Mitochondrial DNA deletion in oculoskeletal myopathy

The case of a patient showing bilateral ophthalmoplegia with proximal limb weakness, severe dysphagia and short stature, without family history, is described. The diagnosis of Kearns-Sayre syndrome was excluded because of the absence of pigmentary retinopathy and of all other common manifestations except short stature. The analysis of mitochondrial DNA of the patient's muscle revealed a deleted form accounting for 65% of the total mitochondrial DNA. The deletion, undetectable in the mitochondrial DNA of peripheral blood leukocytes, was apparently indistinguishable from that already described by others in a far more severe form of classic Kearns-Sayre syndrome.     

Unusual presentation of Kearns-Sayre syndrome in early childhood

Congenital glaucoma and insulin-dependent diabetes mellitus were the predominant presenting signs in a patient with Kearns-Sayre syndrome. Thereafter, he developed short stature, pigmentary retinopathy, progressive external ophthalmoplegia, and ataxia. The diagnosis was confirmed by detecting a deletion of mitochondrial DNA in muscle, thus demonstrating that Kearns-Sayre syndrome can have the unusual presenting signs described above.     

Muscle mitochondrial DNA in encephalomyopathy and ragged red fibres: a Southern blot analysis and literature review

Summary Various mitochondrial DNA abnormalities have been described in patients with encephalomyopathies. We performed Southern blot analysis of skeletal muscle mitochondrial DNA in nine adult patients with clinical features and ragged red fibres suggesting mitochondrial dysfunction. Two patients with encephalomyopathy and two with the MERRF syndrome (myoclonus epilepsy with ragged red fibres) had the normal PvuII restriction pattern of muscle mitchondrial DNA. In contrast, mitochondrial DNA deletion was observed in two of six patients with ophthalmoplegia. One suffered from typical Kearns-Sayre syndrome and the other from isolated external ophthalmoplegia. None of these patients had affected relatives. The detection of mitochondrial DNA deletion in external ophthalmoplegia and their site and size support previously reported data.     

Mitochondrial DNA deletion in a child with megaloblastic anemia and recurrent encephalopathy

A 3 1/2-year-old boy presented with megaloblastic anemia and recurrent episodes of severe lactic acidosis and coma. At age 4 years, he developed sepsis and died; postmortem examination failed to show any gross abnormality in any tissue. Biochemical analysis of muscle showed decreased activities for all respiratory chain enzymes except complex II. Muscle histochemistry revealed diffuse cytochrome c oxidase deficiency. Southern blot analysis of mitochondrial DNA from muscle, liver, and blood showed a heteroplasmic single mitochindrial DNA deletion of 2.4 kb, which removed the genes for cytochrome c oxidase I and II and the transfer ribonucleic acid genes for serine and aspartic acid. Single large-scale deletions in mitochondrial DNA have been associated with Pearson's syndrome, Kearns-Sayre syndrome, and progressive external ophthalmoplegia. This patient's presentation is unusual and suggests an overlap between Pearson's syndrome and Kearns-Sayre syndrome.     

MELAS- and kearns-sayre-type with myopathy and autoimmune polyendocrinopahy

A 35-year-old woman with features of Kearns-Sayre syndrome consisting of progressive ptosis, ophthalmoparesis, mitochondrial myopathy, and pigmentary retinopathy also had autoimmune polyglandular syndrome type I1 (Addison's disease, autoimmune insulin-dependent diabetes meuitus, Hashimoto's thyroiditis, and primary ovarian failure). There was no history of similarly affected relatives. Analysis of muscle mitochondrial DNA (mtDNA) revealed a 2,532-bp deletion of the type seen in Kearns-Sayre syndrome as well as a heteroplasmic A3243G mutation in the tRNA-Leu(UUR) gene of the type seen in mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS). The patient's blood and her mother's blood harbored the A3243G mutation but not the deletion, and the maternal grandmother's blood had neither mutation. In muscle, the species of mtDNA harboring the deletion was exclusively associated with the species harboring the A3243G mutation, suggesting that the point mutation predisposed to the large-scale deletion. The mtDNA species with both mutations accounted for 88% of total muscle mtDNA. Other and as yet unrecognized point mutations in mtDNA might also be associated with, and possible causally related to, largescale mtDNA deletions.     

Kearns-Sayre syndrome presenting as renal tubular acidosis

Renal tubular acidosis and tetany were the 1st manifestations of Kearns-Sayre syndrome in a 5-year-old child. Subsequently, he developed progressive external ophthalmoplegia, ptosis, retinopathy, heart block, and endocrinopathy. There was a 7.5-kb deletion of mitochondrial DNA documented in muscle, kidney, skin fibroblasts, and leukocytes, providing evidence for a multisystem mitochondrial cytopathy.     

Deterioration of Kearns-Sayre syndrome following articaine administration for local anesthesia

Worsening of the neuromuscular manifestations in Kearns-Sayre syndrome after administering local anesthesia with articaine has not been reported. The authors describe a severe adverse reaction to local anesthesia with articaine for tooth extraction in a 28-year-old woman with Kearns-Sayre syndrome due to a 5.9-kb mitochondrial DNA deletion. The patient was subjected to local anesthesia with 1.5 mL (60 mg) articaine in the left submandibular nerve for tooth extraction. Five minutes after the injection the patient developed weakness of the limb muscles, extreme fatigue with increased desire to sleep, a feeling of heat, inappetence, and frequent urination. The adverse reaction resolved spontaneously within 48 hours without sequelae. Administration of articaine may cause severe side effects in patients with Kearns-Sayre syndrome. Articaine should be used with caution in these patients.     

Widespread tissue distribution of mitochondrial DNA deletions in Kearns-Sayre syndrome

We performed Southern analysis of mitochondrial DNA (mtDNA) in 6 tissues from a patient with Kearns-Sayre syndrome and found a single deletion of 4.9 kb in all tissues. The percentage of deleted mtDNAs varied widely between tissues, from only 4% in smooth muscle to approximately 50% in skeletal muscle. Samples of DNA obtained from 3 different skeletal muscles and from separate areas of individual tissues showed little variation in percentage of deleted mtDNA. Biochemical analysis showed no clear correlation between mitochondrial enzyme activity and deleted mtDNAs.     

Severe mitochondrial cytopathy with complete A-V block,PEO, and mtDNA deletions

We describe a 17-year-old male with neurologic and cardiovascular disorders characterized by complete atrioventricular block and a mitochondrial cytopathy with clinical, structural, biochemical, and molecular features shared by chronic progressive external ophthalmoplegia and Kearns-Sayre syndrome. The patient's manifestations included progressive external ophthalmoplegia, bilateral ptosis, muscle weakness, delayed development, and progressive hearing loss with multiple mitochondrial DNA deletions, including an abundant 11-kb novel deletion and reduced specific activities of respiratory complexes I, III, and IV present in skeletal muscle. Ultrastructural analysis of biopsied muscle revealed a heterogenous mixture of normal and abnormal mitochondria with unusual cristae. This unique mitochondrial DNA deletion, which eliminates the origin of mitochondrial DNA replication for the light strand, may be responsible for generating an intermediate clinical phenotype.     

Kearns-Sayre syndrome with a novel mitochondrial DNA deletion

We describe a 17-year-old boy with a clinical neurologic picture consistent with Kearns-Sayre syndrome. His manifestations included progressive external ophthalmoplegia, bilateral ptosis, retinitis pigmentosa, and muscle weakness. He was found to harbor an abundant novel deletion in skeletal muscle mitochondrial DNA. Biochemical analysis of the patient's biopsied skeletal muscle showed that the specific activities of all four respiratory complexes with mitochondrial DNA-encoded subunits were markedly reduced in contrast to normal activity levels of entirely nuclear DNA-encoded enzyme activities (eg, complex II and citrate synthase). Ultrastructural analysis also indicated the presence of strikingly abnormal mitochondria with both unusual cristae and frequent paracrystalline inclusions. The great amount of the deleted mitochondrial DNA in this patient's muscle, as well as the concomitant reduction in specific respiratory complex activity, suggests that the mitochondrial DNA deletion plays a role in the pathogenesis of this neurologic disease.     

Unusual clinical presentation of a patient carrying a novel single 1.8 kb deletion of mitochondrial DNA

Kearns-Sayre syndrome (KSS) is a mitochondrial encephalomyopathy characterized by progressive external ophthalmoplegia (PEO), pigmentary retinopathy and onset before the age of 20 years. Cerebellar ataxia, as well as short stature and increased protein content in the cerebrospinal fluid, are frequent additional symptoms. A single large mitochondrial (mt) DNA deletion of 4,977 bp is the most common molecular defect in KSS. Recently, different mutations have also been associated with incomplete, KSS-like phenotypes. We describe the unusual clinical presentation of a patient carrying a novel 1,814-bp deletion of mtDNA. In contrast with typical KSS, the clinical picture of this patient did not include either palpebral ptosis or PEO and was dominated by an ataxic syndrome.     

Kearns-sayre syndrome. Two clinico-pathological cases

Two clinico-pathological cases of Kearns-Sayre syndrome are reported. In both cases the typical triad (progressive external ophthalmoplegia, heart block, retinitis pigmentosa) was present and spongiosis was the main pathological finding. In one case there was also a marked capillary proliferation, significance of which is discussed. A deletion of the mitochondrial DNA was found in the muscle, spinal cord and brain of this last case.     

Deletion of mitochondrial DNA in patients with combined features of Kearns-Sayre and MELAS syndromes

A 9-year-old girl and an 11-year-old boy had ptosis, progressive external ophthalmoplegia, pigmentary retinopathy, and sensorineural hearing loss. The girl had diabetes mellitus and the boy had hypoparathyroidism. Both children also developed recurrent vomiting and cerebral infarcts with lactic acidosis. Muscle biopsy specimens showed ragged-red fibers and Southern analysis demonstrated a distinct heteroplasmic deletion of muscle mitochondrial DNA in each patient but no evidence of the point mutation in the transfer RNALeu(UUR) gene recently identified in mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). These 2 children had combined features of Kearns-Sayre syndrome and MELAS, suggesting that mitochondrial DNA deletions occasionally can have pleomorphic clinical expression.     

Cricopharyngeal achalasia is a common cause of dysphagia in patients with mtDNA deletions

To assess dysphagia, the authors examined 12 patients with Kearns-Sayre syndrome (KSS) or chronic progressive external ophthalmoplegia (CPEO) due to mitochondrial DNA (mtDNA) deletion by videofluoroscopy and manometry. Cricopharyngeal achalasia was documented in nine of 12 patients (75%), whereas deglutitive coordination problems were found in one patient. Cricopharyngeal myotomy may be an effective treatment in selected cases with severe cricopharyngeal obstruction.     

Progression in a case of Kearns-Sayre syndrome

The quantitative relationship between deleted mitochondrial DNA and the clinical course of patients with Kearns-Sayre syndrome is poorly understood. We investigated this point using tissue samples obtained at age 10 years when the patient was diagnosed as Kearns-Sayre syndrome and at age 20 years when he died of disseminated intravascular coagulation. By long polymerase chain reaction, a shortened mitochondrial genome (8.8 kb; normal, 16.6 kb) was detected in the patient. By quantitative competitive polymerase chain reaction, the percentage of deletion-carrying mitochondrial DNA was not increased as expected and did not differ significantly by tissue type or sampling time or correlate with clinical course. Although we could not demonstrate that the amounts of wild-type mitochondrial DNA decreased with accelerating progression, it was emphasized that such a reduction of mitochondrial DNA in various tissues, including those of the central nervous system, could play a significant pathogenetic role, since only wild-type mitochondrial DNA is functional in patients with large-scale deletions of mitochondrial DNA.     

Are mitochondrial DNA deletions causative in chronic progressive external ophthalmoplegia patients?

Twenty-one patients with long standing unexplained ptosis (3), chronic progressive external ophthalmoplegia (CPEO, 16) or Kearns-Sayre syndrome (KSS, 2) were studied for the presence of mitochondrial DNA (mtDNA) deletions and the major disease-associated mtDNA point mutations with the aim of correlating mitochondrial genetic abnormalities with pathogenesis in these patients. Only 52% were found to have a deletion; of these, 82% harboured the 'common deletion'. Two of 2 KSS patients and 9 of 16 CPEO patients were deletion positive. None of the 3 patients with bilateral ptosis only had a deletion. Of those patients with ragged red fibres (RRF) on histology, 69% had a deletion. No disease associated mtDNA point mutation was observed with the exception of the nucleotide (nt) 11084 A-G mutation associated with mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) in a patient also harbouring the common deletion. The role of deletions in CPEO patients is discussed.     

Clonal expansion of mitochondrial DNA with multiple deletions in autosomal dominant progressive external ophthalmoplegia

Sporadic progressive external ophthalmoplegia and Kearns-Sayre syndrome are usually associated with single large-scale mitochondrial DNA deletions in muscle. In progressive external ophthalmoplegia with autosomal dominant inheritance, multiple mitochondrial DNA deletions have been reported. We studied several members of a Swedish family with autosomal dominant progressive external ophthalmoplegia and multiple mitochondrial DNA deletions by polymerase chain reaction analysis of singl emuscle fibers and by in sit hybridization, combined with enzyme histochemical analysis. Muscle fiber segments with deficiency of cytochrome c oxidase, which is partially encoded by mitochondrial DNA, had accumulated mitochondrial DNA with deletions and showed reduced levels of wild-type mitochondrial DNA. The deletions varied between individual muscle fibers. There was one predominant deletion in each cytochrome c oxidase-deficient muscle fiber segment. Sequencing of the deletion breakpoints showed that most but not all of the deletions were flanked by direct repeats. Young, clinically affected individuals of this family without limb muscle symptoms did not show mitochondral DNA deletions or cytochorme c oxidase-deficient muscle fibers. Our result indicate that a nuclear factor predisposes to the developement of somatic multiple mitochondrial DNA deletions. Mitochondrial DNA with multiple different deletions shows clonal expansion, which leads to mitochondrial myopathy with ragged-red fibers and muscle weakness.     

Deletions of mitochondrial DNA in Kearns-Sayre syndrome

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.     

Delayed diagnosis of Kearns-Sayre syndrome in a 38-year-old male patient: a case report

Kearns-Sayre syndrome is a rare disorder caused by mitochondrial deoxyribonucleic acid deletion. It is characterized by a triad of progressive external ophthalmoplegia, initial symptoms that develop before the age of 20 years, and pigmentary retinopathy. Multisystem involvement is frequently associated with those features. Ragged red fibers can be identified during histopathologic examination and confirmed by electron microscopy. In this article, the case of a 38-year-old man with Kearns-Sayre syndrome in whom diagnosis was delayed despite abundant clinical evidence is presented. A brief review of clinical and laboratory findings in patients with that disorder is also provided.