title: Severe depletion of mitochondrial DNA in spinal muscular atrophy.
abstract: Spinal muscular atrophy (SMA) is a neuromuscular disorder in childhood leading to a dramatic loss of muscle strength. Functional investigations with high-resolution polarography and enzyme measurements of the respiratory chain revealed lowered activities in muscle tissue of SMA patients. To gain a better understanding of this low energy supply we analyzed the amount of mitochondrial DNA (mtDNA) in skeletal muscle of 20 unrelated children with genetically proven SMA and 31 controls. Quantitative Southern blot analysis revealed a severe and homogeneous decrease in the content of muscle mtDNA in relation to nuclear DNA in SMA patients (90.3+/-7.8%), whereas by immunofluorescence no decrease in the number of mitochondria was detected. In addition, a two- to threefold reduction of the nuclear-encoded complex II (succinate dehydrogenase) activity was detected in SMA muscle tissue. Western blot analysis showed a significant reduction of both mitochondrial- and nuclear-encoded cytochrome c oxidase subunits. Our results indicate that mtDNA depletion in SMA is a consequence of severe atrophy, and has to be differentiated by measurement of complex II from an isolated reduction of mtDNA as found in patients with mitochondriocytopathies and the so-called mtDNA depletion syndrome.
authors.affiliation: Department of Pediatrics, General Hospital Salzburg, Muellner Hauptstrasse 48, Austria.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Berger
authors.forename: Johannes A
authors.initials: JA
authors.lastname: Mayr
authors.forename: David
authors.initials: D
authors.lastname: Meierhofer
authors.forename: Ulrike
authors.initials: U
authors.lastname: Fötschl
authors.forename: Reginald
authors.initials: R
authors.lastname: Bittner
authors.forename: Herbert
authors.initials: H
authors.lastname: Budka
authors.forename: Claude
authors.initials: C
authors.lastname: Grethen
authors.forename: Michael
authors.initials: M
authors.lastname: Huemer
authors.forename: Barbara
authors.initials: B
authors.lastname: Kofler
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sperl
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015139:Blotting, Southern; D015153:Blotting, Western; D002648:Child; D002675:Child, Preschool; D004272:DNA, Mitochondrial / Q000032:analysis*; D003576:Electron Transport Complex IV / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006801:Humans; D007223:Infant; D008875:Middle Aged; D008928:Mitochondria / Q000201:enzymology / Q000473:pathology*; D018482:Muscle, Skeletal / Q000737:chemistry* / Q000201:enzymology; D009134:Muscular Atrophy, Spinal / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D013385:Succinate Dehydrogenase / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial; D013385:Succinate Dehydrogenase; D003576:Electron Transport Complex IV