Progressive External Ophthalmoplegia and Vision and Hearing Loss in a Patient With Mutations in POLG2 and OPA1

Abstract

Objective To describe the clinical features, muscle pathological characteristics, and molecular studies of a patient with a mutation in the gene encoding the accessory subunit (p55) of polymerase γ (POLG2) and a mutation in theOPA1gene. Design Clinical examination and morphological, biochemical, and molecular analyses. Setting Tertiary care university hospitals and molecular genetics and scientific computing laboratory. Patient A 42-year-old man experienced hearing loss, progressive external ophthalmoplegia (PEO), loss of central vision, macrocytic anemia, and hypogonadism. His family history was negative for neurological disease, and his serum lactate level was normal. Results A muscle biopsy specimen showed scattered intensely succinate dehydrogenase–positive and cytochrome-coxidase–negative fibers. Southern blot of muscle mitochondrial DNA showed multiple deletions. The results of screening for mutations in the nuclear genes associated with PEO and multiple mitochondrial DNA deletions, including those inPOLG(polymerase γ gene),ANT1(gene encoding adenine nucleotide translocator 1), andPEO1, were negative, but sequencing ofPOLG2revealed a G1247C mutation in exon 7, resulting in the substitution of a highly conserved glycine with an alanine at codon 416 (G416A). Because biochemical analysis of the mutant protein showed no alteration in chromatographic properties and normal ability to protect the catalytic subunit fromN-ethylmaleimide, we also sequenced theOPA1gene and identified a novel heterozygous mutation (Y582C). Conclusion Although we initially focused on the mutation inPOLG2, the mutation inOPA1is more likely to explain the late-onset PEO and multisystem disorder in this patient.