Atypical clinical presentations associated with the MELAS mutation at position 3243 of human mitochondrial DNA

doi:10.1016/0960-8966(93)90040-Q

Neuromuscular Disorders

Volume 3, Issue 1, 1993, Pages 43-50

https://doi.org/10.1016/0960-8966(93)90040-Q Get rights and content

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.

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Citation Excerpt :
In cases of maternal (mitochondrial) inheritance, CPEO is typically associated with heteroplasmic pathogenic mtDNA variants that often affect mitochondrial transfer RNA (tRNA) genes (Sotiriou et al., 2009). The most common of these variants, reported to be present in up to 15% of CPEO patients, is m.3243A>G, associated with Mitochondrial myopathy, Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes (MELAS) (Moraes et al., 1993). Autosomally inherited CPEO tends to be caused by defects to the nuclear genes involved in mtDNA maintenance, thus predisposing individuals to the formation of multiple secondary mtDNA deletions over time (Chinnery et al., 2004).
Chronic progressive external ophthalmoplegia (CPEO) is a common presentation of mitochondrial disease. We performed a retrospective evaluation of the molecular genetic testing and genotype-phenotype correlations in a large cohort of adult-onset CPEO patients (N = 111). One hundred percent of patients tested had at least one mitochondrial DNA (mtDNA) deletion. Genetic testing of nuclear genes encoding mitochondrial proteins identified pathogenic/likely pathogenic variants likely to be associated with CPEO in 7.6% of patients. As expected, the nuclear gene most associated with DNA variation was POLG. A single likely pathogenic mitochondrial DNA variant (m.12278T>C) was identified in two unrelated patients. No significant differences were noted in the clinical phenotypes of patients with pathogenic or likely pathogenic nuclear variants in comparison to those with negative nuclear gene testing. Analysis of deletion size and heteroplasmy in muscle-derived mtDNA showed significant correlations with age of symptom onset but not disease severity (number of canonical CPEO features). Results suggest that smaller mtDNA deletions (p = 0.0127, r² = 0.1201) and higher heteroplasmy of single mtDNA deletions (p = 0.0112, r² = 0.2483) are associated with an earlier age of onset in CPEO patients.

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Research paperAtypical clinical presentations associated with the MELAS mutation at position 3243 of human mitochondrial DNA

Abstract

Neuromusc Disord

Biochem Biophys Res Commun

Lancet

J Pediatr

Lancet

J Neurol Sci

Cell

Biochem Biophys Res Commun

Biochem Biophys Res Commun

J Neurol Sci

Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes: a distinctive clinical syndrome

Ann Neurol

A mutation in the tRNALeu(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies

Nature

Mitochondrial myopathy, encephalopathy, lactic acidosis and strokelike episodes (MELAS): a correlative study on clinical features and mitochondrial DNA mutation

Neurology

MELAS: clinical features, biochemistry, and molecular genetics

Ann Neurol

Defects in mitochondrial protein synthesis and respiratory chain activity segregate with the tRNALeu(UUR) mutation associated with MELAS

Mol Cell Biol

Respiration-deficient cells are caused by a single point mutation in the mitochondrial tRNA-Leu(UUR) gene in mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS)

Am J Hum Genet

MELAS mutation in mtDNA binding site for transcription termination factor causes defects in protein synthesis and in respiration but no changes in levels of upstream and downstream mature transcripts

Mitochondrial DNA deletions in Progessive External Ophthalmoplegia and Kearns-Sayre syndrome

N Engl J Med

Research paper
Atypical clinical presentations associated with the MELAS mutation at position 3243 of human mitochondrial DNA

A mutation in the tRNA^Leu(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies

Defects in mitochondrial protein synthesis and respiratory chain activity segregate with the tRNA^Leu(UUR) mutation associated with MELAS