Kearns-Sayre Syndrome Patients Research Articles

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.

Ventricular arrhythmias in Kearns-Sayre syndrome: A cohort study using the National Inpatient Sample database 2016-2019.

Degeneration of the cardiac conduction system resulting in complete heart block (CHB), ventricular arrhythmias (VA), and sudden cardiac death (SCD) is recognized in patients with Kearns-Sayre syndrome (KSS) and is potentially preventable with permanent pacemaker (PPM) implantation. However, other mechanisms for SCD have been proposed, and the efficacy of implanting a defibrillator instead of PPM remains to be investigated. We utilized the National Inpatient Sample (NIS) database 2016-2019 to investigate the risk of VA or dysrhythmic cardiac arrest (dCA) in KSS patients. We compared the outcomes of KSS to myotonic dystrophy (MD), a more common genetic disorder with similar clinical cardiac features and course. We identified 640 admissions for KSS. VA or dCA were lower in admissions for KSS than MD patients (2.3%vs. 4.5%, p=.009). Device implantation differed between study groups. Approximately, 70% of cases with KSS and conduction abnormalities had pacemaker(±defibrillator) on hospital discharge, compared to 35% in MD. Conduction abnormalities were associated with higher rates of VA or dCA in both study groups. None of the admissions for KSS patients who developed VA or dCA had a pacemaker, and all of them had conduction abnormalities. One-third of admissions for MD patients who developed VA or dCA had a device already implanted prior to the event. Despite its effectiveness in preventing VA, PPM remains underutilized in patients with KSS or MD who have conduction abnormalities. PPM alone do not fully prevent VA in MD patients; therefore, addition of defibrillator capacity might be necessary.

The necessity of implantable cardioverter defibrillators in patients with Kearns-Sayre syndrome - systematic review of the articles -

The most common cardiac feature of Kearns-Sayre syndrome (KSS) is atrioventricular block (AVB), and pacemaker implantations (PMIs) are recommended for KSS patients with advanced AVB. However, some KSS patients develop fatal arrhythmias such as polymorphic ventricular tachycardia (PMVT) and ventricular fibrillation (VF) and die suddenly even after PMIs. We report a patient with KSS who developed PMVT, VF, and QT prolongation, and was treated with mexiletine and successfully managed with an implantable cardioverter defibrillator (ICD). We reviewed the literature on arrhythmias in KSS published from 1975 to 2018. There were 112 patients with arrhythmia-associated KSS, 10 died, and 6 died suddenly after the PMI. The first manifestation of an arrhythmia was bundle branch block, then it progressed to AVB, and developed into complete AVB (CAVB) in about half the KSS patients. Ventricular arrhythmias were documented in 12 patients, and 8 were implanted with defibrillators afterwards. One patient after the implantation of a cardiac resynchronization therapy defibrillator (CRT-D) was treated for VF by an appropriate shock. This fact suggested that VF occurred even under proper pacing, and that defibrillators were effective. Pacemakers may suppress early afterdepolarizations (EADs) associated with a QT prolongation due to bradycardia. Similarly, mexiletine may suppress EADs by blocking the late sodium and Ca currents. Ventricular arrhythmias observed under suppression of EADs may be caused by delayed afterdepolarization (DADs) via an increasing intracellular Ca concentration due to mitochondrial dysfunction. Therefore, a PMI alone may not be sufficient to prevent sudden death, and an ICD implantation should be necessary.

Combination of microdissection and single cell quantitative real-time PCR revealed intercellular mitochondrial DNA heterogeneities in fibroblasts of Kearns-Sayre syndrome patients

Kearns-Sayre syndrome (KSS) is a multisystemic disorder marked by aerobic cell metabolism dysfunction. Fibroblasts derived from KSS patient skin biopsy exhibit heterogeneous occurrence of mitochondrial genomes as those circular DNA molecules partially carry the common deletion. In our approach, we aim to evaluate the intercellular alterations in respect to mitochondrial DNA integrity by laser capture microdissection and multiplex quantitative real-time PCR in single cells. The obtained results give new insights into the understanding of mitochondrial genetics, e.g. postulated sorting of damaged mitochondria, and heterogeneity of cells. Further, we discuss the relevance of intercellular heterogeneities for human mitochondrial disorders in general.

Cerebrospinal fluid monoamines, pterins, and folate in patients with mitochondrial diseases: systematic review and hospital experience.

Mitochondrial diseases are a group of genetic disorders leading to the dysfunction of mitochondrial energy metabolism pathways. We aimed to assess the clinical phenotype and the biochemical cerebrospinal fluid (CSF) biogenic amine profiles of patients with different diagnoses of genetic mitochondrial diseases. We recruited 29 patients with genetically confirmed mitochondrial diseases harboring mutations in either nuclear or mitochondrial DNA (mtDNA) genes. Signs and symptoms of impaired neurotransmission and neuroradiological data were recorded. CSF monoamines, pterins, and 5-methyltetrahydrofolate (5MTHF) concentrations were analyzed using high-performance liquid chromatography with electrochemical and fluorescence detection procedures. The mtDNA mutations were studied by Sanger sequencing, Southern blot, and real-time PCR, and nuclear DNA was assessed either by Sanger or next-generation sequencing. Five out of 29 cases showed predominant dopaminergic signs not attributable to basal ganglia involvement, harboring mutations in different nuclear genes. A chi-square test showed a statistically significant association between high homovanillic acid (HVA) values and low CSF 5-MTHF values (chi-square = 10.916; p = 0.001). Seven out of the eight patients with high CSF HVA values showed cerebral folate deficiency. Five of them harbored mtDNA deletions associated with Kearns-Sayre syndrome (KSS), one had a mitochondrial point mutation at the mtDNA ATPase6 gene, and one had a POLG mutation. In conclusion, dopamine deficiency clinical signs were present in some patients with mitochondrial diseases with different genetic backgrounds. High CSF HVA values, together with a severe cerebral folate deficiency, were observed in KSS patients and in other mtDNA mutation syndromes.

The urinary organic acids profile in single large-scale mitochondrial DNA deletion disorders

Single large-scale mitochondrial DNA deletions disorders are classified into three main phenotypes with frequent clinical overlap: Pearson marrow-pancreas syndrome (PMS), Kearns-Sayre syndrome (KSS) and chronic progressive external ophtalmoplegia (PEO). So far, only few anecdotal studies have reported on the urinary organic acids profile in this disease class.In this single-center retrospective study, we performed quantitative evaluation of urinary organic acids in a series of 15 pediatric patients, 7 with PMS and 8 with KSS.PMS patients showed an organic acids profile almost constantly altered, whereas KSS patients frequently presented with normal profiles. Lactate, 3-hydroxybutyrate, 3-hydroxyisobutyrate, fumarate, pyruvate, 2-hydroxybutyrate, 2-ethyl-3-hydroxypropionate, and 3-methylglutaconate represented the most frequent metabolites observed in PMS urine. We also found novel metabolites, 3-methylglutarate, tiglylglycine and 2-methyl-2,3-dihydroxybutyrate, so far never reported in this disease. Interestingly, patients with a disease onset as PMS evolving overtime into KSS phenotype, presented persistent and more pronounced alterations of organic acid signature than in patients with a pure KSS phenotype.Our study shows that the quantitative analysis of urinary organic acid profile represents a helpful tool for the diagnosis of PMS and for the differential diagnosis with other inherited diseases causing abnormal organic acidurias.

Kearns-sayre Syndrome Treated with Permanent Pacemaker Insertion for Complete Atrioventricular Block

Kearns-Sayre syndrome (KSS) is a rare multisystem mitochondrial disorder associated with progressive external ophthalmoplegia, atypical pigmentary degeneration of the retina, and complete heart block. KSS can lead to a risk of sudden death because of the potential progression of conduction abnormalities such as right or left bundle branch block or complete atrioventricular (AV) block. Here we describe the case of a KSS patient with type I diabetes who experienced syncope in the presence of complete AV block, confirmed by muscular biopsy.

Diagnosis and Management of Kearns-Sayre Syndrome Rely on Comprehensive Clinical Evaluation

We appreciate the readers’ interest and their comprehensive comments and advice about the article,[1] which mainly concerned details of the patients’ information. In this paper, we reported 19 Kearns-Sayre syndrome (KSS) patients whose diagnoses were in accordance with the current clinical diagnostic criteria of KSS, i.e., the triad of progressive external ophthalmoplegia, pigmentary retinopathy, and onset before 20 years of age, plus at least one of the followings: heart block, cerebellar symptoms, or cerebrospinal fluid protein levels above 1000 mg/L.[2] The diagnostic criteria have been widely used.[3] Apart from clinical features, muscle pathology and molecular genetic analysis can play a great role in the diagnostic workup. Muscle pathology showed ragged-red fibers (RRF), ragged-blue fibers (RBF), or cytochrome c-oxidase (COX)-negative fibers in almost all patients.[4] Southern blot or long-range polymerase chain reaction can detect single large-scale deletion in about 90% of KSS patients,[5] while mitochondrial DNA (mtDNA) point mutations or nuclear gene mutations have been reported in other KSS patients.[6] In general, single large-scale deletion can be detected only from the muscle, but not from blood cells of KSS patients.[7] Among the 19 patients reported by us, 15 patients underwent muscle biopsy in our hospital which showed RRF, RBF, and COX-negative fibers in all of them; however, mtDNA mutation detection was available in 11 of them because muscle tissue of the other four (patients 8, 10, 17, and 18) were not enough for further gene analyses; one patient (patient 12) had muscle biopsy in another hospital, and we got a little muscle tissue to do the mutation examination although RBF% cannot be counted. Three patients (patients 2, 5, and 7) refused to receive muscle biopsy, but all of them showed typical KSS features. We performed common mtDNA point mutations analysis (mtDNA A3243G, A8344G) in their blood, which were negative. Biochemical investigations, especially activity assay of respiratory chain complexes in muscle tissues, can also help provide evidence for the diagnosis of mitochondrial disease.[8] Unfortunately, such a detecting platform has not been established in our laboratory. There were several articles studying the exact nature of high signal lesions on diffusion-weighted imaging (DWI) in patients with mitochondrial diseases, especially mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes. However, the results were conflicting since some reported an increase in the apparent diffusion coefficient (ADC) values suggesting vasogenic edema while others described a decrease in the ADC values reflecting cytotoxic edema.[9] In our KSS patients, we also found the same interesting phenomena that the ADC values of the regions with high signal on DWI were not consistent. Some patients showed increased ADC values while the others showed decreased ADC values. We proposed that the discrepancy might be due to the different disease stages in different individual patients although further studies are needed to elucidate the underlying pathophysiological mechanism. The results of Moraes et al.[2] showed cognitive decline in 31% of KSS patients, which was associated with the presence of disability. In our research, the present study was mainly focused on the electrocardiogram and brain magnetic resonance imaging changes of the patients. Cognitive function was only evaluated in one patient, which also showed a moderate decline of cognitive function. In our research, all the patients underwent Holter monitoring, and as we reported in the article, none of them developed ventricular arrhythmias, which was also a big difference from previous reports. Therefore, the cardiologists did not suggest implantable cardioverter defibrillator implantation in these patients. According to the height and weight standardized growth charts for Chinese children and adolescents aged 0–18 years,[10] we only found the heights of three patients more than two standard deviations below the mean for age and gender. The heights of other six patients were below the mean height for age and gender but did not reach the definition for short stature. Again, we show our greatest thanks for the comments and advices, and hope that we can learn more about the disease to bring more effective treatment for the patients in the near future, by our efforts together.

Efficacy of growth hormone therapy in Kearns-Sayre syndrome: the KIGS experience.

Kearns-Sayre syndrome (KSS) is characterized by external ophthalmoplegia, retinal pigmentation and cardiac conduction defects due to mitochondrial DNA (mtDNA) deletions. Short stature and growth hormone (GH) deficiency have been reported in KSS, but data on GH treatment is limited. We describe the clinical presentation, phenotype evolution, and response to GH in a patient with KSS and report data on eight additional KSS patients from the KIGS database. Our patient with KSS and GH deficiency achieved a final adult height at -0.8 SDS. In the KIGS database GH treatment resulted in mean improvement in height from -3.9 to -2.9 SDS in patients with KSS. Two patients did not show growth improvement. Our data shows improvement in height SDS in our patient and mixed results in eight additional patients from the KIGS database after treatment with GH. Heterogeneity in responsiveness may relate to presence of GH deficiency or severity of underlying mitochondrial dysfunction.

Follow-up of folinic acid supplementation for patients with cerebral folate deficiency and Kearns-Sayre syndrome.

BackgroundKearns-Sayre syndrome (KSS) is a mitochondrial DNA deletion syndrome that presents with profound cerebral folate deficiency and other features. Preliminary data support the notion that folinic acid therapy might be useful in the treatment of KSS patients. Our aim was to assess the clinical and neuroimaging outcomes of KSS patients receiving folinic acid therapy.MethodsPatients: We recruited eight patients with diagnoses of KSS. Four cases were treated at 12 de Octubre Hospital, and the other two cases were treated at Sant Joan de Déu Hospital. Two patients refused to participate in the treatment protocol.Methods: Clinical, biochemical and neuroimaging data (magnetic resonance imaging or computed tomography scan) were collected in baseline conditions and at different time points after the initiation of therapy. Cerebrospinal fluid 5-methyltetrahydrofolate levels were analysed with HPLC and fluorescence detection. Large-scale mitochondrial DNA deletions were analysed by Southern blot.Treatment protocol: The follow-up periods ranged from one to eight years. Cases 1–4 received oral folinic acid at a dose of 1 mg/kg/day, and cases 6 and 8 received 3 mg/kg/day.ResultsNo adverse effects of folinic acid treatment were observed. Cerebral 5-methyltetrahydrofolate deficiencies were observed in all cases in the baseline conditions. Moreover, all three patients who accepted lumbar puncture after folinic acid therapy exhibited complete recoveries of their decreased basal cerebrospinal fluid 5-methyltetrahydrofolate levels to normal values. Two cases neurologically improved after folinic therapy. Disease worsened in the other patients.Post-treatment neuroimaging was performed for the 6 cases that received folinic acid therapy. One patient exhibited improvements in white matter abnormalities. The remaining patients displayed progressions in subcortical cerebral white matter, the cerebellum and cerebral atrophy.ConclusionsFour patients exhibited clinical and radiological progression of the disease following folinic acid treatment. Only one patient who was treated in an early stage of the disease exhibited both neurological and radiological improvements following elevated doses of folinic acid, and an additional patient experienced neurological improvement. Early treatment with high-dose folinic acid therapy seems to be advisable for the treatment of KSS.Trial registrationEudracT2007-00-6748-23Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-014-0217-2) contains supplementary material, which is available to authorized users.

Clinical Features of Cardiac Involvement in Patients with Mitochondorial Disease

PurposeMitochondrial diseases frequently involve several organs and present with a wide range of clinical expression. The aim of this study was to evaluate the cardiac involvement in patients with mitochondorial disease.Methods and ResultsWe retrospectively reviewed mitochondrial disease patients at Kochi Medical School Hospital.We have seen eight patients (four male patients) with mitochondorial disease. The diagnosis of mitochondorial disease was based on genetic analysis, family surveys, or tissue confirmation. Age at diagnosis was 42.9±17.2 years. Mean height was 149.8±6.5 cm and weight was 41.1±7.8 kg. Clinical subtypes were MELAS (that is Mitochondrial myopathy, Encephalopathy, Lactic Acidosis, Stroke-like episodes) in four, Kearns-Sayre syndrome (KSS) in one and unclassified in three patients. Various electrocardiographic findings were seen: ST changes in three, T wave inversion in three, high voltage in two, and complete right bundle branch block in one patient. A patient with KSS had permanent pacemaker implantation due to complete atrioventricular block. Echocardiography revealed that five patients (four of them were MELAS) had left ventricular hypertrophy and three patients including a KSS patient showed left ventricular systolic dysfunction like a dilated cardiomyopathy.ConclusionsMitochondrial diseases have great diversity in cardiac presentation. PurposeMitochondrial diseases frequently involve several organs and present with a wide range of clinical expression. The aim of this study was to evaluate the cardiac involvement in patients with mitochondorial disease. Mitochondrial diseases frequently involve several organs and present with a wide range of clinical expression. The aim of this study was to evaluate the cardiac involvement in patients with mitochondorial disease. Methods and ResultsWe retrospectively reviewed mitochondrial disease patients at Kochi Medical School Hospital.We have seen eight patients (four male patients) with mitochondorial disease. The diagnosis of mitochondorial disease was based on genetic analysis, family surveys, or tissue confirmation. Age at diagnosis was 42.9±17.2 years. Mean height was 149.8±6.5 cm and weight was 41.1±7.8 kg. Clinical subtypes were MELAS (that is Mitochondrial myopathy, Encephalopathy, Lactic Acidosis, Stroke-like episodes) in four, Kearns-Sayre syndrome (KSS) in one and unclassified in three patients. Various electrocardiographic findings were seen: ST changes in three, T wave inversion in three, high voltage in two, and complete right bundle branch block in one patient. A patient with KSS had permanent pacemaker implantation due to complete atrioventricular block. Echocardiography revealed that five patients (four of them were MELAS) had left ventricular hypertrophy and three patients including a KSS patient showed left ventricular systolic dysfunction like a dilated cardiomyopathy. We retrospectively reviewed mitochondrial disease patients at Kochi Medical School Hospital. We have seen eight patients (four male patients) with mitochondorial disease. The diagnosis of mitochondorial disease was based on genetic analysis, family surveys, or tissue confirmation. Age at diagnosis was 42.9±17.2 years. Mean height was 149.8±6.5 cm and weight was 41.1±7.8 kg. Clinical subtypes were MELAS (that is Mitochondrial myopathy, Encephalopathy, Lactic Acidosis, Stroke-like episodes) in four, Kearns-Sayre syndrome (KSS) in one and unclassified in three patients. Various electrocardiographic findings were seen: ST changes in three, T wave inversion in three, high voltage in two, and complete right bundle branch block in one patient. A patient with KSS had permanent pacemaker implantation due to complete atrioventricular block. Echocardiography revealed that five patients (four of them were MELAS) had left ventricular hypertrophy and three patients including a KSS patient showed left ventricular systolic dysfunction like a dilated cardiomyopathy. ConclusionsMitochondrial diseases have great diversity in cardiac presentation. Mitochondrial diseases have great diversity in cardiac presentation.

Mitochondrial DNA deletions inhibit proteasomal activity and stimulate an autophagic transcript

Deletions within the mitochondrial DNA (mtDNA) cause Kearns Sayre syndrome (KSS) and chronic progressive external opthalmoplegia (CPEO). The clinical signs of KSS include muscle weakness, heart block, pigmentary retinopathy, ataxia, deafness, short stature, and dementia. The identical deletions occur and rise exponentially as humans age, particularly in substantia nigra. Deletions at >30% concentration cause deficits in basic bioenergetic parameters, including membrane potential and ATP synthesis, but it is poorly understood how these alterations cause the pathologies observed in patients. To better understand the consequences of mtDNA deletions, we microarrayed six cell types containing mtDNA deletions from KSS and CPEO patients. There was a prominent inhibition of transcripts encoding ubiquitin-mediated proteasome activity, and a prominent induction of transcripts involved in the AMP kinase pathway, macroautophagy, and amino acid degradation. In mutant cells, we confirmed a decrease in proteasome biochemical activity, significantly lower concentration of several amino acids, and induction of an autophagic transcript. An interpretation consistent with the data is that mtDNA deletions increase protein damage, inhibit the ubiquitin-proteasome system, decrease amino acid salvage, and activate autophagy. This provides a novel pathophysiological mechanism for these diseases, and suggests potential therapeutic strategies.

Sensorineural hearing loss in patients with chronic progressive external ophthalmoplegia or Kearns–Sayre syndrome

In the present study we assessed the prevalence and nature of hearing loss in patients with chronic progressive external ophthalmoplegia (CPEO) or Kearns-Sayre syndrome (KSS) due to single large-scale mitochondrial DNA (mtDNA) deletion or mtDNA tRNA (Leu (UUR)) A3243G point mutation (A3243G PM). 14 patients with mtDNA deletion and three patients with A3243G PM underwent audiological evaluation comprising pure-tone and speech audiometry as well as transient evoked otoacoustic emissions (OAE). Audiological evaluation revealed hearing impairment in 10/17 patients. Hearing loss was mild to moderate predominantly affecting high frequencies in five patients with subjective hearing problems (three patients with mtDNA deletions, two patients with A3243G PM). Subclinical hearing deficits restricted to high frequencies were seen in further five asymptomatic patients (four patients with mtDNA deletions, one patients with A3243G PM). Audiological findings suggested a cochlear origin of hearing loss in all subjects. Our results demonstrate that CPEO or KSS patients due to mtDNA deletion or A3243G PM are at high risk of developing sensorineural hearing deficits.

Anesthetic management for cardioverter-defibrillator implantation in a patient with Kearns-Sayre syndrome

Kearns-Sayre syndrome (KSS) is a rare mitochondrial myopathy and often involves cardiac conduction abnormality and muscle weakness. We report a patient with KSS who had an implantable cardioverter-defibrillator (ICD) implanted during general anesthesia with propofol and nitrous oxide (N 2O). These anesthetics did not show any effects on respiration, cardiac conduction, or neuromuscular transmission in this case. The surgery was performed successfully, and the postoperative period was uneventful. The authors recommend that propofol and N 2O are suitable general anesthetics for ICD implantation in KSS patients.

Deletions of mitochondrial DNA in Kearns-Sayre syndrome. 1988.

We have identified large-scale deletions in muscle mitochondrial DNA (mtDNA) in seven of seven patients with Kearns-Sayre syndrome (KSS). We found no detectable deletions in the mtDNA of ten non-KSS patients with other mitochondrial myopathies or encephalomyopathies, or three normal controls. The deletions ranged in size from 2.0 to 7.0 kb, and did not localize to any single region of the mitochondrial genome. The proportion of mutated genomes in each KSS patient ranged from 45% to 75% of total mtDNA. There was no correlation between the size or site of the deletion, biochemical abnormality of mitochondrial enzymes, or clinical severity. The data bolster arguments that KSS is a unique disorder and genetic in origin.

Treatment with Cytochrome c and Evaluation of Insulin Secretion in a Patient with Kearns-Sayre Syndrome

A 23-year-old male with Kearns-Sayre syndrome (KSS) and diabetes mellitus (DM) was treated with cytochrome c (Cardiocrome®). We evaluated the insulin secretion by glucagon loading test, as well as changes in DM control after the treatment. When the patient was diagnosed with DM, he had already presented with very low insulin secretion which further deteriorated with time. Symptoms found in KSS patients such as muscle weakness and sensory defects make control of DM more difficult. Cardiocrome did not ameliorate the insulin secretion, probably because almost all the β cells had already been irreversibly damaged. It was the improvement in the patient’s activity in daily life that was responsible for the decreased incidence of extreme hypo- or hyperglycemic episodes. Cardiocrome treatment for KSS may be useful in controlling DM at least through the improvement of the general life condition. For the direct effect on β cells, further investigation with more patients is necessary.

Quantitative analysis of mitochondrial DNA deletion in paraffin embedded muscle tissues from patients with KSS and CPEO

The percentage of common deletion of mitochondrial DNA (mtDNA) was determined quantitatively by a PCR-based, non-radioactive method in DNA extracted from formalin-fixed, paraffin-embedded skeletal muscle tissues from two patients with Kearns Sayre syndrome (KSS) and one with chronic progressive external ophthalmoplegia (CPEO). The method involved PCR cycle titration of wild-type and deleted mtDNA in parallel, staining of gel bands with the sensitive fluorescence dye SYBR Green I, and quantitation of intensity on a computer screen by the NIH image program. We determined 75% and 71% common deletion of mtDNA in the KSS patients and 35% in the CPEO patient.

Oxidative damage to skeletal muscle DNA from patients with mitochondrial encephalomyopathies

To estimate the oxidative damage to skeletal muscle DNA in mitochondrial encephalomyopathies, we studied the amount of 8-hydroxy-deoxyguanosine (8-OH-dG) and the localization of superoxide dismutase (SOD) in the skeletal muscles of patients with progressive external ophthalmoplegia (PEO) or Kearns-Sayre syndrome (KSS). The molar ratio of 8-OH-dG/deoxyguanosine in skeletal muscle from PEO or KSS patients was significantly higher than the control value. The ratio from patients with polymyositis or Duchenne's muscular dystrophy was not significantly elevated. Immunohistochemical staining for both Mn-SOD and Cu,Zn-SOD showed pronounced staining in the subsarcolemmal and intermyofibrillar regions of cytochrome-oxidase-negative ragged red fibers of KSS or PEO muscles. Our findings suggest that overproduction of 8-OH-dG and mitochondrial dysfunction with gene deletions are associated with each other in muscle cells of patients with PEO or KSS, and that free radicals may play an important role in the pathophysiology of mitochondrial encephalomyopathies.

ミトコンドリア脳筋症例に対する人工内耳

Kearns-Sayre syndrome (KSS) is one of a mitochondrial disease characterized by progressive eye disorders, such as pigmentary retinopathy, and complete heart blockage. A recent study revealed that the etiology of this syndrome involves sporadic large scale rearrangements of mitochondrial DNA. Other neurologic symptoms are frequently associated with this syndrome, and hearing loss is the other main symptom. At the age of 37 years, this female patient began to suffer progressive hearing loss, and eventually became completely deaf. MRI imaging showed diffuse, abnormally high signals in the brain white matter, in T2-weighted images. Further neurological examination revealed eye abnormalities, and a genetic analysis confirmed a diagnosis of KSS. In this case, no sensory agnosia or other focal signs of disorder in the brain cortex were found, and the electrophysical criteria for cochlear implant were fulfilled. Cochlear implantation was performed on May 19, 1995. Post-operatively, the patient underwent vowel and consonant recognition tests. The patients scored well with an accuracy of 75% for vowels and 36% for consonants. The accuracy of vowel and consonant recognition with lip reading was elevated to 100% and 72%, respectively. Sound recognition in this patient seemed to be quite high compared to that reported in other implanted patients. The excellent results obtained in this KSS patient suggest pure neural deafness, and raise the possibility of cochlear involvement in this condition.

Heredity of mitochondrial ocular myopathy and Kearns Sayre syndrome

Mitochondrial ocular myopathy (OM) has an infantile onset variant with widespread disease, known as Kearns Sayre syndrome (KSS). Evidence for transmission of the disease from one generation to the other has been denied, especially for KSS. There is however plenty evidence for this transmission from the literature, even for KSS. KSS patients have however a low fertility, so transmission of a KSS picture from parent to child has only scarcely been reported.A mitochondrial inheritance has been claimed but proved to be very unlikely, because of absence of predominant maternal inheritance. Recently, deletions in mitochondrial DNA have been described exclusively in mitochondrial OM and especially KSS patients. In KSS the deletions were apparent in all affected tissues. There is up to now no conclusive evidence that the deletions are pathogenetically linked to OM and KSS, because of the absence of correlation between size and site of the deletions and the mitochondrial enzymatic deficiency or clinical severity. ...