Mitochondrial oculoskeletal myopathy: case report

We report a case of oculoskeletal myopathy with abnormal mitochondria in which the chief clinical feature was ophthalmoplegia. Muscle weakness was mild and there were no retinal or cerebellar abnormalities, no deafness and no cardiac defects. The muscle biopsy specimen revealed subsarcolemmal mitochondrial aggregates and ragged red fibers. Electronmicroscopy showed that the aggregates were made up of mitochondria of variable size with structural abnormalities of the cristae and crystalloid inclusions. We believe that this oculoskeletal myopathy is distinct from Kearn-Sayre syndrome.

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Sommario Viene descritto un caso di miopatia oculo-scheletrica con alterazioni mitocondriali, in cui il sintomo maggiormente rappresentato era l'oftalmoplegia, mentre l'ipostenia muscolare era lieve. Il paziente non presentava anomalie retiniche o cerebellari, sordità o difetti cardiaci. La biopsia muscolare evidenziava aggregati subsarcolemmali e fibre rosse raggiate. A livello ultrastrutturale, questi aggregati erano composti da mitocondri di varie dimensioni, con anomalie strutturali delle creste ed inclusioni cristalloidali. Ě stato concluso che questo caso è da ascrivere ad un gruppo di patologia distinto dalla malattia di Kerns-Sayre.

     

Multiple mitochondrial DNA deletions in hereditary inclusion body myopathy

We have recently described an autosomal dominant hereditary inclusion body myopathy (h-IBM). Clinically it is is characterized by congenital joint contractures and slowly progressive, proximal muscle weakness and ophthalmoplegia. There is deterioration of muscle function between 30 and 50 years of age. While young patients show minor pathological changes in muscle, the middle-aged and old patients show rimmed vacuoles and inclusions of filaments measuring 15–18 nm in diameter. Except for the absence of significant inflammation the histopathology is similar to that found in sporadic inclusion body myositis (s-IBM). In s-IBM mitochondrial alterations including cytochrome c oxidase (COX) -deficient muscle fibers are common. These are due to multiple mitochondrial DNA (mtDNA) deletions. In this study we investigated the occurrence of mitochondrial alterations in autosomal dominant h-IBM. Young affected individuals showed no mitochondrial changes but three patients aged 38, 51 and 59 years, respectively, showed ragged red fibers and COX-deficient muscle fibers. Polymerase chain reaction analysis showed multiple mtDNA deletions. By in situ hybridization clonal expansions of mtDNA with deletions were demonstrated in COX-deficient muscle fibers. Most of the analyzed deletion breakpoints showed nucleotide repeats flanking the deletions. The results show that COX-deficient muscle fibers and somatic mtDNA deletions are present in this family with h-IBM. The same factors may be involved in the development of mtDNA deletions in s-IBM and this family with h-IBM. Received: 13 July 1999 / Revised: 6 October 1999 · Accepted: 12 October 1999     

Multiple mitochondrial DNA deletions in a patient with mitochondrial myopathy and cardiomyopathy but no ophthalmoplegia

Deletions of muscle mitochondrial DNA are known in mitochondrial myopathy patients who have chronic progressive external ophthalmoplegia (CPEO). A 41-year-old patient with no apparent family history of this condition suffers from hypertrophic cardiomyopathy, slight muscle atrophy, and weakness of the extremities, but not from CPEO. A muscle biopsy showed the presence of ragged-red fibers, and Southern blot analysis disclosed multiple deletions of muscle mitochondrial DNA. This combination of clinical features in our patient is atypical in mitochondrial myopathy with demonstrable deleted muscle mitochondrial DNA. Pleomorphic clinical expression is suggested. © John Wiley & Sons, Inc.     

线粒体肌病和脑肌病患者骨骼肌细胞线粒体DNA缺失分析

目的为了检测线粒体肌病和脑肌病患者的骨骼肌细胞的线粒体ＤＮＡ的缺失情况。方法从６例原发性线粒体肌病和１例脑肌病患者的骨骼肌活检标本中，提取总ＤＮＡ，以线粒体ＤＮＡ全长为探针进行分子杂交。结果发现１例ＭＥＲＲＦ患者有５ｋｂ的线粒体ＤＮＡ基因缺失，另１例线粒体肌病患者有１５ｋｂ的线粒体ＤＮＡ基因缺失，剂量分析表明缺失型线粒体ＤＮＡ分别占总线粒体ＤＮＡ的１９．３％和１０．７％。结论线粒体ＤＮＡ基因缺失是线粒体疾病的重要病因之一     

Muscle mitochondrial DNA in encephalomyopathy and ragged red fibres: a Southern blot analysis and literature review

Summary Various mitochondrial DNA abnormalities have been described in patients with encephalomyopathies. We performed Southern blot analysis of skeletal muscle mitochondrial DNA in nine adult patients with clinical features and ragged red fibres suggesting mitochondrial dysfunction. Two patients with encephalomyopathy and two with the MERRF syndrome (myoclonus epilepsy with ragged red fibres) had the normal PvuII restriction pattern of muscle mitchondrial DNA. In contrast, mitochondrial DNA deletion was observed in two of six patients with ophthalmoplegia. One suffered from typical Kearns-Sayre syndrome and the other from isolated external ophthalmoplegia. None of these patients had affected relatives. The detection of mitochondrial DNA deletion in external ophthalmoplegia and their site and size support previously reported data.     

A large-scale deletion of mitochondrial DNA in a case with pure mitochondrial myopathy and neuropathy

Here we report the findings from a male patient with myopathy and neuropathy, who has a large-scale deletion of the mitochondrial genome at nucleotides 6570–14150. In the patient’s history, muscle cramps with intermittent weakness and polyneuropathy with disturbed micturition were the predominant symptoms. Morphological examination of a muscle biopsy sample revealed numerous ragged red fibers and prominent paracrystalline intramitochondrial inclusions. The sural nerve biopsy sample disclosed a chronically progressive neuropathy, predominantly axonal in type with a minor demyelinating component. In previous studies the clinical symptoms mentioned above have been related to point mutations at various positions in the mitochondrial DNA (mtDNA). The present study is the first to describe a large (8 kb) deletion of the mtDNA which had apparently caused myopathy and polyneuropathy without encephalopathy. Received: 27 July 1995 / Revised, accepted: 4 December 1995     

In situ hybridization of muscle mitochondrial mRNA in mitochondrial myopathies

Summary 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 cytochromec 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.Supported in part by a Grant-in-Aid for Scientific Research on Priority Areas from the Ministry of Education and by a grant (62-2-05) from the National Center of Neurology and Psychiatry (NCNP) of the Ministry of Health and Welfare, Japan     

Mitochondrial myopathy and ophthalmoplegia in a sporadic patient with the 5698G-->A mitochondrial DNA mutation

We describe a second patient carrying the 5698G→A transition in the mitochondrial DNA gene encoding tRNA^Asn, who has an apparently isolated mitochondrial myopathy with chronic progressive external ophthalmoplegia. A muscle biopsy showed the presence of ragged-red and COX-negative fibres. Analysis of the mutation load on single muscle fibres showed significant segregation of the 5698G→A with COX-depleted fibres. These results indicate that the 5698G→A is pathogenic.     

Multiple sclerosis and mitochondrial myopathy: An unusual combination of diseases

A woman with definite multiple sclerosis (MS) and mitochondrial myopathy is described. There were widespread white matter lesions on magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) abnormalities and evoked response changes. Muscle biopsy showed ragged red fibres (RRFs) and cytochrome c oxidase (CoX) deficiency. Southern blot analysis revealed a large deletion of mitochondrial DNA (mtDNA). The patient may be affected by two unrelated diseases, MS and mitochondrial myopathy, but this combination has never previously been reported.     

The 8,344 mutation in mitochondrial DNA: A comparison between the proportion of mutant DNA and clinico-pathologic findings

Ten patients, two men and eight women with mitochondrial encephalomyopathy, had an A-G mutation at nucleotide pair 8,344 in the mitochondrial DNA, the most common genetic defect in myoclonus epilepsy with ragged-red fibers (MERRF). Eight patients had the clinical and pathologic characteristics of MERRF including myoclonus, seizures, cerebellar ataxia and myopathy with ragged-red fibers. Two patients had atypical symptoms such as early onset of fatal cardiac failure and late onset of rapid mental deterioration, respectively. The striking feature in our patients with the 8,344 mutation was that four of 10 patients had cardiac involvement and two developed progressive heart failure. In the typical MERRF patients, the proportion of mutant mitochondrial DNA in their skeletal muscles, quantified by a single strand conformation polymorphism analysis, was above 85%. However, there was no significant correlation between clinical severity, histopathological findings and the proportion of mutant mtDNA in muscle biopsy samples, suggesting that non-ragged-red fibers play an important role in the phenotypic expression of the mutants.     

Mitochondrial encephalo-neuro-myopathy with myoclonus epilepsy, basal nuclei calcification and hyperlactacidemia

We report a new case of MERRF (myoclonus epilepsy with ragged red fibers) syndrome with basal nuclei calcification on the brain CT scan, without hormonal abnormalities, with high CSF protein and hyperlactacidemia, juvenile onset and death at 18 years. Biochemical study of mitochondrial muscle enzymes showed decreased NADH-cytochrome-C-reductase and Succinate-cytochrome C-reductase activity, suggesting a Complex III defect of the respiratory chain. Similar reported cases are reviewed.

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Sommario Si riporta un nuovo caso di MERRF, caratterizzato da calcificazioni dei nuclei della base, aumento delle proteine liquorali, iperlattacidemia e morte a 18 anni. Studi biochimici degli enzimi mitocondriali nel muscolo, hanno dimostrato una ridotta attività sia della NADH citocromo-C-reduttasi che della succinato-citocromo-C-reduttasi, suggerendo una alterazione del complesso III della catena respiratoria.

     

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

Summary 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 hetero-plasmic 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 histo-chemical and biochemical data or the severity of the disease, on the other.     

Quantitative evaluation of electron transport system proteins in mitochondrial encephalomyopathy

Summary The levels of mitochondrial electron transport system proteins cytochrome c oxidase (COX) and complex III were measured in muscle fibers of patients with mitochondrial encephalomyopathy using quantitative immunoelectron microscopy. In a patient with Leigh's encephalopathy, immunoreactive COX protein was decreased to 20% of the normal mean value in all muscle fibers examined, while the amount of complex III was within the normal range. In a patient with fatal infantile COX deficiency, the level of COX protein was found to be decreased to 27–40% of the normal value in all muscle fibers examined. In patients with mitochondrial myopathy, encephalopathy, lactic acidosis associated with stroke-like episodes (MELAS) and chronic progressive external ophthalmoplegia (CPEO), COX protein levels were decreased to 20% of normal in muscle fibers lacking COX activity. In normal fibers, however, COX protein levels were also normal. The amount of complex III protein was normal in COX-deficient muscle fibers. In two patients, in situ hybridization was performed for detection of mitochondrial mRNA. Mitochondrial mRNAs were found to be abundant in muscle fibers with decreased COX protein, suggesting a defect at the mitochondrial protein-synthesis level in a COX-deficient muscle fiber.Supported in part by a Grant-in-Aid for Scientic Research No. 63570422 from the Ministry of Education, Science and Culture, and Grant No. 32A-5-08 from the National Center of Neurology and Psychiatry of the Ministry of Health and Welfare, Japan     

Unusual presentation and clinical variability in Belgian pedigrees with progressive external ophthalmoplegia and multiple deletions of mitochondrial DNA

We studied 14 patients from three unrelated Belgian pedigrees with a familial mitochondrial disorder and multiple deletions of mitochondrial DNA (mtDNA). In one family with an oculopharyngeal presentation there is a clear autosomal dominant inheritance. Progressive external ophthalmoplegia (PEO), “ragged red fibres” (RRF) and multiple deletions of mtDNA are common to all three families. Therefore a diagnosis of autosomal dominant progressive ophthalmoplegia with multiple deletions of mtDNA (adPEO) was made in one family at least. Our data confirm the previous observations that adPEO is a systemic disorder rather than a pure myopathy. In our pedigrees frequently associated features include axonal peripheral neuropathy, dysphagia, psychiatric illness, and sudden death. Mild ataxia, pes cavus and mitral valve prolapse with associated mitral insufficiency also occur. In some cases onset is atypical with neuropathy, adolescent onset myopathy or psychiatric illness. In such cases the common features of PEO and muscle weakness always complete the clinical phenotype later during the course of the disease. Biochemical studies on mitochondrial fractions prepared from one patient's muscle, revealed no abnormalities of respiratory chain enzyme activities.     

Oculopharyngeal somatic myopathy in a patient with a novel large-scale 3,399 bp deletion and a homoplasmic T5814C transition of the mitochondrial DNA

We report a 65-year-old woman with a sporadic form of progressive oculopharyngeal somatic myopathy due to a novel large-scale 3,399 base pair (bp) deletion of the mitochondrial DNA (mtDNA) and co-occurrence of a homoplasmic T5814C transition. The onset of myopathy began from chronic progressive external ophthalmoplegia (CPEO) at age of 20 years. Bulbar weakness, neck and proximal limb paralysis, slowly progressed to eventual respiratory failure. The plasma levels of pyruvate (1.5 mg/dL) and lactate (20.2 mg/dL) were elevated. Muscle biopsy showed decreased enzymatic activity of cytochrome c oxidase, but no ragged-red fibers. Electron microscopy showed "parking-lot" paracrystalline inclusions in the enlarged mitochondria suggestive for mitochondrial myopathy. Sequencing of the whole mitochondrial genome of the patient's muscle and leukocytes showed 3,399 bp deletion of the mtDNA from nucleotide position 8,024 to 11,423 and a homoplasmic thymidine to cytosine transition at nucleotide position 5,814 of the tRNA(Cys) gene of mtDNA (T5814C). T5814C was absent in the white blood cells of the patient's daughter and in 205 normal controls. We conclude that a large-scale deletion may coexist with T5814C transition in patients with sporadic form of mitochondrial cytopathy manifested by slowly progressive oculopharyngeal somatic myopathy.     

Mitochondrial encephalomyopathies: a correlation between neuropathological findings and defects in mitochondrial DNA

Neuropathological studies were carried out in two patients with mitochondrial encephalomyopathies in whom the underlying lesions in muscle mitochondrial DNA (mtDNA) and respiratory enzyme complexes have been investigated. The first, a man with Kearns-Sayre syndrome, died at the age of 49 years. Autopsy showed an old parietal lobe infarct, diffuse spongiform leukoencephalopathy of cerebral and cerebellar white matter and mild spongiform change in deep grey matter and brainstem nuclei. Heteroplasmy of skeletal muscle mitochondrial DNA with a 3.5 kb mtDNA deletion in one of two mtDNA populations was found. The second case, a woman, suffering from myoclonic epilepsy, cerebellar ataxia, bilateral sensorineural deafness, several 'stroke-like' episodes died at age 52. At autopsy, an old infarct was seen in the L internal capsule. Severe loss of neurons and gliosis were found in the dentate nuclei, moderate changes in the red nuclei and inferior olivary nuclei and mild changes in the substantial nigra and locus coeruleus. In both patients, skeletal muscle biopsy showed numbers of ragged-red fibres and intramitochondrial paracrystalline inclusions at electron microscopy. A defect in the synthesis of the ND5 subunit of the respiratory complex I was suggested in the second patient in whom a diagnosis of MELAS was made.