Kearns-Sayre syndrome (KSS) is a rare mitochondrial disease that affects young adults, due to a deletion of mitochondrial DNA and characterized by the triad: age of onset lower than 20 years, chronic progressive external ophthalmoplegia, and an atypical pigmentary retinopathy. It is also characterized by other endocrine, neurological, and especially cardiac impairment with a very high risk of cardiac complications during surgical procedures under all types of anesthesia. We report a case of KSS revealed by severe bilateral ptosis and confirmed by a muscle biopsy with \"ragged red fibers.\" The ptosis was surgically managed by cautious Frontal suspension under local anesthesia \"Frontal nerve block.\" Through this case, we discuss challenges in the management of KSS patients.

Mitochondrial myopathies are frequently recognized in childhood as part of a broader multisystem disorder and often overlooked in adulthood. Herein, we describe the phenotypic and genotypic spectrum and long-term outcomes of mitochondrial myopathies diagnosed in adulthood, focusing on neuromuscular features, electrodiagnostic and myopathological findings and survival. We performed a retrospective chart review of adult patients diagnosed with mitochondrial myopathy at Mayo Clinic (2005-21). We identified 94 patients. Median time from symptom onset to diagnosis was 11 years (interquartile range 4-21 years). Median age at diagnosis was 48 years (32-63 years). Primary genetic defects were identified in mitochondrial DNA in 48 patients (10 with single large deletion, 38 with point mutations) and nuclear DNA in 29. Five patients had multiple mitochondrial DNA deletions or depletion without nuclear DNA variants. Twelve patients had histopathological features of mitochondrial myopathy without molecular diagnosis. The most common phenotypes included multisystem disorder (n = 30); mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (14); limb myopathy (13); chronic progressive external ophthalmoplegia (12); and chronic progressive external ophthalmoplegia-plus (12). Isolated skeletal muscle manifestations occurred in 27%. Sixty-nine per cent had CNS and 21% had cardiac involvement. Mutations most frequently involved MT-TL1 (27) and POLG (17); however, a wide spectrum of established and novel molecular defects, with overlapping phenotypes, was identified. Electrodiagnostic studies identified myopathy (77%), fibrillation potentials (27%) and axonal peripheral neuropathy (42%, most common with nuclear DNA variants). Among 42 muscle biopsies available, median percentage counts were highest for cytochrome C oxidase negative fibres (5.1%) then ragged blue (1.4%) and ragged red fibres (0.5%). Skeletal muscle weakness was mild and slowly progressive (decline in strength summated score of 0.01/year). Median time to gait assistance was 5.5 years from diagnosis and 17 years from symptom onset. Thirty patients died, with median survival of 33.4 years from symptom onset and 10.9 years from diagnosis. Median age at death was 55 years. Cardiac involvement was associated with increased mortality [hazard ratio 2.36 (1.05, 5.29)]. There was no difference in survival based on genotype or phenotype. Despite the wide phenotypic and genotypic spectrum, mitochondrial myopathies in adults share similar features with slowly progressive limb weakness, contrasting with common multiorgan involvement and high mortality.

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.
CONCLUSIONS: 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.
CONCLUSIONS: Understanding the varying presentations and genetic aspects of mitochondrial CPEO is crucial for accurate diagnosis and management.

Chronic progressive external ophthalmoplegia (CPEO) is a mitochondrial encephalomyopathy that is characterized by progressive ptosis and impaired ocular motility. Owing to its nonspecific clinical manifestations, CPEO is often misdiagnosed as other conditions. Herein, we present the case of a 34-year-old woman who primarily presented with incomplete left eyelid closure and limited bilateral eye movements. During the 6-year disease course, she was diagnosed with myasthenia gravis and cranial polyneuritis. Finally, skeletal muscle tissue biopsy confirmed the diagnosis. Biopsy revealed pathological changes in mitochondrial myopathy. Furthermore, mitochondrial gene testing of the skeletal muscle revealed a single chrmM:8469-13447 deletion. In addition, we summarized the findings of 26 patients with CPEO/Kearns-Sayre syndrome who were misdiagnosed with other diseases owing to ocular symptoms. In conclusion, we reported a rare clinical case and emphasized the symptomatic diversity of CPEO. Furthermore, we provided a brief review of the diagnosis and differential diagnosis of the disease.

UNASSIGNED: Clinical spectrum of mitochondrial myopathy extends beyond chronic progressive external ophthalmoplegia (CPEO). While information on encephalomyopathies is abundant, clinical data on predominant myopathic presentation of mitochondrial disorders are lacking.
UNASSIGNED: Clinical, electrophysiological, biochemical, and follow-up data of patients with predominant myopathic presentation and muscle biopsy confirmed primary mitochondrial myopathy was obtained. We excluded known syndromes of mitochondrial cytopathies and encephalomyopathies.
UNASSIGNED: Among 16 patients, 7 had CPEO, 4 had CPEO with limb-girdle muscle weakness (LGMW), and 5 had isolated LGMW. Systemic features included seizures with photosensitivity (n = 3), diabetes (n = 1), cardiomyopathy (n = 1), and sensorineural hearing loss (n = 1) and were more common in isolated LGMW. Elevated serum creatine kinase (CK) and lactate levels and electromyography (EMG) myopathic potentials were more frequent with LGMW. During follow-up, LGMW had more severe progression of weakness.
UNASSIGNED: We identified three subsets of mitochondrial myopathy with distinct clinical features and evolutionary patterns. Isolated LGMW was seen in 30% of patients and would represent severe end of the spectrum.

BACKGROUND: Progressive external ophthalmoplegia (PEO) is a common subtype of mitochondrial encephalomyopathy.
OBJECTIVE: The study aimed to investigate the relationship between mitochondrial DNA (mtDNA) abnormalities, muscle pathology, and clinical manifestations in Chinese patients with single large-scale mtDNA deletion presenting with PEO.
METHODS: This is a retrospective single-center study. Patients with PEO who had a single large deletion in mitochondrial DNA were included in this study. The associations were analyzed between mtDNA deletion patterns, myopathological changes, and clinical characteristics.
RESULTS: In total, 155 patients with mitochondrial PEO carrying single large-scale mtDNA mutations were enrolled, including 137 chronic progressive external ophthalmoplegia (CPEO) and 18 Kearns-Sayre syndrome (KSS) patients. The onset ages were 9.61 ± 4.12 in KSS and 20.15 ± 9.06 in CPEO. The mtDNA deletions ranged from 2225 bp to 9131 bp, with m.8470_13446del being the most common. The KSS group showed longer deletions than the CPEO group (p = 0.004). Additionally, a higher number of deleted genes encoding respiratory chain complex subunits (p = 0.001) and tRNA genes (p = 0.009) were also observed in the KSS group. A weak negative correlation between the mtDNA deletion size and ages of onset (p < 0.001, r = -0.369) was observed. The proportion of ragged red fibers, ragged blue fibers, and cytochrome c negative fibers did not correlate significantly with onset ages (p > 0.05). However, a higher percentage of abnormal muscle fibers corresponds to an increased prevalence of exercise intolerance, limb muscle weakness, dysphagia, and cerebellar ataxia.
CONCLUSIONS: We reported a large Chinese cohort consisting of mitochondrial PEO patients with single large-scale mtDNA deletions. Our results demonstrated that the length and locations of mtDNA deletions may influence onset ages and clinical phenotypes. The severity of muscle pathology could not only indicate diagnosis but also may be associated with clinical manifestations beyond the extraocular muscles.

UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.

Mitochondrial DNA depletion syndrome type 11 (MTDPS11) is caused by pathogenic variants in MGME1 gene. We report a woman, 40-year-old, who presented slow progressive drop eyelid at 11-year-old with, learning difficulty and frequent falls. Phisical examination revealed: mild scoliosis, elbow hyperextensibility, flat feet, chronic progressive external ophthalmoplegia with upper eyelid ptosis, diffuse hypotonia, and weakness of arm abduction and neck flexion. Investigation evidenced mild serum creatine kinase increase and glucose intolerance; second-degree atrioventricular block; mild mixed-type respiratory disorder and atrophy and granular appearance of the retinal pigment epithelium. Brain magnetic resonance showed cerebellar atrophy. Muscle biopsy was compatible with mitochondrial myopathy. Genetic panel revealed a homozygous pathogenic variant in the MGME1 gene, consistent with MTDPS11 (c.862C>T; p.Gln288*). This case of MTDPS11 can contribute to the phenotypic characterization of this ultra-rare mitochondrial disorder, presenting milder respiratory and nutritional involvement than the previously reported cases, with possible additional features.

Large single mitochondrial DNA (mtDNA) deletion syndrome is a rare inborn error of metabolism with variable heteroplasmy levels and clinical phenotype among affected individuals. Chronic progressive external ophthalmoplegia (CPEO) is the most common phenotype in adults with this form of mitochondrial disease [J Intern Med. 2020;287(6):592-608 and Biomed Rep. 2016;4(3):259-62]. The common CPEO clinical manifestations are ptosis and ophthalmoplegia. More variable phenotypic manifestations of CPEO (CPEO plus) include involvement of the peripheral nervous system and myopathy. Here, we describe a 62-year-old female with CPEO and the major mtDNA deletion present at 40% heteroplasmy, who had a coexistent previously undescribed CPEO phenotypic feature of persistent unexplained macrocytosis without anemia. Building on this case, we reviewed other major mtDNA deletion cases seen in our Adult Metabolic Diseases Clinic (AMDC) at the University of British Columbia, Vancouver, Canada, from 2016 to 2022. The major mtDNA deletion cases (n = 26) were compared with mtDNA missense variants identified in the clinic over the same period who acted as the comparison group (n = 16). Of these, the most frequent diagnosis was maternally inherited diabetes and deafness and mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes. Ten out of 26 (38%) of mtDNA deletion patients had macrocytosis with elevated mean corpuscular volume (MCV), median (interquartile range) of 108 fL (102-114 fL). Seven of the patients with macrocytosis had no pertinent etiology. None of the comparison group had macrocytosis. There was a significant difference (p = 0.000) between the MCV and MCH in the mtDNA deletion group compared to the comparison group. This communication sheds light on the association of macrocytosis with the mtDNA deletion syndrome. It would be of great interest to determine if the association is found in other mitochondrial disease clinic populations.

OBJECTIVE: Chronic progressive external ophthalmoplegia (CPEO) is a mitochondrial disease characterized by slowly progressive ptosis and limitations in ocular motility. Although exophthalmos is not considered to be a common feature of CPEO, this study focused on the incidence of exophthalmos in patients with CPEO.
METHODS: Retrospective observational case series METHODS: We reviewed the clinical charts of patients who received a diagnosis of CPEO sometime during the period between January 2010 and December 2018. CPEO was diagnosed on the basis of detection of a deletion of mitochondrial DNA (mtDNA) from saliva, buccal mucosa, or extraocular muscle specimens obtained during strabismus surgery. Horizontal MRI/CT images or Hertel ophthalmometry was used in determining exophthalmos.
RESULTS: Seven patients (4 males) were identified. The mean age at diagnosis was 32.6 years (range 13-53 years). mtDNA deletion mutations were detected in the buccal mucous membrane DNA in 5 patients and in the saliva and extraocular muscle DNA in 2 patients. MRI/CT was recorded in 6 patients, four of whom showed exophthalmos (cases 1-4), and case 5 was determined as exophthalmos on the basis of a Hertel ophthalmometer reading. Exophthalmos was bilateral in 4 of the patients (cases 1, 2, 4, and 5) and unilateral in 1 patient (case 3). Exophthalmos was the chief concern of 2 of the patients; however, it was not clinically significant in the other patients.
CONCLUSIONS: Although exophthalmos may not be recognized by either the patient or the clinician, it may be one of the common features of CPEO. A large multiethnic study should be performed.