Disease relevance of Ophthalmoplegia, Chronic Progressive External

• We tested the efficacy of coenzyme Q10 (ubidecarenone, CoQ10) therapy in patients with Kearns-Sayre syndrome and other mitochondrial myopathies with chronic progressive external ophthalmoplegia (CPEO) [1].
• In the muscle biopsy of a female patient with chronic progressive external ophthalmoplegia (CPEO), myopathy, and exercise intolerance, the heteroplasmic deletion of a single nucleotide (DeltaT5885) in the mitochondrial tRNA tyrosine gene (tRNA(Tyr)) was found [2].
• To assess dysphagia, the authors examined 12 patients with Kearns-Sayre syndrome (KSS) or chronic progressive external ophthalmoplegia (CPEO) due to mitochondrial DNA (mtDNA) deletion by videofluoroscopy and manometry [3].
• In 14 cases the clinical phenotype was characterized by mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), while 8 patients had chronic progressive external ophthalmoplegia (CPEO) [4].
• 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 [5].

High impact information on Ophthalmoplegia, Chronic Progressive External

• Screening of the gene encoding Twinkle in individuals with autosomal dominant progressive external ophthalmoplegia (adPEO), associated with multiple mtDNA deletions, identified 11 different coding-region mutations co-segregating with the disorder in 12 adPEO pedigrees of various ethnic origins [6].
• One of three loci previously associated with autosomal dominant progressive external ophthalmoplegia (adPEO) encodes ANT1, a mitochondrial nucleotide transporter [7].
• 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 [8].
• 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 [8].
• Previously, we have shown that different mutations in this same gene cause autosomal dominant progressive external ophthalmoplegia (adPEO) with multiple mtDNA deletions (MIM 606075), a neuromuscular disorder sharing a spectrum of symptoms with IOSCA [9].

Chemical compound and disease context of Ophthalmoplegia, Chronic Progressive External

• Exercise-induced increases in plasma lactate correlated with muscle mutation load in CPEO patients (r = 0.95; p < 0.005) [10].
• These findings suggest that evolutionarily conserved regions in mitochondrial tRNA genes can exhibit a significant polymorphism in humans, and that the mutation at np 12,308 in the tRNA(Leu(CUN)) gene is unlikely to be associated with CPEO and Wolfram syndrome [11].
• Mutation of Tyr955 in pol gamma causes the degenerative disease progressive external ophthalmoplegia in humans, and we show that this residue partially accounts for the ability of pol gamma to incorporate D4T-MP and carbovir [12].
• In the present study free, phosphorylated and total creatine concentrations as well as Mi-CK activity were determined in muscle samples of six patients with chronic progressive external ophthalmoplegia (CPEO) [13].
• 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 [14].

Biological context of Ophthalmoplegia, Chronic Progressive External

• Maximal oxygen uptake (VO(2max)), workload (W(max)), and venous plasma lactate levels were measured during an incremental cycle test to exhaustion in 17 patients with point mutations of mtDNA and in seven with single, large-scale deletions of mtDNA (chronic progressive external ophthalmoplegia [CPEO]) [10].
• Overt diabetes in CPEO seems to be a combination of insulin resistance, an insulin secretion defect, and impaired glucose effectiveness [14].
• These ultrastructural changes may relate to the different expression of the two diseases, resulting in ophthalmoplegia in CPEO and normal eye movements in LHON [15].
• We have analyzed Twinkle, the causative gene for autosomal dominant progressive external ophthalmoplegia (adPEO) on chromosome 10, in 11 Australian autosomal dominant progressive external ophthalmoplegia families of Caucasian origin, and investigated whether there are distinct molecular and clinical features associated with mutations in this gene [16].
• Although the mitochondrial genome of mammals, including humans, appears to be quite stable in comparison to other species, mtDNA instabilities of the type described in fungi were observed in mitochondria of patients with different mitochondrial degenerative disorders (CPEO, KSS, Pearson syndrome, LHON, MERRF, MELAS) [17].

Anatomical context of Ophthalmoplegia, Chronic Progressive External

• 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 [18].
• We investigated whether apoptotic events occurred in skeletal muscles of patients with mitochondrial diseases, including chronic progressive external ophthalmoplegia (CPEO), Kearns-Sayer syndrome (KSS), and mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) [19].
• A similar pattern was observed in the mRNA levels of Mn-SOD and GPx in muscle fibroblasts of all CPEO patients [20].
• Teased single muscle fibers from 6 patients with chronic progressive external ophthalmoplegia (CPEO) showed a segmental defect in cytochrome c oxidase (COX) activity [18].
• Fourteen patients had chronic progressive external ophthalmoplegia (CPEO) associated with a mild to moderate craniosomatic myopathy without any symptoms or signs of central nervous system (CNS) involvement, 2 myoclonic epilepsy with ragged red fibers syndrome, and 1 Kearns-Sayre syndrome [21].

Gene context of Ophthalmoplegia, Chronic Progressive External

• Mean complex I polymorphic frequencies in cytopathic (CPEO, MERRF, MELAS and LHON collectively) patients and in LHON patients differed significantly from controls (P < or = 0.05, t) [22].
• Twinkle is a nuclear-encoded mtDNA helicase, dominant mutations of which cause adult-onset progressive external ophthalmoplegia (PEO) with multiple mtDNA deletions [23].
• Eliminating the Ant1 isoform produces a mouse with CPEO pathology but normal ocular motility [24].
• In the light of these findings, we suggest that the increase in expression of Mn-SOD, ROS production and oxidative damage in affected tissues may play an important role in the pathogenesis and progression of the CPEO syndrome [20].
• Of the patients referred for KSS and CPEO, 17.72% had deletions/rearrangements [25].

Analytical, diagnostic and therapeutic context of Ophthalmoplegia, Chronic Progressive External

• In patients with CPEO/KSS, stainings of Mb, SOD, CAT, and GSH-Px in nonatrophic ragged-red fibers (RRFs) were more intense than those in non-RRFs [26].

References