Sunday, October 1, 2023
Molecular Genetic Profile of our DOA Cohort
Distribution of RNFL Indices for Our OPA1 Cohort
RNFL Thickness Data for OPA1 Patients and Normal Controls
Comparison of RNFL Thickness Between Pure DOA and DOA + Subgroups
This activity is intended for primary care clinicians, ophthalmologists, and other specialists who care for patients with DOA.
The goal of this activity is to review features of DOA and RGC loss in patients with the pure and syndromal forms of DOA.
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The results of our study have confirmed the marked loss of RGC axons previously documented in post-mortem histopathological studies of two patients with DOA.[23,24] OCT imaging performed on 40 patients with molecularly confirmed OPA1 mutations revealed a generalised decrease in peripapillary RNFL thickness, and a regional pattern was apparent, with the temporal quadrant being more severely affected and the nasal quadrant relatively spared. This preferential involvement of the papillomacular bundle is consistent with the characteristic wedge of temporal disc pallor observed clinically in DOA.[5,25] It also supports earlier OCT reports of RGC loss in patients with OPA1 mutations.[26-28] These studies, which only included patients with isolated optic atrophy, revealed a similar pattern of peripapillary RNFL thinning, with the temporal and nasal quadrants being the worst and least affected, respectively. Macular OCT measurements centred at the fovea showed no degeneration of the outer retina, and both the photoreceptor outer and inner segments were of normal thickness.[27,28] Our larger case series included patients with both pure DOA and DOA + phenotypes, allowing a more comprehensive subgroup analysis based on disease severity. Patients with DOA + features had significantly worse visual acuities, and except for the temporal quadrant, RNFL thinning was more pronounced in this group compared with patients with only optic nerve involvement. There was also a strong correlation between RNFL thickness and LogMAR visual acuity. The greater deleterious consequences of some OPA1 mutations on RGC survival is therefore clearly linked to the development of multi-system organ involvement in DOA +. Further studies are warranted to define the pathophysiological pathways involved.[9]
It is important to stress that time-domain OCT has a minimum axial resolution of 30-40 mm,[29] and it is entirely possible that RNFL thickness in the temporal quadrant was actually much lower than the values recorded. This could explain the lack of any significant difference in temporal RNFL thickness between patients with pure DOA and DOA +, and the absence of any significant correlation with LogMAR visual acuity for temporal quadrant measurements. Having already suffered the 'greatest hit' early in the disease process, the papillomacular bundle rapidly falls below the OCT detection threshold, but progression of RNFL thinning in the other quadrants is in keeping with the worsening of visual function and the development of DOA + features.
The Opa1 protein is located within the mitochondrial inner membrane and it regulates several critical cellular functions related to the stability of the mitochondrial network, mitochondrial DNA (mtDNA) replication, and the activity of the respiratory chain complexes.[30] Similar to Leber hereditary optic neuropathy (LHON), which is caused by primary mtDNA point mutations, RGC loss in DOA is ultimately due to disturbed mitochondrial oxidative function and apoptosis.[1,2] It is therefore not surprising that both these mitochondrial optic neuropathies share striking similarities in RNFL abnormalities, with LHON carriers showing pathological thickening of the papillomacular bundle in the asymptomatic phase,[21] and marked temporal thinning with relative nasal sparing in the atrophic phase of the disease.[22]
The assessment of peripapillary RNFL thickness with OCT is a useful tool now routinely available to clinicians when investigating optic nerve function. It is a practical, non-invasive procedure that can provide important structural information in borderline DOA cases and help direct subsequent investigations (Supplementary Figure 4). RNFL thinning in patients with OPA1 mutations is also a dynamic process and this provides an objective outcome measure for documenting disease progression in future treatment trials. Finally, the pattern of RGC loss observed in DOA reflects the intrinsic susceptibilities of different RGC populations to disturbed mitochondrial function. Understanding the key factors involved will be crucial in the development of novel neuroprotective strategies and in defining the therapeutic window for potential intervention.
