Mitochondrial DNA depletion in progressive external ophthalmoplegia caused by POLG1 mutations

To investigate two patients with late onset, progressive external ophthalmoplegia (PEO) and sensory peripheral neuropathy.

The patients aged 86 and 50 years were investigated clinically including magnetic resonance imaging of the brain, electrophysiological studies and, in one, skeletal muscle biopsy. Molecular studies included sequencing of the whole coding region of the POLG1 gene and mitochondrial DNA (mtDNA) analysis for deletions and depletion.

Both patients were compound heterozygous for gene encoding the catalytic subunit of the DNA-polymerase gamma (POLG1) mutations. One had the p.737R and p.W748S mutations while the other carried the p.T251I, p.P587L and p.W748S mutations. While these mutations have been previously described, these combinations are novel. mtDNA studies in skeletal muscle showed evidence of multiple deletions and approximately 64% depletion of the mitochondrial genome.

Our findings broaden the genotypic spectrum of POLG-associated PEO and show that in addition to multiple deletions, mtDNA depletion occurs and may contribute to the pathogenesis of this disorder.