Pediatric single large-scale mtDNA deletion syndromes: The power of patient reported outcomes.

There is a limited understanding of system-level clinical outcomes and interventions associated with single large-scale mitochondrial DNA deletion syndromes (SLSMDS). Additionally, no research exists that describes patient reported outcomes (PROs) of children with SLSMDS. A global and observational registry was established to understand the multi-systemic course of SLSMDS and track clinical outcomes. The development and design of the registry is described. Demographic characteristics, history and diagnoses, and system level prevalence of problems and interventions are reported for 42 children. System level problems and interventions include information on the following body systems: audiology, cardiac, endocrine, gastrointestinal (including pancreatic and hepatobiliary system), hematological, metabolic, neurological (including autonomic, mobility, & learning), ophthalmic, psychiatric, renal, and respiratory. Results emphasize the need of patient registries and suggest that the diagnostic odyssey and burden of disease for children with SLSMDS is significant. System-level findings may help families and clinical providers with diagnosis, prognostication, and treatment. A multidisciplinary team of clinical experts with a central coordinating specialist for children with SLSMDS is recommended.

Kearns Sayre syndrome: a rare etiology of complete atrioventricular block in children (case report).

Kearns Sayre syndrome is a rare mitochondrial abnormality first described in 1958, characterized by a triad associating progressive external ophthalmoplegia, ptosis, and pigmentary retinopathy with progressive alteration of cardiac conduction, which determines the vital prognosis of this entity. Here we report the case of a 13-year-old child of consanguineous parents who consults for recurrent syncope. The clinical exam found bilateral ptosis with complete atrioventricular block on electrocardiogram. The ophthalmological exam found pigmentary retinopathy. The patient underwent successful implantation of a double chamber pacemaker within 24 hours of admission, with an uneventful postoperative course. This case report highlights the interest of systematically assessing cardiac complications in children with mitochondrial disease such as Kearns Sayre syndrome, especially since cardiac involvement is the major prognostic factor in this disease.

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.

Anti-replicative recombinant 5S rRNA molecules can modulate the mtDNA heteroplasmy in a glucose-dependent manner.

Mutations in mitochondrial DNA are an important source of severe and incurable human diseases. The vast majority of these mutations are heteroplasmic, meaning that mutant and wild-type genomes are present simultaneously in the same cell. Only a very high proportion of mutant mitochondrial DNA (heteroplasmy level) leads to pathological consequences. We previously demonstrated that mitochondrial targeting of small RNAs designed to anneal with mutant mtDNA can decrease the heteroplasmy level by specific inhibition of mutant mtDNA replication, thus representing a potential therapy. We have also shown that 5S ribosomal RNA, partially imported into human mitochondria, can be used as a vector to deliver anti-replicative oligoribonucleotides into human mitochondria. So far, the efficiency of cellular expression of recombinant 5S rRNA molecules bearing therapeutic insertions remained very low. In the present study, we designed new versions of anti-replicative recombinant 5S rRNA targeting a large deletion in mitochondrial DNA which causes the KSS syndrome, analyzed their specific annealing to KSS mitochondrial DNA and demonstrated their import into mitochondria of cultured human cells. To obtain an increased level of the recombinant 5S rRNA stable expression, we created transmitochondrial cybrid cell line bearing a site for Flp-recombinase and used this system for the recombinase-mediated integration of genes coding for the anti-replicative recombinant 5S rRNAs into nuclear genome. We demonstrated that stable expression of anti-replicative 5S rRNA versions in human transmitochondrial cybrid cells can induce a shift in heteroplasmy level of KSS mutation in mtDNA. This shift was directly dependent on the level of the recombinant 5S rRNA expression and the sequence of the anti-replicative insertion. Quantification of mtDNA copy number in transfected cells revealed the absence of a non-specific effect on wild type mtDNA replication, indicating that the decreased proportion between mutant and wild type mtDNA molecules is not a consequence of a random repopulation of depleted pool of mtDNA genomes. The heteroplasmy change could be also modulated by cell growth conditions, namely increased by cells culturing in a carbohydrate-free medium, thus forcing them to use oxidative phosphorylation and providing a selective advantage for cells with improved respiration capacities. We discuss the advantages and limitations of this approach and propose further development of the anti-replicative strategy based on the RNA import into human mitochondria.

Heart Block, Ptosis, and Diagnostic Funduscopic Examination: Problems of the Heart Seen Through the Eyes.

Mitochondrial diseases are complex and rare clinical entities that can sometimes be diagnosed by their constellation of simple clinical signs. We describe a 24-year-old insulin-dependent diabetic women who was diagnosed with complete heart block and required permanent pacemaker implantation. Astute physical examination revealed opthalmoparesis, ptosis, and pigmentary retinopathy consistent with a diagnosis of Kearns-Sayre syndrome. When a young patient presents with complete heart block, a neurologic examination including funduscopy can identify Kearns-Sayre syndrome, which has far-reaching consequence for the index patient and offspring.

[MELAS: Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-Like Episodes].

Mitochondrial disease is caused by a deficiency in the energy supply to cells due to mitochondrial dysfunction. Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) is a mitochondrial disease that presents with stroke-like episodes such as acute onset of neurological deficits and characteristic imaging findings. Stroke-like episodes in MELAS have the following features: 1) neurological deficits due to localization of lesions in the brain, 2) episodes often accompany epilepsy, 3) lesions do not follow the vascular supply area, 4) lesions are more often seen in the posterior brain than in the anterior brain, 5) lesions spread to an adjacent area in the brain, and 6) neurological symptoms often disappear together with imaging findings, but later relapse. About 80% of patients with MELAS have an A-to-G transition mutation at the nucleotide pair 3243 in the dihydrouridine loop of mitochondrial tRNALeu(UUR), which causes the absence of posttranscriptional taurine modification at the wobble nucleotide of mitochondrial tRNALeu(UUR) and disrupts protein synthesis. However, the precise pathophysiology of stroke-like episodes is under investigation, with possible hypotheses for these episodes including mitochondrial angiopathy, mitochondrial cytopathy, and neuron-astrocyte uncoupling. With regard to treatment, L-arginine and taurine have recently been suggested for relief of clinical symptoms.

Dilated cardiomyopathy with cardiogenic shock in a child with Kearns-Sayre syndrome.

Kearns-Sayre syndrome (KSS) is a mitochondrial myopathy resulting from mitochondrial DNA deletion. This syndrome primarily involves the central nervous system, eyes, skeletal muscles and the heart. The most well-known cardiac complications involve the conduction system; however, there have been case reports describing cardiomyopathy. We describe a case of a child with KSS who presented with decompensated cardiac failure from dilated cardiomyopathy representing cardiomyocyte involvement of KSS. Our patient had a rapidly progressing course, despite maximal medical management, requiring emergent institution of extracorporeal membrane oxygenation and transition to a ventricular assist device. To the best of our knowledge, this is the youngest patient in the literature to have dilated cardiomyopathy in KSS.

Genetic and biochemical intricacy shapes mitochondrial cytopathies.

The major progress made in the identification of the molecular bases of mitochondrial disease has revealed the huge diversity of their origin. Today up to 300 mutations were identified in the mitochondrial genome and about 200 nuclear genes are possibly mutated. In this review, we highlight a number of features specific to mitochondria which possibly participate in the complexity of these diseases. These features include both the complexity of mitochondrial genetics and the multiplicity of the roles ensured by the organelles in numerous aspects of cell life and death. This spectacular complexity presumably accounts for the present lack of an efficient therapy in the vast majority of cases.

Systematic review of cardiac electrical disease in Kearns-Sayre syndrome and mitochondrial cytopathy.

Kearns-Sayre syndrome (KSS) is a mitochondrial disorder characterised by onset before the age of 20years, progressive external ophthalmoplegia, and pigmentary retinopathy, accompanied by either cardiac conduction defects, elevated cerebrospinal fluid protein or cerebellar ataxia. 50% of patients with KSS develop cardiac complications. The most common cardiac manifestation is conduction disease which may progress to complete atrioventricular block or bradycardia-related polymorphic ventricular tachycardia (PMVT). The management of cardiac electrical disease associated with KSS and mitochondrial cytopathy is systematically reviewed including the case of a 23year-old female patient with KSS who developed a constellation of cardiac arrhythmias including rapidly progressive conduction system disease and monomorphic ventricular tachycardia with myocardial scarring. The emerging role of cardiac magnetic resonance imaging (CMR) in detecting subclinical cardiac involvement is also highlighted. This review illustrates the need for cardiologists to be informed about this rare but emerging condition.

Selected case from the Arkadi M. Rywlin International Pathology Slide Series: Mitochondrial myopathy presenting with chronic progressive external ophthalmoplegia (CPEO): a case report.

A 43-year-old female patient diagnosed with chronic progressive external ophthalmoplegia (CPEO) because of mitochondrial myopathy documented by muscle biopsy is presented. The chief complaints were represented by blepharoptosis and ophthalmoplegia. The muscle biopsy was evaluated by histology, using the appropriate histochemical and histoenzimological stains. Ragged red fibers with Gomori trichrome stain were seen, which showed cytochrome c oxydase deficiency and abnormal succinate dehydrogenase staining in around 20% of muscle fibres. Electron microscopy was also performed which demonstrated abnormal, hyperplastic, pleomorphic, and hypertrophic mitochondria, characterized by paracrystalline inclusions arranged in parallel rows ("parking-lot" inclusions), consisting of rectangular arrays of mitochondrial membranes in a linear or grid-like pattern. In conclusion, mitochondrial myopathy was definitely diagnosed. Although molecular analysis, which was subsequently carried out, failed to reveal mutations in the mitochondrial DNA or in selected nuclear genes, the pathologic diagnosis was not changed. The differential diagnosis of CPEO with other forms of ocular myopathies as well as the possible association of CPEO with systemic syndromes is discussed. Ophtalmologists and medical internists should always suspect CPEO when dealing with patients affected by ocular myopathy, either in its pure form or in association with other myopathic or systemic signs.

Exercise as a therapeutic strategy for primary mitochondrial cytopathies.

Patients with mitochondrial cytopathies often experience exercise intolerance and may have fixed muscle weakness, leading to impaired functional capacity and lower quality of life. Endurance exercise training increases Vo 2 max, respiratory chain enzyme activity, and improves quality of life. Resistance exercise training increases muscle strength and may lower mutational burden in patients with mitochondrial DNA deletions. Both modes of exercise appear to be well tolerated. Patients with mitochondrial cytopathy should consider alternating both types of exercise to derive the benefits from each (endurance = greater aerobic fitness; resistance = greater strength). Patients should start an exercise program at a low intensity and duration, gradually increasing duration and intensity. They should "listen to their body" and not exercise on days they have fever, superimposed illness, muscle pain, or cramps, and/or if they have fasted for more than 12 hours. Children often respond best to play-based exercise and tend to enjoy intermittent activity.

Mitochondrial cytopathies and cardiovascular disease.

The global epidemic of cardiovascular disease remains the leading cause of death in the USA and across the world. Functional and structural integrity of mitochondria are essential for the physiological function of the cardiovascular system. The metabolic adaptation observed in normal heart is lost in the failing myocardium, which becomes progressively energy depleted leading to impaired myocardial contraction and relaxation. Uncoupling of electron transfer from ATP synthesis leads to excess generation of reactive species, leading to widespread cellular injury and cardiovascular disease. Accumulation of mitochondrial DNA mutation has been linked to ischaemic heart disease, cardiomyopathy and atherosclerotic vascular disease. Mitochondria are known to regulate apoptotic and autophagic pathways that have been shown to play an important role in the development of cardiomyopathy and atherosclerosis. A number of pharmacological and non-pharmacological treatment options have been explored in the management of mitochondrial diseases with variable success.

Multiple endocrinopathies (growth hormone deficiency, autoimmune hypothyroidism and diabetes mellitus) in Kearns-Sayre syndrome.

Kearns-Sayre syndrome is characterized by onset before 20 years, chronic progressive external opthalmoplegia, pigmentary retinal degeneration, and ataxia (and/or hearth block, and/or high protein content in the cerebrospinal fluid) in the presence of mtDNA rearrangements. Multiple endocrine dysfunction associated with this syndrome was rarely reported. In this paper, the Authors report on a female patient with Kearns-Sayre syndrome with large heteroplasmic mtDNA deletion, absence of cytochrome c oxidase in many muscle fibers, partial GH deficiency, hypothyroidism and subsequently insulin dependent diabetes mellitus (IDDM). Anti-thyroid peroxidase and antithyreoglobulin antibodies were present in high titer in serum while anti-islet cell antibodies were absent. The patient developed thyroiditis with Hashimoto encephalopathy. The presence of GH deficiency, autoimmune thyroiditis with hypothyroidism and IDDM distinguishes this case from others and confirms the association of Kearns-Sayre syndrome with multiple endocrine dysfunction. Hashimoto encephalopathy and anti-thyroideal antibodies suggest that in this patient, predisposed by a genetic factor (a mitochondrial deletion) anti-thyroideal antibodies may have contributed to the hypothyroidism and, by interfering with cerebral mitochondrial function, may have caused the encephalopathy. GH deficiency and IDDM can be attributed to oxidative phosphorylation deficiency but the autoimmunity may also have played a role in the production of glandular insufficiencies. It seems important to search for endocrine autoimmunity in every case of KSS.

[Diagnosis and therapy of mitochondrial diseases]. / Mitochondrialis betegségek diagnosztikája es terápiája.

Mitochondrial diseases are a significant part of neuromuscular diseases. Majority of them is multisystemic disorder. The diagnosis can be established in more and more cases. Beyond the routine neurological examination imaging methods (MRI and MR-spectroscopy) and electrophysiology (EMG, ENG, EEG, evoked potential tests) might be helpful in setting the diagnosis. Raised blood lactate level supports the diagnosis. Muscle biopsy demonstrates mitochondrial abnormalities in the majority of cases. The positivity of genetic tests is low, because the amount of mitochondrial DNA alterations is different in tissues. Therefore other tissue than blood (mainly muscle) is necessary for genetic tests. The other reason is that the respiratory chain is under double -mitochondrial and nuclear - genetic control, and testing the nuclear genes are available only in selected laboratories. The treatment is limited, mainly symptomatic.

[Kearns-Sayre syndrome: a case report]. / Le syndrome de Kearns-Sayre: à propos d'un cas.

Kearns-Sayre syndrome (KSS), first described in 1958, is a multisystem disease defined by a characteristic triad of progressive external ophthalmoplegia, pigmentary retinopathy and atrioventricular block. These signs are frequently associated with increased cerebrospinal fluid protein level and cerebellar ataxia. This syndrome is caused by deletions in mitochondrial DNA, the age of onset is generally below 20, and the degree of severity differs between patients, as well as the prognosis, which may be fatal. The ocular manifestations include: bilateral ptosis, progressive external ophthalmoplegia and atypical pigmentary retinopathy. By way of this case report, the authors discuss the epidemiologic, clinical and therapeutic aspects of KSS, including the difficulty in managing ptosis in these cases.

Kearns Sayre Syndrome--case report with review of literature.

Kearns-Sayre Syndrome is form of rare mitochondrial cytopathy, first described by Thomas P. Kearns and George Pomeroy Sayre in 1958 and is characterized by progressive external opthalmoplegia, cardiac conduction block, pigmentary retinal degeneration, variable number of red ragged fibers on muscle biopsy. It presents before the child reaches the age of twenty. Kearns-Sayre syndrome may affect many organ systems and additional features may include myopathy, dystonia, bulbar symptoms in the form of dysarthria and nasal regurgitation and bilateral facial weakness. Endocrine abnormalities (e.g., diabetes, growth retardation/short stature, and hypoparathyroidism), bilateral sensorineural deafness, dementia, cataracts, and proximal renal tubular acidosis, skeletal muscle weakness (proximal more than distal) and exercise intolerance are additional features. Kearns Sayre Syndrome occurs as a result of large-scale single deletions (or rearrangements) of mitochondrial DNA (mtDNA), which is usually not inherited but occurs spontaneously, probably at the germ-cell level or very early in embryonic development. No disease-modifying therapy is available for Kearns-Sayre syndrome (KSS). Management is supportive vigilance for detection of associated problems. In the future, potential treatment in patients with Kearns-Sayre syndrome may attempt to inhibit mutant mtDNA replication or encourage replication of wild-type mtDNA.

RNA-mediated restoration of mitochondrial function in cells harboring a Kearns Sayre Syndrome mutation.

Mutations in mitochondrial DNA (mtDNA) generate multi-system disorders due to failure of ATP production. A cybrid containing a 1.9-kb mtDNA deletion from a patient with Kearns Sayre Syndrome is respiration-defective and grows glycolytically. When treated with a ribonucleoprotein (RNP) complex of polycistronic RNA 1 (pcRNA1) containing mtDNA-encoded genes and a multi-subunit carrier complex R8, full-length pcRNA1 was transported to mitochondria. Translation of the pcRNA1-encoded mRNAs was observed in mitochondria from RNP-treated cells. Respiration of the cybrid was rescued to approximately 90% of normal within hours, switching the cells to aerobic growth. These findings have implications for the development of effective mitochondrial gene therapy.

[Kearns-Sayre syndrome : a mitochondrial disease (OMIM #530000)]. / Kearns-Sayre-Syndrom : Eine mitochondriale Erkrankung (OMIM #530000).

Kearns-Sayre syndrome is a rare mitochondrial disease which usually occurs sporadically with the presence of ptosis and the clinical triad of chronic progressive external ophthalmoplegia, atypical retinitis pigmentosa and cardiac conduction disorders. We show on the example of a young patient with unexplained atypical acquired ptosis and eye movement disorders, the correct interpretation of the diagnostic findings. Of importance is the early detection of potentially life-threatening complications which can lead to sudden cardiac death.

Kearns-Sayre syndrome presenting as somatomedin C deficiency and complete heart block.

Kearns-Sayre syndrome (KSS) is a rare mitochondrial disease in which neuromuscular structures, endocrine glands, and cardiac conduction systems are most commonly involved. An 11-year-old boy was admitted with blurred consciousness, respiratory instability, and bradycardia of two-hour onset. He was immediately intubated. His medical history included growth retardation and myopic refractive defect for six years, therapy for somatomedin C deficiency for 15 months, and bilateral ptosis for three months. On physical examination, he was unconscious, had a peak heart rate of 40/min, blood pressure of 60/20 mmHg, and a weak pulse. Laboratory findings showed elevated blood lactate and blood pyruvate levels and an increased lactate/pyruvate ratio. The electrocardiogram showed complete atrioventricular block and echocardiography showed mitral valve prolapse. Following implantation of a temporary transvenous cardiac pacemaker, his heart rate and clinical condition improved. Further analysis with cranial magnetic resonance (MR) imaging demonstrated hyperintense signal changes in the subcortical white matter of the two cerebral hemispheres, bilateral thalamus, putamen, cerebral peduncles, dorsal medulla, and midbrain. The typical clinical and MR findings confirmed the initial diagnosis of KSS. A permanent cardiac pacemaker was implanted into the right ventricle.

Progression of conduction system disease in a paced patient with Kearns-Sayre syndrome.

The Kearns-Sayre syndrome is a rare condition characterized by external ophthalmoplegia, retinal pigmentary degeneration and progressive impairment of cardiac conduction. We report a patient with the permanent pacemaker. The spontaneous cardiac impulse formation disappeared during long-term follow-up in this patient with Kearns-Sayre Syndrome.