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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↗
PubMed1985

Dominant optic nerve atrophy with progressive hearing loss and chronic progressive external ophthalmoplegia (CPEO).

This paper describes a family where chronic progressive external ophthalmoplegia is associated with dominant optic atrophy and progressive sensorineural deafness. This may be a possible association in the same family of two diseases: progressive external ophthalmoplegia and dominant optic atrophy with progressive hearing loss. However, we believe that this family represents an unusual manifestation of ophthalmoplegia plus.

Adult↗
PubMed1997

[Mitochondrial DNA mutations and three major forms of mitochondrial myopathies: CPEO, MELAS and MERRF].

Mitochondrial DNA (mtDNA) mutations were discovered during a few years around 1990 and thought to be assigned to the three major clinical forms of mitochondrial myopathies. Then, several mtDNA mutations were detected in each disease and the common mutations were found in more than one disease, suggesting genotype and phenotype heterogeneity. Heteroplasmy, tissue/cellular specificity and threshold effect have been extensively studied using skeletal muscle and culture cells from the patients, but the major part of the relations up between mtDNA genotype and clinical phenotype remains unknown. Because of the facts that mtDNA mutations have been found in other clinical forms (not myopathies), and frataxin, the product of the responsible gene for Freidreich ataxia, may be associated with mtDNA biogenesis, disease entity accompanied by mtDNA abnormalities could expand more in the future.

DNA, Mitochondrial↗
PubMed2006

Orbital magnetic resonance imaging of extraocular muscles in chronic progressive external ophthalmoplegia: specific diagnostic findings.

INTRODUCTION: Chronic progressive external ophthalmoplegia (CPEO) is characterized by slowly progressive bilateral ophthalmoplegia and blepharoptosis. Molecular diagnosis is problematic because sporadic mitochondrial DNA deletions can be causative. We sought findings using magnetic resonance imaging (MRI) that might support the diagnosis of CPEO. METHODS: Two men (ages 31 and 47 years) and 3 women (ages 40-49 years) with CPEO and symptom durations of 8 months to 28 years underwent high-resolution (2-mm slice thickness, 312 micron pixels), surface coil, T1-weighted orbital MRI in coronal planes. Images were analyzed quantitatively to determine extraocular muscle (EOM) sizes and were compared with 10 age- and gender-matched normal volunteers, one subject with myasthenia gravis, and with 30 subjects having EOM paralysis caused by oculomotor, trochlear,0 and abducens neuropathies. RESULTS: EOM function was clinically diminished in CPEO, most markedly for the superior rectus (SR) and levator muscles. All EOMs in CPEO exhibited unusual qualitative T1 MRI signal abnormalities. Unlike the profound EOM atrophy typical of neurogenic paralysis, anterior volumes of medial rectus, lateral rectus, and inferior rectus muscles in CPEO were not smaller than normal (p>0.003). Anterior volumes of the SR muscle-levator complex and superior oblique were significantly reduced (p<0.003). Denervated EOMs exhibited statistically significant volume reduction when compared with normal and CPEO groups. Volume of the SR muscle-levator complex was the same in subjects with CPEO and oculomotor palsies. CONCLUSIONS: CPEO is associated with minimal EOM volume reduction despite clinically severe weakness. This combination of findings may be specific for CPEO and could resolve the diagnostic dilemma in difficult cases.

Abducens Nerve Diseases↗
PubMed1997

Cardiac dysfunction in patients with chronic progressive external ophthalmoplegia.

BACKGROUND: Chronic progressive external ophthalmoplegia (CPEO), which includes Kearns-Sayre syndrome, is a mitochondrial disorder with large deletions of mitochondrial DNA. Recently, mtDNA deletions in cardiac muscle cells were thought to be a cause of dilated cardiomyopathy. However, the cardiac involvement in patients with CPEO is generally considered to be limited to the cardiac conduction system. HYPOTHESIS: The purpose of this study was to evaluate left ventricular function in patients with CPEO. METHODS: We evaluated the cardiac function of five patients with CPEO by means of carotid pulse recording and Doppler echocardiography. RESULTS: The ratio of the pre-ejection period to ejection time was increased to 0.67 in one patient and to 0.50 in another. Echocardiography showed left ventricular dilatation and diffuse hypokinetic wall motion in both cases. Left ventricular fractional shortening was decreased to 5 and 19%, respectively, and the mean rate of circumferential shortening was decreased to 0.12 and 0.63 circ/s, respectively. One of the two patient died of congestive heart failure 2 months after the study. The Doppler pattern of left ventricular filling in the three remaining patients showed a decrease in the ratio of peak flow velocity in early diastole to that in late diastole, with an increase in deceleration time. CONCLUSION: Although cardiac involvement in patients with CPEO is generally considered to be limited to the cardiac conduction system, left ventricular dysfunction may be present and should receive more attention in the management of patients with CPEO.

Adult↗
PubMed1995

Mitochondrial encephalomyopathy with autosomal dominant inheritance: a clinical and genetic entity of mitochondrial diseases.

We report a Japanese family with chronic progressive external ophthalmoplegia (CPEO) with autosomal dominant inheritance, and review 54 reported CPEO patients in seven families (including the present family) with autosomal dominant inheritance and mtDNA deletions in the skeletal muscle. Mean age at onset in the CPEO was 26 years, which is older than that in published solitary cases. In addition to blepharoptosis and external opthalmoplegia, proximal muscle atrophy and weakness were found in 62%, hearing loss in 25%, and ataxia in 17% of the patients. Retinal degeneration was not found, and cardiac involvement was very rare. mtDNA deletions in the muscle were multiple and large scale, and all such deletions were located in the non-D-loop region. Autosomal dominant CPEO has unique clinical features which differ from those of solitary CPEO, and is associated with multiple large-scale mtDNA deletions. Thus, autosomal dominant CPEO can be considered a clinical and genetic entity of mitochondrial diseases.

Base Sequence↗
PubMed2002

Impaired glucose effectiveness in chronic progressive external ophthalmoplegia.

Mitochondrial gene mutations have been recognized to be associated with diabetes mellitus. The incidence of diabetes mellitus in patients with other mitochondrial diseases, such as chronic progressive external ophthalmoplegia (CPEO), seems to be several times higher than in the normal population. The aim of the present investigation was to study insulin sensitivity index (SI), insulin secretion (AIR(Glucose)), and glucose effectiveness (Sg) in patients with CPEO. Six unrelated patients with CPEO and 6 matched-pair, unrelated, healthy control subjects underwent a modified intravenous glucose tolerance test (IVGTT) (Bergman's minimal model). Three patients demonstrated an impaired glucose tolerance (IGT), 1 patient already had diabetes mellitus. No significant difference between patients and controls could be demonstrated for SI, AIR(Glucose), or fasting insulin. However, there was a significant difference for glucose effectiveness Sg (P =.016) indicating an impaired glucose effectiveness in the CPEO patients. The diabetic patient showed insulin resistance, low AIR(Glucose), and low Sg. We conclude that there is a high incidence of IGT and diabetes mellitus in patients with CPEO. Impaired glucose effectiveness seems to play a major role in early pathogenesis. Overt diabetes in CPEO seems to be a combination of insulin resistance, an insulin secretion defect, and impaired glucose effectiveness.

Adult↗
PubMed2005

Human extraocular muscles in mitochondrial diseases: comparing chronic progressive external ophthalmoplegia with Leber's hereditary optic neuropathy.

AIMS: To compare the ultrastructural aspects of human extraocular muscles in two types of mitochondrial disease: chronic progressive external ophthalmoplegia (CPEO) and Leber's hereditary optic neuropathy (LHON). METHODS: Muscle samples of the medial rectus obtained from surgery in a sporadic case of CPEO associated with deleted mitochondrial DNA, and post mortem in a case of 3460/ND1 LHON were processed for electron microscopy (EM). The medial rectus from an autoptic time to fixation matched control was used to exclude postmortem artefacts. RESULTS: The CPEO specimen revealed focal areas of disruption and abnormalities of mitochondria in some muscle fibres, creating a "mosaic-like" pattern. In the LHON specimen a diffuse increase in both number and size of mitochondria (mean diameter 0.85 mum v 0.65 mum of control, p<0.0001) with swollen appearance and disorganised cristae filled all spaces of sarcoplasmic reticulum. In some areas the excessive number of mitochondria slightly distorted myofibrils. CONCLUSION: EM investigation of extraocular muscles in CPEO and LHON reveals marked differences. A "mosaic-like" pattern caused by a selective damage of muscle fibres was evident in CPEO, whereas a diffuse increase in mitochondria with preservation of myofibrils characterised the LHON case. These ultrastructural changes may relate to the different expression of the two diseases, resulting in ophthalmoplegia in CPEO and normal eye movements in LHON.

Aged↗
PubMed1997

[A case of mitochondrial encephalomyopathy showing ophthalmoplegia, diabetes mellitus and hearing loss associated with the A3243G mutation of mitochondrial DNA].

We report a 47-year-old female patient showing clinical features of chronic progressive external ophthalmoplegia (CPEO) without stroke-like episodes. Large scale deletion of mitochondrial DNA (mtDNA) was not found in her biopsied muscle, whereas the A-->G transition at position 3243 (A3243G) was detected. The patient's mother had diabetes mellitus, suggesting maternal inheritance. This mutation is usually associated with MELAS, but wide clinical variety of the mutation has been recognized. Although several patients of CPEO with A3243G mutation (CPEO3243) have been found in the Western countries, only one case has been reported in detail in Japan. The CPEO3243 patients, including ours, show retinopathy less frequently, but diabetes mellitus and hearing loss more frequently than CPEO patients with deletions of mtDNA (CPEO delta). CPEO3243 is usually inherited maternally, but almost all CPEO delta is sporadic. With regard to COX activity of biopsied muscles, CPEO3243 resembles CPEO delta more than MELAS3243. This suggests that how the mutant mtDNA is distributed among cells or tissues may have more significant effect on clinical phenotype than what type of mtDNA mutation exists. The presence of such a CPEO3243 patient like ours could be an important suggestion toward further understanding of mitochondrial diseases.

DNA, Mitochondrial↗
PubMed1998

MR of extraocular muscles in chronic progressive external ophthalmoplegia.

PURPOSE: Our goal was to determine whether the extraocular muscles in patients with chronic progressive external ophthalmoplegia (CPEO) could be distinguished from those of age-matched control subjects by MR imaging. METHODS: Nine patients with CPEO and eight age-matched healthy control subjects were studied. The extraocular muscles of eight of the patients (16 eyes) and all the control subjects (16 eyes) were measured digitally. Images consisted of 1.5-mm contiguous sections acquired using a volume (three-dimensional) gradient-echo acquisition. In all, measurements were performed on 11 interpolated 1.0-mm coronal sections, five on each side of the muscle center. Only the medial, inferior, and lateral rectus muscles were evaluated. The superior rectus was omitted to avoid averaging problems with the superior ophthalmic vein and levator palpebrae muscle. The 11 sections were summed to obtain a volume measurement of the central portion of each muscle. RESULTS: The digitally measured extraocular muscles in the patients with CPEO had statistically significantly smaller volumes than those of the control subjects. The average muscle volumes for the patients with CPEO were 215 mm3 for the medial rectus, 202 mm3 for the inferior rectus, and 269 mm3 for the lateral rectus. The average extraocular muscle volumes for the control subjects were 366 mm3 for the medial rectus, 365 mm3 for the inferior rectus, and 425 mm3 for the lateral rectus. CONCLUSION: MR imaging can show small extraocular muscles in patients with CPEO, which may help to distinguish this disorder from other entities. Since denervated extraocular muscles do not readily atrophy, this MR sign would support a myogenic pathologic substrate for CPEO. Variation in the degree of extraocular muscle atrophy may simply reflect the length of time the mitochondrial defect and ophthalmoplegia have been present.

Adolescent↗
PubMed2006

Humanin expression in skeletal muscles of patients with chronic progressive external ophthalmoplegia.

We showed that humanin (HN), an endogenous peptide against Alzheimer disease-related insults, was expressed in muscles of patients with chronic progressive external ophthalmoplegia (CPEO), a major mitochondrial disease. Because HN was recently found to block proapoptotic Bax function and exert its versatile cytoprotective effects in association with an increase in ATP levels, HN expression may thus reflect a physiological response against degenerative changes in the muscles of patients with CPEO. We found HN expression in all four patients examined, each of whom had different mitochondrial DNA mutations including two different single DNA deletions, multiple deletions, and no major mutations detected. We also found that HN expression was not linked to focal cytochrome c deficiency, strongly associated with the subtype of CPEO with single deletions. These results suggest that HN expression is more closely related to degenerative changes in all types of CPEO. Notably, HN was also expressed in non-degenerative muscle fibers of patients with CPEO or Leigh syndrome, who had the 8993T>G mutation in the mitochondrial ATPase 6 gene known to be associated with impaired ATP synthesis. Collectively, our findings suggest that HN may be specifically expressed in response to defects in energy production in muscles with mitochondrial abnormalities.

Adolescent↗
PubMed2006

Frequency of dystrophic muscle abnormalities in chronic progressive external ophthalmoplegia: analysis of 86 patients.

BACKGROUND: There are few reports describing the coexistence of dystrophic features with those typical of mitochondrial myopathies in muscle biopsy. A recent study suggested that dystrophic features are frequent in patients with chronic progressive external ophthalmoplegia (CPEO) with a high mutation load, but the actual frequency of these abnormalities in CPEO remains undetermined. OBJECTIVE: To review the occurrence of dystrophic abnormalities in a large series of patients with CPEO to assess the frequency of such abnormalities and to verify whether they are correlated with specific mitochondrial DNA (mtDNA) mutations. METHODS: Retrospective survey of case series (86 patients with CPEO). RESULTS: Only three cases with dystrophic abnormalities were found: two with a large scale mtDNA deletion and one with the A3251G mutation. All three patients showed predominantly proximal muscular weakness resembling limb girdle muscular dystrophy. CONCLUSIONS: Dystrophic abnormalities are rare in CPEO and are not correlated with a specific molecular defect.

Adult↗
PubMed2006

Chronic progressive external ophthalmoplegia: MR spectroscopy and MR diffusion studies in the brain.

OBJECTIVE: The purpose of our study was to show how, despite pathognomonic signs of cerebral involvement in chronic progressive external ophthalmoplegia (CPEO), mitochondrial respiratory chain insufficiency is associated with increased lactate and reduced N-acetylaspartate. CPEO and mitochondrial myopathy are caused by mitochondrial DNA mutations leading to impaired oxidative phosphorylation. Cortical and subcortical metabolites, cerebral diffusivity, and structural MRI were assessed to characterize possible subclinical cerebral pathology in CPEO. SUBJECTS AND METHODS: Ten patients with CPEO (n = 8), mitochondrial myopathy (n = 1), and Kearns-Sayre syndrome (n = 1) and 13 control group volunteers were studied by MRI, both long TE (144) proton MR spectroscopic imaging (1H MRSI), and diffusion-weighted imaging. Relative concentrations of N-acetylaspartate, choline, creatine, and lactate were estimated by Linear Combination of Model Spectra (LCModel) in healthy-appearing white matter, gray matter, and white matter hyperintensities. RESULTS: Of five patients with cortical atrophy, it was moderate in three and severe in two. One patient had severe and four had moderate cerebellar atrophy. Six of 10 patients showed unspecific white matter lesions, whereas the remainder had hyperintensities in the pyramidal tract (n =2) and middle cerebellar peduncle (n = 1) despite clinical signs. No basal ganglia lesions were found. Physiologic metabolite ratios were normal and lactate was absent in supratentorial healthy-appearing cortex and subcortical white matter. Global diffusion histogram metrics revealed no abnormalities. CONCLUSION: Normal spectroscopic imaging in radiologic unaffected brain and healthy global brain parenchymal diffusion findings do not support the hypothesis of a generalized cerebral energy loss in CPEO. Bilateral structural alteration of central motor pathways in two patients without clinical pyramidal signs may, however, reflect subclinical axonal injury in predilection sites in some patients.

Adult↗