Autosomal Dominant Optic Atrophy

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Original article contributed by: Sun Young Lee, MD, PhD
All contributors: Sun Young Lee, MD, PhD and WikiWorks
Review: Not reviewed
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Disease Entity[edit | edit source]

Autosomal dominant optic atrophy(ADOA) is believed to be the most common hereditary optic neuropathy with an estimated disease prevalence of 1:50,5000.1

Disease[edit | edit source]

The typical onset of visual loss is in the first or second decade of life, although most patients cannot identify a precise onset of reduced acuity due to the gradual progression and lack of abrupt onset. Visual acuity loss is commonly bilateral and relatively symmetric and is usually mild, slow, and insidious. More than 80 % of patients maintain better than 20/200 vision, although there is variable interfamilial and intrafamilial variation.2 Color vision deficits are also invariably present.


Pathophysiology[edit | edit source]

ADOA is associated with mutations in the nuclear OPA1 gene that encodes for a mitochondrial-targeted protein that appears to be involved in mitochondrial membrane biogenesis and stabilization of membrane integrity.3,4

Mitochondrial ds.jpg

Figure 1. Hereditary optic neuropathies and a proposed common pathophysiology through mitochondrial dysfunction. This schematic diagram of a cell shows how proteins coded for in the nucleus and in the mitochondria both contribute to mitochondrial function.5 The bold arrows indicated where the genetic defects underlying dominant optic atrophy (DOA), Leber hereditary optic neuropathy (LHON), and Wolfram syndrome (DIDMOAD) may cause mitochondrial dysfunction and optic atrophy. mRNA=messenger RNA; mtDNA=mitochondrial DNA;oxphos=oxidative phosphorylation.

Diagnosis[edit | edit source]

Individuals typically present with bilateral and slow vision loss starting in the first or second decade of life. Family history of similar presentation is common, but may be absent due to considerable interfamilial and intrafamilial variation in visual acuity. As a result, optic atrophy with little or no vision loss is frequently discovered in otherwise undiagnosed and “asymptomatic” family members.
Optic disc atrophy typically shows focal, wedged-shaped temporal optic atrophy, however diffuse atrophy may be present. As the primary pathology is the papillomacular bundle, central, centrocecal and paracentral scotomas are the most common visual field defects. Color vision deficits are common. Visual-evoked responses in affected individuals show diminished amplitudes and prolonged latencies. Pattern electroretinograms show a reduced N95 component.4

ADOA fd.jpg

ADOA VF.jpg[edit | edit source]

RNFL.jpg

Figure 2. Both optic nerve heads present temporal pallor as seen on fundus photography and those are often more prominent at red-free fundus photo. Humphrey visual field test shows cecocentral scotoma in right eye and central scotoma in left eye. Optic coherence tomography (OCT) evaluating retinal nerve fiber layer (RNFL) shows decreased average thickness predominantly at temporal aspect in both eyes.

Laboratory test[edit | edit source]

Although OPA 1 is known to be the major gene involved, because of the large number of different causative mutations, a simple, rapid DNA test, such as that used for LOHN, is not possible except in those families in which the mutation is known.5

Management[edit | edit source]

There is no established medical treatment for ADOA. ADOA is regarded as representative of one of the two classic paradigms of mitochondrial dysfunction in optic neuropathies (LHON being the other). Nutritional supplements such as vitamin B12 and C, Coenzyme-Q10, and lutein have been suggested to reduce reacitive oxygen species induced stress in the optic nerve. Topical agents deemes neuroprotective or antiapoptotic, such as bromonidine, have also been suggested. However, the evidence of their efficay remains anecdotal.6

References[edit | edit source]


1. Kjer B, Eiberg H, Kjer P, Rosenberg T. Dominant optic atrophy mapped to chromosome 3q region. II. Clinical and epidemiological aspects. Acta Ophthalmol Scand. 1996;74(1):3-7.

2. Votruba M, Fitzke FW, Holder CE, Carter A, Bhattacharya SS, Moore AT. Clinical features in affected individuals from 21 pedigrees with dominant optic atrophy. Arch Ophthalmol. 1998;116(3):353-358.

3. Delettre C, Lenaers G, Pelloquin L, Belenguer P, Hamel CP. OPA1 (Kjer type) dominant optic atrophy: a novel mitochondrial disease. Mol Genet Metab. 2002;75(2):97-107.

4. Kline LB, Glaser JS. Dominant optic atrophy: The clinical profile. Arch Ophthalmol. 1979;97(9):245-251.

5. Newman NJ. Hereditary Optic Neuropathies: from the mitochondria to the optic nerve. Am J Ophthal. 2005;140(3):517-523.

6. Carelli V, La Morgia C, Sadun AA. Mitochondrial dysfunction in optic neuropathies: animal models and therapeutic options. Curr Opin Neurol. 2013;26(1):52-58.