Document Detail


Multiple mtDNA deletions features in autosomal dominant and recessive diseases suggest distinct pathogeneses.
MedLine Citation:
PMID:  9443465     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Multiple mitochondrial DNA (mtDNA) deletions have been described in patients with autosomal dominant progressive external ophthalmoplegia (AD-PEO) and in autosomal recessive disorders including mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) and autosomal recessive cardiomyopathy ophthalmoplegia (ARCO). The pathogenic bases of these disorders are unknown. We studied three patients with AD-PEO and three patients with autosomal recessive (AR)-PEO (two patients with MNGIE and one patient with ARCO). Histochemistry and Southern blot analyses of DNA were performed in skeletal muscle from the patients. Muscle mtDNA was used to characterize the pattern and amounts of the multiple mtDNA rearrangements; PCR analysis was performed to obtain finer maps of the deleted regions in both conditions. The patients with AD-PEO had myopathic features; the patients with AR-PEO had multisystem disorders. The percentage of ragged-red and cytochrome c oxidase-negative fibers tended to be higher in muscle from the patients with AD-PEO (19% +/- 13.9, 29.7 +/- 26.3) than in muscle from the patients with AR-PEO (1.4% +/- 1.4, 3.3% +/- 3.2; p < 0.10). The sizes of the multiple mtDNA deletions ranged from approximately 4.0 to 10.0 kilobases in muscle from both groups of patients, and in both groups, we identified only deleted and no duplicated mtDNA molecules. Patients with AD-PEO harbored a greater proportion of deleted mtDNA species in muscle (31% +/- 5.3) than did patients with AR-PEO (9.7% +/- 9.1; p < 0.05). In the patients with AD-PEO, we identified a deletion that included the mtDNA heavy strand promoter (HSP) region, which had been previously described as the HSP deletion. The HSP deletion was not present in the patients with AR-PEO. Our findings show the clinical, histologic, and molecular genetic heterogeneity of these complex disorders. In particular, the proportions of multiple mtDNA deletions were higher in muscle samples from patients with AD-PEO than in those from patients with AR-PEO.
Authors:
R Carrozzo; M Hirano; B Fromenty; C Casali; F M Santorelli; E Bonilla; S DiMauro; E A Schon; A F Miranda
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Neurology     Volume:  50     ISSN:  0028-3878     ISO Abbreviation:  Neurology     Publication Date:  1998 Jan 
Date Detail:
Created Date:  1998-02-06     Completed Date:  1998-02-06     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  0401060     Medline TA:  Neurology     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  99-106     Citation Subset:  AIM; IM    
Affiliation:
Department of Neurology, H. Houston Merritt Clinical Research Center for Muscular Dystrophy and Related Diseases, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
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MeSH Terms
Descriptor/Qualifier:
Adult
Biopsy
Blotting, Southern
Chromosome Aberrations
Chromosome Disorders
Citrate (si)-Synthase / metabolism
DNA, Mitochondrial / analysis,  genetics*
Female
Gene Deletion*
Genes, Dominant
Genes, Recessive
Genetic Heterogeneity
Humans
Male
Middle Aged
Mitochondrial Encephalomyopathies / etiology,  genetics*,  pathology
Muscle, Skeletal / enzymology,  pathology
Ophthalmoplegia / etiology,  genetics*,  pathology
Polymerase Chain Reaction
Grant Support
ID/Acronym/Agency:
HD32062/HD/NICHD NIH HHS; NS11766/NS/NINDS NIH HHS; NS28828/NS/NINDS NIH HHS
Chemical
Reg. No./Substance:
0/DNA, Mitochondrial; EC 2.3.3.1/Citrate (si)-Synthase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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