Biomedical subjects

I Nonaka

Publications and source records attributed to I Nonaka.

At least 289 records · Page 16Linked to original sources

PubMed1992

Mitochondrial diseases.

With the discovery of mitochondrial DNA (mtDNA) mutations in different neuromuscular disorders, investigations now seek to clarify how the mutant mtDNA induces biochemical and morphologic defects. In one of the most important approaches human mutant mtDNA is transferred into cells that lack mtDNA to examine the relationship between the amount of mutant mtDNA and defects in cell growth, respiration and enzyme activities. The resulting cells are 'cybrids'; these clonal cells contain the heteroplasmic mutant and normal mtDNA from patients with mitochondrial diseases. The mitochondria become functionally defective when the amount of mutant mtDNA exceeds a certain threshold, which differs from mutation to mutation: 60 to 70% in chronic progressive external ophthalmoplegia (CPEO) and probably 95% in the syndromes of mitochondrial encephalopathy, myopathy, lactic acidosis, and stroke-like episodes (MELAS), and myoclonic epilepsy with ragged red fibers (MERRF). This threshold effect may explain the tissue-specific patterns of clinical expression.

Chromosome Deletion↗

PubMed1992

[Strongly succinate dehydrogenase-reactive blood vessels (SSV) in various neuromuscular diseases].

The strongly succinate dehydrogenase-reactive blood vessels (SSV) are shown to have increased numbers of enlarged mitochondria in smooth muscle cells of the vessel wall on electron microscopy. They are seen in biopsied skeletal muscles from patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) at high frequency. The present study was done to examine the incidence of SSV in biopsied muscles from various neuromuscular diseases. Among 107 patients with mitochondrial encephalomyopathies (MEM) including 50 with chronic progressive external ophthalmoplegia (CPEO), 7 with myoclonus epilepsy with ragged-red fibers (MERRF), and 50 with MELAS, SSV were seen in nearly a half of the patients, and comprised approximately 24% of small arteries. On the other hand, SSV in 100 patients with various neuromuscular diseases other than MEM were exceptional, and only one of 8 patients with myotonic dystrophy had SSV. These findings suggest that the SSV are induced by functional abnormality of mitochondria in smooth muscle cells, and that an identification of the SSV is an additional crucial evidence to make a pathological diagnosis of MEM.

Blood Vessels↗

PubMed1992

[A case of autoimmune polyglandular deficiency associated with progressive myopathy].

We reported a 29-year-old woman with autoimmune polyglandular deficiency (APGD) type 1 accompanied by progressive myopathy. She had chronic mucocutaneous candidiasis at the age of 3, primary hypothyroidism at 12, insulin dependent diabetes mellitus at 27, and adrenal insufficiency at 29 years. Laboratory findings indicated an underlying defect in cell mediated immunity. Meanwhile, she had progressive muscular weakness and wasting at the age of 22 years which brought her to our hospital at 29 years. On admission, she could not walk without support and raise her arms up to the level of shoulders. Moderate to severe muscle wasting as well as weakness was observed in the limb girdle muscles. Serum CK levels were mildly elevated. A needle EMG examination disclosed short-duration and low-amplitude polyphasic motor units at voluntary contraction with few fibrillations and positive sharp waves at rest. On muscle CT examination, decreased density was detected in the neck extensor, paravertebral, rectus femoris, vastus intermedius, biceps femoris and soleus muscles. Muscle biopsy was performed on the biceps brachii and rectus femoris muscles. The former showed chronic dystrophic changes including marked variation in fiber size with necrotic and degenerating process, interstitial fibrosis, and lobulated and right fibers. In the latter, in addition to variation in fiber size with some necrotic fibers and occasional multi-core structures, nemaline bodies were seen in approximately 30% of muscle fibers. The progressive muscle involvement in our patient might be induced from 1) endocrine abnormality, 2) autoimmune disorder, and/or 3) coincidental complication of nemaline myopathy or limb girdle muscular dystrophy. The clinical and laboratory examinations, however, failed to support any of them.(ABSTRACT TRUNCATED AT 250 WORDS)

Addison Disease↗

PubMed1992

[Vascular pathology in chronic progressive external ophthalmoplegia with ragged-red fibers].

Vascular involvement in biopsied muscle specimens from 11 patients with chronic progressive external ophthalmoplegia (CPEO) with ragged-red fibers (RRF) was studied. Almost none of 69 intramuscular arteries examined were strongly stained with succinate dehydrogenase (SDH) except one patient who had 2 SSV (strongly SDH-reactive blood vessels) in his muscle biopsy. Although RRF and focal cytochrome c oxidase (CCO) deficiency in muscle fibers were the common histochemical changes in muscle biopsy specimens from CPEO patients, all mitochondria in both endothelial and smooth muscle cells of the arteries had normal morphology except for the two SSV and all mitochondria in the blood vessels had normal CCO activity by electron cytochemistry. The findings obtained from the present study were quite different from those in mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), and myoclonus epilepsy associated with ragged-red fibers (MERRF) in which the striking vascular involvement with SSV is the most common and major abnormality in muscle biopsy specimens. To study vascular involvement in mitochondrial encephalomyopathies is the one of very important clues to understand the pathophysiology of phenotypic expressions in mitochondrial encephalomyopathies.

Adolescent↗

PubMed1992

[Ergometric and pathologic study of a family with complex I deficiency].

We studied a family with a myopathic form of complex I deficiency with regard to the clinical symptoms, usefulness of the exercise tolerance test with an ergometer for screening of mitochondrial abnormalities, pathological findings in biopsied muscles and genetics. In this family, none of the members had disorders of the central nervous system, such as convulsions, mental deterioration or stroke-like episodes. In the two affected generations, three mothers and three children had mitochondrial abnormalities. Two children were diagnosed as having complex I deficiency. One of them, an 8-year-old girl with normal psychomotor development during infancy, began to experience easy fatigability at about 3 years of age. At the age of 5 years, she experienced respiratory distress and became unconscious. Thereafter, she had similar episodic respiratory problems with lactic acidosis. Ragged-red fibers and respiratory chain enzyme defects were detected in the biopsied muscle. Another child, a 15-year-old boy with easy fatigability but no muscle weakness, had normal respiratory chain enzyme activities and a normal oxysogram: oxygen consumption showed a normal responses when malate and pyruvate were added as substrates for the isolated mitochondria. His muscle pathology revealed rare ragged-red fibers and abnormal subsarcolemmal mitochondrial aggregation. An investigation with an ergometer showed elevated serum lactate and pyruvate levels. Only one mother had muscle weakness and hyper-lactic acidemia. The other two mothers had no muscle symptoms, but abnormal results were obtained with the ergometer.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1991

Introduction of disease-related mitochondrial DNA deletions into HeLa cells lacking mitochondrial DNA results in mitochondrial dysfunction.

Mutant mitochondrial DNA with large-scale deletions (delta-mtDNA) has been frequently observed in patients with chronic progressive external ophthalmoplegia (CPEO), a subgroup of the mitochondrial encephalomyopathies. To exclude involvement of the nuclear genome in expression of the mitochondrial dysfunction characteristic of CPEO, we introduced the mtDNA of a CPEO patient into clonal mtDNA-less HeLa cells and isolated cybrid clones. Quantitation of delta-mtDNA in the cybrids revealed that delta-mtDNA was selectively propagated with higher levels of delta-mtDNA correlating with slower cellular growth rate. In these cybrid clones, translational complementation of the missing tRNAs occurred only when delta-mtDNA was less than 60% of the total mtDNA, whereas accumulation of delta-mtDNA to greater than 60% resulted in progressive inhibition of overall mitochondrial translation as well as reduction of cytochrome c oxidase activity throughout the organelle population. Because these cybrids shared the same nuclear background as HeLa cells, these results suggest that large-scale deletion mutations of mtDNA alone are sufficient for the mitochondrial dysfunction characteristic of CPEO.

Adolescent↗

PubMed1991

Dystrophin-related protein in the fetal and denervated skeletal muscles of normal and mdx mice.

The amino acid sequence of the polyclonal antibodies we developed against the carboxyl terminus of the dystrophin-related protein, the putative gene product of B3 cDNA, had no homologous sequence to the dystrophin molecule except for two amino acids located at its ends for immunization. By immunohistochemical examination in C57B1/10ScSn and C57B1/10ScSn-mdx mice we found that the DRP was expressed on the surface membrane of fetal muscle fibers, was assembled at the neuromuscular junctions of the mature muscle fibers, and reappeared on the surface membrane of muscle fibers after denervation. Its localization was similar to that of the acetylcholine receptor, suggesting that DRP is one of the cytoskeletons which organize and stabilize the cytoplasmic domain of the acetylcholine receptor.

Aging↗

PubMed1991

A new mtDNA mutation associated with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS).

In 3 of 40 MELAS patients, a new common mutation, a T-to-C transition at nucleotide position 3271 in the mitochondrial tRNA(Leu(UUR] gene was recognized and was very near to the most common mutation site at 3243. With a simple detection method using polymerase chain reaction with a mismatch primer, none of 46 patients with other mitochondrial diseases and 50 controls had this mutation.

Acidosis, Lactic↗

PubMed1991

Quantitation of mitochondrial DNA carrying tRNALys mutation in MERRF patients.

An A to G transition at nucleotide position 8,344 in tRNALys of mitochondrial DNA has been recently identified as a causative mutation of myoclonus epilepsy associated with ragged-red fibers (MERRF). To investigate if the degree of heteroplasmy of mitochondrial DNA is correlated with the severity of MERRF, we have developed a novel method for quantitation of the mutant mitochondrial DNA by polymerase chain reaction using a mismatched primer. With the method, populations of mutant mtDNAs from 5 cases of MERRF carrying the tRNALys mutation were analyzed. The tight linkage of the severity of symptoms and the degree of heteroplasmies is not necessarily observed for all cases, though there is a tendency that patients with less wild type mtDNAs show severer clinical symptoms and earlier onset.

Adolescent↗

PubMed1991

Renal and skin involvement in a patient with complete Kearns-Sayre syndrome.

We report on a 13-year-old girl with complete Kearns-Sayre syndrome (KSS) and unusual manifestations of anhidrosis and de Toni-Fanconi-Debré syndrome which preceded by several years the onset of KSS triad. Histochemical examination of skeletal muscle showed focal deficiency of cytochrome c oxidase (CCO). Southern blot analysis of mitochondrial DNA (mtDNA) demonstrated a deletion of 5.4 kb in 60% of the total mtDNAs isolated from the muscle and kidney. On electron microscopy, epithelial cells of the proximal and distal renal tubules and the sweat glands showed an increased number of giant mitochondria with complicated and concentric cristae. This appears to be the first report of complete KSS associated with renal and skin involvement. Data obtained in this patient provide important information on the clinical heterogeneity and tissue specificity of CCO deficiency.

Adolescent↗

PubMed1991

Strongly succinate dehydrogenase-reactive blood vessels in muscles from patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes.

Intramuscular blood vessels were examined with succinate dehydrogenase stain in skeletal muscle biopsy specimens from 6 patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). Almost all arteries had large granular deposits with high succinate dehydrogenase activity in their walls. Electron microscopic examination of serial frozen sections of these biopsies showed that the smooth muscle cells of the strongly succinate dehydrogenase-reactive blood vessels contained markedly proliferated mitochondria, characteristic of patients with MELAS. The presence of strongly succinate dehydrogenase-reactive blood vessels in muscle biopsy specimens provides an important clue toward understanding the underlying pathogenetic mechanism in patients with MELAS as well as another approach to the diagnosis of this disorder.

Acidosis, Lactic↗

PubMed1991

Muscle histology in Becker muscular dystrophy.

Twenty patients with Becker muscular dystrophy (BMD), confirmed by dystrophin tests, were studied histologically. There were several morphological differences between younger (less than or equal to 15-year-old) and older (greater than 15-year-old) patients. In the younger patients, active muscle fiber necrosis followed by a regenerating process was conspicuous. In the older patients, the active degenerative changes appeared less prominent and, instead, more chronic myopathic changes such as moth-eaten fibers, fiber splitting, and hypertrophic fibers were evident. These age-dependent differences in the pathology of BMD were irrespective of the duration of clinical symptoms, i.e., BMD patients of a similar age showed a similar morphological feature regardless of age at onset. Although the presence of mild fiber type grouping and some small angulated atrophic fibers suggested a certain degree of neurogenic involvement, none of biopsies showed significant grouped atrophy as seen in neuropathic disorders. There was no correlation between the histological changes and the specific dystrophin abnormality.

Adolescent↗

PubMed1991

Mitochondrial encephalomyopathies and cytochrome c oxidase deficiency: muscle culture study.

The populations of cytochrome c oxidase (CCO)-positive and -negative mitochondria were analyzed in the elongated cells containing occasional multiple nuclei (myotubes) in primary muscle cultures derived from patients with various forms of mitochondrial encephalomyopathies with CCO deficiency. Even in control muscle cultures, CCO-positive (79.7%) and -negative (20.3%) mitochondria were distributed randomly, showing intracellular mosaicism. All mitochondria in all muscle cultures from two patients with clinical characteristics of Leigh's disease exhibited faint to negative CCO activity. In these patients no enzyme activity could be detected in any tissue including intrafusal fibers and fibroblasts in muscle biopsies. In patients with the fatal infantile and the encephalomyopathic forms of CCO deficiency, and myoclonic epilepsy with ragged-red fibers, two different types of myotubes containing mostly CCO-positive mitochondria and only negative mitochondria, respectively, representing intercellular mosaicism, were demonstrated. The intercellular mosaicism in biopsied and cultured muscles in the case of CCO deficiency supports the contention that both CCO-positive and -negative mitochondria coexist in the early myogenic cell and are later randomly segregated during cell division (mitotic segregation), forming two different cells.

Adolescent↗

PubMed1991

Immunocytochemical analysis of dystrophin in congenital muscular dystrophy.

Using immunocytochemical methods, we examined the intensity and distribution of dystrophin and spectrin immunostaining of skeletal muscles from 51 congenital muscular dystrophy (CMD) patients including 36 Fukuyama congenital muscular dystrophy (FCMD) and 15 non-FCMD (other CMD). 17 age-matched spinal muscular atrophy (SMA) and 5 Duchenne muscular dystrophy (DMD) patient biopsies were studied as controls. All 15 non-FCMD and SMA patients showed normal localization of dystrophin at the surface membrane of each muscle fiber which was undetectable in DMD. In contrast, 34 of 36 FCMD patients exhibited an unusual immunostaining pattern with occasional (17-43%; mean = 28) negative or abnormally immunoreacted (partially deficient, fluffy or intense) fibers for dystrophin. Dystrophin was absent in 2 of 36 patients having a clinical diagnosis of FCMD, and intragenic deletion of the DMD gene was detected in one. Spectrin, a membrane cytoskeletal protein related to dystrophin, also showed an increased number of abnormally immunostained fibers in FCMD (25%), but not so high in age-matched DMD (9%) or SMA patient muscle (0%). Thus, our results suggested the presence of intrinsic factor(s) that produce abnormality of the plasma membrane of FCMD muscle.

Adolescent↗

PubMed1991

Muscle histopathology in myoclonus epilepsy with ragged-red fibers (MERRF).

Histopathologic findings were examined in skeletal muscle biopsies from 6 patients with myoclonus epilepsy with ragged-red fibers (MERRF) who had an A to G base substitution at mitochondrial DNA (mtDNA) nucleotide pair 8344. In addition to variation in fiber size and ragged-red fibers, all specimens in cross sections showed focal cytochrome c oxidase (CCO) deficiency, suggesting that this finding is crucial in elucidating the role of the mutant mtDNA in the pathogenesis of this disorder. Along the length of single muscle fibers, defects in CCO activity were distributed segmentally with blurred borders in 5 patients which were in contrast with segmental defects with sharply delineated borders seen in chronic progressive external ophthalmoplegia with deleted mtDNA. These morphologically heterogeneous defects in CCO activity may in part be due to differing populations of and distributions of wild and mutants mtDNAs.

Adolescent↗

PubMed1991

Muscle coenzyme Q10 in mitochondrial encephalomyopathies.

Coenzyme Q10 (CoQ) content was measured in isolated muscle mitochondria from 25 patients with mitochondrial encephalomyopathies (MEM), most of whom had mitochondrial DNA mutations. The CoQ level was significantly lower in MEM patients than in controls. CoQ levels varied widely from patient to patient, especially in those with chronic progressive external ophthalmoplegia including Kearns-Sayre syndrome, which may explain, at least in part, the variable response of patients to CoQ administration.

Adolescent↗

PubMed1991

Japanese quail and human acid maltase deficiency: a comparative study.

A morphological study was carried out on the skeletal muscle of a mutant Japanese quail with acid maltase deficiency (AMD). The affected quails began to experience difficulty in lifting their wings about 6 weeks after hatching. Four weeks after hatching, before symptoms appeared, alpha-1, 4-glucosidase activity in skeletal muscle was decreased to less than 10% of the control level, and muscle fibers possessed many vacuoles containing periodic acid Schiff (PAS) positive material which was digested by diastase, and showed high acid phosphatase activity. Although both red and white muscles were involved, the pectoralis superficialis (PS, white) muscle was preferentially affected, showing intracytoplasmic vacuoles, variation in fiber size and fatty tissue replacement relatively early in the disease. The quails' disease closely resembled human late onset AMD in the slow clinical course, the presence of residual acid alpha-glucosidase activity and the muscle pathology. This mutant quail seems a useful model for elucidation of the muscle degeneration in human AMD (glycogen storage disease type 2).

Adolescent↗

PubMed1991

Facioscapulohumeral muscular dystrophy: muscle fiber type analysis with particular reference to small angular fibers.

Muscle biopsies from 14 patients with facioscapulohumeral muscular dystrophy (FSHD) aged from 5 to 45 years were studied histochemically with fiber type analysis, focusing on small angular fibers (SAF) to clarify their significance. There were no duration-related or age-dependent histopathological differences between child and adult patients. Variations in fiber size and SAF were observed in all, myonecrosis with occasional phagocytosis in 10 and regenerating fibers in 12 biopsies. Cellular responses including inflammatory cell infiltration (7 biopsies) and connective tissue proliferation (8 biopsies), and fiber architectural changes (9 biopsies) were additional common findings. Although SAF are also commonly seen in patients with Kugelberg-Welander disease and amyotrophic lateral sclerosis, in FSHD they were mostly type 2C fibers which frequently exhibit alkaline phosphatase-positive activity. Therefore SAF in FSHD are mostly the products of a regeneration rather than denervation process.

Adolescent↗