External Ophthalmoplegia Research Articles

Detecting mitochondrial electron transport chain enzyme defects in low-heteroplasmy single large-scale mtDNA deletion syndromes (SLSMDSs).

Efficacy of FcRn antagonist efgartigimod in the treatment of Miller-Fisher/Guillain-Barré overlap syndrome: Two case reports.

Primary mitochondrial myopathies (PMM) are disorders that involve defects in oxidative phosphorylation (OXPHOS) and impair mainly, but not exclusively, skeletal muscles. Progressive external ophthalmoplegia (PEO), eyelid ptosis, exercise intolerance and skeletal muscle weakness are the most common symptoms of myopathy in mitochondrial diseases, impairing ocular motility and visual abilities. Twenty-five patients underwent complete ophthalmological examination, including best corrected visual acuity (BCVA), ptosis evaluation, dilated fundus examination, and orthoptic examinations, including cover and cover-uncover test, ocular motility analysis, fusional amplitude (FA) vergence for near and for distance, Bagolini striated glasses test (BSGs) and Worth four-dot lights test (WFDT). Mean age at evaluation was of 47,2 ± 16.07years. Twenty-two (88%) out of 25 patients had a PEO disease, while three (12%) of them a Kearn-Sayre syndrome (KSS). Ocular motility impairment was found in 92% of the population. Fifteen patients (60%) didn't complain of double vision in casual seeing condition despite some of them showed manifest strabismus both at far (53%) and at near (60%). A compensation sensorial mechanism, mainly suppression, was detected through sensory tests. The near and distance fusional capabilities in convergence and in divergence (CFAs and DFAs) were absent in 68 and 72% of the whole sample respectively. PEO manifests at an older age than KSS (p = 0.003), diplopia does not correlate with disease duration (p = 0.06) and no predictive factors for diplopia can be identified. A significant number of patients not complaining of double vision in casual seeing state showed manifest or latent/manifest strabismus at FAoD and NAoD. Most strabismic patients had a monocular suppression or alternate diplopia and suppression at sensory tests (BSGs and WFDT). The pathophysiology of these sensory adaptations in an adult visual system can only be hypothesized. A multidisciplinary approach is essential for proper clinical management and to analyze an understand clinical features pathogenesis.

Guillain-Barré syndrome (GBS) is a peripheral neuropathy mediated by immunoglobulin G (IgG) autoantibodies, which can cause acute flaccid paralysis. Miller-Fisher syndrome (MFS) is a variant of GBS, and in some cases, MFS may overlap with GBS (MFS-GBS overlap syndrome), potentially delaying the disease's progression. Apart from intravenous immunoglobulin (IVIg) and plasma exchange (PLEX), which are currently the clinical standard of care. However, at least 20-30% of patients develop acute respiratory failure during or shortly after IVIg or PLEX, and about 3-7% of patients die. Efgartigimod is an antagonist that targets the neonatal Fc receptor (FcRn) and shows promise in the treatment of GBS. We present a case with MFS-GBS overlap syndrome who tested positive for serum ganglioside IgG antibodies. Despite completing a prescribed course of IVIg medication, the patient's symptoms continued to worsen, and she eventually developed respiratory failure. Subsequently, efgartigimod was used for treatment at a dose of 800mg, administered four times in total. The patient's symptoms were relieved, leaving only external ophthalmoplegia. Additionally, using efgartigimod caused a gradual drop in the serum IgG level. This treatment regimen is the first reported. For MFS-GBS overlap syndrome patients with poor IVIg response, we discovered that sequential treatment with efgartigimod (800mg, four doses) was safe, effective, and could reduce the course of the disease. Efgartigimod is anticipated to represent a significant advancement in treating GBS through ongoing, thorough basic and clinical research.

Miller Fisher Syndrome (MFS) is a rare neurological disorder characterized by ataxia, areflexia, and ophthalmoplegia. It is considered a variant of Guillain-Barré syndrome (GBS). Infections frequently precede the onset of MFS. A 44-year-old patient was referred to our Neurology Department due to rapidly progressive bilateral limb ataxia, areflexia, and external ophthalmoplegia following acute tonsillitis with fever and oral mucosal lesions. Initial extensive diagnostic work-up, including immunoglobulin M (IgM) serum antibodies against cytomegalovirus (CMV), was negative. However, due to clinical suspicion, anti-CMV IgM was tested again and subsequently found to be positive. Interestingly, antibodies against Q1B ganglioside, which are specific for MFS, were also negative. Our patient gradually improved after intravenous immunoglobulin administration and symptomatic treatment. No underlying cause of immunocompromise was identified. This case underscores the importance of persistent testing for CMV antibodies in immunocompetent patients, even in rare cases of GBS like MFS, to ensure accurate diagnosis and optimize treatment plans.

Background: The TWNK gene encodes a protein that colocalizes with mitochondrial DNA (mtDNA) in mitochondrial nucleoids. It acts as mtDNA helicase during replication, thus playing a pivotal role in the replication and maintenance of mtDNA stability. TWNK mutations are associated with a wide spectrum of clinical phenotypes and a marked heterogeneity. However, heterozygous nonsense variants in the gene have never been described in association with disease. Methods: We analyzed a next-generation sequencing (NGS) targeted gene panel in a cohort including 40 patients with high clinical suspicion of mitochondrial disorders. Selected patients underwent a complete neurological examination, electrophysiology tests, and muscle biopsy. Segregation analysis was performed in available family members. The 3D structure of twinkle was visualized and analyzed using Swiss Model and Pymol version 3.1.6.1. Results: We found four TWNK-mutated subjects from two unrelated families. They exhibited a variable clinical spectrum, ranging from asymptomatic individuals to subjects with psychiatric disorder, chronic progressive external ophthalmoplegia (CPEO), and CPEO-plus. All the subjects shared the heterozygous TWNK p.Glu665Ter variant. Discussion and Conclusions: We describe the clinical phenotype and muscle biopsy findings associated with the first reported heterozygous nonsense TWNK variant, thus expanding the current knowledge of Twinkle-related disorders. Our findings are in line with the high intrafamilial clinical variability associated with TWNK mutations. Although PEO and skeletal muscle involvement remain hallmarks of the disease, extra-muscular features should be carefully assessed.

352PType 6 autosomal dominant progressive external ophthalmoplegia associated with a probable novel pathogenic DNA2 gene variant

353PUnexpected attenuated phenotype in autosomal recessive progressive external ophthalmoplegia linked to a novel homozygous pathogenic RRM2B gene variant

Primary Lateral Sclerosis (PLS) is a rare, adult-onset neurodegenerative disease that predominantly affects upper motor neurons. Despite being considered mostly sporadic, familial cases and rare genetic variants in genes associated with amyotrophic lateral sclerosis, hereditary spastic paraplegia and other neurological disorders have been reported in some PLS cases. Due to its rare prevalence among general population, large genetic studies of PLS are lacking. Fifty patients diagnosed with PLS based on consensus criteria were enrolled between 2013 and 2022 for comprehensive phenotypic and genotypic analysis using whole genome sequencing. We analyzed rare single nucleotide variants (SNVs), deemed pathogenic, likely pathogenic or of uncertain significance (VUS) based on the American College of Medical Genetics and Genomics criteria, and repeat expansions (REs) exceeding the pathogenic threshold, in 290 genes involved in neurological disorders. We identified mutations in 7 patients (13.7%), specifically SNVs in CAPN1 (Spastic paraplegia 76), TBK1 (amyotrophic lateral sclerosis/frontotemporal dementia, ALS4/FTD), LITAF (Charcot-Marie-Tooth disease 1C), POLG (chronic progressive external ophthalmoplegia), APP (Alzheimer's disease) and OPTN (ALS12 ± FTD), and one RE in ATXN8OS (spinocerebellar ataxia 8). Additionally, two VUS were found in ANTXR2, a candidate gene for PLS recently identified via truncating variant collapsing analysis, but none of them was loss-of-function (one synonymous and one in-frame insertion). Our study demonstrates a notable genetic intersection between PLS and various neurological disorders, including motor neuron diseases, neuropathies, mitochondrial disorders, ataxias, and dementias. These findings underscore the relevance of further investigation in larger cohorts to fully elucidate PLS genetic architecture and highlight the need to reconsider the role of genetic testing in its diagnostic criteria.

BACKGROUND Kearns-Sayre syndrome (KSS) is a rare genetic, mitochondrial disorder characterized by a triad of chronic progressive external ophthalmoplegia, pigmentary retina degeneration, and cardiac conduction disorders, with onset before the age of 20 years. The disease can also manifest as several cardiovascular (CV) disorders, such as conduction disorders or dilated cardiomyopathy, along with neuromuscular and endocrinological complications. CASE REPORT A 46-year-old man diagnosed with KSS was admitted to the Institute of Heart Diseases in the qualification process for heart transplantation (Htx). The patient's medical history began with a diagnosis of third-degree atrioventricular block, treated with pacemaker (PM) implantation at age 25. However, due to progressing left ventricle (LV) function deterioration, PM was upgraded to cardiac resynchronization therapy with defibrillator 10 years later. In the year before the admission, he had undergone 2 hospitalizations caused by acute decompensations of heart failure (ADHF). Upon admission, physical examination revealed features of congestion. Transthoracic echocardiography showed an enlarged LV with global hypokinesia, reduced ejection fraction, and right ventricle dysfunction. Due to the neurological complications and poor functional condition, the Heart Team qualified him for conservative treatment. The next hospitalization due to ADHF ended in the patient's death. CONCLUSIONS CV disorders are an important aspect of treatment of KSS patients. Our patient was referred with excessively developed complications, so he could not benefit from Htx or mechanical circulatory support. This case highlights the importance of early diagnosis and monitoring of KSS patients before the full development of complications, including HF.

Primary mitochondrial myopathies (PMMs), a group of genetic mitochondrial oxidative phosphorylation disorders, primarily affect skeletal muscle function. No approved treatments for PMM exist, and patient information is limited. The international RePOWER registry (NCT03048617) assessed genotypic and phenotypic relationships in PMM and identified patients for MMPOWER-3 (elamipretide Phase 3 study). RePOWER enrolled screened and ambulatory patients aged 16-80 years. With signs and/or symptoms of PMM (N = 376; 60.4% female; mean [SD] age 42.6 [14.4] years; ~75% with an mtDNA variant and ~25% with an nDNA variant). Baseline information, current symptoms, qualityoflife, and functional assessments (6-Minute Walk Test [6MWT], Triple-Timed Up-and-Go [3TUG] Test, and 5-Times Sit-to-Stand Test [5XSST]) were captured. Accredited laboratory and genetic testing methods were available to most patients. The majority of enrolled PMM patients presented with progressive external ophthalmoplegia and fatigue. US patients were observed to use more medical interventions. Compared to non-US patients, US patients did not perform as well on the 6MWT (mean 364.6 vs. 375.2 m) and 5XSST (mean 21.6 vs. 18.6 s); US patients performed better on the 3TUG test (mean 40.2 vs. 45.0 s). The RePOWER registry provided data on patients with genetically confirmed PMM, thereby improving our understanding of PMM diagnosis and treatment and the differences in global mitochondrial clinical practice.

Kearns-Sayre Syndrome (KSS) is a rare mitochondrial disorder characterized by progressive external ophthalmoplegia (PEO), pigmentary retinopathy, and cardiac conduction defects, typically presenting before the age of 20. It results from large-scale deletions or mutations in mitochondrial DNA (mtDNA), leading to impaired oxidative phosphorylation and decreased ATP production, especially in high-energy-demand tissues such as the eyes, heart, brain, and muscles. KSS follows a non-Mendelian, usually sporadic pattern of inheritance due to the unique properties of mtDNA. Patients often experience ptosis, muscle weakness, hearing loss, cerebellar ataxia, short stature, endocrine dysfunctions, and cognitive decline. Diagnosis is based on clinical presentation, supported by genetic testing, muscle biopsy, and imaging studies. Although there is no cure, treatment is supportive, including pacemaker implantation for cardiac issues, ptosis surgery, hormone replacement, and supplements like coenzyme Q10 and carnitine. KSS can overlap with other mitochondrial syndromes, including Pearson syndrome and progressive external ophthalmoplegia as isolated presentations. Early diagnosis and multidisciplinary management are critical for improving quality of life and minimizing complications.

Single large-scale mitochondrial DNA deletion syndromes (SLSMDSs) are rare mitochondrial disorders that present a continuum of phenotypes, including Pearson syndrome, Kearns-Sayre syndrome, and progressive external ophthalmoplegia. Neuroimaging findings in SLSMDSs are underreported, and their role in diagnosis and disease monitoring remains inadequately defined.This study aims to characterize clinical features and analyze neuroimaging findings, including spectroscopy and diffusion imaging, in patients with SLSMDSs. A retrospective review of 11 patients diagnosed with SLSMDSs at a tertiary referral center between 2013 and 2024 was conducted. Clinical, genetic, and neuroimaging data were analyzed. MRI scans were reviewed for abnormalities in various brain regions, including white matter, basal ganglia, thalami, corpus callosum, cerebellum, and brainstem. The cohort had a mean age of 8.3 years (63.6% female). MRI was normal in 4 patients. Among the remaining 7, symmetrical T2/FLAIR hyperintensities, with or without diffusion alterations, were frequently observed, involving the dorsal brainstem in 7/7 and the cerebellum in 6/7 of patients. Globi pallidi involvement was also present in 6 of 7 patients. MR basal ganglia spectroscopy demonstrated elevated lactate in 3 of 7 patients with available spectroscopy. Subcortical and deep white matter abnormalities were identified in 3 patients, sparing the periventricular regions. Imaging progression was noted in patients with serial studies (4 patients). Neuroimaging in SLSMDSs typically demonstrates characteristic involvement of the dorsal brainstem, cerebellum, and basal ganglia, and may show diffusion alterations, a finding suggestive of metabolic injury. The observed pattern of subcortical white matter involvement with periventricular sparing may aid in differentiating this disorder from others. Normal imaging may be present in early or less severe disease. MRI, including diffusion imaging and spectroscopy, can support diagnosis and longitudinal monitoring.

Mitochondria elicit various metabolic stress responses, the roles of which in diseases are poorly understood. Here, we explore how different muscles of one individual-extraocular muscles (EOMs) and quadriceps femoris (QFs) muscles-respond to mitochondrial disease. The aim is to explain why EOMs atrophy early in the disease, unlike other muscles. We used a mouse model for mitochondrial myopathy ("deletor"), which manifests progressive respiratory chain deficiency and human disease hallmarks in itsmuscles. Analyses included histology, ultrastructure, bulk and single-nuclear RNA-sequencing, metabolomics, and mitochondrial turnover assessed through in vivo mitophagy using transgenic mito-QC marker mice crossed to deletors. In mitochondrial muscle disease, large QFs upregulate glucose uptake that drives anabolic glycolytic one-carbon metabolism and mitochondrial integrated stress response. EOMs, however, react in an opposite manner, inhibiting glucose and pyruvate oxidation by activating PDK4, a pyruvate dehydrogenase kinase and inhibitor. Instead, EOMs upregulate acetyl-CoA synthesis and fatty-acid oxidation pathways, and accumulate lipids. In QFs, Pdk4 transcription is not induced.- Amino acid levels are increased in QFs but are low in EOMs suggesting their catabolic use for energy metabolism. Mitophagy is stalled in both muscle types, in the most affected fibers. Our evidence indicates that different muscles respond differently to mitochondrial disease even in one individual. While large muscles switch to anabolic mode and glycolysis, EOMs actively inhibit glucose usage. They upregulate lipid oxidation pathway, a non-optimal fuel choice in mitochondrial myopathy, leading to lipid accumulation and possibly increased reliance on amino acid oxidation. We propose that these consequences of non-optimal nutrient responses lead to EOMatrophy and progressive external ophthalmoplegia in patients. Our evidence highlights the importance of PDK4 and aberrant nutrient signaling underlying muscle atrophies.

An inherited mtDNA rearrangement, mimicking a single large-scale deletion, associated with MIDD and a primary cardiological phenotype.

This report presents 2 cases of chronic progressive external ophthalmoplegia (CPEO) with progressive bilateral ptosis, managed successfully using Müller muscle-conjunctival resection with tarsectomy (MMCRT). The first case involved a 59-year-old female, and the second a 45-year-old male, both presenting with longstanding histories of worsening ptosis and significant limitations in extraocular motility. Postoperatively, both patients exhibited substantial improvements in eyelid elevation without complications such as lagophthalmos or exposure keratopathy, commonly seen in alternative surgical approaches. These cases demonstrate MMCRT as a promising technique for managing CPEO-related ptosis, highlighting its potential advantages and the need for further studies to confirm its efficacy and safety in broader clinical applications.

Ptosis correction with frontalis sling surgery in a patient with bilateral chronic progressive external ophthalmoplegia: A case report

Recognizing the evolution of clinical syndrome spectrum progression in individuals with single large-scale mitochondrial DNA deletion syndromes (SLSMDS).

280th ENMC International Workshop: The ERN EURO-NMD mitochondrial diseases working group; diagnostic criteria and outcome measures in primary mitochondrial myopathies. Hoofddorp, the Netherlands, 22-24 November 2024.

Single large-scale mitochondrial deletion syndrome (SLSMD) comprises devastating mitochondrial diseases often classified into 3 major clinical syndromes: Kearns-Sayre syndrome (KSS), chronic progressive external ophthalmoplegia (CPEO), and Pearson syndrome (PS). Nevertheless, there remains large clinical variability and overlap among these SLSMD groups. Therefore, further stratification is required for more precise prognostication and clinical management. Through detailed description and analysis of longitudinal neuroimaging changes, we sought to determine the neuroradiologic hallmarks of SLSMDs and define their expected imaging progression to further delineate their natural history. A retrospective, longitudinal study of 40 children with SLSMDs at 3 mitochondrial disease centers was performed. MRI review assessed the prevalence and progression of brain lesions in different regions with statistical significance testing and Kaplan-Meier analysis. Hierarchical cluster analysis was performed for involved brain regions to stratify findings into imaging phenotype groups. Among 40 patients with SLSMD (median age 9.26 years; interquartile range: 5.16-13.1), 67.5% had KSS, 15% had KSS with a prior history of PS (PS→KSS), and 10% had PS only. A well-delineated phenotype could not be specified for 1 (2.5%) and 2 (5%) individuals who had CPEO-plus (CPEO + extraocular symptoms). Regardless of presentation, initial MRI of patients with KSS revealed lesions within selective areas of the upper brainstem tegmentum. Follow-up MRIs in 26 patients showed well-defined progression along other select brainstem and white matter regions. Log-rank tests demonstrated varying onset times by lesion type. Cluster analysis revealed 2 distinct neuroimaging groups: 1) KSS, CPEO-plus, and PS→KSS versus 2) PS and not otherwise specified individuals. KSS, CPEO-plus, and PS→KSS showed indistinguishable neuroimaging features regardless of the initial clinical presentation. We describe the first comprehensive longitudinal neuroimaging pattern analysis in a multicenter, international SLSMDs disease pediatric cohort, delineating a predictable progression of brain lesions, regardless of clinical phenotype.