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Table 1.  

Molecular Genetic Profile of our DOA Cohort

Table 2.  

Distribution of RNFL Indices for Our OPA1 Cohort

Table 3.  

RNFL Thickness Data for OPA1 Patients and Normal Controls

Table 4.  

Comparison of RNFL Thickness Between Pure DOA and DOA + Subgroups

CME

Pattern of Retinal Ganglion Cell Loss in Dominant Optic Atrophy Due to OPA1 Mutations

  • Authors: Patrick Yu-Wai-Man, MRCOphth; Maura Bailie; Alaa Atawan; Patrick F. Chinnery, PhD, FRCPath; Philip G. Griffiths, FRCOphth
  • CME Released: 3/4/2011
  • THIS ACTIVITY HAS EXPIRED FOR CREDIT
  • Valid for credit through: 3/4/2012
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Target Audience and Goal Statement

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.

Upon completion of this activity, participants will be able to:

  1. Describe the clinical features of DOA
  2. Identify extraocular features associated with DOA
  3. Identify the peripapillary retinal nerve fibre layer (RNFL) quadrants most affected in patients with OPA1 mutations
  4. Differentiate the pattern of RNFL thinning between patients with pure DOA and DOA+ phenotypes


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Author(s)

  • Patrick Yu-Wai-Man, MRCOphth

    Mitochondrial Research Group, Institute for Ageing and Health, The Medical School, Newcastle University, United Kingdom; Department of Ophthalmology, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom; Institute of Human Genetics, Newcastle University, United Kingdom

    Disclosures

    Disclosure: Patrick Yu-Wai-Man, MRCOphth, has disclosed no relevant financial relationships.

  • Maura Bailie

    Department of Ophthalmology, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom

    Disclosures

    Disclosure: Maura Bailie has disclosed no relevant financial relationships.

  • Alaa Atawan

    Department of Ophthalmology, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom

    Disclosures

    Disclosure: Alaa Atawan has disclosed no relevant financial relationships.

  • Patrick F. Chinnery, PhD, FRCPath

    Mitochondrial Research Group, Institute for Ageing and Health, The Medical School, Newcastle University, United Kingdom; Institute of Human Genetics, Newcastle University, United Kingdom

    Disclosures

    Disclosure: Patrick F. Chinnery, PhD, FRCPath, has disclosed no relevant financial relationships.

  • Philip G. Griffiths, FRCOphth

    Mitochondrial Research Group, Institute for Ageing and Health, The Medical School, Newcastle University, United Kingdom; Department of Ophthalmology, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom

    Disclosures

    Disclosure: Philip G. Griffiths, FRCOphth, has disclosed no relevant financial relationships.

Editor(s)

  • A.J. Lotery, MD, FRCOphth

    Editor-in-Chief, Eye

    Disclosures

    Disclosure: A.J. Lotery, MD, FRCOphth, has disclosed the following relevant financial relationships:
    Received grants for clinical research from: Novartis Pharmaceuticals Corporation
    Served as an advisor or consultant for: Alcon Laboratories, Inc.
    Served as a speaker or member of a speakers bureau for: Bausch & Lomb Inc.

CME Author(s)

  • Désirée Lie, MD, MSEd

    Clinical Professor; Director of Research and Faculty Development, Department of Family Medicine, University of California, Irvine at Orange

    Disclosures

    Disclosure: Désirée Lie, MD, MSEd, has disclosed the following relevant financial relationship:
    Served as a nonproduct speaker for: "Topics in Health" for Merck Speaker Services

CME Reviewer(s)

  • Nafeez Zawahir, MD

    CME Clinical Director, Medscape, LLC

    Disclosures

    Disclosure: Nafeez Zawahir, MD, has disclosed no relevant financial relationships.

  • Sarah Fleischman

    CME Program Manager, Medscape, LLC

    Disclosures

    Disclosure: Sarah Fleischman has disclosed no relevant financial relationships.


Accreditation Statements

    For Physicians

  • This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of Medscape, LLC and Nature Publishing Group. Medscape, LLC is accredited by the ACCME to provide continuing medical education for physicians.

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CME

Pattern of Retinal Ganglion Cell Loss in Dominant Optic Atrophy Due to OPA1 Mutations: Discussion

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Discussion

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.