Disorders associated with multiple deletions of mitochondrial DNA.
Multiple deletions of mitochondrial DNA (mtDNA) have recently been described in a number of patients with neurological disorders. Most cases have been clinically characterized by autosomal dominant inheritance, adult onset, and a slowly progressive course with external ophthalmoplegia and muscle weakness. Some patients have had evidence of central or peripheral nervous system involvement or episodes of myoglobinuria. Muscle biopsy findings include ragged-red fibres (RRF), muscle fibres with absent COX-activity and abundant abnormal mitochondria with paracrystalline inclusions. Biochemically, a generalized reduction in the activities of mtDNA-encoded enzymes is observed in skeletal muscle. Southern blotting or PCR analysis reveal multiple populations of deleted mtDNA. The deletions occur at multiple sites between the replication initiation sites, involving a large portion of mtDNA, and most deletions seem to be flanked by direct sequence repeats, shown to be "hot spots" in the case of single large deletions. Apparently, a defect in a nuclear gene results in multiple deletions of mtDNA. Both clinical, genetic and molecular genetic observations indicate heterogeneity of this new disease category, apparently based on a disturbance in the "cross-talk" between the nuclear and the mitochondrial genomes.
Haltia
M
M
Department of Pathology, University of Helsinki, Finland.
Suomalainen
A
A
Majander
A
A
Somer
H
H
D004272:DNA, Mitochondrial / Q000235:genetics*; D003576:Electron Transport Complex IV / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008931:Mitochondria, Muscle / Q000201:enzymology / Q000473:pathology / Q000648:ultrastructure; D017237:Mitochondrial Encephalomyopathies / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D009132:Muscles / Q000473:pathology; D010375:Pedigree; D016133:Polymerase Chain Reaction; D012508:Sarcolemma / Q000473:pathology / Q000648:ultrastructure; D017384:Sequence Deletion
D004272:DNA, Mitochondrial; D003576:Electron Transport Complex IV