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G. Lenaers, V. Carelli, P. Amati-Bonneau, D. Milea, C. P. Hamel; New Genotype-Phenotype Correlations in OPA1 Patients With Inherited Optic Neuropathies. Invest. Ophthalmol. Vis. Sci. 2008;49(13):3114. doi: https://doi.org/.
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Inherited Optic Neuropathies are mitochondriopathies associated to mutations either in the mitochondrial DNA, as in Leber Hereditary Optic Neuropathy (LHON, MIM 535000) or in nuclear genes, as in Kjer disease linked to OPA1 (Dominant Optic Atrophy, DOA, MIM 165500). In most cases, the OPA1 mutations (n>100) induced non syndromic optic atrophy resulting from a chronic loss of retinal ganglion cells, with variable severity but without clear genotype-phenotype correlations.
Ophthalmological and Neurological consultations, genetic and cellular diagnosis and anathomo-pathological analyses were performed on new patients presenting with atypical optic neuropathy.
We have uncovered two additional clinical presentations associated to novel OPA1 mutations. First, we disclosed a severe syndromic optic neuropathy associated to sensorineural deafness, chronic progressive external ophthalmoplegia, ataxia and mitochondrial myopathy (evidenced by the presence of mtDNA deletions and ragged red fibres in muscle biopsies), associated to singular mutations in the OPA1 GTPase domain. Second, we described a reversible acute optic neuropathy associated to a mutation in the alternatively spliced OPA1 exon5b. Concerning the patho-physiological mechanisms, a mitochondrial metabolic deficit is associated to non syndromic optic neuropathies, and an additional impairment of the mitochondrial nucleotide pools is suspected in syndromic forms, as evidenced for other genes involved in mitochondrial myopathies. Finally, all the clinical presentations, including the exon5b reversible optic neuropathy form, are associated to an important increase in susceptibility to apoptotic stimuli.
Together these data establish new genotype-phenotype-physiopathological correlations associated to OPA1 gene and dominant optic atrophy, emphasizing the highly variable severity and diversity of clinical presentations in mitochondriopathies.
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