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Valerio Carelli, Leonardo Caporali, Rocco Liguori, Chiara La Morgia, Piero Barboni, Raffaele Lodi, Maria L. Valentino; Opa1/twinkle Double Trouble Underlying ‘Doa Plus’ Phenotype. Invest. Ophthalmol. Vis. Sci. 2012;53(14):1555.
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© ARVO (1962-2015); The Authors (2016-present)
To report the complex molecular features of a patient with dominant chronic progressive external ophthalmoplegia (adCPEO) inherited from the maternal side and dominant optic atrophy (DOA) inherited from the paternal side. The combination of CPEO and optic atrophy defines the recently described phenotype of "DOA plus", associated with accumulation of mitochondrial DNA (mtDNA) multiple deletions in the skeletal muscle.
The proband, a 42 years old male, had bilateral optic atrophy, reduced visual acuity and central scotoma since 15 years. After 30 he progressively developed ptosis and CPEO, with pathologically elevated creatine kinase and lactic acid. His mother also had ptosis and CPEO, but without visual complains. A second patient from the same geographical area, possibly related to the proband on the paternal side, had optic atrophy and slowly progressive loss of central vision since childhood, similar to his mother. This patient also had pathologically elevated lactic acid after exercise. Both patients were investigated by optical coherence tomography (OCT) (Stratus), muscle biopsy, brain and muscle MR-spectroscopy, and genetic analysis.
Both patients had reduced retinal nerve fiber layer thickness at OCT, mitochondrial myopathy with numerous cytochrome c oxidase negative fibers and accumulation of mtDNA multiple deletions. MR spectroscopy showed mild bioenergetic impairment in muscle and brain in the second patient, whereas was essentially normal in the proband. Screening of the known genes associated with defective mtDNA maintenance was positive for the heterozygous c.907C>T mutation (p.Arg303Trp) in the PEO1 gene (Twinkle) in the proband. He was also positive for the heterozygous c.703C>T mutation (p.Arg235stop) in exon 7 of the OPA1 gene. His mother had only the PEO1 mutation. The second patient carried only the same OPA1 mutation on the same haplotype, suggesting a common founder.
This report highlights the complex molecular basis of a "DOA plus" case combining CPEO/ptosis, optic atrophy and mtDNA multiple deletions. The Twinkle mutation was responsible for the adCPEO/ptosis, inherited from the mother. The combined OPA1 mutation was responsible for the optic atrophy. However, the OPA1 mutation alone in the second patient was still associated with mitochondrial myopahty and mtDNA multiple deletions, pointing to defective mtDNA maintenance as a common consequence shared by both Twinkle and OPA1 mutations.
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