External Ophthalmoplegia Research Articles

Progressive external ophthalmoplegia – A case report

Progressive external ophthalmoplegia is a slowly progressive hereditary mitochondrial myopathy. Most mitochondrial disorders overlap clinically, enzymatically, and genetically. The most common enzyme defect is the combined deficit of complexes I and IV. Progressive external ophthalmoplegia particularly affects the extraocular muscles and is characterised by ophthalmoplegia, and bilateral ptosis. The ptosis and ophthalmoplegia is unresponsive to anticholinergics, with no effective treatment, but corrective surgery for ptosis as a palliative one. In this article, we report a rare case of a 16-year-old female with characterstic histological features consistent with progressive external ophthalmoplegia.

Myosin Myopathy Presenting as Chronic Progressive External Ophthalmoplegia.

Myosin Myopathy Presenting as Chronic Progressive External Ophthalmoplegia.

Frontalis sling in a bilateral ptosis with external ophthalmoplegia and poor bell’s phenomenon: A 5-year follow-up

Congenital ptosis with ophthalmoplegia is a rare condition. We present a 17-year-old patient with congenital ptosis with severe restriction of ocular movements with poor Bell’s phenomenon. He was managed with silicone rod frontalis sling surgery. After 5 years, the sling is intact with no lagophthalmos and exposure keratopathy.

Reversible Brain Death

Snakebite is a serious public health problem and one of the priorities in WHO's list of neglected tropical diseases. It significantly increases morbidity and mortality associated with envenomation in India. A neurotoxic snakebite can present in the form of symptoms ranging from asymptomatic presentation, ptosis, and complete external and internal ophthalmoplegia to complete respiratory failure. This is a case report of a 22-year-old male, who presented with bilateral ptosis and impending respiratory failure. He soon became deeply comatose, with absent brain stem reflexes (mute plantar, fixed pupils, and the absence of the doll's eye reflex) which were suggestive of brain death. He was treated with polyvalent anti-snake venom, anticholinesterases, and supportive therapy and recovered completely with an excellent outcome.

Retinal involvement in mitochondrial disease

AbstractRetinal involvement in mitochondrial disease is a variable feature of mitochondrial dysfunction. The retinal pigment epithelium and photoreceptor layers can both be affected. It manifests with signs ranging from asymptomatic peripheral salt‐and‐pepper retinopathy to classic bone‐spicule pigmentary changes. The consequences can be progressive mild or severe visual field constriction and central visual acuity loss. The pathophysiological mechanisms involved in retinal dysfunction in mitochondrial disease are still being elucidated and may include a range of metabolic and bioenergetic defects.Mitochondrial conditions affecting the eye that display prominent outer retinal involvement include.(a) mitochondrial encephalomyopathy, lactic acidosis and stroke‐like episodes (MELAS) secondary to the m.3243A > G mtDNA mutation in MT‐TL1,(b) neuropathy, ataxia and retinitis pigmentosa (NARP) secondary to the m.8993 T > G mtDNA mutation in MT‐ATP6,(c) chronic progressive external ophthalmoplegia (CPEO), in particular the Kearns‐Sayre syndrome (KSS) secondary to single large‐scale mtDNA deletions, and.(d) some newer entities, such as optic neuropathy and pigmentary retinopathy seen in patients with mutations in the gene SSBP1.The features and diagnostic pathway for these conditions will be illustrated and discussed.

Chronic progressive external ophthalmoplegia

AbstractChronic progressive external ophthalmoplegia (CPEO) is an array of genetic condition which causes progressive paralysis of the extraocular muscles and lid ptosis. CPEO can occur in isolation or in association with other systemic features (CPEO‐plus) including myopathy, dysarthria, ataxia, and parkinsonism. The condition can be part of a neurological syndrome such as Kern‐Sayre Syndrome (KSS), were pigmentary retinopathy, cerebellar ataxia, heart block and/or elevated CSF protein occur in addition to progressive external ophthalmoplegia.The condition is caused by disfunction of oxidative phosphorylation and several genes in both the mitochondrial DNA and nuclear DNA have been demonstrated to cause CPEO. This results in a varied inheritance pattern, depending on the gene involved in the individual pedigree.Clinically, most patients with CPEO develop a progressive symmetrical external ophthalmoplegia and thus do not typically experience diplopia. If diplopia is present, however, it can usually be managed by prism lenses although some patients do require surgical correction. This contrasts with the clinically significant ptosis, which typically requires surgical correction.In this session we will review the clinical features and the genetic variants associated with CPEO along with the clinical management and pitfalls in caring for patient with CPEO.

Neuroradiological findings in a young patient bearing a new single mitochondrial gene mutation (case report)

BackgroundWe present the clinical, MRI and CT findings in a case of a new mitochondrial genome mutation (tRNA arginine gene), characterized by brain calcifications which are indicative of Kearns–Sayre syndrome (KSS). Some radiological features resembled those of Fahr’s disease (affecting the PDGFRB gene).Case presentationA 36-year-old male presented some typical clinical features of KSS, including onset before 20 years of age, pigmentary retinopathy, progressive external ophthalmoplegia and ptosis. However, the hallmark radiological finding of diffuse calcifications in the nuclear ganglia resembles some cases related to the PDGRFB mutation. Genetic investigation revealed a new mutation in the mitochondrial tRNA-arginine gene.ConclusionsBrain calcifications are a common feature of mitochondrial diseases, but little is known about their pathophysiology. Here, we describe radiological similarities between a new mitochondrial DNA mutation and other genetic conditions, which are related to Fahr’s disease. These similarities could provide new insights into putative genotype–phenotype correlations.

Abstract 11298: Bioenergetics-Independent Stress Response to Mitochondrial Protein Import Clogging in the Heart

Mitochondria are double-membraned organelles indispensable in metabolically active organs such as the heart. Much of the mitochondrial proteome is encoded by the nuclear genome and requires import into mitochondria via channels present on the outer and inner mitochondrial membranes. If protein import goes awry at any step, it can cause unimported mitochondrial proteins to accumulate in the cytosol, leading to mitochondrial Precursor Overaccumulation Stress (mPOS). Defects in mitochondrial protein import have been linked to many forms of heart disease such as Senger’s syndrome, cardiac arrhythmia, and chronic atrial fibrillation. The A123D mutation in adenine nucleotide translocase 1 (Ant1), an ATP/ADP antiporter present on the mitochondrial inner membrane, has been shown to cause hypertrophic cardiomyopathy, while other mutations in Ant1 (A114P, A90D, V289M, L98P) have been shown to cause Autosomal Dominant Progressive External Ophthalmoplegia. Our studies suggested that the mutant ANT1 can cause mitochondrial protein import clogging. To characterize the pathophysiology induced by mitochondrial protein import clogging, we developed a mouse model (the “clogger mouse”) expressing two clinically relevant mutations in Ant1 , namely A114P and A123D . While prior work on this model revealed a low-penetrant neurodegenerative and mild myopathic phenotype, the impact of this mutation on the heart has not been studied. In the current study, we show that expression of Ant1 A114P, A123D has little effect on mitochondrial respiration and heart function. This is consistent with the rapid degradation of Ant1 A114P, A123D in the heart. Interestingly, transcriptomic analysis revealed an altered expression of circadian regulator and output genes such as Clock, Ciart, Per1-3, Cebpb and Hlf in the clogger mouse relative to wild type. These data suggest that mitochondrial protein import clogging can induce a stress response independent of bioenergetics. It also led us to hypothesize that the circadian pathway plays a role in adapting to mitochondria-induced proteostatic stress in the heart. Our current experiments focused on testing this hypothesis are anticipated to help us understand how the heart can uniquely adapt to mitochondrial protein import clogging.

Cerebellar restricted diffusion in Wernicke's encephalopathy.

A 50-year-old woman presented to an outside hospital for acute onset bilateral lower limb pain. She was diagnosed with aortoiliac stenosis and underwent stent placement. Post-procedure, she was noted to have altered mental status, truncal ataxia, neck titubation, and incomplete external ophthalmoplegia. She rapidly declined to a stuporous state. She had a history of uterine cancer treated with chemoradiation which was complicated by chronic radiation enteritis. She was also reported to have poor oral intake, recurrent emesis, and weight loss for a month before her presentation. After an extensive work up, she arrived at our facility where an MRI of the brain showed restricted diffusion and T2-FLAIR sequence showed hyperintensities of bilateral cerebellum. T2-FLAIR hyperintensities of bilateral dorsomedial thalami, fornix, and post-contrast-enhancement of mammillary bodies were also noted. The clinical picture with imaging findings was concerning for possible thiamine deficiency. In Wernicke's encephalopathy, restricted diffusion, T2-FLAIR hyperintensities, and contrast enhancement may be seen in mammillary bodies, dorsomedial thalami, tectal plate, periaqueductal grey matter, and rarely in the cerebellum as well. Her thiamine level was 70 nmol/l (reference range: 70-180 nmol/l). Thiamine levels can be falsely elevated in patients who are on enteral feeds, which was the case in our patient. She was started on high dose thiamine replacement. At time of discharge, repeat MRI brain revealed resolution of cerebellar changes with mild atrophy and patient had subtle neurological improvement including consistent eye opening, tracking, and attending to examiner, as well as mumbling words.

A case of chronic progressive external ophthalmoplegia presenting with central neurogenic hyperventilation

We report a female patient with typical chronic progressive external ophthalmoplegia (CPEO) presented with central neurogenic hyperventilation (CNH), which is characterized by sustained hyperventilation during awake and sleep. CNH is usually caused by brain stem lesions. While her brain MRI was unremarkable, brain magnetic resonance spectroscopy revealed an increased lactate level in the frontal lobe, suggesting abnormal mitochondrial respiration. CPEO mainly presents a progressive weakness in extraocular muscles and rarely presents neurological symptoms, while abnormal respiration, including tachypnea, is relatively common in other mitochondrial disorders, such as Leigh syndrome, in which the apparent abnormal brain lesions were observed. These mitochondrial disorders, including CPEO, share the same mitochondrial gene mutations. This case illustrates the clinical heterogeneity of mitochondrial disorders.

Diagnosing myasthenia gravis using orthoptic measurements: assessing extraocular muscle fatiguability

IntroductionDiagnosing ocular myasthenia gravis (MG) can be challenging because serum antibodies are often not detected. We aimed to explore whether determining extraocular muscle (EOM) weakness using orthoptic measures, including an...

P.79 Late onset oculopharyngeal muscular dystrophy in a POLG1-related progressive external ophthalmoplegia (PEO), a diagnostic challenge

POLG1, a nuclear gene, encodes the catalytic subunit of mitochondrial DNA polymerase γ involved in mtDNA maintenance. Autosomal dominant or recessive inherited phenotypes related to POLG1 mutations display clinical variability, including isolated or syndromic progressive external ophthalmoplegia (PEO). Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset autosomal dominant myopathy characterized by progressive ptosis, dysphagia, and limb weakness. In OPMD patients, the 5’ (GCN)10 repeat region of the PABPN1 gene is abnormally expanded up to 17 repeats. The (GCN)11 enlarged repeat allele is described as a polymorphism or a recessive allele. However, rare cases of patients with a single (GCN)11 heterozygous allele are known to express a late-onset OPMD phenotype. Reporting a patient associating POLG1 compound heterozygous mutations and a PABPN1 (GCN)11 heterozygous expansion with mixed phenotype, we aim to point out the potential clinical overlap and diagnostic challenge linked to these entities. A 74-year-old male patient presented with progressive bilateral ptosis and mild dysphagia at the age of 70. CK and lactate levels were normal. Electrodiagnostic tests demonstrated a mild sensory neuropathy and muscle biopsy showed atrophic and necrotic fibers, increased internal nuclei and twelve COX-negative fibers. Electron microscopy identified electrodense deposits in mitochondria but no intranuclear inclusions. Muscle oxidative phosphorylation analyses demonstrated complexes I and II diminished activities. POLG1 sequencing revealed the previously described c.1760C>T, p.(Pro587Leu) pathogenic variant and the c.233T>A, p.(Met78Lys) novel variant. Segregation study allowed to conclude a trans conformation in the proband. We report a patient presenting with progressive ptosis associated with two potential coexisting etiologies ascertained by polemic evidence. On one hand, biallelic variants were found on his POLG1 gene, associated with features of mitochondrial defects on muscle biopsy. On the other hand, the phenotype also fits with OPMD and is associated with a PABPN1 (GCN)11 heterozygous expansion allele. This peculiar observation illustrates the potential diagnostic challenge that may represent a progressive ptosis, especially in elderly patients. POLG1, a nuclear gene, encodes the catalytic subunit of mitochondrial DNA polymerase γ involved in mtDNA maintenance. Autosomal dominant or recessive inherited phenotypes related to POLG1 mutations display clinical variability, including isolated or syndromic progressive external ophthalmoplegia (PEO). Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset autosomal dominant myopathy characterized by progressive ptosis, dysphagia, and limb weakness. In OPMD patients, the 5’ (GCN)10 repeat region of the PABPN1 gene is abnormally expanded up to 17 repeats. The (GCN)11 enlarged repeat allele is described as a polymorphism or a recessive allele. However, rare cases of patients with a single (GCN)11 heterozygous allele are known to express a late-onset OPMD phenotype. Reporting a patient associating POLG1 compound heterozygous mutations and a PABPN1 (GCN)11 heterozygous expansion with mixed phenotype, we aim to point out the potential clinical overlap and diagnostic challenge linked to these entities. A 74-year-old male patient presented with progressive bilateral ptosis and mild dysphagia at the age of 70. CK and lactate levels were normal. Electrodiagnostic tests demonstrated a mild sensory neuropathy and muscle biopsy showed atrophic and necrotic fibers, increased internal nuclei and twelve COX-negative fibers. Electron microscopy identified electrodense deposits in mitochondria but no intranuclear inclusions. Muscle oxidative phosphorylation analyses demonstrated complexes I and II diminished activities. POLG1 sequencing revealed the previously described c.1760C>T, p.(Pro587Leu) pathogenic variant and the c.233T>A, p.(Met78Lys) novel variant. Segregation study allowed to conclude a trans conformation in the proband. We report a patient presenting with progressive ptosis associated with two potential coexisting etiologies ascertained by polemic evidence. On one hand, biallelic variants were found on his POLG1 gene, associated with features of mitochondrial defects on muscle biopsy. On the other hand, the phenotype also fits with OPMD and is associated with a PABPN1 (GCN)11 heterozygous expansion allele. This peculiar observation illustrates the potential diagnostic challenge that may represent a progressive ptosis, especially in elderly patients.

Clinical and imaging clues to the diagnosis and follow-up of ptosis and ophthalmoparesis.

Ophthalmoparesis and ptosis can be caused by a wide range of rare or more prevalent diseases, several of which can be successfully treated. In this review, we provide clues to aid in the diagnosis of these diseases, based on the clinical symptoms, the involvement pattern and imaging features of extra-ocular muscles (EOM). Dysfunction of EOM including the levator palpebrae can be due to muscle weakness, anatomical restrictions or pathology affecting the innervation. A comprehensive literature review was performed to find clinical and imaging clues for the diagnosis and follow-up of ptosis and ophthalmoparesis. We used five patterns as a framework for differential diagnostic reasoning and for pattern recognition in symptomatology, EOM involvement and imaging results of individual patients. The five patterns were characterized by the presence of combination of ptosis, ophthalmoparesis, diplopia, pain, proptosis, nystagmus, extra-orbital symptoms, symmetry or fluctuations in symptoms. Each pattern was linked to anatomical locations and either hereditary or acquired diseases. Hereditary muscle diseases often lead to ophthalmoparesis without diplopia as a predominant feature, while in acquired eye muscle diseases ophthalmoparesis is often asymmetrical and can be accompanied by proptosis and pain. Fluctuation is a hallmark of an acquired synaptic disease like myasthenia gravis. Nystagmus is indicative of a central nervous system lesion. Second, specific EOM involvement patterns can also provide valuable diagnostic clues. In hereditary muscle diseases like chronic progressive external ophthalmoplegia (CPEO) and oculo-pharyngeal muscular dystrophy (OPMD) the superior rectus is often involved. In neuropathic disease, the pattern of involvement of the EOM can be linked to specific cranial nerves. In myasthenia gravis this pattern is variable within patients over time. Lastly, orbital imaging can aid in the diagnosis. Fat replacement of the EOM is commonly observed in hereditary myopathic diseases, such as CPEO. In contrast, inflammation and volume increases are often observed in acquired muscle diseases such as Graves' orbitopathy. In diseases with ophthalmoparesis and ptosis specific patterns of clinical symptoms, the EOM involvement pattern and orbital imaging provide valuable information for diagnosis and could prove valuable in the follow-up of disease progression and the understanding of disease pathophysiology.

Electrical myotonia and antibiotic induced myasthenic crises: A novel CHRNE variant

We describe a middle-aged lady who had developed childhood-onset chronic progressive external ophthalmoplegia, fatigable ptosis, and myopathic facies. Unique features of her clinical phenotype included facial weakness that failed to respond to treatment, exacerbation with antibiotic use and electrical myotonia. She responded well to 3,4-diaminopyridine. We highlight aspects of her presentation that led to clinical diagnosis – and, ultimately, genetic confirmation – of a congenital myasthenic syndrome. This underscores the importance of taking a family history and considering inherited causes in cases of seronegative myasthenia.

Primary mitochondrial myopathy: 12-month follow-up results of an Italian cohort

ObjectivesTo assess natural history and 12-month change of a series of scales and functional outcome measures in a cohort of 117 patients with primary mitochondrial myopathy (PMM).MethodsTwelve months follow-up data of 117 patients with PMM were collected. We analysed the 6-min walk test (6MWT), timed up-and-go test (× 3) (3TUG), five-times sit-to-stand test (5XSST), timed water swallow test (TWST), and test of masticating and swallowing solids (TOMASS) as functional outcome measures; the Fatigue Severity Scale and West Haven-Yale Multidimensional pain inventory as patient-reported outcome measures. PMM patients were divided into three phenotypic categories: mitochondrial myopathy (MiMy) without extraocular muscles involvement, pure chronic progressive external ophthalmoplegia (PEO) and PEO&MiMy. As 6MWT is recognized to have significant test–retest variability, we calculated MCID (minimal clinically important difference) as one third of baseline 6 min walking distance (6MWD) standard deviation.ResultsAt 12-month follow-up, 3TUG, 5XSST and FSS were stable, while TWST and the perceived pain severity (WHYMPI) worsened. 6MWD significantly increased in the entire cohort, especially in the higher percentiles and in PEO patients, while was substantially stable in the lower percentile (< 408 m) and MiMy patients. This increase in 6MWD was considered not significant, as inferior to MCID (33.3 m). NMDAS total score showed a slight but significant decline at 12 months (0.9 point). The perceived pain severity significantly worsened. Patients with PEO performed better in functional measures than patients with PEO&MiMy or MiMy, and had lower values of NMDAS.ConclusionsPMM patients showed a slow global decline valued by NMDAS at 12 months; 6MWT was a more reliable measurement below 408 m, substantially stable at 12 months. PEO patients had better motor performance and lower NMDAS than PEO&MiMy and MiMy also at 12 months of follow-up.

Mitochondrial neurogastrointestinal encephalomyopathy syndrome mimicking Guillain-Barre syndrome: A case report and literature review

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is rare autosomal recessive multisystem disorder characterized by severe gastrointestinal dysmotility and leads to cachexia, ptosis, external ophthalmoplegia, peripheral neuropathy, and leukoencephalopathy. Due to its complex clinical findings and non-specific symptoms, diagnosis may be delayed or patients may be misdiagnosed. Multidisciplinary follow-up and treatment of patients is important because it affects many systems and does not have a specific treatment.

Epidemiology of extraocular muscle palsies and internal ophthalmoplegia after herpes zoster ophthalmicus

Herpes zoster ophthalmicus (HZO) is more frequently seen in older and immunocompromised patients. Uncommon associated manifestations include external and internal ophthalmoplegia which are rarely symptomatic. The purpose of this study was to analyze the presentation and course of patients with acute onset symptomatic ophthalmoplegia secondary to HZO.

Structural insight and characterization of human Twinkle helicase in mitochondrial disease

Twinkle is the mammalian helicase vital for replication and integrity of mitochondrial DNA. Over 90 Twinkle helicase disease variants have been linked to progressive external ophthalmoplegia and ataxia neuropathies among other mitochondrial diseases. Despite the biological and clinical importance, Twinkle represents the only remaining component of the human minimal mitochondrial replisome that has yet to be structurally characterized. Here, we present 3-dimensional structures of human Twinkle W315L. Employing cryo-electron microscopy (cryo-EM), we characterize the oligomeric assemblies of human full-length Twinkle W315L, define its multimeric interface, and map clinical variants associated with Twinkle in inherited mitochondrial disease. Cryo-EM, crosslinking-mass spectrometry, and molecular dynamics simulations provide insight into the dynamic movement and molecular consequences of the W315L clinical variant. Collectively, this ensemble of structures outlines a framework for studying Twinkle function in mitochondrial DNA replication and associated disease states.

Low Prevalence of Cardiomyopathy in Patients with Mitochondrial Disease and Neurological Manifestations

Patients with mitochondrial diseases can develop cardiomyopathy but with variable expressivity and penetrance. Our prospective study enrolled and evaluated a cohort of 53 patients diagnosed with chronic progressive ophthalmoplegia (CPEO, n = 34), Kearns–Sayre syndrome (KSS, n = 3), neuropathy ataxia and retinitis pigmentosa (NARP, n = 1), myoclonic epilepsy with ragged red fibers (MERRF, n = 1), Harel–Yoon Syndrome (HYS, n = 1) and 13 patients with undefined mitochondrial diseases, presenting primarily with neurological symptoms. Over a 4-year period, six patients in our study cohort were diagnosed with heart disease (11.3%), with only three patients having defined cardiomyopathy (5.7%). Cardiomyopathy was present in a 21-year-old patient with HYS and two CPEO patients having mild cardiomyopathy at an older age. Two CPEO patients had congenital heart disease, and a third CPEO had LV hypertrophy secondary to hypertension. In three patients, traditional risk factors for heart disease, including dyslipidemia, hypertension, and respiratory disease, were present. The majority of our adult cohort of patients have normal cardiac investigations with a median left ventricular (LV) ejection fraction of 59.0%, indexed LV mass of 67.0 g/m2, and normal diastolic and valvular function at baseline. A 12-lead electrocardiogram showed normal cardiac conduction across the study cohort. Importantly, follow-up assessments showed consistent cardiac structure and function. Our study shows a low prevalence of cardiomyopathy and highlights the breadth of phenotypic variability in patients with mitochondrial disorders. The presence of cardiovascular risk factors and aging are important comorbidities in our cohort.

Novel TOP3A Variant Associated With Mitochondrial Disease

ObjectivesTopoisomerase III alpha plays a key role in the dissolution of double Holliday junctions and is required for mitochondrial DNA (mtDNA) replication and maintenance. Sequence variants in the TOP3A gene have been associated with the Bloom syndrome–like disorder and described in an adult patient with progressive external ophthalmoplegia. The purpose of this report is to expand the clinical phenotype of the TOP3A-related diseases and clarify the role of this gene in primary mitochondrial disorders.MethodsA 44-year-old woman was referred to our hospital because of exercise intolerance and creatine kinase increase. Muscle biopsy and a targeted next-generation sequencing (NGS) analysis were performed.ResultsA histopathologic assessment documented a mitochondrial myopathy, and a molecular analysis revealed a novel homozygous variant in the TOP3A gene associated with multiple mtDNA deletions.DiscussionThis case suggests that TOP3A is one of the several nuclear genes associated with mtDNA maintenance disorder and expands the spectrum of its associated phenotypes, ranging from a clinical condition defined Bloom syndrome–like disorder to canonical mitochondrial syndromes.