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.     

慢性进行性眼外肌瘫痪的临床和病理学特点

目的探讨慢性进行性眼外肌瘫痪(CPEO)的临床和病理学特点。方法回顾性分析7例CPEO患者的临床资料。结果本组7例患者均有不同程度的双侧眼睑下垂,6例有明显的眼球活动障碍。1例患者在发病16年后出现吞咽费力和肢体肌力下降。7例患者肌电图检查示,1例患者部分被检肌呈神经源性损害。7例患者肌肉活检均可见破碎红边纤维(RRF),其中2例伴有部分肌纤维脂质增多,2例患者显示Ⅰ、Ⅱ型纤维分布异常,可见群组化现象。本组有2例患者行电镜检查示肌膜下和肌原纤维间有异常线粒体聚集。结论 CPEO是一种以慢性进行性眼睑下垂和眼球运动障碍为主要临床表现的线粒体脑肌病,临床上容易误诊为眼肌型重症肌无力、眼咽型肌营养不良症和眼科疾病。骨骼肌活检病理检查发现RRF或异常线粒体聚集,是确诊本病的重要依据。     

Coenzyme Q in serum and muscle of 5 patients with Kearns-Sayre syndrome and 12 patients with ophthalmoplegia plus

Summary Coenzyme Q₁₀ (CoQ) was measured in serum and muscle of 17 patients with ophthalmoplegia plus (including 5 patients with Kearns-Sayre syndrome), in muscle of 9 patients with neurogenic atrophies, 5 patients with myositis, and 5 patients with progressive muscular dystrophies (including 1 patient with oculopharyngeal dystrophy), and in serum and muscle of normal controls. CoQ was markedly decreased in serum and muscle of 1 patient with Kearns-Sayre syndrome and treatment with CoQ resulted in a significant clinical improvement. The other 4 patients with Kearns-Sayre syndrome and the patients with ophthalmoplegia plus exhibited normal concentrations of CoQ in serum and muscle. CoQ levels in muscle of patients with progressive muscular dystrophies, myositis or neurogenic atrophies were within the normal range. Concentrations of CoQ in serum and muscle of normal controls were independent of age and showed no sex difference. The data indicate that CoQ deficiency might be the specific cause of mitochondrial encephalomyopathy in 1 patient but it was not the underlying defect common to all cases with Kearns-Sayre syndrome and ophthalmoplegia plus, although the possibility of a focal CoQ deficiency affecting only single muscle fibres cannot be excluded.Dedicated to the late Dr. Saburo Ogasahara     

慢性进行性眼外肌麻痹的临床、病理及诊断（附6例报道）

目的:探讨慢性进行性眼外肌麻痹(CPEO)的临床、病理及诊断。方法:对6例CPEO患者的临床表现、病理特点进行分析并与另5组CPEO比较。结果:6例患者中男3例,女3例,平均起病年龄13岁。2例为同胞兄弟。6例均有进行性加重的双睑下垂和眼球活动障碍,其中1例起病不对称。除眼外肌麻痹外,3例闭目肌力减退、1例轻度吞咽困难、1例轻度肢体无力。3例伴内分泌功能异常。肌活检破碎红纤维(RRF)阳性肌纤维数和细胞色素氧化酶(cytochromeoxidase,COX)阴性肌纤维数均明显>2%。结论:CPEO的主要临床表现为进行性发展的眼外肌麻痹,可伴肢体肌无力、视网膜色素变性、听力障碍、心脏传导异常、内分泌异常等。诊断主要依赖临床和肌肉活检中发现>2%的RRF 肌纤维、COX-肌纤维。     

Familiäre mitochondriale chronisch progressive externe Ophthalmoplegie Fünf Familien mit unterschiedlicher Genetik

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.     

Quantitative near-infrared spectroscopy discriminates between mitochondrial myopathies and normal muscle.

Five patients with chronic progressive external ophthalmoplegia (CPEO) and 27 healthy controls were examined by near-infrared spectroscopy (NIRS) for the noninvasive and direct quantitative measurement of muscle oxygen consumption and forearm blood flow. NIRS measurements were obtained in rest and during static isometric handgrip exercise at 10% of the maximum voluntary contraction (MVC) force. A significantly decreased oxygen consumption at rest as well as during exercise was found in patients with CPEO. Our results suggest that NIRS is able to discriminate between CPEO patients and healthy controls, which makes NIRS a valuable tool in the diagnostic workup of patients suspected to have a mitochondrial myopathy.     

Contribution of muscle biopsy and genetics to the diagnosis of chronic progressive external opthalmoplegia of mitochondrial origin

Chronic progressive external opthalmoplegia (CPEO) is the most common phenotypic syndrome of the mitochondrial myopathies. Muscle biopsy, which provides important morphological clues for the diagnosis of mitochondrial disorders, is normal in approximately 25% of patients with CPEO, thus necessitating molecular genetic analysis for more accurate diagnosis. We aimed to study the utility of various histochemical stains in the diagnosis of CPEO on muscle biopsy and to correlate these results with genetic studies. Between May 2005 and November 2007 all 45 patients diagnosed with CPEO were included in the study (23 males; mean age at presentation, 35 years). Thirty-nine patients had CPEO only and six had CPEO plus; two had a positive family history but the remaining 39 patients had sporadic CPEO. Muscle biopsy samples were stained with hematoxylin and eosin, modified Gomori’s trichrome stain, succinic dehydrogenase (SDH), cytochrome C oxidase (COX) and combined COX-SDH. Ragged red fibers were seen in 27 biopsies; seven showed characteristics of neurogenic atrophy only, and 11 were normal. The abnormal fibers were best identified on COX-SDH stain. A complete mitochondrial genome was amplified in muscle and blood samples of all patients. Mutations were found in transfer RNA, ribosomal RNA, ND, CYTB, COX I, II and III genes. Mitochondrial gene mutations were found in ten of the 11 patients with a normal muscle biopsy. The genetic mutations were classified according to their significance. The observed muscle biopsy findings were correlated with genetic mutations noted. Histological studies should be combined with genetic studies for the definitive diagnosis of CPEO syndrome.     

Progressive fat replacement of muscle contributes to the disease mechanism of patients with single,large-scale deletions of mitochondrial DNA

Muscle dysfunction in mitochondrial myopathy is predominantly caused by insufficient generation of energy. We hypothesise that structural changes in muscles could also contribute to their pathophysiology. The aims of this study were to determine fat fractions and strength in selected muscles in patients with chronic progressive external ophthalmoplegia (CPEO), and compare progression of muscle fat fraction with age in individuals with CPEO vs. healthy controls and patients with the m.3243A>G mutation of mitochondrial DNA (mtDNA). Seventeen patients with CPEO and single large-scale deletions of mtDNA, 52 healthy controls, and 12 patients carrying the m.3243A>G mtDNA mutation were included. Muscle fat fractions were measured from cross-sections of paraspinal and leg muscles. Peak muscle strength was assessed from a static dynamometer. There was a direct correlation between age and fat fraction in all muscle groups in CPEO patients and healthy controls (p < 0.05). Analysis of covariance showed a higher progression rate of fat replacement in CPEO patients vs. healthy controls in studied muscle groups (p < 0.05). Patients with the m.3243A>G mutation had slower progression rates of fat replacement. Muscle strength decreased with increasing muscular fat fraction in CPEO patients, no correlation was seen in other groups. This indicates that structural muscle changes contribute to the phenotype of older patients affected by CPEO and large-scale deletions. It should therefore be considered, along with known energy deficiencies, as the cause of exercise intolerance.     

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.     

Late-onset cerebellar ataxia with hypogonadism and muscle coenzyme Q10 deficiency

Two brothers had late-onset progressive ataxia, cerebellar atrophy, and hypergonadotropic hypogonadism associated with coenzyme Q10 (CoQ10) deficiency in skeletal muscle. Both patients improved on high-dose CoQ10 supplementation, stressing the importance of CoQ10 deficiency in the differential diagnosis of cerebellar ataxia, even when onset is late.     

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.     

Koenzym Q10 beim Morbus Parkinson

Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive loss of dopaminergic neurons within the substantia nigra pars compacta. Experimental and clinical data point to a defect of the mitochondrial respiratory chain as a major pathogenetic factor in PD. Although the restoration of mitochondrial respiration and reduction of oxidative stress by coenzyme Q(10) (CoQ10) could induce neuroprotective effects against the dopaminergic cell death in PD, these effects of CoQ10 could also improve the dopaminergic dysfunction. Thus CoQ10 might theoretically exert both neuroprotective and symptomatic effects in PD. Current data from controlled clinical trials are not sufficient to answer conclusively whether CoQ10 is neuroprotective in PD. Moreover, several open and controlled pilot studies on symptomatic effects of CoQ10 revealed inconsistent results. A recent randomized, double-blind, placebo-controlled trial showed no symptomatic effects in PD. CoQ10 is well tolerated and safe as both monotherapy and add-on medication in PD patients. The present review discusses the current knowledge on neuroprotective and symptomatic actions of CoQ10 in PD.     

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

We report a Japanese family with chronic progressive external ophthal-moplegia (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 ophthalmoplegia, 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. © 1995 John Wiley & Sons, Inc.     

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.     

Chronic progressive external ophthalmoplegia. I. A quantitative histochemical study of skeletal muscles

This study quantitates the major morphological and cytochemical changes in limb muscle biopsies from 37 patients with the syndrome of chronic progressive external ophthalmoplegia (CPEO). The aim was to assess the value of limb muscle biopsy in the diagnosis of this syndrome; to define the myopathological changes and to determine whether there were any specific clinico-pathological correlations. Patients were divided into three clinical groups--11 patients with CPEO with facial and/or limb muscle weakness; 10 with CPEO with facial and/or limb muscle weakness and a positive family history; 16 with CPEO with one or more of the following: pigmentary retinopathy, cerebellar ataxia, pyramidal signs and peripheral neuropathy. The following parameters were measured: the proportions of histochemical fibre types, the muscle fibre areas and the percentage of muscle fibres showing increased oxidative enzyme activity. Pooled results for each of the clinical categories were compared. Statistical analysis of fibre areas and the percentage of fibres with increased oxidative enzyme activity, showed that group 2 differed from the others (p less than 0.05). Patients in group 2 showed the highest incidence of type 1 fibre hypertrophy, type 2A atrophy and the lowest incidence of fibres with increased oxidative activity. Fibre type disproportions occurred in all three groups but the differences were not significant.     

Early mitochondrial changes in chronic progressive ocular myopathy

Two sisters with chronic progressive external ophthalmoplegia (CPEO) and their in all 7 healthy children were investigated. Both ophthalmoplegic patients had histopathological changes typical of mitochondrial myopathy. The same type of muscular pathology was also found among the healthy children. The most common muscular changes were subsarcolemmal accumulation of pathological mitochondria, including vacuoles, abnormal cristae and sometimes also inclusion bodies. Biochemical studies showed partial complex III deficiency, with low succinate-cytochrome c reductase activity in 1 of the ophthalmoplegic patients. These findings suggest that CPEO is a slowly progressive muscle disease, starting early in life. The widespread occurrence among the children may indicate maternal inheritance.     

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.     

Investigation on mtDNA deletions and twinkle gene mutation (G1423C) in Iranian patients with chronic progressive external opthalmoplagia

BACKGROUND: Chronic progressive external ophthalmoplagia (CPEO) is a phenotypic mitochondrial disorder that affects external ocular and skeletal muscles and is associated with a single or multiple mitochondrial DNA (mtDNA) deletions and also nuclear gene mutations. There are also some reports about the relationship between CPEO and the nuclear Twinkle gene which encodes a kind of mitochondrial protein called Twinkle. AIMS: To study the mtDNA deletions and Twinkle gene G1423C point mutation in Iranian patients with CPEO. MATERIALS AND METHODS: We collected 23 muscle samples from patients with CPEO, 9 women (mean age 34.3 years) and 14 men (36.7 years). Multiplex polymerase chain reaction (PCR) method was used to find the presence of single or multiple deletions in mtDNA. Single stranded conformational polymorphism (SSCP) and restriction fragment length polymorphism (PCR-RFLP) methods were carried out to investigate point mutation (G1423C) in the Twinkle gene in all DNA samples. RESULTS: Different sizes of mtDNA deletions were detected in 16 patients (69.6%). Each of the 5.5, 7, 7.5 and 9 kb deletions existed only in 1 patient. Common deletion (4977bp) and 8 kb deletion were detected in 5 and 3 patients respectively. Multiple deletions were also present in 4 patients. Out of 23 patients included in our study, two cases (8.7%) had Twinkle gene mutation (G1423C) and 5 patients (21.7%) did not show any deletions in mtDNA or the Twinkle gene mutation. CONCLUSION: Our study provides evidence that the investigation of mtDNA and Twinkle gene mutations in CPEO may help with early diagnosis and prevention of the disease. Patients who did not show deletions in the mtDNA or G1423C mutation in the Twinkle gene may have other mtDNA, Twinkle or nuclear gene mutations.     

“All-or-none” cytochrome C oxidase positivity in mitochondria in chronic progressive external ophthalmoplegia: An ultrastructural—cytochemical study

Teased single muscle fibers from 6 patients with chronic progressive external ophthalmoplegia (CPEO) showed a segmental defect in cytochrome c oxidase (COX) activity. On ultrastructural–cytochemical examination, the majority of mitochondria in COX-positive segments were COX-positive, whereas all mitochondria in COX-negative segments were COX-negative. This “all-or-none” COX positivity in mitochondria in CPEO with deleted mitochondrial DNA can be explained by the “threshold effect,” which induces the tissue-specific involvement and clinical heterogeneity. © 1993 John Wiley & Sons, Inc.     

Coenzyme Q10 serum levels in Huntington's disease

Mitochondrial dysfunction contributes to the neurodegenerative process in Huntington's disease (HD). Coenzyme Q10 (CoQ10) enhances mitochondrial complex I activity and may therefore provide a therapeutic benefit in HD. We compared serum CoQ10 levels of previously untreated-and treated HD patients with those of healthy controls. CoQ10 did not significantly (ANCOVA F(dF 2, dF 55) = 2.57; p=0.086) differ between all three groups. However, the post hoc analysis showed no significant (p = 0.4) difference between treated HD patients ([CoQ10]: 88.12 [mean]+/-24.44 [SD], [range] 48.75-146.32 [pg/million platelets]) and controls (93.71+/-20.72, 65.31-157.94), however previously untreated HD patients (70.10+/-21.12, 38.67-106.14) had marked (p = 0.051) lower CoQ10 results than treated HD patients and controls (p = 0.017). Our results support that CoQ10 supplementation in HD patients may reduce impaired mitochondrial function in HD.