Chronic Progressive External Ophthalmoplegia Patients Research Articles

Ellipsoid Zone Reflectivity: Exploring its Potential as a Novel Non-Invasive Biomarker for Assessing Mitochondrial Function

ABSTRACT The ellipsoid zone (EZ) on macular optical coherence tomography (OCT) scans exhibits high intensity due to a high density of light-scattering mitochondria, making its reflectivity a potential marker for mitochondrial function. Here, we developed a reliable analysis tool for extracting relative EZ reflectivity and explore its potential as a biomarker in various diseases. We analysed OCT scans of patients with optic neuritis (ON), primary progressive optic neuropathy (PPON), chronic progressive external ophthalmoplegia (CPEO), dominant optic atrophy (DOA), and healthy controls. EZ reflectivity (normalised to the retina pigment epithelium (RPE) and outer nuclear layer (ONL)) was evaluated. Reliability was assessed using intraclass correlation coefficients (ICC), and group differences were analysed through multivariable linear regression, adjusting for relevant confounders. In total, 12 controls, 23 ON patients, 7 CPEO patients, 13 DOA patients, and 13 PPON patients were included. EZ/RPE20% and EZ/ONL ratios demonstrated good test–retest reliability with ICCs of 0.76 (p < .001) and 0.63 (p = .013), respectively. Multivariable regression analysis revealed that median EZ/RPE20% and EZ/ONL ratios were lower in CPEO (r = -0.12, p = .036, and r = -0.59, p = .011), DOA (r = -0.16, p = .049, and r = -0.55, p = .082), PPON (r = -0.17, p = .014, and r = -0.57, p = .037), and ON (r = -0.11, p = .013, and r = -0.42, p = .006) compared to controls, respectively. These data show that EZ reflectivity can be reliably determined from OCT scans and appears to be reduced in neuroinflammatory and mitochondrial disorders. Further validation in larger prospective cohorts is warranted, but our findings suggest that EZ reflectivity might serve as a non-invasive in-vivo biomarker for mitochondrial health.

Videographic analysis of blink dynamics in patients with chronic progressive external ophthalmoplegia, myogenic ptosis, and facial nerve palsy using smartphone camera: A comparative analysis.

Congenital myogenic ptosis (CMP), chronic progressive external ophthalmoplegia (CPEO), and facial nerve palsy (FNP) are among the disorders which can seriously affect the blink dynamics of patients. Smartphone videography is a simple, convenient, and inexpensive way to capture eyelid movement. This study has measured and compared a variety of blink dynamics in these patients compared to healthy controls using 2-dimensional smartphone videography to enhance the utility of this method in both clinical and research settings. A total of 30 adult participants with a complaint of impaired eyelid movements including 10 with CMP, 10 with CPEO, and 10 with unilateral FNP, as well as 10 healthy controls were recruited. Using a smartphone camera with a resolution of 240 frames per second in 720 p, various blink dynamics were measured. All case groups had significantly lower values of peak and average closing velocities, average opening velocity, and palpebral aperture and significantly higher values of eyelid closing duration, compared to controls. FNP participants also had significantly lower values in the full blink rate and peak opening velocity (POV) measures, and CPEO patients showed significantly lower values in the POV. Other measures were not statistically significantly different compared to healthy controls. Our results indicated that all patients with CMP, FNP, and CPEO had different blinking dynamics compared to healthy controls, which is consistent with previous studies. Smartphone videography has achieved sufficient resolution and frame-rate to provide valuable information and anatomic details for clinical and research purposes. Further studies could utilize smartphone videography for further investigation and confirmation of the methodology in various conditions.

Eye Muscle MRI in Myasthenia Gravis and Other Neuromuscular Disorders.

MRI of extra-ocular muscles (EOM) in patients with myasthenia gravis (MG) could aid in diagnosis and provide insights in therapy-resistant ophthalmoplegia. We used quantitative MRI to study the EOM in MG, healthy and disease controls, including Graves' ophthalmopathy (GO), oculopharyngeal muscular dystrophy (OPMD) and chronic progressive external ophthalmoplegia (CPEO). Twenty recently diagnosed MG (59±19yrs), nineteen chronic MG (51±16yrs), fourteen seronegative MG (57±9yrs) and sixteen healthy controls (54±13yrs) were included. Six CPEO (49±14yrs), OPMD (62±10yrs) and GO patients (44±12yrs) served as disease controls. We quantified muscle fat fraction (FF), T2water and volume. Eye ductions and gaze deviations were assessed by synoptophore and Hess-charting. Chronic, but not recent onset, MG patients showed volume increases (e.g. superior rectus and levator palpebrae [SR+LPS] 985±155 mm3 compared to 884±269 mm3 for healthy controls, p < 0.05). As expected, in CPEO volume was decreased (e.g. SR+LPS 602±193 mm3, p < 0.0001), and in GO volume was increased (e.g. SR+LPS 1419±457 mm3, p < 0.0001). FF was increased in chronic MG (e.g. medial rectus increased 0.017, p < 0.05). In CPEO and OPMD the FF was more severely increased. The severity of ophthalmoplegia did not correlate with EOM volume in MG, but did in CPEO and OPMD. No differences in T2water were found. We observed small increases in EOM volume and FF in chronic MG compared to healthy controls. Surprisingly, we found no atrophy in MG, even in patients with long-term ophthalmoplegia. This implies that even long-term ophthalmoplegia in MG does not lead to secondary structural myopathic changes precluding functional recovery.

Multi-Omics Approach to Mitochondrial DNA Damage in Human Muscle Fibers.

Mitochondrial DNA deletions affect energy metabolism at tissue-specific and cell-specific threshold levels, but the pathophysiological mechanisms determining cell fate remain poorly understood. Chronic progressive external ophthalmoplegia (CPEO) is caused by mtDNA deletions and characterized by a mosaic distribution of muscle fibers with defective cytochrome oxidase (COX) activity, interspersed among fibers with retained functional respiratory chain. We used diagnostic histochemistry to distinguish COX-negative from COX-positive fibers in nine muscle biopsies from CPEO patients and performed laser capture microdissection (LCM) coupled to genome-wide gene expression analysis. To gain molecular insight into the pathogenesis, we applied network and pathway analysis to highlight molecular differences of the COX-positive and COX-negative fiber transcriptome. We then integrated our results with proteomics data that we previously obtained comparing COX-positive and COX-negative fiber sections from three other patients. By virtue of the combination of LCM and a multi-omics approach, we here provide a comprehensive resource to tackle the pathogenic changes leading to progressive respiratory chain deficiency and disease in mitochondrial deletion syndromes. Our data show that COX-negative fibers upregulate transcripts involved in translational elongation and protein synthesis. Furthermore, based on functional annotation analysis, we find that mitochondrial transcripts are the most enriched among those with significantly different expression between COX-positive and COX-negative fibers, indicating that our unbiased large-scale approach resolves the core of the pathogenic changes. Further enrichments include transcripts encoding LIM domain proteins, ubiquitin ligases, proteins involved in RNA turnover, and, interestingly, cell cycle arrest and cell death. These pathways may thus have a functional association to the molecular pathogenesis of the disease. Overall, the transcriptome and proteome show a low degree of correlation in CPEO patients, suggesting a relevant contribution of post-transcriptional mechanisms in shaping this disease phenotype.

The cover photo shows different neovascularization types from the paper by Smid et al.

The cover photo shows different neovascularization types from the paper by Smid et al.

Strabismus in chronic progressive external ophthalmoplegia.

To elucidate the patterns of strabismus and ophthalmoplegia associated with chronic progressive external ophthalmoplegia (CPEO) confirmed by mitochondrial DNA (mtDNA) deletions in Asians. A total of 10 patients confirmed to have mtDNA deletion associated with CPEO were included. Long-range PCR encompassing the entire mtDNA was carried out. In the cases with mtDNA deletion, the exact deletion ranges of mtDNA were identified by sequencing. A full ophthalmologic examination including prism and alternate cover test in the primary position, evaluation of ductions and versions, and binocularity was performed in 10 patients with confirmed mtDNA deletions associated with CPEO. All of the patients showed ophthalmoplegia as well as ptosis, even after eyelid surgeries. Ophthalmoplegia was symmetric between both eyes in nine patients (90%) while one patient (10%) showed asymmetric ophthalmoplegia with esotropia and left hypotropia. Among the nine patients with symmetric involvement, four patients (44%) showed exotropia, three (33%) had exotropia with vertical deviation, and the remaining two patients (22%) showed orthotropia. Five out of 10 patients (50%) complained of diplopia associated with strabismus, four of whom (80%) had vertical deviation. Three out of five patients (60%) without diplopia showed exotropia of 20 prism diopters (PD) to 50 PD. Exotropia with/without vertical deviation is the most common form of strabismus in Asian patients with CPEO and only one of them showed a small angle of esotropia. Ophthalmoplegia could be asymmetric in 10% of CPEO patients.

Electrophysiological study of neuromuscular junction in congenital myasthenic syndromes, congenital myopathies, and chronic progressive external ophthalmoplegia

This study was designed to analyze the sensitivity, specificity, and accuracy of jitter parameters combined with repetitive nerve stimulation (RNS) in congenital myasthenic syndrome (CMS), chronic progressive external ophthalmoplegia (CPEO), and congenital myopathies (CM). Jitter was obtained with a concentric needle electrode during voluntary activation of the Orbicularis Oculi muscle in CMS (n = 21), CPEO (n = 20), and CM (n = 18) patients and in controls (n = 14). RNS (3 Hz) was performed in six different muscles for all patients (Abductor Digiti Minimi, Tibialis Anterior, upper Trapezius, Deltoideus, Orbicularis Oculi, and Nasalis). RNS was abnormal in 90.5% of CMS patients and in only one CM patient. Jitter was abnormal in 95.2% of CMS, 20% of CPEO, and 11.1% of CM patients. No patient with CPEO or CM presented a mean jitter higher than 53.6 µs or more than 30% abnormal individual jitter (> 45 µs). No patient with CPEO or CM and mild abnormal jitter values presented an abnormal decrement. Jitter and RNS assessment are valuable tools for diagnosing neuromuscular transmission abnormalities in CMS patients. A mean jitter value above 53.6 µs or the presence of more than 30% abnormal individual jitter (> 45 µs) strongly suggests CMS compared with CPEO and CM.

Genotypes of chronic progressive external ophthalmoplegia in a large adult-onset cohort

Chronic progressive external ophthalmoplegia (CPEO) is a common presentation of mitochondrial disease. We performed a retrospective evaluation of the molecular genetic testing and genotype-phenotype correlations in a large cohort of adult-onset CPEO patients (N = 111). One hundred percent of patients tested had at least one mitochondrial DNA (mtDNA) deletion. Genetic testing of nuclear genes encoding mitochondrial proteins identified pathogenic/likely pathogenic variants likely to be associated with CPEO in 7.6% of patients. As expected, the nuclear gene most associated with DNA variation was POLG. A single likely pathogenic mitochondrial DNA variant (m.12278T>C) was identified in two unrelated patients. No significant differences were noted in the clinical phenotypes of patients with pathogenic or likely pathogenic nuclear variants in comparison to those with negative nuclear gene testing. Analysis of deletion size and heteroplasmy in muscle-derived mtDNA showed significant correlations with age of symptom onset but not disease severity (number of canonical CPEO features). Results suggest that smaller mtDNA deletions (p = 0.0127, r2 = 0.1201) and higher heteroplasmy of single mtDNA deletions (p = 0.0112, r2 = 0.2483) are associated with an earlier age of onset in CPEO patients.

Appendicular skeletal muscle mass: A more sensitive biomarker of disease severity than BMI in adults with mitochondrial diseases

The study aimed to evaluate the body composition of patients with mitochondrial diseases (MD) and correlate it with disease severity. Overall, 89 patients (age ≥ 18 years) with MD were recruited, including 49 with chronic progressive external ophthalmoplegia (CPEO) and 40 with mitochondrial encephalomyopathy with lactate acidosis and stroke-like episodes (MELAS). Body composition, including fat mass index (FMI), fat-free mass index (FFMI), skeletal muscle mass index (SMI), and appendicular skeletal muscle mass index (ASMI), were examined using multifrequency bioelectric impedance analysis. Clinical assessments, including muscle strength, usual gait speed, and disease severity determined by the Newcastle Mitochondrial Disease Adult Scale score (NMDAS), were performed. The comparisons between patients group and age- and gender-matched healthy controls, as well as the correlations between anthropometric measurements, body composition, and disease severity were analyzed. Height, weight, body mass index (BMI), FFMI, SMI, and ASMI were significantly lower in patients with MD than in healthy controls. Notably, low muscle mass was noted in 69.7% (62/89) of MD patients, with 22 patients also presenting with compromised physical performance as indicated by decreased gait speed, resulting in 24.7% satisfied the sarcopenia diagnostic criteria. Disease severity was more negatively correlated with ASMI than it was with height, weight, and BMI. Subgroup analysis showed that in the MELAS subgroup, disease severity was negatively correlated with height, weight, and ASMI; whereas in the CPEO subgroup, it was only negatively correlated with ASMI and SMI. Additionally, ASMI was positively associated with muscle strength. Altogether, compared with BMI, ASMI is a more sensitive biomarker predicting disease severity of MD, both in MELAS and CPEO patients.

Optical coherence tomography findings in chronic progressive external ophthalmoplegia.

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.

MITOCHONDRIAL DISEASES (Posters): P.191Single muscle fiber analysis of extraocular and skeletal muscles in a CPEO patient harboring a pathogenic point mutation in the MT-TN gene

Chronic progressive external ophthalmoplegia (CPEO) is a frequent feature of mitochondrial disorders and usually associated with mitochondrial DNA (mtDNA) mutations. Skeletal muscle (SKM) tissue is most frequently used for biochemical analyses and mitochondrial genome testing. However, extraocular muscle (EOM) is the clinically most affected tissue but usually not available for routine work-up. Consequently, systematic data on EOM is limited and the reason for preferential clinical affection remains unclear. We addressed this unsolved question by histochemical and genetic analyses of EOM and SKM single muscle fibers in a patient with isolated CPEO caused by a heteroplasmic point mutation in the MT-TN gene. The histochemical analysis showed higher absolute numbers of cytochrome c oxidase (COX)-deficient EOM fibers compared to COX-deficient SKM fibers. However, genetic analyses by restriction fragment length polymorphism revealed no significant difference in the mutation loads between COX-negative single muscle fibers in EOM compared to SKM. Quantitative single fiber real-time PCR revealed higher mtDNA copy numbers in single muscle fibers of EOM compared to SKM. COX-negative single muscle fibers of EOM and SKM showed significantly higher mtDNA copy numbers compared to COX-positive fibers suggestive of a compensatory mtDNA proliferation. We show that high loads of the MT-TN mutation correlate with a biochemical loss of COX activity in single muscle fibers of EOM and SKM at a similar threshold. The higher absolute numbers of COX-negative fibers in EOM compared to SKM might be caused by facilitated segregation of the mutation into the EOM providing thereby a possible explanation of the preferential ocular manifestation in CPEO.

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.

Ophthalmoplegia in Mitochondrial Disease.

PurposeTo evaluate the classification, diagnosis, and natural course of ophthalmoplegia associated with mitochondrial disease.Materials and MethodsAmong 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).ResultsThe 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.ConclusionPatients 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.

Clinical and demographic features of chronic progressive external ophthalmoplegia in a large adult-onset cohort

Chronic progressive external ophthalmoplegia (CPEO) is a common mitochondrial disease. We evaluated the impact of sex and smoking status upon knee extension strength and the phenotypic spectrum of disease in a large cohort of adult-onset CPEO patients (N=116) using retrospective chart analysis. The CPEO patients showed significantly lower knee extension strength as compared to the age- and sex-matched control population (−37%, P<0.05). Smoking also negatively impacted knee extension strength only in women with CPEO (−26%, P<0.05). We conclude that smoking and female sex interact negatively in CPEO patients.

Disclosing the functional changes of two genetic alterations in a patient with Chronic Progressive External Ophthalmoplegia: Report of the novel mtDNA m.7486G>A variant

Chronic Progressive External Ophthalmoplegia (CPEO) is characterized by ptosis and ophthalmoplegia and is usually caused by mitochondrial DNA (mtDNA) deletions or mt-tRNA mutations. The aim of the present work was to clarify the genetic defect in a patient presenting with CPEO and elucidate the underlying pathogenic mechanism. This 62-year-old female first developed ptosis of the right eye at the age of 12 and subsequently the left eye at 45 years, and was found to have external ophthalmoplegia at the age of 55 years. Histopathological abnormalities were detected in the patient's muscle, including ragged-red fibres, a mosaic pattern of COX-deficient muscle fibres and combined deficiency of respiratory chain complexes I and IV. Genetic investigation revealed the “common deletion” in the patient's muscle and fibroblasts. Moreover, a novel, heteroplasmic mt-tRNASer(UCN) variant (m.7486G>A) in the anticodon loop was detected in muscle homogenate (50%), fibroblasts (11%) and blood (4%). Single-fibre analysis showed segregation with COX-deficient fibres for both genetic alterations. Assembly defects of mtDNA-encoded complexes were demonstrated in fibroblasts. Functional analyses showed significant bioenergetic dysfunction, reduction in respiration rate and ATP production and mitochondrial depolarization. Multilamellar bodies were detected by electron microscopy, suggesting disturbance in autophagy. In conclusion, we report a CPEO patient with two possible genetic origins, both segregating with biochemical and histochemical defect. The “common mtDNA deletion” is the most likely cause, yet the potential pathogenic effect of a novel mt-tRNASer(UCN) variant cannot be fully excluded.

Nerve excitability changes related to muscle weakness in chronic progressive external ophthalmoplegia.

To explore potential spreading to peripheral nerves of the mitochondrial dysfunction in chronic progressive external ophthalmoplegia (CPEO) by assessing axonal excitability. CPEO patients (n=13) with large size deletion of mitochondrial DNA and matching healthy controls (n=22) were included in a case-control study. Muscle strength was quantified using MRC sum-score and used to define two groups of patients: CPEO-weak and CPEO-normal (normal strength). Nerve excitability properties of median motor axons were assessed with the TROND protocol and changes interpreted with the aid of a model. Alterations of nerve excitability strongly correlated with scores of muscle strength. CPEO-weak displayed abnormal nerve excitability compared to CPEO-normal and healthy controls, with increased superexcitability and responses to hyperpolarizing current. Modeling indicated that the CPEO-weak recordings were best explained by an increase in the 'Barrett-Barrett' conductance across the myelin sheath. CPEO patients with skeletal weakness presented sub-clinical nerve excitability changes, which were not consistent with axonal membrane depolarization, but suggested Schwann cell involvement. This study provides new insights into the spreading of large size deletion of mitochondrial DNA to Schwann cells in CPEO patients.

Nature and frequency of respiratory involvement in chronic progressive external ophthalmoplegia

Chronic progressive external ophthalmoplegia (CPEO) is a relatively common mitochondrial disorder. Weakness of the extra-ocular, limb girdle and laryngeal muscles are established clinical features. Respiratory muscle involvement however has never been studied systematically, even though respiratory complications are one of the main causes of death. We therefore determined the prevalence and nature of respiratory muscle involvement in 23 patients with genetically confirmed CPEO. The main finding was decreased respiratory muscle strength, both expiratory (76.8% of predicted, p = 0.002) and inspiratory (79.5% of predicted, p = 0.004). Although the inspiratory vital capacity (92.5% of predicted, p = 0.021) and the forced expiratory volume in 1 s (89.3% of predicted, p = 0.002) were below predicted values, both were still within the normal range in the majority of patients. Expiratory weakness was associated with a decreased vital capacity (ρ = 0.502, p = 0.015) and decreased peak expiratory flow (ρ = 0.422, p = 0.045). Moreover, expiratory muscle strength was lower in patients with limb girdle weakness (62.6 ± 26.1% of predicted vs. 98.9 ± 22.5% in patients with normal limb girdle strength, p = 0.003), but was not associated with other clinical features, subjective respiratory complaints, disease severity or disease duration. Since respiratory involvement in CPEO is associated with severe morbidity and mortality, the present data justify periodic assessment of respiratory functions in all CPEO patients.

Hemifacial presentation of mitochondrial myopathy

Chronic progressive external ophthalmoplegia (CPEO) is a common presentation of mitochondrial disease and is typically bilaterally symmetric. We present an unusual case of CPEO that remained unilateral and, therefore, eluded diagnosis for nearly 30 years. A 39-year-old woman presented with horizontal diplopia. She had a long standing right partial ptosis from her early twenties. There were no other neurological symptoms or relevant features in the history. Examination showed a right mild, non-fatigable ptosis, with limited adduction, elevation and depression of the right eye. The left eye and remaining ophthalmic and neurological examination were normal. Computer tomography (CT) imaging of brain and orbits was unremarkable and conservative management was pursued. Seven years later (age 46 years) the patient developed a droop of the right lower eyelid and mouth. Examination confirmed new facial weakness and the previous ptosis and ophthalmoplegia, all confined to the right side of the face (Fig. 1). There were no other neurological findings and no response to intravenous edrophonium test. Cranial CT and magnetic resonance imaging (MRI) were once again normal and the diagnosis remained elusive. Two years later, however (age 48), a limitation of depression and abduction developed in the left eye. Bilateral ophthalmoplegia now suggested the possibility of CPEO. Left triceps muscle biopsy was performed. Although there were no ragged red fibres, histochemistry demonstrated occasional cytochrome-C oxidase (COX)deficient fibres. Electron microscopy showed peripheral collections of glycogen-rich cytoplasm, containing small aggregates of mitochondria. Screening of the mitochondrial DNA for deletions using long range PCR followed by Southern blotting revealed the presence of a single large scale deletion of the mitochondrial genome. Sequencing across the deletion breakpoint confirmed the presence of the ‘‘common’’ deletion of 4,977 base pairs, with break points in the flanking repeats between nucleotide (nt) 8,470 and 8,482, and nt 13,447 and 13,459. CPEO is characterised by bilateral ptosis and global restriction of eye movements [1]. It is the commonest ocular manifestation of the mitochondrial myopathies and can occur in isolation or with additional non-ocular features [2, 3]. Diagnosis is often delayed for many years [4, 5]. In our case, two atypical features failed to suggest the diagnosis (1) the strict unilaterality of the ptosis and ophthalmoplegia for decades, and (2) the additional feature of unilateral facial weakness. Bilateral ptosis is a hallmark of CPEO and is the presenting complaint in up to 90% of cases [1]. The ptosis can be asymmetric, however [2]. Unilateral or asymmetric ptosis was noted in 11 patients out of 27 in a recent CPEO series [6]. Although unilateral or asymmetric ptosis may occur in early disease, bilateral ptosis becomes the norm as the disease progresses. Our case was very atypical because the ptosis remained unilateral throughout. Ophthalmoplegia in CPEO is usually symmetric and, in advanced cases, often complete [1]. Although asymmetric ophthalmoplegia does occur in a minority of CPEO patients [1, 7], accurate measurements of ocular motility have shown that the extent of asymmetry is very small [8]. The marked asymmetry of ophthalmoplegia in our case is therefore surprising. N. Ali (&) J. Acheson Department of Neuro-Ophthalmology, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK e-mail: nadeem.ali@nhs.net

Multisystem Disorder in Late-Onset Chronic Progressive External Ophthalmoplegia

Chronic progressive external ophthalmoplegia (CPEO) is a mitochondrial syndrome on a disease spectrum with Kearns-Sayre syndrome (KSS). Clinical presentation is variable and our experience suggested that phenotypic differences exist in CPEO with onset after age 20. This descriptive study is a retrospective chart review of 40 patients with late-onset CPEO. Clinical features, laboratory and neurophysiology results were reviewed. Multisystem dysfunction was very common in this series. Gastrointestinal dysfunction was more common than expected (60%) as was migraine headache (40%). Clinical characteristics on the KSS disease spectrum were uncommon in this series with only 2.5% having pigmentary retinopathy, 5% with cardiac conduction abnormality, and 22.5% having endocrinopathy (most often thyroid dysfunction rather than diabetes). Neurophysiology abnormalities included length-dependent axonal polyneuropathy in 44% (sometimes subclinical) and myopathic EMG changes in 26%. Exposure to sources of acquired mitochondrial toxicity including cigarette use and hepatitis C infection were more common than expected in this series. Phenotype was different in this late-onset series compared with previous reports in CPEO patients. In this series of late-onset patients, multi-organ dysfunction was more common than previously reported in CPEO, and some classical mitochondrial manifestations, such as pigmentary retinopathy were rare. We suggest that acquired mitochondrial toxicity may have a role in the pathogenesis of adult-onset CPEO.

Mitochondrial DNA Defects and Selective Extraocular Muscle Involvement in CPEO

PURPOSE. Chronic progressive external ophthalmoplegia (CPEO) is a prominent, and often the only, presentation among patients with mitochondrial diseases. The mechanisms underlying the preferential involvement of extraocular muscles (EOMs) in CPEO were explored in a comprehensive histologic and molecular genetic study, to define the extent of mitochondrial dysfunction in EOMs compared with that in skeletal muscle from the same patient. METHODS. A well-characterized cohort of 13 CPEO patients harboring a variety of primary and secondary mitochondrial (mt)DNA defects was studied. Mitochondrial enzyme function was determined in EOM and quadriceps muscle sections with cytochrome c oxidase (COX)/succinate dehydrogenase (SDH) histochemistry, and the mutation load in single muscle fibers was quantified by real-time PCR and PCR-RFLP assays. RESULTS. CPEO patients with mtDNA deletions had more COX-deficient fibers in EOM (41.6%) than in skeletal muscle (13.7%, P > 0.0001), and single-fiber analysis revealed a lower mutational threshold for COX deficiency in EOM. Patients with mtDNA point mutations had a less severe ocular phenotype, and there was no significant difference in the absolute level of COX deficiency or mutational threshold between these two muscle groups. CONCLUSIONS. The more pronounced mitochondrial biochemical defect and lower mutational threshold in EOM compared with skeletal muscle fibers provide an explanation of the selective muscle involvement in CPEO. The data also suggest that tissue-specific mechanisms are involved in the clonal expansion and expression of secondary mtDNA deletions in CPEO patients with nuclear genetic defects.