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In the past decade there have been reports of over 100 mitochondrial (mt) DNA mutations associated with neuromuscular disease. These have included large scale mtDNA rearrangements, common point mutations in mt tRNA genes, and mutations affecting structural genes of mtDNA encoded respiratory chain subunits. The tRNA mutation of MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) is located in the tRNALeu (UUR) gene and another 13 pathogenic mutations associated with neurodegenerative disorders have been described in this gene. Mutations in tRNAIle, tRNALys, and tRNASer(UCN) have been associated with encephalomyopathies or non-syndromic deafness. A tRNAAla mutation has been described in a patient with late onset progressive external ophthalmoplegia and dysphagia. A different heteroplasmic G>A mutation at position 5650 of mt tRNAAla was reported in a 53 year old patient with symptoms of cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) together with a myopathy with numerous ragged red fibres. Now workers in Germany have described a patient with a mitochondrial myopathy and features of muscular dystrophy who has a heteroplasmic G5650 mutation in the mtDNA encoded tRNAAla gene.
The patient’s mother died of a stroke at the age of 36. He was normal up to the age of 14 when he developed weakness on exercise and difficulty climbing stairs. There was slow progression of proximal muscle weakness and atrophy in the legs and proximal arm weakness was first noticed at the age of 32. Muscle biopsy at age 36 showed appearances of chronic myopathy and 5–10% of fibres had ragged red and/or ragged blue appearance, indicating a mixed degenerative myopathy and mitochondrial disorder. EMG showed myotonic discharges. On electron microscopy there was marked mitochondrial proliferation with structural abnormalities of mitochondria. Screening of the entire mtDNA revealed a heteroplasmic mutation in tRNAAla at np5650. The mutation was concentrated particularly in ragged red fibres. The rate of apopotosis in muscle cells was not increased.