Retinal Phenotypes Associated with Mitochondrial DNA Point Substitutions

1. Leo Sheck^1,2
2. Dianne Sharp²
3. Rachael Barnes²
4. Andrea Vincent^1,2

¹Department of Ophthalmology, New Zealand National Eye Centre, Faculty of Medical and Health Sciences, University of Auckland
²Department of Ophthlamology, Greenlane Clinical Centre, Auckland District Health Board

Purpose
To report the phenotypic characteristics and spectrum of macular dystrophies caused by mitochondrial point substitutions, including two variants not previously reported to have ocular associations.

Methods
Patients with retinal dystrophies and mitochondrial variants were identified from Ocular Genetics Clinic in Auckland District Health Board. A comprehensive clinical and family history were taken, and clinical examination included electrophysiology, optical coherent tomography (OCT) and fundal autofluorescence (FAF). Mitochondrial DNA was extracted from peripheral venous blood, or buccal mouth wash specimens, and mutational analysis by automated bidirectional fluorescent DNA sequencing.

Results
Four patients with mitochondrial sequence changes were identified. Mean age is 61.8 years (range 54-66). Presenting visual acuity ranges from 6/7.5 to counting fingers. Mutational analysis identified the m.3243A>G mutation (n=2) responsible for the maternally inherited diabetes and deafness (MIDD) phenotype; .m.5628T>C (n=1) encoding the mitochondrial tRNAAla gene; and m.3394T>C (n=1) in the MT-ND1 gene with p.ND1:Tyr30His substitution. Patients with m.3243A>G mutations demonstrated perifoveal atrophy with sparing of central fovea, corresponding to hypofluorescence on FAF with surrounding speckle hyperfluorescence. The phenotype with m.5628T>C showed well-defined atrophic changes from the inferior temporal arcade to peripheral inferior retina, with bone spicule pigment, hypofluorescent on FAF but without surrounding speckled hyperfluorescence. The phenotype of the m.3394T>C variant showed bilateral perifoveal atrophy, with foveal involvement in the left. This atrophy was also hypofluorescent on FAF, with surrounding speckled hyperfluorescence. OCT demonstrated loss of the outer retinal layer in atrophic areas in all subjects.

Conclusion
Similar but variable retinal phenotypes are associated with mitochondrial point substitutions.