 |
|
Progressive External Ophthalmoplegia and Vision and Hearing Loss in a Patient With Mutations in POLG2 and OPA1
Silvio Ferraris, MD;
Susanna Clark, PhD;
Emanuela Garelli, PhD;
Guido Davidzon, MD;
Steven A. Moore, MD, PhD;
Randy H. Kardon, MD, PhD;
Rachelle J. Bienstock, PhD;
Matthew J. Longley, PhD;
Michelangelo Mancuso, MD;
Purificación Gutiérrez Ríos, MS;
Michio Hirano, MD;
William C. Copeland, PhD;
Salvatore DiMauro, MD
Arch Neurol. 2008;65(1):125-131.
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  (POLG2) and a mutation in the OPA1 gene.
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-c oxidase–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 in POLG (polymerase gene), ANT1 (gene encoding adenine nucleotide translocator 1), and PEO1, were negative, but sequencing of POLG2 revealed 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 from N-ethylmaleimide, we also sequenced the OPA1 gene and identified a novel heterozygous mutation (Y582C).
Conclusion Although we initially focused on the mutation in POLG2, the mutation in OPA1 is more likely to explain the late-onset PEO and multisystem disorder in this patient.
Author Affiliations: Department of Pediatrics, University of Turin, Turin, Italy (Drs Ferraris and Garelli); Laboratory of Molecular Genetics and Scientific Computing Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina (Drs Clark, Bienstock, Longley, and Copeland); Department of Neurology, Columbia University Medical Center, New York, New York (Drs Davidzon, Hirano, and DiMauro, and Ms Gutiérrez Ríos); Departments of Pathology (Dr Moore) and Ophthalmology and Visual Sciences (Dr Kardon), University of Iowa, Iowa City; and Department of Neurosciences, Neurological Institute, University of Pisa, Pisa, Italy (Dr Mancuso).
|
