An unusual ophthalmologic finding in a patient with congenital central hypoventilation syndrome.

INTRODUCTION: Congenital Central Hypoventilation Syndrome (CCHS) is a rare disease due to a severely impaired central control of breathing and dysfunction of the autonomic nervous system. Ophthalmologic abnormalities are common in patients with CCHS and include horizontal strabismus, pupil and iris abnormalities and ptosis. We report a unique case of CCHS in association with monocular elevation deficit (MED) in a boy diagnosed with CCHS at birth. CASE DESCRIPTION: We report a case of a boy with a confirmed diagnosis of CCHS (complete sequencing of the paired-like homeobox 2b (PHOX2B) gene) after presenting little respiratory effort and cyanosis at birth. The ophthalmological examination shows an impaired elevation of the left eye, both in adduction and abduction, associated with mild and variable left ptosis. His mother has observed that the left eyelid elevates when the child feeds. A deviation in the primary gaze position or a chin-up position are not present. The funduscopic examination is normal. Given that deviation is limited to upgaze, the ptosis is mild and the patient's age, observation is decided. CONCLUSIONS: Ophthalmologic abnormalities are common in patients with CCHS and include horizontal strabismus, pupil and iris abnormalities and ptosis. To the best of our knowledge, this is the first report of MED in association with CCHS. Further studies are needed to determine if an association between MED and CCHS exists or is just a casual finding in this case.

Mitochondrial Chronic Progressive External Ophthalmoplegia.

BACKGROUND: Chronic progressive external ophthalmoplegia (CPEO) is a rare disorder that can be at the forefront of several mitochondrial diseases. This review overviews mitochondrial CPEO encephalomyopathies to enhance accurate recognition and diagnosis for proper management. METHODS: This study is conducted based on publications and guidelines obtained by selective review in PubMed. Randomized, double-blind, placebo-controlled trials, Cochrane reviews, and literature meta-analyses were particularly sought. DISCUSSION: CPEO is a common presentation of mitochondrial encephalomyopathies, which can result from alterations in mitochondrial or nuclear DNA. Genetic sequencing is the gold standard for diagnosing mitochondrial encephalomyopathies, preceded by non-invasive tests such as fibroblast growth factor-21 and growth differentiation factor-15. More invasive options include a muscle biopsy, which can be carried out after uncertain diagnostic testing. No definitive treatment option is available for mitochondrial diseases, and management is mainly focused on lifestyle risk modification and supplementation to reduce mitochondrial load and symptomatic relief, such as ptosis repair in the case of CPEO. Nevertheless, various clinical trials and endeavors are still at large for achieving beneficial therapeutic outcomes for mitochondrial encephalomyopathies. KEY MESSAGES: Understanding the varying presentations and genetic aspects of mitochondrial CPEO is crucial for accurate diagnosis and management.

Acute acquired concomitant esotropia: May COVID-19 lockdowns have changed its presentation?

PURPOSE: To evaluate the effects of COVID-19 lockdown in Italy on the features of Acute Acquired Concomitant Esotropia (AACE). SUBJECTS: Patients of the Polyclinic Hospital of Bari diagnosed with AACE between January 2018 and December 2021, subdivided in pre-lockdown group - diagnosed before March 2020 - and post-lockdown group. METHODS: Medical records were reviewed, and statistical analysis performed. Deviation size was assessed in the 9 cardinal positions of gaze with refractive correction. Wilcoxon test for unpaired samples was used to compare data of age, near maximum deviation and best corrected visual acuity (BCVA) for each eye; Student's t test was used to compare far maximum deviation, difference far/near maximum deviation and spherical equivalent data. Fisher exact test was used to compare subtype cases (Bielschowsky vs Non-Bielschowsky) in the two groups. A p-value lower than 0.05 was considered statistically significant.The primary outcome measure was the difference in AACE subtypes between the two groups. RESULTS: Nineteen patients were included, of which 12 males (63.2%); 7 belong to the pre-lockdown group and 12 to the post-lockdown group. The difference in types between the two groups proved to be statistically significant (p = 0.01977).The differences in the mean of age, right BCVA, right spherical equivalent and mean spherical equivalent between the two groups proved to be statistically significant (p < 0.05). CONCLUSIONS: After the COVID-19 pandemic, the profile of the typical patient with AACE has probably changed, and now it is more probably myopic and elderly than before. Thus, we observed an increase in the Bielschowsky subtype.

Mitochondrial encephalomyopathy.

Mitochondrial dysfunction, especially perturbation of oxidative phosphorylation and adenosine triphosphate (ATP) generation, disrupts cellular homeostasis and is a surprisingly frequent cause of central and peripheral nervous system pathology. Mitochondrial disease is an umbrella term that encompasses a host of clinical syndromes and features caused by in excess of 300 different genetic defects affecting the mitochondrial and nuclear genomes. Patients with mitochondrial disease can present at any age, ranging from neonatal onset to late adult life, with variable organ involvement and neurological manifestations including neurodevelopmental delay, seizures, stroke-like episodes, movement disorders, optic neuropathy, myopathy, and neuropathy. Until relatively recently, analysis of skeletal muscle biopsy was the focus of diagnostic algorithms, but step-changes in the scope and availability of next-generation sequencing technology and multiomics analysis have revolutionized mitochondrial disease diagnosis. Currently, there is no specific therapy for most types of mitochondrial disease, although clinical trials research in the field is gathering momentum. In that context, active management of epilepsy, stroke-like episodes, dystonia, brainstem dysfunction, and Parkinsonism are all the more important in improving patient quality of life and reducing mortality.

Pontine stroke in a patient with Chronic Progressive External Ophthalmoplegia (CPEO): a case report.

BACKGROUND: Chronic progressive external ophthalmoplegia (CPEO) is a mitochondrial disease with slowly progressive bilateral ptosis and symmetric ophthalmoplegia due to a genetic mutation that results in defective oxidative phosphorylation. Common genes that are implicated in CPEO include POLG, RRM2B, ANT1 and PEO1/TWNK. Here, we report a case of a patient diagnosed with CPEO caused by a novel mutation in PEO/TWNK after suffering a right pontine stroke. CASE PRESENTATION: A 70-year-old man with history of chronic progressive bilateral ptosis and ophthalmoplegia, as well as similar ocular symptoms in his father and grandfather, presented with acute onset of right hemifacial weakness and dysarthria. Brain MRI revealed an acute ischemic stroke in the right dorsal pons. The patient did not experience diplopia due to severe baseline ophthalmoplegia. Creatine kinase was elevated to 6,080 U/L upon admission and normalized over the course of one week; electromyography revealed a myopathic process. Genetic testing revealed a novel mutation c.1510G > A (p. Ala504Thr) in a pathogenic "hot spot" of the C10ORF2 gene (TWNK/PEO1), which is associated with CPEO. The mutation appears to be deleterious using several pathogenicity prediction tools. CONCLUSIONS: This case report describes a patient with late-onset CPEO caused by a novel, likely pathogenic, mutation in the TWNK gene. Although the patient presented with a pontine stroke, it manifested with solely new onset facial palsy, as he had a severe underlying ophthalmoplegia secondary to his CPEO.

Aberrant regeneration in an international registry of patients with 3rd-nerve palsy.

BACKGROUND/AIMS: To describe the patterns of pre-operative aberrant regeneration and motility outcomes reported in an international registry of patients with 3rd-nerve palsy treated with nasal transposition of the split lateral rectus muscle (NTSLR). METHODS: This cross-sectional study used data from an international, multicentre registry of patients with 3rd-nerve palsy treated with NTSLR. Patients with aberrant regeneration were identified, and patterns of innervation described. Demographics and postoperative success defined as horizontal alignment ≤15 PD were compared based on the presence, and type, of aberrant regeneration using Wilcoxon rank sum and Fisher's exact tests. RESULTS: Aberrant regeneration was reported in 16% (21/129) of patients. Age at diagnosis, sex, and aetiology of palsy were not significantly associated with aberrant regeneration. Abnormal movements were triggered by adduction in 52% (11/21), infraduction in 23% (5/21), and supraduction in 23% (5/21) of cases. Presentation patterns involved rectus muscle innervation in 29% (6/21) and levator muscle innervation in 71% (15/21) of cases. Although patients with aberrant regeneration had similar probability of success in comparison to those without following NTLSR (76% vs. 69%, p = 0.5), those with abnormal innervation of a rectus muscle had a lower success rate than those with abnormal innervation of the levator palpebrae superioris muscle (17% vs. 93%; p = 0.002). CONCLUSION: Successful treatment of a 3rd nerve palsy with NTSLR was not influenced by aberrant regeneration involving the levator muscle. Alternative surgical interventions should be considered when aberrant regeneration alters rectus muscle function given its adverse impact on motor outcomes with NTSLR.

MYH2-related Myopathy: Expanding the Clinical Spectrum of Chronic Progressive External Ophthalmoplegia (CPEO).

Chronic progressive external ophthalmoplegia (CPEO) is symptom complex with progressive ptosis and restricted ocular motility without diplopia. MYH2 myopathy is rare disorder presenting with CPEO and muscle weakness. We report two Indian patients of MYH2 myopathy with unique features. Patient-1 presented with early adult-onset esophageal reflux followed by, proximal lower limb weakness, proptosis, CPEO without ptosis. He had elevated creatine kinase along with characteristic muscle MRI findings of prominent semitendinosus and medial gastrocnemius involvement. Patient -2 presented with early adult onset CPEO without limb weakness. His creatine kinase was normal. Both the patients had novel MYH2 mutations: a homozygous 5'splice variation in intron 4 (c.348 + 2dup) in patient 1 and homozygous single base pair deletion in exon 32 (p. Ala1480ProfsTer11) in patient 2. Unique features noted include adult onset, isolated CPEO, proptosis, esophageal reflux disease and absence of skeletal abnormalities. MYH2 myopathy has to be considered in adult patients with CPEO.

Eye Muscle MRI in Myasthenia Gravis and Other Neuromuscular Disorders.

INTRODUCTION: 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). METHODS: 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. RESULTS: 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. INTERPRETATION: 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.

A review of surgical management of progressive myogenic ptosis.

PURPOSE: Surgical correction of myogenic ptosis is a sophisticated endeavor, as the disease is progressive and the post-operative course is prone to significant complications. We sought to review the literature for repair techniques in different types of myogenic ptosis. METHODS: A PubMed/MEDLINE literature search of publications pertaining to surgical outcomes of progressive myogenic ptosis repair was performed. Studies included were original retrospective studies with a minimum of four patients. RESULTS: A total of 27 articles were identified and divided by etiology of myogenic ptosis; either chronic progressive external ophthalmoplegia (CPEO), oculopharyngeal muscular dystrophy (OPMD), myasthenia gravis (MG), or mixed. Surgical techniques predominantly involved levator advancement, levator resection, frontalis sling, blepharoplasty, and Fasanella-Servat. Success rates ranged from 60.5% to 100%. Significant postoperative complications included ptosis recurrence, under-correction, over-correction, keratopathy, lagophthalmos, sling exposure, and sling infection. CONCLUSION: Like surgical repair for other forms of ptosis, correction of progressive myogenic ptosis is guided by levator excursion. However, myogenic ptosis is especially challenging as it is characterized by worsening ptosis and the loss of protective corneal mechanisms. The goals of care with myogenic ptosis involves repairing ptosis just sufficiently to alleviate visual obstruction while avoiding adverse post-operative complications. This intentional under-correction subsequently increases susceptibility for ptosis recurrence. Myogenic ptosis repair therefore requires delicate balancing between function, sustained repair, and corneal protection.

[Chronic progressive external ophthalmoplegia that could not be diagnosed by biceps muscle biopsy, but was genetically diagnosed by extraocular muscle biopsy].

A 48-year-old Japanese male experienced slowly progressive diplopia. He had no family history and was negative for the edrophonium chloride test. Blood analysis showed elevated lactic acid and pyruvic acid levels, suggesting mitochondrial disease. A muscle biopsy from the biceps brachii was performed, but no pathological or genetical mitochondrial abnormalities were detected. Subsequently, he underwent muscle plication for diplopia in which the right inferior rectus muscle was biopsied. Genetic examination of genomic DNA extracted from the extraocular muscle tissue revealed multiple mitochondrial gene deletions, with a heteroplasmy rate of approximately 35%, resulting in the diagnosis of chronic progressive external ophthalmoplegia. In mitochondrial diseases, the tissue distribution of mitochondria with disease-associated variants in mtDNA should be noted, and it is important to select the affected muscle when performing a biopsy for an accurate diagnosis.

Case Report: Rare Homozygous RNASEH1 Mutations Associated With Adult-Onset Mitochondrial Encephalomyopathy and Multiple Mitochondrial DNA Deletions.

Mitochondrial DNA (mtDNA) maintenance disorders embrace a broad range of clinical syndromes distinguished by the evidence of mtDNA depletion and/or deletions in affected tissues. Among the nuclear genes associated with mtDNA maintenance disorders, RNASEH1 mutations produce a homogeneous phenotype, with progressive external ophthalmoplegia (PEO), ptosis, limb weakness, cerebellar ataxia, and dysphagia. The encoded enzyme, ribonuclease H1, is involved in mtDNA replication, whose impairment leads to an increase in replication intermediates resulting from mtDNA replication slowdown. Here, we describe two unrelated Italian probands (Patient 1 and Patient 2) affected by chronic PEO, ptosis, and muscle weakness. Cerebellar features and severe dysphagia requiring enteral feeding were observed in one patient. In both cases, muscle biopsy revealed diffuse mitochondrial abnormalities and multiple mtDNA deletions. A targeted next-generation sequencing analysis revealed the homozygous RNASEH1 mutations c.129-3C>G and c.424G>A in patients 1 and 2, respectively. The c.129-3C>G substitution has never been described as disease-related and resulted in the loss of exon 2 in Patient 1 muscle RNASEH1 transcript. Overall, we recommend implementing the use of high-throughput sequencing approaches in the clinical setting to reach genetic diagnosis in case of suspected presentations with impaired mtDNA homeostasis.

Neuropathic Pain as Main Manifestation of POLG-Related Disease: A Case Report.

Mutations in nuclear-encoded genes that are involved in mitochondrial DNA replication and maintenance (e.g., POLG) have been associated with chronic progressive external ophthalmoplegia (CPEO) phenotype. These nuclear genome mutations may lead to multiple mitochondrial DNA deletions or mitochondrial DNA depletion. On the other hand, primary genetic defects of mitochondrial DNA (such as single large-scale deletion or point mutations) have also been associated with the CPEO phenotype. Chronic progressive external ophthalmoplegia (CPEO) may be a manifestation of specific syndromes that, when clinically recognized, prompt clinicians to investigate specific genetic defects. Thus, CPEO, as part of Kearns Sayre syndrome, suggests the presence of a large-scale deletion of mitochondrial DNA. However, in pure CPEO or CPEO plus phenotypes, it is more difficult to know whether causative genetic defects affect the nuclear or mitochondrial DNA. Here, we present a patient with a long-standing history of CPEO plus phenotype, in whom the sequencing of mitochondrial DNA from skeletal muscle was normal, and no other genetic defect was suspected at first. At the time of our evaluation, the presence of polyneuropathy and neuropathic pain prompted us to investigate nuclear genetic defects and, specifically, mutations in the POLG gene. Thus, the sequencing of the POLG gene revealed p.Thr251Ile and p.Pro587Leu mutations in one allele, and p.Ala467Thr mutation in another allele. Although one would expect that mutations in POLG lead to multiple mitochondrial DNA deletions or depletion (loss of copies), the absence of mitochondrial DNA abnormalities in tissue may be explained by heteroplasmy, a lack or no significant involvement of biopsied tissue, or a sampling bias. So, the absence of secondary mitochondrial DNA alterations should not discourage clinicians from further investigating mutations in nuclear-encoded genes. Lastly, mitochondrial point mutations and single mitochondrial DNA deletions very rarely cause CPEO associated with polyneuropathy and neuropathic pain, and POLG-related disease should be considered in this scenario, instead.

Mitochondrial DNA replication and repair defects: Clinical phenotypes and therapeutic interventions.

Mitochondria is a unique cellular organelle involved in multiple cellular processes and is critical for maintaining cellular homeostasis. This semi-autonomous organelle contains its circular genome - mtDNA (mitochondrial DNA), that undergoes continuous cycles of replication and repair to maintain the mitochondrial genome integrity. The majority of the mitochondrial genes, including mitochondrial replisome and repair genes, are nuclear-encoded. Although the repair machinery of mitochondria is quite efficient, the mitochondrial genome is highly susceptible to oxidative damage and other types of exogenous and endogenous agent-induced DNA damage, due to the absence of protective histones and their proximity to the main ROS production sites. Mutations in replication and repair genes of mitochondria can result in mtDNA depletion and deletions subsequently leading to mitochondrial genome instability. The combined action of mutations and deletions can result in compromised mitochondrial genome maintenance and lead to various mitochondrial disorders. Here, we review the mechanism of mitochondrial DNA replication and repair process, key proteins involved, and their altered function in mitochondrial disorders. The focus of this review will be on the key genes of mitochondrial DNA replication and repair machinery and the clinical phenotypes associated with mutations in these genes.

Post-surgical left oculomotor nerve neuromyotonia: Cause or coincidence?

Ocular neuromyotonia (ONM) is characterized by episodes of binocular diplopia usually triggered by an eye movement requiring contraction of the affected extraocular muscle. It consists of an involuntary, sometimes painful contraction of one or more extraocular muscles. It is most often secondary to radiotherapy of the para-sellar region, although other aetiologies have been reported. Some cases do not have a clearly identified aetiology and are classified as idiopathic. Most cases of ONMs are unilateral but bilateral ONMs have also been described.1-4 We report a case of left ONM in a 55-year-old female patient, several weeks after simultaneous surgical resection of two meningiomas, situated on the right side (Simpson II). The particularity of this case is linked to its puzzling presentation, its similarity with spasm of the near reflex and the putative mechanism through which surgery might have precipitated the symptoms.

Bilateral true muscle transplantation for correction of very large angle exotropia.

A 59-year old man with very large exotropia and bilateral limitation of adduction, underwent bilateral true muscle transplantation, involving the sutured transfer of resected segment of medial rectus (MR) onto the distal end of lateral rectus (LR), prior to recession of the thus elongated LR muscle. Following this he was left with mild residual exotropia and improved adduction, which has remained stable for 6 months following surgery.

Mitochondrial Medicine in the COVID-19 Era.

Mitochondrial disorders are a remarkably complex group of diseases caused by impairment of the mitochondrial respiratory chain (or electron transport chain) [...].

Lactate peak in muscle disclosed by magnetic resonance spectroscopy in a patient with CPEO-plus syndrome.

A 25-year-old man complained of progressive diplopia and limb weakness for 3 years. Mitochondrial myopathy was suspected according to clinical presentation, elevated serum lactate concentration, and muscle histopathology. However, next-generation mtDNA sequencing (mtDNA NGS) of the blood only revealed a likely benign variant in the MT-CO1 gene (m.6510G > A). An mtDNA NGS study on the muscle sample revealed a large mtDNA deletion (m.5788-m.16071). The patient was diagnosed as having CPEO-plus syndrome related to the large mtDNA deletion. Notably, magnetic resonance spectroscopy revealed a doublet peak at 1-2 ppm in his edematous right vastus lateralis, which indicated lactate accumulation. Thus, muscle imaging and appropriate genetic tests facilitated the diagnosis of mitochondrial myopathy.

Mitochondrial Syndromes Revisited.

In the last ten years, the knowledge of the genetic basis of mitochondrial diseases has significantly advanced. However, the vast phenotypic variability linked to mitochondrial disorders and the peculiar characteristics of their genetics make mitochondrial disorders a complex group of disorders. Although specific genetic alterations have been associated with some syndromic presentations, the genotype-phenotype relationship in mitochondrial disorders is complex (a single mutation can cause several clinical syndromes, while different genetic alterations can cause similar phenotypes). This review will revisit the most common syndromic pictures of mitochondrial disorders, from a clinical rather than a molecular perspective. We believe that the new phenotype definitions implemented by recent large multicenter studies, and revised here, may contribute to a more homogeneous patient categorization, which will be useful in future studies on natural history and clinical trials.

Ptosis, ophthalmoplegia and corneal endothelial disease - ocular manifestations of mitochondrial disease.

PURPOSE: To describe two patients with bilateral ptosis, ophthalmoplegia, cataracts and corneal endothelial disease requiring corneal transplantation. OBSERVATIONS: Histopathological analysis of muscle biopsy samples from both patients identified features consistent with a mitochondrial cytopathy. A single multigenic mitochondrial deoxyribonucleic acid (DNA) deletion was detected in the first patient. Pathogenic mutations in the POLG gene which codes for mitochondrial DNA polymerase, tasked with replicating the mitochondrial genome were identified in the second patient. CONCLUSION: The collection of clinical features present in both cases described can be explained by a diagnosis of mitochondrial disease. IMPORTANCE: Corneal endothelial disease, in addition to ptosis, ophthalmoplegia, cataract, pigmentary retinopathy and optic atrophy should be recognised as a feature of mitochondrial disease.

Headache and migraine in mitochondrial disease and its impact on life-results from a cross-sectional, questionnaire-based study.

Headache is frequent in patients with mitochondrial disorders. Previous studies point to a higher prevalence of headache in these patients than in the general population. As mitochondrial disorders often present a variety of other symptoms, the question arises how much the presence of headache really influences daily life. We performed a cross-sectional, questionnaire-based study investigation with 61 patients with a genetically proved mitochondrial disease mainly composed of CPEO phenotype. Headache was examined using a standardized questionnaire, and classified according to ICHD-2. Headache-related disability was evaluated by the Headache-Impact-Test-6 (HIT-6). Additionally, depression and anxiety were examined using the Hospital Anxiety and Depression Scale (HADS) and Short-Form-Health Survey (SF-12) was used to investigate the health-related quality of life. Headache was reported by 43/61 (70.5%) of the patients. 35/61 patients (57.4%) described a Tension-type headache (TTH) and 26 patients (42.6%) a migraine. Patients reporting headache had a significantly higher HIT-6 score than those without (mean: 54.47 vs. 38.47, p < 0.001). The HIT-6 score was significantly higher in patients reporting a migraine compared to those with a tension-type headache (mean: 62.13 vs. 46.18, p < 0.001). In the HADS score and in the SF-12 were not significantly influenced by the occurrence of headache. This study confirms the previously reported frequent occurrence of headache in a large cohort of patients with a confirmed mitochondrial disease. Migraine had the greatest impact on daily living, which appeared not to be confounded by depression and anxiety. Thus, we conclude that Migraine may be a substantial contributor for burden of disease in patients with mitochondrial diseases.