Mitochondrial DNA depletion in progressive external ophthalmoplegia caused by POLG1 mutations Introduction Progressive external ophthalmoplegia (PEO) is a genetically heterogeneous mitochondrial disorder characterized by ptosis, external ophthalmoplegia and a variable degree of proximal muscle weak- ness. Additional features may include: ataxia, peripheral neuropathy, deafness, cataract, hypo- gonadism and Parkinsonism (1–3). Sporadic and maternally inherited PEO can be caused by single, heteroplasmic deletions or point mutations of mitochondrial DNA (mtDNA). Autosomal domi- nant PEO is caused by mutations in nuclear genes including POLG1 and POLG2, encoding the catalytic and accessory subunits of the mtDNA polymerase gamma, respectively, PEO1 encoding the mitochondrial helicase twinkle and ANT1 that encodes the muscle and heart isoforms of the adenine nucleotide translocator 1. Autosomal recessive PEO is associated with mutations in POLG1 (4). Over 120 pathogenic mutations have been described in POLG1 and at least 60 of these are associated with PEO, either in isolation or as a part of more complex neurological syndromes such as mito- chondrial spinocerebellar ataxia with epilepsy (MSCAE) (5, 6), sensory ataxia neuropathy dysar- thria and ophthalmoparesis (SANDO) (1) and Parkinsonian syndromes (3). POLG1 mutations also cause AlpersÕ syndrome (7). At the molecular level, POLG-related disease is associated with sec- ondary damage of the mtDNA in the form of multiple deletions and quantitative depletion. Tissue-specific mtDNA depletion affecting the liver, skeletal muscle and brain is typically found in patients with AlpersÕ syndrome (7, 8). Multiple deletions are mostly associated with PEO and depletion has not been reported in these patients (1, 9–13). Acta Neurol Scand 2009: 120 (Suppl. 189): 38–41 Ó 2009 John Wiley & Sons A ⁄ S ACTA NEUROLOGICA SCANDINAVICA Tzoulis C, Papingji M, Fiskestrand T, Røste LS, Bindoff LA. Mitochondrial DNA depletion in progressive external ophthalmoplegia caused by POLG1 mutations. Acta Neurol Scand 2009: 120 (Suppl. 189): 38–41. Ó 2009 John Wiley & Sons A ⁄ S. Objectives – To investigate two patients with late onset, progressive external ophthalmoplegia (PEO) and sensory peripheral neuropathy. Materials & Methods – 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. Results – 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. Conclusion – 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. C. Tzoulis 1,2 , M. Papingji 1 , T. Fiskestrand 3 , L. S. Røste 4 , L. A. Bindoff 1,2 1 Department of Neurology, Haukeland University Hospital, Bergen, Norway; 2 Department of Clinical Medicine, University of Bergen, Bergen, Norway; 3 Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway; 4 Department of Neurology, Division of Clinical Neuroscience, Rikshospitalet University Hospital, Oslo, Norway Key words: progressive external ophthalmoplegia; POLG; mtDNA; depletion Laurence Bindoff, Department of Neurology, Haukeland University Hospital, 5021 Bergen, Norway Tel.: +47 559 75096 Fax: +47 559 75165 e-mail: laurence.bindoff@nevro.uib.no Conflicts of interest: The authors declare no conflicts of interest. 38