Limits...
Dominant optic atrophy.

Lenaers G, Hamel C, Delettre C, Amati-Bonneau P, Procaccio V, Bonneau D, Reynier P, Milea D - Orphanet J Rare Dis (2012)

Bottom Line: The prevalence of the disease varies from 1/10000 in Denmark due to a founder effect, to 1/30000 in the rest of the world.To date, there is no preventative or curative treatment in DOA; severely visually impaired patients may benefit from low vision aids.Gene and pharmacological therapies for DOA are currently under investigation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institut des Neurosciences de Montpellier, U1051 de l'INSERM, Université de Montpellier I et II, BP 74103, F-34091 Montpellier cedex 05, France. guy.lenaers@inserm.fr

ABSTRACT

Unlabelled: DEFINITION OF THE DISEASE: Dominant Optic Atrophy (DOA) is a neuro-ophthalmic condition characterized by a bilateral degeneration of the optic nerves, causing insidious visual loss, typically starting during the first decade of life. The disease affects primary the retinal ganglion cells (RGC) and their axons forming the optic nerve, which transfer the visual information from the photoreceptors to the lateral geniculus in the brain.

Epidemiology: The prevalence of the disease varies from 1/10000 in Denmark due to a founder effect, to 1/30000 in the rest of the world.

Clinical description: DOA patients usually suffer of moderate visual loss, associated with central or paracentral visual field deficits and color vision defects. The severity of the disease is highly variable, the visual acuity ranging from normal to legal blindness. The ophthalmic examination discloses on fundoscopy isolated optic disc pallor or atrophy, related to the RGC death. About 20% of DOA patients harbour extraocular multi-systemic features, including neurosensory hearing loss, or less commonly chronic progressive external ophthalmoplegia, myopathy, peripheral neuropathy, multiple sclerosis-like illness, spastic paraplegia or cataracts.

Aetiology: Two genes (OPA1, OPA3) encoding inner mitochondrial membrane proteins and three loci (OPA4, OPA5, OPA8) are currently known for DOA. Additional loci and genes (OPA2, OPA6 and OPA7) are responsible for X-linked or recessive optic atrophy. All OPA genes yet identified encode mitochondrial proteins embedded in the inner membrane and ubiquitously expressed, as are the proteins mutated in the Leber Hereditary Optic Neuropathy. OPA1 mutations affect mitochondrial fusion, energy metabolism, control of apoptosis, calcium clearance and maintenance of mitochondrial genome integrity. OPA3 mutations only affect the energy metabolism and the control of apoptosis.

Diagnosis: Patients are usually diagnosed during their early childhood, because of bilateral, mild, otherwise unexplained visual loss related to optic discs pallor or atrophy, and typically occurring in the context of a family history of DOA. Optical Coherence Tomography further discloses non-specific thinning of retinal nerve fiber layer, but a normal morphology of the photoreceptors layers. Abnormal visual evoked potentials and pattern ERG may also reflect the dysfunction of the RGCs and their axons. Molecular diagnosis is provided by the identification of a mutation in the OPA1 gene (75% of DOA patients) or in the OPA3 gene (1% of patients).

Prognosis: Visual loss in DOA may progress during puberty until adulthood, with very slow subsequent chronic progression in most of the cases. On the opposite, in DOA patients with associated extra-ocular features, the visual loss may be more severe over time.

Management: To date, there is no preventative or curative treatment in DOA; severely visually impaired patients may benefit from low vision aids. Genetic counseling is commonly offered and patients are advised to avoid alcohol and tobacco consumption, as well as the use of medications that may interfere with mitochondrial metabolism. Gene and pharmacological therapies for DOA are currently under investigation.

Show MeSH

Related in: MedlinePlus

Ophthalmological description of a DOA patient. Results from ophthalmological examination of a paradigm Dominant Optic Atrophy patient with the c.2708delTTAG mutation in OPA1 (Right) compared to a control patient (Left). (A): Eye fundus examination showing the pallor of the optic nerve in the DOA patient, in particular on the temporal side, whereas the rest of the retina appears totally unaffected. (B): Optical Coherence Tomography measures of the retinal nerve fiber layer thickness (black line), at the emergence of the optic disc. In a DOA patient, there is a general reduction in all quadrants, prevailing on the temporal side, compared to a control patient. (C): Visual field examination disclosing the caeco-central scotoma in the DOA patient, whereas only the blind spot is detected in control patient. (D): Results from a desaturated 15-Hue test presenting the characteristic tritanopia (blue-yellow axis) dyschromatopsia defect in the DOA patient.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3526509&req=5

Figure 1: Ophthalmological description of a DOA patient. Results from ophthalmological examination of a paradigm Dominant Optic Atrophy patient with the c.2708delTTAG mutation in OPA1 (Right) compared to a control patient (Left). (A): Eye fundus examination showing the pallor of the optic nerve in the DOA patient, in particular on the temporal side, whereas the rest of the retina appears totally unaffected. (B): Optical Coherence Tomography measures of the retinal nerve fiber layer thickness (black line), at the emergence of the optic disc. In a DOA patient, there is a general reduction in all quadrants, prevailing on the temporal side, compared to a control patient. (C): Visual field examination disclosing the caeco-central scotoma in the DOA patient, whereas only the blind spot is detected in control patient. (D): Results from a desaturated 15-Hue test presenting the characteristic tritanopia (blue-yellow axis) dyschromatopsia defect in the DOA patient.

Mentions: On fundus examination, the optic disk typically presents a bilateral and symmetrical pallor of its temporal side, witnessing the loss of RGC fibers entering the optic nerve (Figure1A). The optic nerve rim is atrophic and a temporal grey crescent is often present. Optic disc excavation is not unusual, but its clinical features vary in most of the cases from that of glaucoma. Optical Coherence Tomography (OCT) discloses the reduction of the thickness of the peripapillary retinal nerve fiber layer in all four quadrants, but does not disclose alteration of other retinal layers[22,23] (Figure1B). The visual field typically shows a caecocentral scotoma, and less frequently a central or paracentral scotoma, while peripheral visual field remains normal (Figure1C). Importantly, there is a specific tritanopia, i.e. a blue-yellow axis of color confusion, which, when found, is strongly indicative of Kjer disease[24,25] (Figure1D). However, in severe cases or in patients with congenital dyschromatopsia (daltonism), interpretation of the color vision defect may be more difficult. The pupillary reflex and circadian rhythms are not affected, suggesting that the melanopsin RGC are spared during the course of the disease[26,27].


Dominant optic atrophy.

Lenaers G, Hamel C, Delettre C, Amati-Bonneau P, Procaccio V, Bonneau D, Reynier P, Milea D - Orphanet J Rare Dis (2012)

Ophthalmological description of a DOA patient. Results from ophthalmological examination of a paradigm Dominant Optic Atrophy patient with the c.2708delTTAG mutation in OPA1 (Right) compared to a control patient (Left). (A): Eye fundus examination showing the pallor of the optic nerve in the DOA patient, in particular on the temporal side, whereas the rest of the retina appears totally unaffected. (B): Optical Coherence Tomography measures of the retinal nerve fiber layer thickness (black line), at the emergence of the optic disc. In a DOA patient, there is a general reduction in all quadrants, prevailing on the temporal side, compared to a control patient. (C): Visual field examination disclosing the caeco-central scotoma in the DOA patient, whereas only the blind spot is detected in control patient. (D): Results from a desaturated 15-Hue test presenting the characteristic tritanopia (blue-yellow axis) dyschromatopsia defect in the DOA patient.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3526509&req=5

Figure 1: Ophthalmological description of a DOA patient. Results from ophthalmological examination of a paradigm Dominant Optic Atrophy patient with the c.2708delTTAG mutation in OPA1 (Right) compared to a control patient (Left). (A): Eye fundus examination showing the pallor of the optic nerve in the DOA patient, in particular on the temporal side, whereas the rest of the retina appears totally unaffected. (B): Optical Coherence Tomography measures of the retinal nerve fiber layer thickness (black line), at the emergence of the optic disc. In a DOA patient, there is a general reduction in all quadrants, prevailing on the temporal side, compared to a control patient. (C): Visual field examination disclosing the caeco-central scotoma in the DOA patient, whereas only the blind spot is detected in control patient. (D): Results from a desaturated 15-Hue test presenting the characteristic tritanopia (blue-yellow axis) dyschromatopsia defect in the DOA patient.
Mentions: On fundus examination, the optic disk typically presents a bilateral and symmetrical pallor of its temporal side, witnessing the loss of RGC fibers entering the optic nerve (Figure1A). The optic nerve rim is atrophic and a temporal grey crescent is often present. Optic disc excavation is not unusual, but its clinical features vary in most of the cases from that of glaucoma. Optical Coherence Tomography (OCT) discloses the reduction of the thickness of the peripapillary retinal nerve fiber layer in all four quadrants, but does not disclose alteration of other retinal layers[22,23] (Figure1B). The visual field typically shows a caecocentral scotoma, and less frequently a central or paracentral scotoma, while peripheral visual field remains normal (Figure1C). Importantly, there is a specific tritanopia, i.e. a blue-yellow axis of color confusion, which, when found, is strongly indicative of Kjer disease[24,25] (Figure1D). However, in severe cases or in patients with congenital dyschromatopsia (daltonism), interpretation of the color vision defect may be more difficult. The pupillary reflex and circadian rhythms are not affected, suggesting that the melanopsin RGC are spared during the course of the disease[26,27].

Bottom Line: The prevalence of the disease varies from 1/10000 in Denmark due to a founder effect, to 1/30000 in the rest of the world.To date, there is no preventative or curative treatment in DOA; severely visually impaired patients may benefit from low vision aids.Gene and pharmacological therapies for DOA are currently under investigation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institut des Neurosciences de Montpellier, U1051 de l'INSERM, Université de Montpellier I et II, BP 74103, F-34091 Montpellier cedex 05, France. guy.lenaers@inserm.fr

ABSTRACT

Unlabelled: DEFINITION OF THE DISEASE: Dominant Optic Atrophy (DOA) is a neuro-ophthalmic condition characterized by a bilateral degeneration of the optic nerves, causing insidious visual loss, typically starting during the first decade of life. The disease affects primary the retinal ganglion cells (RGC) and their axons forming the optic nerve, which transfer the visual information from the photoreceptors to the lateral geniculus in the brain.

Epidemiology: The prevalence of the disease varies from 1/10000 in Denmark due to a founder effect, to 1/30000 in the rest of the world.

Clinical description: DOA patients usually suffer of moderate visual loss, associated with central or paracentral visual field deficits and color vision defects. The severity of the disease is highly variable, the visual acuity ranging from normal to legal blindness. The ophthalmic examination discloses on fundoscopy isolated optic disc pallor or atrophy, related to the RGC death. About 20% of DOA patients harbour extraocular multi-systemic features, including neurosensory hearing loss, or less commonly chronic progressive external ophthalmoplegia, myopathy, peripheral neuropathy, multiple sclerosis-like illness, spastic paraplegia or cataracts.

Aetiology: Two genes (OPA1, OPA3) encoding inner mitochondrial membrane proteins and three loci (OPA4, OPA5, OPA8) are currently known for DOA. Additional loci and genes (OPA2, OPA6 and OPA7) are responsible for X-linked or recessive optic atrophy. All OPA genes yet identified encode mitochondrial proteins embedded in the inner membrane and ubiquitously expressed, as are the proteins mutated in the Leber Hereditary Optic Neuropathy. OPA1 mutations affect mitochondrial fusion, energy metabolism, control of apoptosis, calcium clearance and maintenance of mitochondrial genome integrity. OPA3 mutations only affect the energy metabolism and the control of apoptosis.

Diagnosis: Patients are usually diagnosed during their early childhood, because of bilateral, mild, otherwise unexplained visual loss related to optic discs pallor or atrophy, and typically occurring in the context of a family history of DOA. Optical Coherence Tomography further discloses non-specific thinning of retinal nerve fiber layer, but a normal morphology of the photoreceptors layers. Abnormal visual evoked potentials and pattern ERG may also reflect the dysfunction of the RGCs and their axons. Molecular diagnosis is provided by the identification of a mutation in the OPA1 gene (75% of DOA patients) or in the OPA3 gene (1% of patients).

Prognosis: Visual loss in DOA may progress during puberty until adulthood, with very slow subsequent chronic progression in most of the cases. On the opposite, in DOA patients with associated extra-ocular features, the visual loss may be more severe over time.

Management: To date, there is no preventative or curative treatment in DOA; severely visually impaired patients may benefit from low vision aids. Genetic counseling is commonly offered and patients are advised to avoid alcohol and tobacco consumption, as well as the use of medications that may interfere with mitochondrial metabolism. Gene and pharmacological therapies for DOA are currently under investigation.

Show MeSH
Related in: MedlinePlus