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Abstract: We report a family where a predominantly proximal myopathy has become increasingly severe with successive generations of the maternal lineage. This pure myopathy has been caused by a mutation (m.5650G>A) in the mt-tRNAAla gene that has been reported only once previously in a patient with CADASIL where the phenotype was dominated by neurological complications. This report is therefore the first description of the phenotype associated solely with this mutation and confirms its pathogenicity. [Copyright &y& Elsevier]

We describe a young woman with a progressive mitochondrial myopathy that started with muscle weakness and went on to include deafness, dementia and ataxia. Skeletal muscle showed the histological and biochemical features of mitochondrial respiratory chain dysfunction. Genetic analysis identified a novel, heteroplasmic, A to G transition in tRNASer(UCN) at position 7480 affecting a highly conserved base in the anticodon loop. Single-fibre PCR showed highest levels of mutation in cytochrome c-oxidase-deficient fibres and quantification in two biopsies taken 5 years apart showed no change in percentage heteroplasmy. The mutation was present at lower levels in the patient''s blood, but was not found in either her mother''s or sister''s blood and skeletal muscle, suggesting a sporadic occurrence. This is the eighth disease-causing mutation in this tRNA gene and confirms serine (UCN) as one of the most common sites for mtDNA mutation. [Copyright &y& Elsevier]

Heteroplasmic mitochondrial DNA mutations often cause a skeletal myopathy associated with a mosaic distribution of cytochrome c oxidase-deficient muscle fibres. The function of an individual muscle fibre is dependent upon the metabolic activity throughout its length, but little is known about the length of cytochrome c oxidase-deficient segments in human skeletal muscle in patients with mitochondrial disease. We studied cytochrome c oxidase activity by serial section analysis of quadriceps muscle from two patients. We observed a striking variation in the length of the cytochrome c oxidase-negative segments. The shortest segments were 10 μm long, and the longest segment was the entire length of the larger biopsy (≥1.2 mm). The lengths of the cytochrome c oxidase-negative segments were generally shorter in the less severely affected biopsy, and we frequently observed non-contiguous segments of cytochrome c oxidase deficiency within the same muscle fibre. The findings have important implications for our understanding of the pathogenesis and progression of mitochondrial DNA myopathy. [Copyright &y& Elsevier]

We describe a novel mutation in the mitochondrial tRNAIle gene, an A to G transition at nucleotide position 4267, in a 37-year-old woman with myopathy, ataxia and sensorineural hearing loss. The A4267G mutation was heteroplasmic in several of the proband''s tissues and single fibre analysis revealed significantly higher levels of mutated mitochondrial DNA in cytochrome c oxidase-deficient fibres than cytochrome c oxidase-positive fibres. It is predicted to disrupt a highly conserved base pair within the aminoacyl acceptor stem of the tRNA causing functional impairment, and as such fulfils all the accepted criteria for pathogenicity. Moreover, we were unable to detect the A4267G mutation in lymphocytes, buccal epithelia and hair of the patient''s mother and two siblings, implying that the A4267G transition represents a sporadic, germline mutation. [Copyright &y& Elsevier]