Abstract

Objectives: We report here the clinical and genetic features of two new families with autosomal dominant progressive external ophthalmoplegia (adPEO).

Patients and methods: The examination of index patients included a detailed clinical characterisation, histological analysis of muscle biopsy specimens, and genetic testing of mitochondrial and nuclear DNA extracted from muscle and leucocytes.

Results: Index patients in both families presented with PEO and developed other clinical disease manifestations, such as myopathy and cardiomyopathy (patient 1) and axonal neuropathy, diabetes mellitus, hearing loss, and myopathy (patient 2), later in the course of illness. Both patients had ragged red fibres on muscle histology. Southern blot of mtDNA from muscle of patient 2 showed multiple deletions. In this case, a novel heterozygous missense mutation F485L was identified in the nuclear encoded putative mitochondrial helicase Twinkle. The mutation co-segregated with the clinical phenotype in the family and was not detected in 150 control chromosomes. In the other index patient, sequencing of ANT1, C10orf2 (encoding for Twinkle), and POLG1 did not reveal pathogenic mutations.

Conclusions: Our cases illustrate the clinical variability of adPEO, add a novel pathogenic mutation in Twinkle (F485L) to the growing list of genetic abnormalities in adPEO, and reinforce the relevance of other yet unidentified genes in mtDNA maintenance and pathogenesis of adPEO.