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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↗
PubMed1987

Single fiber electromyography in chronic progressive external ophthalmoplegia.

We have reviewed the electromyographic (EMG) studies of 17 patients with chronic progressive external ophthalmoplegia (CPEO). In 13 of 17 patients, conventional concentric needle EMG demonstrated a "myopathic" pattern, usually predominating in the shoulder muscles. Single-fiber EMG showed increased jitter and/or blocking in at least one muscle in 13 of 16 patients. Jitter was increased in the frontalis muscle in 10 of 13 patients and in an arm muscle in 5 of 12. When both muscles were tested, jitter was greater in the frontalis muscle in 5 patients and in the arm muscle in 2. These observations demonstrate that it may be difficult to distinguish myasthenia gravis from CPEO by EMG. The frequency with which abnormal jitter is found in CPEO suggests that, in addition to a mild generalized myopathy, a primary defect in neuromuscular transmission may be present.

Chronic Disease↗
PubMed1995

Superoxide dismutases of muscle in mitochondrial encephalomyopathies.

Immunohistochemical analyses were made of the superoxide dismutases (Mn-SOD and Cu/Zn-SOD) in biopsied muscles from 7 patients with mitochondrial encephalomyopathies that included mitochondrial encephalomyopathy, lactic acidosis and strokelike episodes (MELAS), and chronic progressive external ophthalmoplegia (CPEO). Mn-SOD mainly was present in the subsarcolemmal region, but it also was found in a coarsely granular, reticular, or diffuse pattern of staining within the muscle fibers. These Mn-SOD-positive fibers corresponded almost completely to the ragged-red fibers. The immunoreaction for Cu/Zn-SOD was weakly positive in some of the muscle fibers positive for Mn-SOD. In CPEO, Mn-SOD-positive fibers predominantly showed decreased cytochrome c oxidase (COX) activity. In MELAS, Mn-SOD-positive fibers tended to be stained deeply for COX although a few were COX-negative. These findings suggest that Mn-SOD-positive fibers can be used to make a differential diagnosis between CPEO and MELAS and that in mitochondrial encephalomyopathies Mn-SOD in the ragged-red fibers may protect against oxidative stress.

Adult↗
PubMed1994

Chronic progressive external ophthalmoplegia is associated with a novel mutation in the mitochondrial tRNA(Asn) gene.

Chronic progressive external ophthalmoplegia (CPEO) is caused by a decreased oxidative phosphorylation (OXPHOS) activity due to large-scale deletions of the mitochondrial genome in 50% of the patients. The deletions encompass structural OXPHOS genes as well as tRNA genes, required for their expression so that the pathogenesis could be due to the deleted OXPHOS subunits or to an impaired mitochondrial translation. We have analyzed the mitochondrial genome of a patient presenting with CPEO for single base substitutions and discovered a novel heteroplasmic mutation in the tRNA(Asn) gene at position 5692 that converts a highly conserved adenine into a guanine. This mutation is unique because it is located at the transition of the anticodon loop to the anticodon stem and it leads to an additional base pair, thus reducing the number of loop-forming nucleotides from seven to five. Our findings suggest that CPEO can be caused by a single base substitution in a mitochondrial tRNA gene so that the mitochondrial protein synthesis becomes the rate limiting step in OXPHOS fidelity.

Base Sequence↗
PubMed1999

Quantitative measurement of oxygen consumption and forearm blood flow in patients with mitochondrial myopathies.

Five patients with chronic progressive external ophthalmoplegia (CPEO) and 27 healthy controls were examined by near-infrared spectroscopy (NIRS) for the non-invasive and direct quantitative measurement of muscle oxygen consumption during rest as well as during static isometric handgrip exercise at 10% of their maximum voluntary contraction. In patients with CPEO, we found a significantly decreased oxygen consumption during exercise, but more remarkably already during rest. Our results suggest that NIRS is able to discriminate between CPEO patients and healthy controls, which makes NIRS a promising tool in the diagnostic work-up of patients suspected of a mitochondrial myopathy.

Adult↗
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↗
PubMed2001

[Familial mitochondrial chronic progressive external ophthalmoplegia. Five families with differing genetics].

UNLABELLED: Chronic progressive external ophthalmoplegia (CPEO) is considered the most frequent form of mitochondrial encephalomyopathies. Most cases occur sporadically. We investigated 18 consecutive patients with CPEO. Thirteen cases were sporadic and five cases were familial. In one family with maternal inheritance the mitochondrial point mutation A3243G was identified. In index patients of three other families multiple deletions of mitochondrial DNA were found. One of these families showed autosomal recessive inheritance. In the two other pedigrees a definitive determination of the mode of inheritance was impossible. The fifth family revealed autosomal dominant or maternal inheritance. In their index patient no alteration of mitochondrial DNA could be identified (including sequencing of hot spots for mitochondrial mutations). CONCLUSIONS: CPEO was familial in 28% of our patients. There are three different modes of inheritance: (i) maternal transmission associated with mitochondrial point mutations as it is known for other mitochondrial disorders, (ii) autosomal recessive, and (iii) autosomal dominant inheritance. In contrast to sporadic cases with single mitochondrial deletions autosomal inheritance can be associated with multiple deletions of mitochondrial DNA. They are due to so far unknown nuclear mutations.

Adult↗
PubMed2002

Apoptosis is suspended in muscle of mitochondrial encephalomyopathies.

Over the past few years, many studies have been done on the apoptotic involvement in muscle fiber degeneration in various myopathies, but the occurrence of apoptosis in muscles of mitochondrial encephalomyopathies is still controversial. To confirm whether apoptotic processes are truly related to muscle fiber degeneration in mitochondrial encephalomyopathies, we performed the TUNEL method not only at the light microscopic (LM) but also at the electron microscopic (EM) level for muscles of five MELAS, five CPEO and five MERRF patients and five control muscles. Immunohistochemical studies of Bcl-2, Bax, cytochrome c, Apaf-1, activated caspase-3 and human inhibitor of apoptosis protein XIAP, and immunoblotting of Apaf-1 and XIAP were also carried out. In LM-TUNEL, MELAS, CPEO and MERRF patients had only very small numbers of TUNEL-positive myonuclei: 0.13+/-0.10%, 0.15+/-0.14% and 0.04+/-0.09%, respectively. Almost all of them were seen in ragged-red fibers (RRFs). EM-TUNEL showed no significant increase of DNA fragmentation in RRFs despite mild peripheral chromatin condensation. However, Bax and Apaf-1 expression and cytochrome c release from mitochondria were seen in RRFs. Caspase-3 activation was confirmed in 9.0+/-3.7%, 12.0+/-4.4% and 12.4+/-3.8% of RRFs in MELAS, CPEO and MERRF, respectively, but not in control muscles. Almost all RRFs showed sarcoplasmic expression of XIAP. Thus, there is a possibility that, although apoptotic reactions started in muscles of mitochondrial encephalomyopathies, their execution is rarely completed. Sarcoplasmic expression of XIAP probably leads to the suspension of the apoptotic process in mitochondrial encephalomyopathies.

Adolescent↗
PubMed1985

Partial cytochrome oxidase deficiency without subsarcolemmal accumulation of mitochondria in chronic progressive external ophthalmoplegia.

Chronic progressive external ophthalmoplegia (CPEO) associated with proximal myopathy and/or craniosomatic abnormalities is a rare syndrome in which morphological mitochondrial changes have been found in some fibres (subsarcolemmal accumulation of mitochondria or "ragged red" fibres). We report a 14-year-old boy with CPEO and a mild proximal myopathy without these characteristic "ragged red" fibres. Histochemistry of skeletal muscle showed a mosaic of fibres without detectable cytochrome oxidase activity, while other mitochondrial enzymes were normal. The total cytochrome oxidase activity and cytochrome aa3 concentration in muscle mitochondrial fractions were only 40% of normal. This case is unique in that a biochemical defect was not accompanied by morphological abnormalities and may represent an early stage of CPEO before the development of morphological changes, or alternatively, a new variant of the disease.

Adolescent↗
PubMed1998

A protocol for detection of mitochondrial DNA deletions: characterization of a novel deletion.

OBJECTIVES: To develop a protocol capable of identifying deletions in mitochondrial DNA and use it to identify the breakpoints of a mtDNA deletion in a patient with chronic progressive external ophthalmoplegia (CPEO). DESIGN AND METHODS: Deletions in mtDNA were identified by a combination of long range PCR and Southern blotting. The precise breakpoints were determined by automated DNA sequencing. RESULTS: A series of DNA samples from patients with suspected mitochondrial disease was subjected to a protocol, which combines long range PCR and Southern blotting. We found a unique deletion in a patient with CPEO and we identified the precise location of this deletion through DNA sequencing. CONCLUSIONS: Long range PCR has the advantages of speed, minimal samples requirements, and sensitivity. Southern blotting is better able to evaluate heteroplasmy and detect duplications. We suggest a protocol that enables us to identify precisely the breakpoints in a unique mutation of mtDNA in a patient with CPEO.

Adolescent↗
PubMed1997

Mitochondrial DNA defects in Brazilian patients with chronic progressive external ophthalmoplegia.

We report herein on eleven Brazilian patients with mitochondrial DNA (mtDNA) deletions, found among thirteen patients with chronic progressive external ophthalmoplegia (CPEO) and ragged-red fibers (RRF). The molecular data was correlated with the morphological and clinical findings. The muscle biopsies were studied by histochemistry, immunohistochemistry and DNA analysis. Muscle mtDNA deletions were mapped and quantitated by Southern blot analysis, polymerase chain reaction and sequencing. Of the eleven patients, ten had CPEO without multisystemic involvement and one had Kearns-Sayre syndrome. Three patients had multiple deletions, two of them with no apparent family history. Eight patients showed heteroplasmic single deletions, ranging in length from 2309 to 7566 bp; three of them had the same 'common deletion' of 4977 bp. The proportion of deleted mtDNA ranged from 14 to 89%. Immunohistochemical studies revealed decreased reactivity with the mtDNA-encoded subunit II of cytochrome c oxidase (COX) in all patients, but preserved activity with the nuclear-encoded COX subunit IV in COX-deficient fibers. Two cases presented a few COX-negative fibers with reduced COX IV immunostaining. We found a high frequency of mtDNA deletions in Brazilian patients with CPEO. There was no correlation between clinical severity, morphological findings and the size or amount of the mutated mtDNA in muscle, suggesting that there are still unknown factors influencing the disease phenotype.

Adolescent↗
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↗
PubMed2006

Assessment of visual function in chronic progressive external ophthalmoplegia.

AIMS: To assess the visual function of patients with chronic progressive external ophthalmoplegia (CPEO) using the Visual Function Index (VF-14). To identify discriminatory questions that reflect visual disability in mitochondrial ocular myopathies. To investigate the relationship between visual impairment and the ocular parameters routinely measured in clinical practice. METHODS: We studied 40 CPEO patients. Each patient underwent ophthalmological assessment, including best-corrected visual acuity, ptosis measures, and fundus examination for pigmentary retinopathy, and orthoptic assessment including cover test in the primary position, assessment of diplopia, and measurement of uniocular fields of fixation using the Goldmann perimeter. Patients were interviewed by telephone by an independent observer and their visual function was assessed using the VF-14. RESULTS: A total of 38 patients (95%) were visually impaired. The mean VF-14 was 72 (95% CI 66-79). Patients reported having the most difficulty with reading small print and driving at night. No significant correlation was found between the VF-14 and ocular motility parameters, ptosis, or pigmentary retinopathy. CONCLUSIONS: CPEO is associated with significant visual impairment. Measures of visual disability should be included in studies of natural history and treatment of mitochondrial ocular myopathies.

Activities of Daily Living↗
PubMed1994

Are duplications of mitochondrial DNA characteristic of Kearns-Sayre syndrome?

The phenotypes of Kearns-Sayre syndrome (KSS) and chronic progressive external ophthalmoplegia (CPEO) are closely associated with deletions of mitochondrial DNA (mtDNA). Recent evidence suggesting that more than one type of rearrangement may be present in KSS led us to reinvestigate 18 patients with KSS or CPEO for the presence of mtDNA rearrangements other than deletion. mtDNA duplication was detectable in 10 of 10 patients with KSS, while deletion monomers were the only recombinant mtDNA easily detectable in eight of eight patients with CPEO. Deletion dimers were found only in cases having duplications. Thus, duplications of mtDNA seem to be a hallmark of KSS, including a patient where Pearson's syndrome was the first manifestation. We suggest that duplication of mtDNA is characteristic of the early-onset disease KSS, and that the balance of mtDNA rearrangements may be central to the pathogenesis of this unique group of disorders.

Adolescent↗
PubMed1987

Management of ptosis in chronic progressive external ophthalmoplegia.

Patients with chronic progressive external ophthalmoplegia (CPEO) are often disabled by ptosis; however, conventional ptosis surgery may induce lagophthalmos and exposure keratitis. Ten patients with CPEO underwent ptosis correction via bilateral frontalis suspensions, using monofilament synthetic material. Three of these patients were also treated with lower eyelid horizontal tightening. The frontalis sling was adjusted to provide a firm linkage between the eyebrow and eyelid, but was loose enough to allow eyelid closure when the frontalis muscle is relaxed. All patients experienced lessening of ptosis and relief from visual obstruction. One patient required reoperation of one eyelid for undercorrection. No lagophthalmos or corneal complications occurred. The rationale for treatment, preoperative evaluation, and operative procedure in CPEO is discussed herein.

Adult↗
PubMed1993

Chronic progressive external ophthalmoplegia and myalgia associated with tubular aggregates.

Tubular aggregates represent a distinct myopathological feature characterized by basophilic sharply demarcated irregularly shaped subsarcolemmal zones consisting of parallel double-walled tubules of unknown subcellular origin. They are found on rare occasions in a wide spectrum of myopathies, but their significance for the development of muscular symptoms has not yet been fully established. We describe a patient with chronic progressive external ophthalmoplegia (CPEO) associated with exercise-induced myalgia and tubular aggregates in skeletal muscle. The association of CPEO with tubular aggregates has not been reported before and represents an important differential diagnosis to other syndromes associated with CPEO, especially mitochondrial encephalomyopathies.

Biopsy↗
PubMed1998

Brain metabolic profiles obtained by proton MRS in two forms of mitochondriopathies: Leber's hereditary optic neuropathy and chronic progressive external ophthalmoplegia.

The status of brain metabolism has been evaluated using monovoxel short echo time (20 ms) 1H magnetic resonance spectroscopy in 6 patients with two forms of mitochondrial disorders without clinical cerebral involvement: 2 patients with Leber's hereditary optic neuropathy (LHON) and 4 patients with chronic progressive external ophthalmoplegia (CPEO). Patients with LHON displayed normal spectra. In all patients with CPEO, the brain metabolic profiles were abnormal, with no single uniform pattern. No typical cerebral metabolic profile was found even when these disorders were classified either by syndrome or by biochemical defect. No lactate signal was detected. The metabolic alterations observed in CPEO patients contrasted with the absence of clinical signs of encephalopathy. The absence of a typical metabolic profile reflects the large variability in the clinical expression of biochemical defects in mitochondriopathies, and the lack of convergence between genetic deletions, biochemical anomalies and clinical syndromes.

Adult↗
PubMed2000

[Surgical treatment in a case of chronic progressive external ophthalmoplegia].

PURPOSE/METHODS: The purpose is to discuss the surgical result in a case with chronic progressive external ophthalmoplegia (CPEO) associated with strabismus and diplopia. The authors present a patient with mitochondrial myopathy and CPEO who was treated using adjustable recessions with local anaesthesia. RESULTS/CONCLUSIONS: Five months after surgery improvement in ductions were maintained and there was no diplopia or torticollis. We support operating these cases with CPEO associated with strabismus. The adjustable suture technique allowed us a satisfactory result in immediate postoperative.

Adult↗