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A MERRF/MELAS overlap syndrome associated with a new point mutation in the mitochondrial DNA tRNA(Lys) gene
M Zeviani1, F Muntoni, N Savarese
1Divisione di Biochimica e Genetica, Istituto Nazionale Neurologico C. Besta, Milano, Italia.
Abstract:
Several members of a three-generation kindred from Sardinia were affected by a maternally inherited syndrome characterized by features of both myoclonus epilepsy with ragged-red fibers (MERRF) and mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS). Clinically, symptoms such as myoclonus epilepsy, neural deafness and ataxia were variably associated with stroke-like episodes and/or migrainous attacks. Morphologically, numerous MELAS-associated SDH-stained vessels were observed in muscle biopsies, either alone or in combination with ragged-red fibers, the morphological hallmark of MERRF. Sequence analysis of the mtDNA tRNA genes revealed the presence of a single, heteroplasmic T-->C transition at nt 8356, in the region of the tRNA(Lys) gene corresponding to the T-psi-C stem. The T-->C(8356) transition was exclusively found in the maternal lineage of our family, and the relative amount of the mutant mtDNA species in muscle was correlated with the severity of the clinical presentation. Therefore, we propose that the T-->C(8356) transition is responsible for the mitochondrial encephalomyopathy found in our family, and must be added to the expanding list of the pathogenetically relevant mutations of human mtDNA.
Insights
A novel mitochondrial DNA mutation, T-to-C at 8356 in the tRNA(Lys) gene, causes a syndrome combining features of myoclonus epilepsy with ragged-red fibers (MERRF) and mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS). This mutation is maternally inherited and linked to disease severity.
Area of Science:
- Genetics
- Neurology
- Mitochondrial Biology
Background:
- Mitochondrial disorders often present with complex, overlapping clinical and morphological features.
- Distinguishing between syndromes like MERRF and MELAS can be challenging due to shared symptoms and pathologies.
Observation:
- A Sardinian family exhibited a maternally inherited syndrome with features of both MERRF and MELAS.
- Muscle biopsies revealed ragged-red fibers (MERRF hallmark) and MELAS-associated SDH-stained vessels.
- Clinical symptoms included myoclonus epilepsy, neural deafness, ataxia, stroke-like episodes, and migrainous attacks.
Findings:
- Sequence analysis identified a heteroplasmic T-to-C transition at nucleotide 8356 in the mtDNA tRNA(Lys) gene.
- This T-to-C(8356) mutation was exclusively present in the maternal lineage.
- The mutant mtDNA load in muscle correlated with the severity of the patient's clinical presentation.
Implications:
- The T-to-C(8356) transition is proposed as the causative mutation for this family's mitochondrial encephalomyopathy.
- This finding expands the known spectrum of pathogenic mutations in human mitochondrial DNA.
- Highlights the importance of mtDNA tRNA gene analysis in diagnosing complex mitochondrial disorders.