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At least 19 recordsLinked to original sources
PubMed1991

[Chronic progressive external ophthalmoplegia (CPEO); mitochondrial DNA deletion, brain MRI and electrophysiological studies].

To evaluate the correlation of clinical symptoms and deletion of mitochondrial DNA (mtDNA) in CPEO, we examined brain MRI, lower limb SSEP and mtDNA in 19 patients (nine men, ten women) with CPEO averaging 44.9 years of age. Of these patients, three had typical Kearns-Sayre syndrome (KSS) as defined by the presence of the invariable triad of CPEO, retinitis pigmentosa and an onset before the age of 20, as well as at least one of the followings: heart conduction block, cerebellar ataxia and elevated CSF protein. One patient was diagnosed as having probable KSS because the symptoms had begun at the age of 33. All patients with typical and probable KSS had one or more of the following common manifestations: mental retardation or dementia, hearing loss, short stature, and endocrinological disorder. All other 15 patients had ocular myopathy with limb muscle weakness. Total DNA was isolated from 19 biopsied muscles, and analyzed by the methods of Southern blot hybridization and PCR. Thirteen patients has heteroplasmy with the deleted and normal mtDNA, and six patients who had ocular myopathy did not have mtDNA deletion. The age of onset in the patients with mtDNA deletion averaged 23.0 years of age, while that without mtDNA deletion averaged 39 years of age. All KSS and two ocular myopathy patients shared the common site in mtDNA deletion, while nine with ocular myopathy showed the different sizes of deletion ranging from 2.3 to 9.5 kb in the different sites. Brain MRI was obtained from 12 of the 19 patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1992

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↗
PubMed1989

Chronic progressive external ophthalmoplegia (CPEO) with 'ragged red fibers'--a case report.

Chronic progressive external ophthalmoplegia (CPEO) is a rare clinical syndrome characterized by slowly progressive paralysis of extraocular muscles. We report a male patient who had a 20 year history of CPEO. Histological examination of left deltoid muscle showed characteristic ragged red fibers. Electron microscopy revealed a number of abnormal mitochondria which contain paracrystalline inclusion bodies.

Biopsy↗
PubMed1989

[Chronic progressive external ophthalmoplegia (CPEO) with deleted mitochondrial DNA].

A 19-year-old man with chronic progressive external ophthalmoplegia with deleted mitochondrial DNA was reported. Neurological examination revealed bilateral external ophthalmoplegia, hearing loss of sensorineural type, short stature, mental retardation, muscle atrophy and weakness in the proximal muscles. Lactate and pyruvate levels were elevated in both serum and cerebrospinal fluid (CSF). Protein concentration was slightly increased in CSF. Electromyogram showed myopathic changes on all the muscles examined. Ragged-red fibers were found in biopsied rectus femoris muscle, stained with modified Gomori trichrome. Scattered cytochrome c oxidase deficient fibers were encountered. The computed tomography of the brain showed mild cerebral and cerebellar atrophy without any abnormal calcification or hypo-lucency. Southern blot analysis of the mitochondrial DNA (mtDNA) extracted from the patient's muscle revealed mixed population of mtDNA, consisting of the normal one and partially deleted one. The size of the deletion was about 4.5-kilobase. The region included the sequences coding for at least four subunits of Complex I, one subunit of Complex IV, two subunits of Complex V and five tRNAs. There may be a "hot area" on the mitochondrial genome that is more prone to be deleted than other regions of mtDNA. Southern blot analysis is usefull for the diagnosis of KSS or CPEO.

Adult↗
PubMed1978

Pigment changes of the retina in chronic progressive external ophthalmoplegia (CPEO).

A study was made of the retinal functions in 4 patients with chronic progressive external ophthalmoplegia, general myopathy, EEG anomalies and pigment changes of the fundus oculi (ophthalmoplegia-plus). Three of them exhibited typical, granular pigmentations in a linear or reticular arrangement at the periphery. All four showed slight to moderate pigment epithelial defects in the maculae, mostly only discernible with fluorescence angiography. In all 4 cases, a slight decrease of the visual acuity, a mildly abnormal ERG, mild concentric restriction of the field of vision and, in two cases, an abnormal dark-adaptation curve led to the conclusion of a mild diffuse, widely disseminated receptor affection of the retina (both rods and cones). The EOG appeared normal in 3, and at the lower limit of normal in 1 case. On the basis of a detailed study of the literature we can conclude that the retinal lesions in chronic progressive external ophthalmoplegia may vary from benign pigmentations without functional impairment to genuine 'retinitis pigmentosa' with all gradations of rod-cone or cone-rod dystrophy. Emphasis is laid on the possibility of a correlation between the mitochondrial abnormalities encountered in ocular myopathy and ophthalmoplegia-plus on the one hand, and the retinal abnormalities on the other, with special reference to a possible disorder of the utilization of pyruvate in the citric-acid cycle and a loose coupling of the oxidative phosphorylation.

Adult↗
PubMed1990

Mitochondrial myopathies: divergences of genetic deletions, biochemical defects and the clinical syndromes.

Genomic Southern analysis of muscle mitochondrial (mt) DNA from 16 patients with mitochondrial myopathies was performed; 14 of 16 patients had chronic progressive external ophthalmoplegia (CPEO), while 2 patients had mitochondrial myopathies without CPEO. Eleven patients with CPEO, including 5 who exhibited the complete triad of symptoms characteristic of the Kearns-Sayre syndrome (i.e. CPEO, retinal degeneration and heart block) had heteroplasmic mtDNA with deletions ranging from 2.0 to 8.0 kb in length. There was no clear-cut correlation between the size and location of the deletions, on the one hand, and the histochemical and biochemical data or the severity of the disease, on the other.

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↗
PubMed1990

Heteroplasmy in chronic external ophthalmoplegia: clinical and molecular observations.

Chronic progressive external ophthalmoplegia (CPEO) describes a recognizable clinical syndrome frequently associated with variable dysfunction in other organ systems. Histochemical and biochemical studies suggested primary dysfunction of oxidative phosphorylation. This has recently been confirmed by demonstration of partially deleted as well as normal mitochondrial DNA--heteroplasmy--in some of these patients, most of them sporadic. In the six heteroplasmic CPEO patients that we have examined to date, the partially deleted species has been detected in all tissues tested, albeit in vastly different proportions. We report here detection of physiologically significant proportions of partially deleted mitochondrial DNA in several organs taken at autopsy from a CPEO patient with severe multisystem disease. We discuss the relationship of CPEO to several other clinical phenotypes associated with mitochondrial dysfunction, and discuss the possible implications of heteroplasmy for the development of variable phenotypes.

Child↗
PubMed1992

[Clinical study on myocardial imaging with beta-methyl-p-(123I)-iodophenyl-pentadecanoic acid in patients with mitochondrial myopathy].

Myocardial imaging with beta-methyl-p-(123I)-iodophenyl-pentadecanoic acid (123I-BMIPP), a new radiopharmaceutical designed to evaluate myocardial fatty acid metabolism, was performed in 7 patients with mitochondrial myopathy to detect their myocardial damages in comparison with 201Tl myocardial imaging. These patients were divided into 4 chronic progressive external ophthalmoplegia (CPEO) cases, 2 mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) cases and 1 myoclonus epilepsy with ragged-red fibers (MERRF). In visual assessment, we observed more myocardial segments with decreased uptake of 123I-BMIPP compared to 201Tl in MELAS cases than in CPEO cases. The mean myocardial uptake of 123I-BMIPP was higher than that of 201Tl in CPEO cases. On the other hand, in MELAS and MERRF cases, the mean myocardial uptake of 123I-BMIPP was lower than that of 201Tl. Abnormal findings suggesting myocardial damages were observed in echocardiogram and/or in electrocardiogram in MELAS and MERRF cases, while no such abnormal findings were observed in CPEO cases. Along with the previously reported experimental result that the impairment of rat myocardial mitochondria decreased myocardial uptake of 125I-BMIPP, these results suggest that 123I-BMIPP may be useful to detect myocardial damages in patients with mitochondrial myopathy.

Adolescent↗
PubMed1979

Extraocular muscle biopsy in chronic progressive external ophthalmoplegia.

A quantitatives assessment of the pathological changes in extraocular muscle is presented in 8 patients with chronic progressive external ophthalmoplegia (CPEO). Serial cross-sections of extraocular muscle were stained with a battery of histochemical and immunohistochemical techniques and compared with 36 normal extraocular muscles and 1 muscle from a patient who had longstanding third nerve plasy with anomalous reinnervation. Several of the patients had a striking increase in the number of ragged-red fibers in extraocular muscle, particularly if frequent ragged-red fibers also were found on limb muscle biopsy. One patients demonstrated extrajunctional acetylcholine receptor (AChR) in a small percentage of fibers, although this finding was not present in the reinnervated muscle. Numerous darkly staining central regions were noted in the ocular muscle fibers of a patient with Stephens syndrome (CPEO, peripheral neuropathy, and cerebellar disease) and in the reinnervated muscle. A patient with myotubular myopathy had single central nuclei in both limb and ocular muscle. All patients demonstrated in their extraocular muscles variation in both the size and distribution of each of the three histochemical fiber types. Extraocular muscle biopsy proved to be a safe, reliable technique. As a similar quantitative analysis is applied to the study of further patients, a better understanding of the pathogenesis of CPEO should be possible.

Adolescent↗
PubMed1990

In situ hybridization of muscle mitochondrial mRNA in mitochondrial myopathies.

To determine whether a mitochondrial mRNA deficiency exists in mitochondrial myopathies, muscle biopsies from a patient with chronic progressive external ophthalmoplegia (CPEO) and a patient with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) were studied using in situ hybridization. Histochemistry and immunohistochemistry were performed along with hybridization. Hybridization reactions were widely distributed over the sarcoplasm of all muscle fibers in the patient with MELAS. In the patient with CPEO, 80% of the fibers showed a marked decrease in density of autoradiographic grains. This marked decrease corresponded to the histochemical and immunohistochemical findings of a very weak staining of cytochrome c oxidase (CCO). The isotope-labeled cDNA probe used in in situ hybridization in this study complements a part of subunit I of CCO and a part of subunit II of complex I in the mitochondrial gene. Our results suggest a defect in the mRNA in this CPEO patient.

Adult↗
PubMed1990

A mutation in the tRNA(Leu)(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies.

Mitochondrial encephalomyopathies are usually divided into three distinct clinical subgroups: (1) mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS); (2) myoclonus epilepsy associated with ragged-red fibres (MERRF); and (3) chronic progressive external ophthalmoplegia (CPEO) including Kearns-Sayre syndrome. Large deletions of human mitochondrial DNA and a transition mutation at the mitochondrial transfer RNALys gene give rise to CPEO including Kearns-Sayre syndrome and MERRF, respectively. Here we report an A-to-G transition mutation at nucleotide pair 3,243 in the dihydrouridine loop of mitochondrial tRNA(Leu)(UUR) that is specific to patients with MELAS. Because this mutation creates an ApaI restriction site, we could perform a simple molecular diagnostic test for the disease. The mutation was present in 26 out of 31 independent MELAS patients and 1 out of 29 CPEO patients, but absent in the 5 MERRF and 50 controls tested. Southern blot analysis confirmed that the mutant DNA always coexists with the wild-type DNA (heteroplasmy).

Base Sequence↗
PubMed1992

[Clinical application of molecular diagnosis for mitochondrial encephalomyopathies].

Among various mitochondrial encephalomyopathies, there are three distinct clinical entities, including chronic progressive external ophthalmoplegia (CPEO), myoclonus epilepsy associated with ragged-red fibers (MERRF), and mitochondrial myopathy, encephalopathy, lactic acidosis and strokelike episodes (MELAS). They are now clearly demonstrated to have the respective specific mitochondrial (mt) DNA mutations, which facilitate us to analyse mtDNA for practical diagnosis. With molecular analysis on 40 CPEO, 6 MERRF and 40 MELAS patients, most patients in the individual disorders had the disease-specific mutations. In CPEO, 31 of 40 patients had deleted mtDNA in a heteroplasmic distribution; the mutant mtDNA were present in a large amount in the skeletal muscle and other symptomatically affected organs as observed on Southern blotting and polymerase chain reaction (PCR). In MERRF (6 out of 6 patients) and MELAS (32 out of 40 patients), mutant mtDNA was easily detectable with PCR not only in skeletal muscle but also in blood cells from several patients examined. The results lead us to conclude that molecular analysis helps to obtain definite diagnosis of the diseases without loss of time.

Base Sequence↗
PubMed1992

[A case of chronic progressive external ophthalmoplegia associated with familial hypercholesterolemia].

A 52-year-old woman with chronic progressive external ophthalmoplegia (CPEO) with familial hypercholesterolemia (FH) was reported. Her mother died from heart disease, and her elder sister has hypercholesterolemia with swelling of Achilles tendons. She had slowly progressive external ophthalmoplegia, bilateral ptosis, swelling of Achilles tendons since twenties. At 40 years of age, she was pointed out hypercholesterolemia. Physical examination was within normal limits except for bilateral swelling of Achilles tendons. Neurological findings showed bilateral ptosis, disturbance of eye movements, mild proximal muscle weakness and dysesthesia in bilateral hands. Routine laboratory findings were within normal limits except for high serum cholesterol level (512 mg/dl). In the biopsied muscle, there was mild variation in fiber size with several ragged-red fibers and focal cytochrome c oxidase defective fibers. Biochemical analysis of the biopsied muscle revealed normal values in the mitochondrial fraction. Southern blot analysis of the mitochondrial DNA (mtDNA) of the muscle disclosed mixed population of mtDNA, consisting of the normal one and partially deleted (4.9-kilobase). Southern blot analysis of the leukocytes from the patient against the cDNA of LDL receptor was normal at least using the restriction enzyme of BglII, XbaI, EcoRI, PvuII and BamHI. This case has CPEO with deleted mtDNA associated with familial hypercholesterolemia, which is caused to nuclear DNA abnormalities, and is thought to be an important case for us to study the relationship between deleted mtDNA and abnormal nuclear DNA in CPEO.

Chromosome Deletion↗
PubMed1992

Enzyme activity analyses along ragged-red and normal single muscle fibres.

Mitochondrial myopathies are morphologically characterized by ragged-red fibres (RRF). Serial cross-section revealed that the ragged-red appearance was only focal. This is in agreement with a partial cytochrome c oxidase (COX) deficiency in chronic progressive external ophthalmoplegia (CPEO). Since most of these patients show deletions of the mitochondrial genome single fibre analyses were performed determining COX and succinate dehydrogenase (SDH) in serial muscle sections from two patients with CPEO. High SDH activity was demonstrated in RRF; in contrast COX activity was lower in RRF in a patient, possibly representing a focal assembly of mitochondria with deletions in their genomes. The variation of enzyme activities along the muscle fibre was especially high in RRF. This study presents the first quantitative evidence that enzyme activities vary considerably along fibres in muscle from patients with a mitochondrial myopathy.

Adult↗
PubMed1992

Morphometric analysis of skeletal muscle fibres and capillaries in mitochondrial myopathies.

A morphological and quantitative study of skeletal muscle fibres and of capillary supply was performed on needle and open biopsies of quadriceps femoris muscle from 40 patients with chronic progressive external ophthalmoplegia (CPEO) with partial deficiency of cytochrome c oxidase (COX). Muscle biopsies from 5 healthy adult subjects were used as control. The study was carried out by light and electron microscopy, using an Automatic Interactive Image Analysis System (IBAS I,II). A significant decrease in fibre diameters and preferential type I fibre atrophy was seen. Red ragged fibres and fibres with cytoarchitectural changes after enzyme-histochemical reactions for detection of oxidative activities were also observed. Seventy per cent of affected fibres showed an intense subsarcolemmal rim of oxidative activity corresponding to ultrastructural accumulation of enlarged, polymorphous mitochondria in subsarcolemmal areas. The study of the capillary distribution in muscle revealed a reduction of the number of capillaries per fibre and surrounding a fibre. The primary metabolic error of the disease with defects in the oxygen utilisation, the fibre atrophy and the muscle disuse are the possible variables influencing the capillary number in CPEO patients.

Adult↗