upstream and downstream mature transcripts.
The pathogenetic mechanism of the mitochondrial tRNA(LeuUUR) gene mutation responsible for the MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) syndrome was investigated in transformants obtained by transfer of mitochondria from three genetically unrelated MELAS patients into human mitochondrial DNA (mtDNA)-less (rho 0) cells. Marked defects in mitochondrial protein synthesis and respiratory activity were observed in transformants containing virtually pure mutant mtDNA, as compared to the parent of the rho 0 cells (the 143B cell line) or to transformants containing exclusively wild-type mtDNA, derived from one of the patients or a maternally related asymptomatic individual. A striking protective effect against the mutation was exerted in the transformants by levels of residual wild-type mtDNA above 6%. The MELAS mutation occurs within the mtDNA binding site for a protein factor (mTERF) that promotes termination of transcription at the 16S rRNA/tRNA(LeuUUR) gene boundary. A marked decrease in affinity of purified mTERF for the mutant target sequence was observed in in vitro assays. By contrast, RNA transfer hybridization experiments failed to show any significant change in the steady-state amounts of the two rRNA species, encoded upstream of the termination site, and of the mRNAs encoded downstream, in the transformants carrying the MELAS mutation.
Acidosis, Lactic↗
Possible influences on the expression of X chromosome-linked dystrophin abnormalities by heterozygosity for autosomal recessive Fukuyama congenital muscular dystrophy.
Abnormalities of dystrophin, a cytoskeletal protein of muscle and nerve, are generally considered specific for Duchenne and Becker muscular dystrophy. However, several patients have recently been identified with dystrophin deficiency who, before dystrophin testing, were considered to have Fukuyama congenital muscular dystrophy (FCMD) on the basis of clinical findings. Epidemiologic data suggest that only 1/3500 males with autosomal recessive FCMD should have abnormal dystrophin. To explain the observation of 3/23 FCMD males with abnormal dystrophin, we propose that dystrophin and the FCMD gene product interact and that the earlier onset and greater severity of these patients' phenotype (relative to Duchenne muscular dystrophy) are due to their being heterozygous for the FCMD mutation in addition to being hemizygous for Duchenne muscular dystrophy, a genotype that is predicted to occur in 1/175,000 Japanese males. This model may help explain the genetic basis for some of the clinical and pathological variability seen among patients with FCMD, and it has potential implications for understanding the inheritance of other autosomal recessive disorders in general. For example, sex ratios for rare autosomal recessive disorders caused by mutations in proteins that interact with X chromosome-linked gene products may display predictable deviation from 1:1.
Abnormalities, Multiple↗
A novel point mutation in the mitochondrial tRNA(Leu)(UUR) gene in a family with mitochondrial myopathy.
A T-to-C transition mutation at nucleotide position 3,250 in the mitochondrial tRNA(Leu)(UUR) gene was present in a family with mitochondrial myopathy. Two of three muscle biopsies examined had complex I (NADH-ubiquinone oxidoreductase) deficiency. Heteroplasmy of wild and mutant mitochondrial DNA was detected by Nae I digestion of the polymerase chain reaction products with a modified primer. This was found in blood or muscle samples or both from all seven members examined. Similar to the 3,243 mutation in most patients with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes), the new mutation site was located in the dihydrouridine loop and embedded in the binding region of mitochondrial transcription termination factor. Elucidation of the effects of this mutation may help clarify the role of mitochondrial tRNAs and transcription termination.
Base Sequence↗
Mitochondrial DNA mutation and Leigh's syndrome.
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Child↗
Segmental cytochrome c-oxidase deficiency in CPEO: teased muscle fiber analysis.
In an attempt to elucidate the pathogenesis of focal cytochrome c-oxidase (COX) deficiency in skeletal muscle from patients with chronic progressive external ophthalmoplegia (CPEO), we examined the longitudinal distribution of COX activity in single muscle fibers from 6 CPEO patients with muscle mitochondrial DNA (mtDNA) deletions. A new method for teasing single muscle fibers, recently developed in our laboratory, revealed fibers with COX-positive and -negative segments in all 6 patients. The borders between the enzyme-positive and -negative segments in these fibers were sharply delineated, so that the length of each COX-negative segments could be accurately measured. The proportion of the sum of the lengths of the enzyme-negative segments to the total length of the muscle fibers correlated well with the proportion of deleted mtDNA, suggesting that abnormal mitochondria harboring mutant mtDNA may be responsible for the focal loss of COX activity.
Adolescent↗
An experimental model of mitochondrial myopathy: germanium-induced myopathy and coenzyme Q10 administration.
In skeletal muscles from rats treated with germanium for 23 weeks, there were numerous ragged-red fibers and cytochrome-c oxidase (COX)-deficient fibers. Biochemically, germanium reduced the enzyme activities in the mitochondrial respiratory chain. Rotenone-sensitive NADH-cytochrome-c reductase as well as COX activities were markedly reduced, while succinate-cytochrome-c reductase was less severely, but significantly, affected. The histopathological findings in these muscles were similar to those seen in patients with mitochondrial encephalomyopathy, suggesting that germanium-induced myopathy may be a useful experimental model. Coenzyme Q10 administration appeared to be ineffective in preventing this experimental myopathy.
Animals↗
Comparison of behavior in muscle fiber regeneration after bupivacaine hydrochloride- and acid anhydride-induced myonecrosis.
We compared the morphologic characteristics of muscle fiber necrosis and subsequent regeneration after injury induced by intramuscular injections of bupivacaine hydrochloride (BPVC) and a variety of solutions at acid and alkaline pH (acetic anhydride, citric acid buffer, and sodium carbonate buffer). After BPVC injection the necrotic muscle fibers were rapidly invaded by phagocytic cells, followed by active regeneration and very little fibrous scar formation. The regenerating muscle fibers increased rapidly in size and attained complete fiber type differentiation and regained their initial fiber diameter within 1 month. Both alkaline and acid solutions induced muscle fiber necrosis followed by regeneration. Fiber necrosis induced by alkaline buffers and acetic anhydride solutions above pH 5.0 produced changes quite similar to that induced by BPVC. However, injection with 0.1 M acetic anhydride at pH below 4.0 resulted in coagulative necrosis of the injured muscle with very little phagocytic infiltration with poor regenerative activity and dense fibrous tissue scarring. Thus, pH 4.0 appears to be the critical pH determining the type of muscle injury and subsequent poor phagocytic and regenerative activities. This model of acidic acetic anhydride injury may lead to the identification of factors which interfere with regeneration and cause fibrous tissue scarring in human muscular dystrophy.
Anhydrides↗
Recovery of the missing tumorigenicity in mitochondrial DNA-less HeLa cells by introduction of mitochondrial DNA from normal human cells.
The role of mitochondrial DNA (mtDNA) in the expression of the transformed phenotype was examined using mtDNA-less HeLa cells. Complete depletion of mtDNA and its products in the mtDNA-less HeLa cell line, EB8, was confirmed by Southern blot analysis and by [35S]methionine labeling of mitochondrially synthesized polypeptides. The tumorigenicity of the EB8 cells was assayed by inoculation of 1 x 10(7) cells subcutaneously into the backs of nude mice. The results showed that the tumorigenicity of HeLa cells was lost in good correspondence with the loss of mtDNA. However, the growth of EB8 cells in culture was very poor compared with that of HeLa cells, indicating that the apparent loss of tumorigenicity in EB8 cells could possibly be due to poor growth of the cells. Introduction of mtDNA from normal human fibroblasts into EB8 cells restored both the missing tumorigenicity and growth of the EB8 cells. These observations could be interpreted to show that mtDNA is required for expression of tumorigenicity, but that mutational changes of the mtDNA are not required for modulation of the phenotype in our experiments.
Animals↗
Congenital focal muscle dysplasia in the lower extremities from probable abnormal innervation: a case report.
A two-year-seven-month-old girl with pes equinovarus congenita, muscle hypotonia and weakness limited to the lower extremities is presented. Upon admission to our hospital, she could stand with support but could not walk alone. Serum creatine kinase level was normal and the electromyogram was nondiagnostic. The muscle CT disclosed an almost total absence of bilateral vastus lateralis and medialis, rectus femoris and gastrocnemius muscles. The biopsied vastus lateralis muscle was almost completely replaced by fat tissue, and a small amount of muscle tissue showed uniform type 1 fiber and an aggregate of atrophic fibers in one fascicle. Because of an absence of progressive muscle weakness and neurogenic EMG findings, the authors conclude that the muscle pathology was due to the congenital anomalous condition of probable abnormal innervation to developing muscles.
Child, Preschool↗
Infantile polymyositis: a case report.
A 10-month-old Japanese boy developed progressive muscle weakness and hypotonia at 3 months of age. Because of striking inflammatory cellular infiltration in his muscle biopsy, he was diagnosed as having infantile polymyositis and was placed on steroid and immunosuppressive medication when he was 10-month-old. His physical condition was not significantly altered, though serum creatine kinase (CK) level was normalized (1,500 iu/l----90 iu/l). These findings contrast with previous reports documenting improvement with steroid administration.
Adrenal Cortex Hormones↗
Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS): a correlative study of the clinical features and mitochondrial DNA mutation.
We studied 40 MELAS patients (21 male and 19 female) to characterize the clinical features and biochemical and muscle biopsy findings related to the mtDNA mutation at the nucleotide position of 3,243, the most common genetic defect in MELAS. The most frequent symptom was episodic sudden headache with vomiting and convulsions, which commonly affected patients aged 5 to 15 years (80%). Biochemical defects in the muscle were variable; 13 patients had complex I, seven complex IV, and four complexes I + IV deficiencies. In four muscle biopsies without ragged-red fibers or any enzyme defect, we based the diagnosis on the identification of strongly SDH-reactive blood vessels, which occurred in 87.5% of the biopsies. The mtDNA mutation was present in 32 of 40 patients (80%). We conclude that there are no clinical and pathologic differences between the patients with and without this mtDNA mutation.
Acidosis, Lactic↗
[Reducing body myopathy--a case report].
A 2-year-old girl with reducing body myopathy was reported. She had no family history of neuromuscular disease. She developed normally with no delay in milestones during infancy. She had no muscle weakness or hypotonia up to 2 years of age when she received mumps vaccination. Three days after the injection, she was first noticed to have limb muscle weakness. The muscle weakness progressed rapidly with increasing difficulty in gait and raising the upper arms, particularly the left. Four months later, she had difficulty in keeping her head up and could no longer climb the stairs. On physical examination, she had proximal dominant generalized muscle weakness, with a preferential neck muscle involvement. She walked waddlingly and stood up with Gowers' maneuver. Facial and ocular muscles were intact. No dysarthria, dysphagia or respiratory difficulty was noted. EMG showed myopathic pattern. Serum creatine kinase level was moderately elevated to 739 IU/l. In the biopsied left biceps muscle, there was marked variation in fiber size, but no apparent necrotic or regenerating fibers. The most striking feature was the presence of numerous eosinophilic inclusions which reduced nitroblue tetrazolium (NBT) and were, therefore, stained dark with menadione-linked alpha-glycerophosphate dehydrogenase even without the substrate of menadione, showing the histochemical characteristics of "reducing" body. The bodies were predominantly seen in fibers with disorganized intermyofibrillar networks and with high acid phosphatase activity. On electron microscopy, the reducing bodies consisted of fine granular material with the similar electron density to the chromatin granules and were located mostly around the degenerated nuclei, suggesting the nuclear degeneration playing a role in forming the reducing bodies.(ABSTRACT TRUNCATED AT 250 WORDS)
Child, Preschool↗