Case reportA novel m.7539C>T point mutation in the mt-tRNAAsp gene associated with multisystemic mitochondrial disease

- Identification of a novel m.7539C > T mutation in the mt-tRNAAsp gene.
- Confirmation of pathogenicity by single muscle fibre segregation studies.
- Extension of spectrum of pathogenic mutations in the mt-tRNAAsp gene.
- Affirmation of association of mutations in this gene with multisystemic disease.

Mitochondrial transfer RNA (mt-tRNA) mutations are the commonest sub-type of mitochondrial (mtDNA) mutations associated with human disease. We report a patient with multisytemic disease characterised by myopathy, spinal ataxia, sensorineural hearing loss, cataract and cognitive impairment in whom a novel m.7539C>T mt-tRNAAsp transition was identified. Muscle biopsy revealed extensive histopathological findings including cytochrome c oxidase (COX)-deficient fibres. Pyrosequencing confirmed mtDNA heteroplasmy for the mutation whilst single muscle fibre segregation studies revealed statistically significant higher mutation loads in COX-deficient fibres than in COX-positive fibres. Absence from control databases, hierarchical mt-tRNA mutation segregation within tissues, and occurrence at conserved sequence positions, further confirm this novel mt-tRNA mutation to be pathogenic. To date only three mt-tRNAAsp gene mutations have been described with clear evidence of pathogenicity. The novel m.7539C>T mt-tRNAAsp gene mutation extends the spectrum of pathogenic mutations in this gene, further supporting the notion that mt-tRNAAsp gene mutations are associated with multisystemic disease presentations.