Optic atrophy

Author: Doctor Christophe Orssaud1

Creation Date: August 2002
Update: November 2003

Scientific Editor: Professor Jean-Louis Dufier

1
Service d'ophtalmologie, Hôpital Européen Georges Pompidou, 20 rue Leblanc, 75908 PARIS Cedex 15,
France. Christophe.Orssaud@hop.egp.ap-hop-paris.fr

Abstract
Keywords
Included diseases
Excluded diseases
Definition/Diagnosis criteria
Differential diagnosis
Frequency
Clinical description
Diagnosis
Etiology
Treatment
References

Abstract
Optic atrophies (OA) refer to a specific group of hereditary optic neuropathies in which the cause of the
optic nerve dysfunction is inherited either in an autosomal dominant or autosomal recessive pattern.
Autosomal dominant optic atrophy (ADOA), type Kjer, is the most common OA, whereas autosomal
recessive optic atrophy (AROA) is a rare form. Prevalence of ADOA ranges from 1:50,000 to 1:10,000.
The frequency of AROA is unknown but the disease seems rare. MRI of patients with ADOA reflects the
important loss of tissue of the optic nerve due to a dramatic reduction of the retinal ganglion cells. The
age at onset of ADOA is usually between 4 and 6 years, although visual symptoms are usually
imperceptible until late in life due to the slowly progressive decrease in visual acuity. There is no
neurological deficit. However, a mild hearing loss may be encountered. In the pure congenital AROA,
optic atrophy is never associated with neurological disorder and visual impairment is severe. Since the
visual symptoms are important, AROA can be discovered very early, usually before the age of 4 years.
ADOA has been associated with More than 60 mutations in the OPA1 gene. OPA1 maps to 3q28 and
encodes an homologue of yeast dynamin-related GTPase, which is ubiquitously expressed in retinal
ganglion cells and optic nerve. To date, no causative gene has been identified in the recessive form of
OA.

Keywords
Optic atrophy, hereditary optic neuropathy, ADOA, AROA, OPA1 gene

Included diseases -Wolfram syndrome

-autosomal dominant optic atrophy, type Kjer; -Normal tension glaucoma
-autosomal recessive optic atrophy. -Acquired optic atrophies
Excluded diseases Definition/Diagnosis criteria
-Leber's hereditary optic neuropathy Optic atrophies (OA) refer to a specific group of
-Leigh syndrome hereditary optic neuropathies in which the cause

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of the optic nerve dysfunction is inherited either are usually mild until late in life due to the slowly
in an autosomal dominant or autosomal progressive decrease in visual acuity. In most
recessive pattern. Autosomal dominant optic cases, visual acuity is equally reduced in both
atrophy (ADOA), type Kjer, is the most common eyes. Intra or interfamilial phenotypic variations
OA, whereas autosomal recessive optic atrophy are important. Although the entire optic disc may
(AROA) is a rare form. be affected, it sometimes only displays temporal
pallor with an absence of vessels or capillaries.
Differential diagnosis Visual field exhibits central or paracentral
Leber's hereditary optic neuropathy, a maternally scotomas. A blue-yellow dyschromatopsia is
inherited optic atrophy due to mutations of the characteristically observed in color vision testing
mitochondrial DNA, and many other inherited in ADOA patients. MRI of patients with ADOA
optic atrophies such as Leigh syndrome, reveals a significant thinning of the optic nerve
Wolfram syndrome, Costeff optic atrophy along its length, confirming the important loss of
syndrome, can be differentiated from OA by the tissue of the optic nerve due to a dramatic
clinical findings and family history. reduction of the ganglion cells. There is no
Normal tension glaucoma (NTG) is particularly neurological deficit. Hearing loss may be
important to differentiate from OA since it leads encountered during the course of ADOA. But this
also to an optic atrophy and may have a genetic deficit is usually mild.
basis. The characteristic enlargement of the
optic is not specific of NTG and it can be Recessive form
observed in the course of OA. Thus, it is not In the pure congenital AROA, visual impairment
possible to rule out the diagnosis of AO with appears very early and is present at birth or
slow visual impairment when such optic disc appears in the first year of life. In addition, visual
enlargement is observed. High value must be impairment is severe, leading to visually disabled
attributed to the visual field defects or to vascular or to blind children. Since the visual symptoms
manifestations. In addition, it has been stated are important, AROA is discovered very early,
that polymorphisms of the OPA1 gene could be usually before the age of 4 years. Sensory
associated with NTG. nystagmus is the rule. At fundus examination,
normal retina contrasts with the diffuse pallor of
Frequency the optic disc. A cupping may develop with age.
The frequency of each OA varies depending on However, in very young children, it might be
their pattern of inheritance. Prevalence of ADOA difficult to differentiate AROA from Leber’s
ranges from 1:50,000 to 1:10,000. The congenital amaurosis or other retinal
frequency of AROA is unknown but the disease degenerations, since narrowing of retinal vessels
seems rare. and abnormalities of retinal pigmentation, which
are characteristic of these congenital retinal
Clinical description disorders, are delayed in juvenile forms.
OA are characterized by a primary degeneration Electrophysiological testing enables the
of retinal ganglion cells, the axons of which join diagnosis to be confirmed. Electroretinogram
to form the optic nerve. This degeneration leads (ERG) is normal in pure congenital AROA,
to ascending atrophy of the optic nerve and is whereas no responses are obtained in
responsible for the clinical manifestations of the congenital retinal degenerations. Visual evoked
OA, which consist mainly in a decreased visual potentials are absent in AROA, confirming the
acuity, abnormalities of the central visual field pathology of the optic tract. Visual field testing,
and a typical color vision defect. when possible, shows a central scotoma. This
form of optic atrophy is never associated with
Dominant form neurological disorder.
ADOA is characterized by a selective
degeneration of the retinal ganglion cells and Diagnosis
fibers of the papillo-macular bundle. This Diagnosis of OA forms is established on the
involvement of the smallest fibers of the optic basis of clinical findings and family history.
nerve is not specific to ADAO since it may be
also encountered in all genetic and acquired Etiology
optic neuropathies resulting from mitochondrial Linkage analysis revealed genetic heterogeneity
dysfunction. The age of onset is usually between in ADOA. Two loci have been identified, one
4 and 6 years, but ADAO rarely causes severe located on chromosome 3 (3q28-qter) and the
impairment of vision in childhood. Acuity ranges other one on chromosome 18 (18 q12.2-q12.3).
from 20/20 to 20/200 in 85% of young adult OPA1, the gene mapping to 3q28, is responsible
patients and is lower than 20/200 in the for most ADOA cases. This OPA1 gene
remaining 15%. But, visual impairment can comprises 28 coding exons and 8 mRNA
major quickly in adults. Thus visual symptoms isoforms have been reported, due to the

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alternative splicing of 3 different exons. More neuropathies. Neurochemistery. 2002. 40:573-
than 60 OPA1 mutations have been described. 84.
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homology with a yeast mitochondrial dynamin- Dominant optic atrophy (OPA1) mapped to
related GTPase, Msp1. This Msp1 protein is chromosome 3q region. I. Linkage analysis. Hum
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has been suggested that OPA1 mutations lead Kjer type: identification of a second locus on
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Treatment is not currently available. intra-orbital optic nerve in patients with
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