Mitochondrial cytopathies represent a heterogeneous group of multisystem disorders which preferentially affect the muscle and nervous systems. They are caused either by mutations in the maternally inherited mitochondrial genome, or by nuclear DNA-mutations. Today, approximately 200 different disease causing mutations of mitochondrial DNA (mtDNA) are known, and due to the increased knowledge about nuclear genetics during the last few years, more and more nuclear mutations are being described. Owing to the non-uniform distribution of mitochondria in tissues and the co-existence of mutated and wildtype mtDNA (heteroplasmy) in these organelles, these disorders may present with a huge variety of symptoms, even if the same mutation is involved. Diagnostic investigations should include the measurement of serum and CSF lactate, neuroradiological tests and a muscle biopsy to show the characteristic ragged-red fibres and cytochrome c oxidase deficient cells and also to provide material for genetic analysis. To date, the treatment of these diseases remains supportive and should focus on typical complications such as cardiac dysrhythmia and endocrinopathy.
Synaptosome cybrids were used to confirm the presence of heteroplasmic mtDNA sequence variants in the human brain. Synaptosomes contain one to several mitochondria, and when fused to mtDNA-deficient (rho degrees ) mouse or human cell lines result in viable cybrid cell lines. The brain origin of mouse synaptosome cybrid mtDNAs was confirmed using sequence polymorphisms in the mtDNA COIII, ND3 and tRNA(Arg)genes. The brain origin of the human synaptosome cybrids was confirmed using a rare mtDNA Mbo I polymorphism. Fusion of synaptosomes from the brain of a 35-year-old woman resulted in 71 synaptosome cybrids. Sequencing the mtDNA control region of these cybrid clones revealed differences in the number of Cs in a poly C track between nucleotide pairs (nps) 301 and 309. Three percent of the cybrid clones had mtDNAs with 10 Cs, 76% had nine, 18% had eight and 3% had seven Cs. Comparable results were obtained by PCR amplification, cloning and sequencing of mtDNA control regions directly from the patient's brain tissue, but not when the control region was amplified and cloned from a synaptosome cybrid homoplasmic for a mtDNA with nine Cs. Thus, we have clonally recovered mtDNA control region length variants from an adult human brain without recourse to PCR, and established the variant mtDNAs within living cultured cells. This confirms that some mtDNA heteroplasmy can exist in human neurons, and provides the opportunity to study its functional significance.
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.
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