Optical coherence tomography findings in chronic progressive external ophthalmoplegia / 中华医学杂志(英文版)

Background:@#Chronic progressive external ophthalmoplegia (CPEO) is a mitochondrial encephalomyopathy caused by multiple mtDNA abnormalities. There is little information about the changes of ocular fundus with CPEO. The aim of this work was to measure and evaluate changes in the macular retinal thickness and optic nerve head in patients with CPEO using spectral-domain optical coherence tomography and to compare the findings with those of healthy individuals.@*Methods:@#Totally, 18 CPEO patients were enrolled in this study. Healthy volunteers matched for gender, age, and diopter settings were included as a control group. The retinal thickness of macular central fovea, inner and outer retinal layer thickness of perifoveal macular, optic nerve head parameters, and peripapillay retinal nerve fiber layer thickness (pRNFLT) for all included cases were measured using spectral-domain optical coherence tomography. A paired t test was used to compare the differences in the studied parameters between the two groups. The correlations between macular retinal thickness, pRNFLT, disease duration, and age of onset were also analyzed.@*Results:@#Among the macular parameters, retinal thickness of macular central fovea (t = -2.135, P < 0.05) and outer retinal layer thickness (t = -1.994, P < 0.05) of patients in the CPEO group were statistically significant lower than those of patients in the normal control group. For the optic nerve head parameters, the patients in the CPEO group showed a larger rim volume (t = -2.499, P < 0.05) and nerve head volume (t = -2.103, P < 0.05). The overall pRNFLT of patients in the CPEO group was statistically significant lower than that of patients in the control group (t = -4.125, P < 0.05). The comparison of pRNFLT in eight sectors showed that the pRNFLT of patients in the CPEO group was statistically significant lower than that of the control group mainly in the inferior and temporal sectors. The degree of pRNFL defect negatively correlated with the disease duration (r = -0.583, P < 0.05).@*Conclusions:@#The retinal thickness of patients with CPEO was significantly thinner, which was mostly the outer retina. The patients’ optic discs had a low volume and the loss of the retinal nerve fiber layer was obvious. With the extension of the disease duration, the retinal nerve fiber layer defect was even more significant.

Quantitation of muscle pathology abnormalities in 18 patients with mitochondrial disorders / Quantificação das anormalidades patológicas musculares em 18 pacientes com desordens mitocondriais

ABSTRACT INTRODUCTION: Mitochondrial disorders can lead to the accumulation of mitochondria in muscle fibers, as indicated by ragged red (RRF) or ragged blue fibers when stained with modified Gomori trichrome or succinate dehydrogenase (SDH+), respectively, and, absence of activity of cytochrome c oxidase, COX negative fibers (COX-). The combined COX-SDH stain (COMBO+) can reveal even more COX-deficient fibers. OBJECTIVE: To quantify RRFs, SDH+, COX-, and COMBO+ fibers in muscle biopsies with mitochondrial findings. MATERIAL AND METHODS: We retrospectively selected 18 muscle biopsies with mitochondrial abnormalities based on the Walker criteria (percentage of RRFs/COX- fibers, and clinical picture), and/or the Sleigh criteria (percentage of RRFs, SDH+, and COX- fibers). RESULTS: Females represented 83.3%, with a mean age of 38.6 years (5 months-70 years). Patients were diagnosed with chronic progressive external ophthalmoplegia (CPEO, 66.7%), proximal myopathy (22.2%), idiopathic hyperCKemia (11.1%), Kearns-Sayre syndrome (5.6%), mitochondrial encephalomyopathy with ragged red fibers and stroke-like episodes (5.6%), and a dystrophic pattern (5.6%). Some cases of CPEO were combined with proximal myopathy. The quantitative pathologic findings were: RRFs, 3.95% ± 3.17%; SDH+, 7.55% ± 6.1%; COX-, 10.9% ± 7.2%; COMBO+, 14.22% ± 12.79%. We found a slight variation in the diameter of muscle fibers, no necrosis or proliferative connective tissue, few fibers with internal nuclei, and some cases with fiber type grouping. CONCLUSION: Pathologic events, grouped in ascending order of frequency, were RRFs, SDH+ fibers, COX- fibers, and COMBO+ fibers. These data emphasize the importance of the COMBO technique in revealing occult COX deficiency in muscle fibers.

RESUMO INTRODUÇÃO: Desordens mitocondriais são usualmente caracterizadas por: 1. acúmulo de mitocôndria nas fibras musculares que aparecem como fibras vermelhas rasgadas (FVR) ou azuis rasgadas quando coradas, respectivamente, pelo tricrômio modificado de Gomori ou pelo succinato desidrogenase (SDH+); 2. ausência de atividade da citocromo c oxidase (COX), originando fibras COX negativa (COX-). A combinação de colorações COX e SDH pode revelar ainda mais fibras COX deficiente (COMBO+). Objetivos: Quantificar FVR, SDH+, COX- e COMBO+ em biópsias musculares com anormalidades mitocondriais. MATERIAL E MÉTODOS: Foram analisadas retrospectivamente 18 biópsias com anormalidades mitocondriais com base no critério de Walker (percentagem de FVR/ COX- e quadro clínico) e/ou critério de Sleigh (percentagem de FVR, SDH+ e COX-). RESULTADOS: Sexo feminino representou 83, 3% e média de idade 38, 6 anos (5 meses a 70 anos). Oftalmoplegia externa progressiva crônica (OEPC) representou 66, 7%; miopatia proximal, 22, 2%; hiperCKemia idiopática, 11, 1%; síndrome de Kearns-Sayre, 5, 6%; encefalopatia mitocondrial com FVR e episódios semelhantes a acidente vascular cerebral, 5, 6%; e padrão distrófico, 5, 6%. Alguns casos de OEPC estavam associados à miopatia proximal. Achados patológicos quantitativos: FVR, 3, 95% ± 3, 17%; SDH+, 7, 55% ± 6, 1%; COX-, 10, 9% ± 7, 2%; COMBO+, 14, 22% ± 12, 79%. Encontramos leve variação de calibre das fibras musculares sem necrose ou proliferação de tecido conjuntivo, poucas fibras com núcleos internos e alguns casos com agrupamento de fibras. CONCLUSÃO: As anormalidades patológicas nas fibras musculares em ordem ascendente de frequência foram: FVR, SDH+, COX- e COMBO+. Nossos achados enfatizam a importância da técnica COMBO (COX + SDH) para aumento na frequência de fibras musculares COX deficiente ocultas.

Ophthalmoplegia in Mitochondrial Disease

PURPOSE: To evaluate the classification, diagnosis, and natural course of ophthalmoplegia associated with mitochondrial disease. MATERIALS AND METHODS: Among 372 patients with mitochondrial disease who visited our hospital between January 2006 and January 2016, 21 patients with ophthalmoplegia were retrospectively identified. Inclusion criteria included onset before 20 years of age, pigmentary retinopathy, and cardiac involvement. The 16 patients who were finally included in the study were divided into three groups according to disease type: Kearns-Sayre syndrome (KSS), KSS-like, and chronic progressive external ophthalmoplegia (CPEO). RESULTS: The prevalences of clinical findings were as follows: ptosis and retinopathy, both over 80%; myopathy, including extraocular muscles, 75%; lactic acidosis, 71%; and elevated levels of serum creatine kinase, 47%. Half of the patients had normal magnetic resonance imaging findings. A biochemical enzyme assay revealed mitochondrial respiratory chain complex I defect as the most common (50%). The prevalence of abnormal muscle findings in light or electron microscopic examinations was 50% each, while that of large-scale mitochondrial DNA (mtDNA) deletions in a gene study was 25%. We compared the KSS and KSS-like groups with the CPEO patient group, which showed pigmentary retinopathy (p < 0.001), cardiac conduction disease (p=0.013), and large-scale mtDNA deletions (p=0.038). KSS and KSS-like groups also had gastrointestinal tract disorders such as abnormal gastrointestinal motility (p=0.013) unlike the CPEO group. CONCLUSION: Patients with KSS had gastrointestinal symptoms, which may indicate another aspect of systemic involvement. The presence of large-scale mtDNA deletions was an objective diagnostic factor for KSS and a gene study may be helpful for evaluating patients with KSS.

Síndrome de Kearns-Sayre / Kearns-Sayre syndrome

A síndrome de Kearns-Sayre é uma patologia rara, que acarreta piora da qualidade de vida; caracteriza-se por oftalmoplegia externa progressiva, fraqueza muscular e distúrbios na condução cardíaca. A entidade integra um grupo de desordens do metabolismo mitocondrial, denominadas miopatias mitocondriais ou citopatias mitocondriais.

Kearns-Sayres syndrome is a rare pathology which leads to a worse quality of life of the individual; it is characterized by progressive external ophthalmoplegia, muscular weakness, and cardiac conduction defects. The disease belongs to a group of mitochondrial metabolic disorders, named mitochondrial myopathies of mitochondrial cytopathies.

Molecular Diagnosis for Mitochondrial DNA Aberrations in Chronic Progressive External Ophthalmoplegia

PURPOSE: To evaluate the spectrum of mitochondrial DNA (mtDNA) aberrations in patients with suspected chronic progressive external ophthalmoplegia (CPEO) and to establish the molecular diagnostic method for CPEO in Koreans. METHODS: We performed mtDNA analyses for single deletions with long-range PCR and direct sequencing, and for the nine important point mutations including 3243A>G and 8344A>G with PCR/RFLP in muscles, bloods and paraffin-embedded muscle sections of 16 Korean patients with suspected CPEO. RESULTS: Three novel single mtDNA deletions were identified in three patients' muscles: 3159bp deletion from np 6657 to np 9815, 7591bp from np 8429 to np 16019, and 6191bp from np 7799 to np 13989. In addition, multiple mtDNA deletions were found in one patient. None of the blood specimen had mtDNA deletions even in the patients with mtDNA deletion in muscle. All single deletion junctions were flanked by direct repeats of 6-8 bp. None of the nine mtDNA point mutations were found in muscles, bloods or paraffin-embedded muscle sections. CONCLUSIONS: We identified three novel single deletions by mtDNA analyses in the muscles of 3 patients with CPEO. However, point mutations were not found. Furthermore, we established a molecular diagnostic method for CPEO in Korea. Long-range PCR and direct sequencing of the muscles were appropriate as a molecular diagnostic method for CPEO in Koreans.

Clinical and pathological features of chronic progressive external ophthalmoplegia / 临床神经病学杂志

Objective To investigate the clinical and skeletal muscular pathological features of chronic progressive external ophthalmoplegia(CPEO).Methods The clinical and skeletal muscular pathological data of 6 patients with CPEO were analyzed retrospectively.Results All of the 6 patients onset were 4 to 18 years old.The first symptom was blepharoptosis.The clinical mainly manifestations were limited activity of eyeball,accompanied with limbs muscle fatigue,weakness and level elevatation of serum creatine kinase(CK).5 cases had myogenic changes in electromyography(EMG).The skeletal muscular pathological examination showed that the ragged red fibers(RRF)were scattered among the muscle fibers,and the deficient or absent of COX activity in many fibers.A few degenerating and necrotic fibers were observed in 4 cases.Lipid-drops were increased by oil red "O" stain in 3 cases.Electromicroscope showed that abnormal mitochondria increased in number and aggregated under sarcolemma or in cytoplasm.Crystalloid inclusion body could be observed.Conclusions The clinical mainly features of CPEO are external ophthalmoplegia and accompanied with limbs weakness.RRF and COX activity deficiency or absence according to skeletal muscle pathology can be suggest and support the diagnosis of CPEO.Gene sequencing based on skeletal muscle biopsy is necessary to make the final diagnosis of CPEO.