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Atypical clinical presentations associated with the MELAS mutation at position 3243 of human mitochondrial DNA
C T Moraes1, F Ciacci, G Silvestri
1H. Houston Merritt Clinical Research Center for Muscular Dystrophy and Related Disorders, College of Physicians and Surgeons, Columbia University, New York, NY 10032.
Abstract:
Mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) is commonly associated with an A-->G transition at position 3243 of the mitochondrial DNA. To determine the diversity of clinical syndromes associated with this mutation, 91 patients with mitochondrial encephalomyopathies that did not conform to the MELAS phenotype were screened. Twenty one patients with the 3243 mutation, most of whom had progressive external ophthalmoplegia (PEO) were found. Clinical features did not distinguish PEO patients with the 3243 mutation from those with large-scale deletions of mtDNA. However, most cases with single large-scale mtDNA deletions were sporadic, whereas most patients with the 3243 mutation had affected maternal relatives. Histochemical studies of muscle showed that cytochrome c oxidase (COX) deficiency was more severe in patients with PEO than in patients with typical MELAS, even though PEO patients had a lower percentage of mutant genomes in muscle. These data imply that the 3243 mutation is a major cause of familial PEO, and suggests that the threshold number of mtDNAs harboring the 3243 mutation necessary to affect a particular tissue vary in different patients. The proportion of mutant genomes in combination with other, still undefined, tissue-specific modulating factors seem to determine the overall clinical syndrome.
Insights
The A3243G mitochondrial DNA mutation, often linked to MELAS, also causes progressive external ophthalmoplegia (PEO). This mutation is a significant factor in familial PEO, with severity influenced by mutation levels and tissue-specific factors.
Area of Science:
- Genetics
- Neurology
- Mitochondrial Diseases
Background:
- Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is typically linked to the A3243G mitochondrial DNA mutation.
- The clinical spectrum of this mutation is not fully understood.
Purpose of the Study:
- To investigate the diversity of clinical syndromes associated with the A3243G mitochondrial DNA mutation.
- To identify patients with the A3243G mutation among those with mitochondrial encephalomyopathies not fitting the MELAS phenotype.
Main Methods:
- Screening of 91 patients with mitochondrial encephalomyopathies.
- Genetic analysis for the A3243G mutation in mitochondrial DNA.
- Clinical evaluation and histochemical studies of muscle tissue.
Main Results:
- Twenty-one patients with the A3243G mutation were identified, predominantly presenting with progressive external ophthalmoplegia (PEO).
- Clinical features of PEO patients with the A3243G mutation were indistinguishable from those with large-scale mtDNA deletions.
- While large-scale mtDNA deletions often occurred sporadically, the A3243G mutation was frequently observed in maternal relatives.
- Cytochrome c oxidase (COX) deficiency was more severe in PEO patients with the A3243G mutation compared to typical MELAS, despite a lower percentage of mutant genomes in muscle.
Conclusions:
- The A3243G mitochondrial DNA mutation is a significant cause of familial PEO.
- The threshold for mutant mtDNA required to cause disease varies between tissues and individuals.
- The clinical presentation is likely determined by the proportion of mutant genomes and other tissue-specific factors.