The Molecular Etiology of Progressive External Ophthalmoplegia (PEO) Associated with Mitochondrial Myopathy (IN7-1.006)

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Objective: To elucidate the molecular etiology of Progressive External Ophathalmoplegia (PEO) associated with mitochondrial myopathy and to determine the prevalence of different gene defects. Background PEO with mitochondrial myopathy can be caused by autosomal dominant mutations in POLG1, ANT1, and TWINKLE. Two autosomal recessive POLG1 mutations can also result in autosomal recessive PEO (arPEO). Recently, mutations in POLG2 and RRM2B have also been reported to be associated with PEO. These genes are involved in mitochondrial DNA (mtDNA) replication (POLG1&2, TWINKLE) and the maintenance of deoxynucleotide pools for mtDNA synthesis (ANT1, RRM2B). Thus, defects in thees genes generally result in the loss of mtDNA integrity. Design/Methods: The coding regions and exon-intron boundaries of POLG1, ANT1, and TWINKLE were sequenced in 187 patients (> 10 yr) suspected of PEO. RRM2B gene was sequence analyzed in 25 patients negative for mutations in the above three genes. Southern blot and/or PCR were used to detect mtDNA deletions in muscle specimens of 5 patients who carried 2 POLG1 mutations. Results: In this cohort, 21 patients (11.2%) had a definite molecular diagnosis of PEO and mitochondrial myopathy. These include 12 patients with arPEO casused by 2 mutant alleles in POLG1 and 9 patients with adPEO caused by a heterozygous mutation in POLG1 (1), ANT1 (1), or TWINKLE (7). In addition, 5 patients were heterozygous for a POLG1 mutation usually found in compound heterozygosity with another mutation. No mutation was detected in the RRM2B gene. In all the 5 patients with muscle specimen available for analysis, multiple mtDNA deletions were detected (100%). Conclusions: Our data suggest that POLG1 (ar) and TWINKLE (ad) represent the most frequent molecular defects in PEO patients associated with mitochondrial myopathy. Multiple mtDNA deletion in the muscle is a cardinal feature for these patients, indicating that compromised mtDNA integrity plays an important role in the etiology of PEO. Disclosure: Dr. Tang has nothing to disclose. Dr. Huang has nothing to disclose. Dr. Milone has nothing to disclose. Dr. Wong has nothing to disclose.