Kearns-Sayre Syndrome Research Articles

Endocrine disorders in Kearns-Sayre syndrome with different severity of symptoms: two case reports and a literature review.

Kearns-Sayre Syndrome (KSS) is a variant of mitochondrial disorder caused by a Mitochondrial Deoxyribonucleic Acid (mtDNA) deletion. Clinical manifestations of KSS can include different organ and system involvement. Different organ malfunctions, more often cardiac dysfunction, can lead to death. No effective treatment of this condition exists to date. Here, we report two patients with KSS. Female patient with a large-scale deletion of 7,020 base pairs (bp) suffered from hypogonadism, diabetes mellitus with fluctuating glucose levels, and had poor general health. A male patient with a common 4,977 bp deletion did not have diabetes mellitus but had impaired glucose tolerance. He also had a higher level of general health than our female patient. Both patients had reduced Bone Mineral Density (BMD). In female patients, calcium and vitamin D supplementation combined with metabolic therapy and nutritional drink supplements helped increase BMD (up to 32% in L1-L4). Comparing these two patients suggests that the larger the mtDNA deletion is, the more severe the course of the disease is. Not only does the size of the mtDNA deletion probably determine the severity of the disease, but also such factors as mtDNA heteroplasmy level, presence of mtDNA duplications, and pleioplasmy. Moreover, continuous nonconsecutive metabolic therapy and nutritional supplements are helpful in the prevention of deterioration of symptoms and general health.

Long-term hematopoietic dysfunction in patients with large-scale mitochondrial DNA deletion syndromes.

Pearson syndrome (PS) and Kearns-Sayre syndrome (KSS) are single large-scale mitochondrial DNA deletion (SLSMD) syndromes. PS is characterized by severe, transient childhood cytopenia, whereas KSS typically manifests later in life without hematologic abnormalities. Despite distinct clinical presentations, both share a common mitochondrial DNA deletion. Recent observations suggest a potential link between PS progression and myeloid malignancy development, indicating that bone marrow failure (BMF) may be a key aspect of PS pathology and potentially universal across SLSMDs. This study explores longitudinal hematological manifestations of SLSMD syndromes, focusing on bone marrow (BM) dysfunction. Sixteen patients with SLSMDs (13 PS and 3 KSS) were followed, of whom 75% experienced cytopenia, necessitating blood transfusions in 56%. Despite achieving transfusion independence at a median age of 24 months, persistent hematological abnormalities were noted. Comprehensive longitudinal BM studies were conducted in 62% of subjects and consistently revealed signs of marrow dysfunction, even without concurrent cytopenia. Median BM cellularity at a median age of four years and eight months was 50%, with histological signs of dyserythropoiesis, abnormal megakaryocytes, and signs suggesting myelodysplasia. Reduced CD34+ counts and BM colony-forming unit capacity were noted, alongside chromosome 7 aberrations in 16% of patients on cytogenetic studies. Our findings establish BM dysfunction as a persistent hallmark of SLSMD syndromes, posing a risk of clonal evolution and acquisition of chromosome 7 aberrations. This aligns with recent literature, emphasizing enduring BMF in SLSMD syndromes and advocating for tailored hematological monitoring guidelines for this unique patient cohort.

Mitochondrial disorders are associated with morphological neuromuscular junction defects

We aimed to evaluate whether inherited mitochondrial dysfunction is associated with neuromuscular junction remodeling in patients with mitochondrial disorders.Muscle biopsies from 15 patients with mitochondrial disorders and 10 control patients were analyzed through immunostaining for various neuromuscular junction components. The patient group, with a mean age of 49.9 years, exhibited various mitochondrial disorders including chronic progressive external ophthalmoplegia, Kearns-Sayre syndrome, and mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes. Patients with mitochondrial disorders had a high percentage of remodeled (p=0.0001), neoformed (p=0.0049) and dilated (p=0.016) endplates. There was a trend toward an increased proportion of neuromuscular junctions with terminal Schwann cell extension in these patients (p=0.052). No significant difference was found in myofiber diameter between the groups. The observed neuromuscular junction defects varied widely across different mitochondrial disorder phenotypes and were present even without accompanying muscle weakness or neuropathy.This suggest that mitochondrial disorders are associated with a primary NMJ remodeling independent of muscle structural damage. Pathomechanisms underpinning this remodeling of the neuromuscular junction, as well as clinical factors predictive of this remodeling, remain to be fully characterized.

A case of kearns-sayer syndrome presenting with hypoglycaemia and adrenal insufficiency

A case of kearns-sayer syndrome presenting with hypoglycaemia and adrenal insufficiency

Syncope in Kearns–Sayre syndrome may not only be due to AV-block, but may also have other causes due to the multiorgan nature of the disease

Syncope in Kearns–Sayre syndrome may not only be due to AV-block, but may also have other causes due to the multiorgan nature of the disease

New Insights into Mitochondria in Health and Diseases.

Mitochondria are a unique type of semi-autonomous organelle within the cell that carry out essential functions crucial for the cell's survival and well-being. They are the location where eukaryotic cells carry out energy metabolism. Aside from producing the majority of ATP through oxidative phosphorylation, which provides essential energy for cellular functions, mitochondria also participate in other metabolic processes within the cell, such as the electron transport chain, citric acid cycle, and β-oxidation of fatty acids. Furthermore, mitochondria regulate the production and elimination of ROS, the synthesis of nucleotides and amino acids, the balance of calcium ions, and the process of cell death. Therefore, it is widely accepted that mitochondrial dysfunction is a factor that causes or contributes to the development and advancement of various diseases. These include common systemic diseases, such as aging, diabetes, Parkinson's disease, and cancer, as well as rare metabolic disorders, like Kearns-Sayre syndrome, Leigh disease, and mitochondrial myopathy. This overview outlines the various mechanisms by which mitochondria are involved in numerous illnesses and cellular physiological activities. Additionally, it provides new discoveries regarding the involvement of mitochondria in both disorders and the maintenance of good health.

A - 102 Neuropsychological Insights into Kearns-Sayre Syndrome: a Case Study

Abstract Objective Kearns-Sayre Syndrome (KSS) is a genetic mitochondrial and neuromuscular condition with multisystemic effects, including the eyes, heart, muscles, and cognition. Very little is known regarding the cognitive profile of patients with KSS, and existing studies have presented mixed findings. Results in one study revealed impairments in visuospatial abilities and attention, while another study found impairments in global cognition and word-finding. Interestingly, both studies revealed impairments in executive functions. Method This abstract presents the case of a 46-year-old right-handed, African American female diagnosed with KSS in 2021. Symptoms of KSS first appeared in 2010 with progressive vision loss and bilateral ptosis. Genetic testing revealed MT-T1 mutation consistent with KSS. Electroretinography findings revealed mild cone atrophy and mild-to-moderate concentric visual field defects. Attentional difficulties were noted in 2016 and resulted in a diagnosis of ADHD. Memory problems were first noticed in 2016 and have persisted since then. Magnetic resonance imaging results from May 2023 revealed no structural abnormalities in the brain. Results A comprehensive neuropsychological evaluation completed in March 2024 revealed mostly intact neurocognitive functioning. Notably, performance on memory and visuospatial measures were within normal limits. However, poor performance was revealed on one measure of executive functioning. Conclusions It remains unclear whether the poor performance seen on a measure of executive functioning reflects a true cognitive deficit or just chance variation. Even so, with little information regarding the cognitive profile of KSS, baseline neuropsychological testing should be considered to monitor related cognitive changes over time.

Kearns-Sayre Syndrome: a rare mitochondrial cytopathy complicated with complete heart block in a teenager

Kearns-Sayre Syndrome: a rare mitochondrial cytopathy complicated with complete heart block in a teenager

Complete heart block; a clue to Kearns-Sayre syndrome: A case report

Complete heart block; a clue to Kearns-Sayre syndrome: A case report

Prospective Evaluation and Monitoring for Multisystem Involvement may improve the outcome of Kearns-Sayre Syndrome

Prospective Evaluation and Monitoring for Multisystem Involvement may improve the outcome of Kearns-Sayre Syndrome

Management of Ptosis in Kearns-Sayre Syndrome: A Case Report and Literature Review.

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.

Kearns–Sayre Syndrome with Bilateral Ptosis and External Ophthalmoplegia: A Rare Case Report

Abstract
 Introduction : Kearns-Sayre syndrome (KSS) is a rare genetic disorder caused by a deletion of mitochondrial DNA (mtDNA) segment, typically characterized by a triad of symptoms includes external ophthalmoplegia, pigmentary retinopathy and appeared before the age of 20. The prevalence rate is about 1–3 per 100.000 individuals. It was diagnosed based on clinical features and supported by biochemical, radiological, histologic, and molecular genetic tests.
 Case Illustration : 26-year-old male with bilateral ptosis, chronic progressive external ophthalmoplegia, pigmentary retinopathy was shown from ophthalmology examination and associated with hearing loss. Physical examination showed short stature, wasting, and weakness of limb muscles. MRI examination revealed focal brain atrophy on bilateral parietal regions.
 Discussion : Mitochondrial DNA defect led to dysfunction of the central nervous system, endocrine system, extraocular muscle, myocardium, skeletal muscle, and other multiple systems. The clinical findings in this patient are appropriate for classical signs and symptoms of KSS. Central nervous involvementis shown by the neuroimaging result. There is no cardiac involvement suggested by normal cardiology examination. Although muscle pathology and molecular genetic analysis can play a great role to diagnose KSS, the classical triad of clinical signs plus one of the other symptoms could establish KSS diagnosis.
 Conclusion : KSS is a rare genetic disorder and challenging to diagnose. However, if a patient presents with the classic triad of symptoms, clinicians should have a high level of suspicion for the disorder. Additionally, It is important to perform a thorough evaluation to rule out other conditions that can cause similar symptoms.

Cellular and Molecular Responses to Mitochondrial DNA Deletions in Kearns-Sayre Syndrome: Some Underlying Mechanisms.

Kearns-Sayre syndrome (KSS) is a rare multisystem mitochondrial disorder. It is caused by mitochondrial DNA (mtDNA) rearrangements, mostly large-scale deletions of 1.1-10kb. These deletions primarily affect energy supply through impaired oxidative phosphorylation and reduced ATP production. This impairment gives rise to dysfunction of several tissues, in particular those with high energy demand like brain and muscles. Over the past decades, changes in respiratory chain complexes and energy metabolism have been emphasized, whereas little attention has been paid to other reports on ROS overproduction, protein synthesis inhibition, myelin vacuolation, demyelination, autophagy, apoptosis, and involvement of lipid raft and oligodendrocytes in KSS. Therefore, this paper draws attention towards these relatively underemphasized findings that might further clarify the pathologic cascades following deletions in the mtDNA.

Kearns–Sayre syndrome with type 1 diabetes mellitus: A case report

Kearns–Sayre syndrome (KSS) is a rare genetic mitochondrial myopathy with a typical onset before 20 years of age. It is a variant of chronic progressive external ophthalmoplegia. It is defined by a characteristic triad of progressive external ophthalmoplegia, pigmentary retinopathy, and cardiac conduction abnormalities. The prevalence rate of KSS is ~1–3 per 100,000 individuals. Here, we report a rare case of an 18 year-old Indian female with KSS and type 1 diabetes mellitus.

Chapter 4 - Primary mitochondrial diseases

Primary mitochondrial diseases (PMDs) are a heterogeneous group of hereditary disorders characterized by an impairment of the mitochondrial respiratory chain. They are the most common group of genetic metabolic disorders, with a prevalence of 1 in 4,300 people. The presence of leukoencephalopathy is recognized as an important feature in many PMDs and can be a manifestation of mutations in both mitochondrial DNA (classic syndromes such as mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes; myoclonic epilepsy with ragged-red fibers [RRFs]; Leigh syndrome; and Kearns-Sayre syndrome) and nuclear DNA (mutations in maintenance genes such as POLG, MPV17, and TYMP; Leigh syndrome; and mitochondrial aminoacyl-tRNA synthetase disorders). In this chapter, PMDs associated with white matter involvement are outlined, including details of clinical presentations, brain MRI features, and elements of differential diagnoses. The current approach to the diagnosis of PMDs and management strategies are also discussed. A PMD diagnosis in a subject with leukoencephalopathy should be considered in the presence of specific brain MRI features (for example, cyst-like lesions, bilateral basal ganglia lesions, and involvement of both cerebral hemispheres and cerebellum), in addition to a complex neurologic or multisystem disorder. Establishing a genetic diagnosis is crucial to ensure appropriate genetic counseling, multidisciplinary team input, and eligibility for clinical trials.

Diagnosing Kearns-Sayre syndrome requires clinical and genetic evidence.

Diagnosing Kearns-Sayre syndrome requires clinical and genetic evidence.

The clinical, myopathological, and genetic analysis of 155 Chinese mitochondrial ophthalmoplegia patients with mitochondrial DNA single large deletions.

Progressive external ophthalmoplegia (PEO) is a common subtype of mitochondrial encephalomyopathy. 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. 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. 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. 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.

Long-Term Hematopoietic Dysfunction in Patients with Single Large-Scale Mitochondrial DNA Deletion Syndromes

Pearson syndrome (PS) is the only single large-scale mitochondrial DNA deletion syndrome (SLSMDs) presenting substantial hematologic manifestations, usually a severe though transient cytopenia of childhood. Recently, progression to myeloid malignancies has been described among PS patients. Older PS patients, as well as patients with SLSMDs presenting with Kearns-Sayre syndrome (KSS) or with progressive external ophthalmoplegia (PEO), do not display hematologic abnormalities. Since the underlying mitochondrial DNA deletion is similar in all SLSMDs, we hypothesized that bone marrow (BM) dysfunction is a common and persistent manifestation in these patients. We studied 16 patients with molecular-confirmed SLSMDs: 13 with PS, and three with KSS. The median age at diagnosis was 25 months (range 2-136 months). Seventy-five percent of patients presented with cytopenia in infancy, and 56% required blood products. Resolution of cytopenia occurred in 92% of this subgroup, at a median age of 24 months (range 12-39 months). BM studies were performed in all patients, and 56% of patients had multiple BM evaluations. All BM biopsies examined showed signs of marrow dysfunction, including in patients without a history of cytopenia. Median BM cellularity was 50% (range 30-80%) at a median age of 5 years. BM samples showed a paucity of precursor myeloid cells, signs of dyserythropoiesis, and abnormal or missing megakaryocytes. We report low hematopoietic stem and progenitor cell functionality in patients with SLSMDs: The median CD34+ count was 0.68% (range 0.27-1.92%, expected range 1-2%). BM colony forming unit (CFU) capacity was reduced in SLSMD patients: the median CFU in patients was 280 per 10 6 cells compared to 1090 per 10 6 cells in healthy controls (p=0.004). Conventional cytogenetic analysis was done on 10 patients (62%), and FISH analysis was done on 15 patients (93%). Monosomy 7 was identified in seven patients (44%): in one patient the monosomy 7 resolved in a follow-up BM assay. Another patient with signs of myelodysplasia and 30% of the BM cells having monosomy 7 was referred to an allogeneic bone marrow transplantation. To conclude, long-term BM dysfunction is evident in all patients with SLSMD and includes a risk of developing clonal evolution and monosomy 7. This data, combined with other recent publications, highlights the ongoing marrow failure and suggest that SLSMD syndromes should be included under inherited BM failure syndromes.

Genetic, Hematological, and Endocrine Involvement in a Patient with Pearson Syndrome: Clinical Management and Discussion

Background: Pearson syndrome (PS) is a rare mitochondrial DNA deletion disorder characterized by pancytopenia and exocrine pancreas dysfunction. Currently, there are less than 150 cases ever reported. The mutations are predominately de novo with only a handful of instances of mother to child inheritance documented. Mortality is typically in early childhood or those making it past oftentimes developing chronic progressive external ophthalmoplegia (CPEO) or Kearns-Sayre syndrome (KSS). While no curative treatment exists today, our goal is to document the clinical phenotype of a patient with PS to allow for a greater understanding and management for future patients. Diagnosis: We present the case of a child with PS and associated findings of resolved pancytopenia, ringed sideroblasts, failure to thrive, and renal tubular acidosis. Born premature at 32 weeks and anemic at birth, he required PRBC transfusions twice during his one-month NICU admission. At 2 months old, he was vomiting and appeared pale in which he was admitted and had a hemoglobin of 3.5 g/dL. Found then to have pancytopenia, a bone marrow aspiration and biopsy was performed showing ringed sideroblasts, hypocellularity at 60%, 5-8% blasts, moderate dyserythropoiesis, and dysmyelopoiesis. Phenotypically, he was also referred to genetics for facial dysmorphism with a flat nasal bridge, thin philtrum, and small ears. Upon further genetic testing, he had an 80% Heteroplasmic 5kb deletion including m.8483_13459 encompassing the following genes: MT-ATP8, MT-ATP6, MT-CO3, MT-TG, MT-ND3, MT-TR, MT-ND4L, MT-ND4, MT-TH, MT-TS2, MT-TL2, MT-ND, consistent with PS. Since diagnosis, he has been admitted on several occasions for emesis and metabolic acidosis. Management: Patient has been following up with genetics, hematology, endocrinology, cardiology, gastroenterology, neurology, and nephrology. He had been receiving granulocyte colony-stimulating factor (G-CSF) until the age of 1 and more than 20 transfusions up until 1.5 years old with the pancytopenia having since resolved. Most recent values show a hemoglobin of 13.9 g/dL, WBC 5,600/mcL, and platelets still low at 86,000/mcL. He has been evaluated for short stature with height and weight both below the 1st percentile and IGF-1 low at 25 leading to considerations for a G-tube and/or GH supplementation. He continues to receive physical therapy for low muscle mass. He is currently taking sodium bicarbonate, magnesium bicarbonate, and levocarnitine due to deficiencies, pancrelipase for exocrine pancreatic insufficiency, and leucovorin for anemia. He is also seeing dermatology for a hemangioma, facial telangiectasias on the forehead and cheeks, as well as skin photosensitivity and hypopigmentation of the arms and legs. Discussion/Conclusion: With PS being discovered less than 50 years ago, more research still needs to be done to better understand clinical phenotype and treatment management. Resolved pancytopenia, ringed sideroblasts, failure to thrive, and renal tubular acidosis have all been seen in the literature and in our patient. Other areas however are still being assessed. While failure to thrive has been reported, the efficacy of growth hormone supplementation has not been adequately described. With regards to skin findings, hypopigmentation has been reported in the literature in reference to various mitochondrial diseases, however there are limited findings in specific with reference to PS. Furthermore, it would be beneficial to see whether others with PS have any of the same facial dysmorphisms to aid in future diagnosis. Gene therapies and other therapeutics are newly emerging for mitochondrial diseases and it is our hope that PS will have more advanced treatment options in the future.

Abstract 16396: A Tale of Two Maladies: An Interplay of Mendelian Principles

A 22-year-old male with no medical history presented in acute decompensated heart failure and cardiogenic shock. Physical exam showed a thin body habitus, reduced muscle bulk, bilateral ptosis, limited extraocular motion, and upper extremity weakness. An echocardiogram revealed severe biventricular dilation and systolic dysfunction. Invasive hemodynamics revealed elevated cardiac filling pressures and low cardiac output. Coronary angiography excluded coronary artery disease and anatomical variants. He was initiated on dobutamine and eventually milrinone given persistently low index and elevated lactate. An evaluation for the etiology of his cardiomyopathy focused on nutritional deficiencies (e.g., Wet Beriberi), myocarditis, genetic mutations, infiltrative cardiomyopathy (e.g., Friedrich’s ataxia), and mitochondrial and myopathy-related cardiomyopathy. CMR had globally elevated T1 and normal T2 values ruling out acute myocarditis or infiltrative processes. Serum thiamine, TSH and B12 were within normal range. Muscle biopsy and mitochondrial genetic testing revealed a pathogenic deletion (m.7416_14556) and 70% heteroplasmy. Physical exam, biopsy and mitochondrial genetics were diagnostic of Kearns-Sayre Syndrome (KSS). Notably KSS does not typically cause severe cardiomyopathy suggesting an alternative cause. A genetic cardiomyopathy panel was sent revealing a pathologic mutation in the plakophilin 2 gene which was the suspected cause of his cardiomyopathy. A heart transplant evaluation was initiated as he developed refractory shock requiring mechanical support via an Impella 5.5, placed via the right innominate artery due to his small body and vessel size. He underwent an uncomplicated heart transplantation and is doing well. This case underscores the significance of a broad differential diagnosis, multidisciplinary collaboration, and a detailed physical examination in diagnosing and managing complex cardiac conditions.