Kjer's optic neuropathy

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Other

names

Autosomal dominant optic

atrophy, Kjer type; Kjer optic

atrophy; or, Kjer's autosomal

dominant optic atrophy.

Dominant optic atrophy (DOA)

, or

autosomal dominant optic atrophy

(ADOA), (Kjer's type)

is an

inherited disease that affects the

, causing reduced

and

beginning in

childhood. However, the disease can seem to re-present a second time with

further vision loss due to the early onset of presbyopia symptoms (i.e.,

difficulty in viewing objects up close).

DOA is characterized as affecting

neurons called

(RGCs). This condition is due to

dysfunction mediating the death of optic nerve fibers. The RGCs

axons form the optic nerve. Therefore, the disease can be considered of the central nervous system.

Dominant optic

atrophy was first described clinically by Batten in 1896 and named Kjer's optic

in 1959 after Danish

, who studied 19 families with the disease.

Although dominant optic atrophy is the most

common autosomally inherited optic neuropathy (i.e., disease of the optic nerves), it is often misdiagnosed.

Presentation

[

]

Autosomal dominant optic atrophy can present clinically as an isolated bilateral optic neuropathy (non-syndromic

form) or rather as a complicated phenotype with extra-ocular signs (syndromic form). Dominant optic atrophy usually

affects both eyes roughly symmetrically in a slowly progressive pattern of

beginning in childhood and is

hence a contributor to

[

]

A Humphrey Visual Field (HVF) can detect where areas of impaired vision have occurred, which usually shows up as

central, centrocaecal, or paracentral scotomas for DOA patients.

Another visual test—

(OCT) analyzes the optic nerve head—shows other structural consequences of the disease as retinal nerve fiber layer

(RNFL) and ganglion cell layer thinning. Photographs of the fundus shows the typical optic atrophy worse on the

temporal side of the optic disc in the shape of a wedge.

Cupping of the optic disc was found in 89% of DOA patients

in at least one of their eyes.

With loss of the central visual fields, there is impairment of color vision in addition to loss of

varying from mild to severe, typically ranging from 6/6 (in meters, equivalent to 20/20, ft) to 6/60 (20/200, ft) with

a median value of 6/36 (roughly equivalent to 20/125 ft), corrected vision. Vision loss may sometimes be more

severe.

[

]

Characteristic changes of the

evident on examination includes optic atrophy. In some cases, this may

include optic disc cupping similar in appearance to glaucoma of the optic disc. Because the onset of Dominant optic

atrophy is insidious, symptoms are often not noticed by the patients in its early stages and are picked up by chance

in routine school eye screenings. The first signs of DOA typically present between 6–10 years of age, though

presentation at as early as 1 year of age has been reported. In some cases, Dominant optic atrophy may remain

subclinical until early adulthood. While symptoms typically begin to present in childhood, adult patients (around the

age of 35) commonly complain of new onset loss of vision at near.

[

]

The emergence of premature presbyopia occurs from DOA patients being accustomed to holding objects closer to their

faces to read. As a result, Donder's curve should not be used to prescribe them lenses to correct premature

presbyopia. Instead of calculating based on individuals reading from about 16 inches from the face, DOA patients

should be calculated at around 8 inches due to their shortened reading distance.

Progression of dominant optic atrophy varies even within the same family. Some have mild cases with visual acuity

stabilizing in adolescence, others have slowly but constantly progressing cases, and others still have sudden step-

like decreases in visual acuity. Generally, the severity of the condition by adolescence reflects the overall level of

visual function to be expected throughout most of the patient's adult life (Votruba, 1998). Slow decline in acuity is

known to occur in late middle age in some families.

[

]

In complicated cases of autosomal dominant optic atrophy, in addition to bilateral optic neuropathy, several other

neurological signs of neurological involvement can rarely be observed: peripheral neuropathy, deafness, cerebellar

ataxia, spastic paraparesis, myopathy.

Genetics

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]

Dominant optic atrophy is inherited in an

manner. That is, a

patient with the disease

has a 50% chance of passing on the disease to each offspring, assuming his/her partner does not have the disease.

Males and females are affected at the same rate. Although DOA has a high

(98%), severity and progression of

DOA are extremely variable even within the same family.

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Pathophysiology

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Vision loss in dominant optic atrophy is due to optic nerve fiber loss from mitochondria dysfunction. Dominant optic

atrophy is associated with mutation of the

gene

found on chromosome 3, region q28-qter. Also, 5 other

chromosomal genes are described as causing optic atrophy: OPA2 (x-linked), OPA3 (dominant), OPA4 (dominant), OPA5

(dominant) and OPA6 (recessive) (see OMIM 165500).

The OPA1 gene codes for a dynamin-related GTPase protein targeted to the mitochondrial inner membrane. OPA1 has

distinct roles in the fusion of mitochondrial inner membranes during mitochondrial fusion events, and in regulation of

cell death.

are subcellular structures that generate and transform energy from

into discrete usable units

(

) for the cell's functions (See

(

) make up the

and have a long

portion, hence the high energy demand and sensitivity

to mitochondrial dysfunction. This is especially the case for smaller

such as those found in the papillomacular

bundle of the

, which transmit information corresponding to the central

. The surface ratios of

these smaller axons make them even more vulnerable to mitochondrial impairments. Biochemical and mitochondrial

morphological studies on cells from patients affected by autosomal dominant optic atrophy have shown a severe defect

in the shape (with a very remarkable fragmentation of the mitochondrial tubules in small spheres) and distribution of

mitochondria, occurring independently from a bioenergetic defect (respiratory chain function,

, and

reactive oxygen species production) or apoptosis, indicating that the

defect is the primary

pathogenetic mechanism,

although variable bioenergetic defects can also occur as a secondary phenomenon,

especially in severe cases with complicated phenotypes and accumulation of multiple mitochondrial-DNA deletions.

Over 200 different mutations of the OPA1 gene causing DOA have been reported, most of which occur in the catalytic

domain of the protein.

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Mutations at the OPA1 gene are also associated with normal tension

(OMIM 606657) and deafness (OMIM 125250).

Management

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Currently, there are no curative therapies available for dominant optic atrophy. Some studies have found usage of

idebenone to be associated with mild improvement in visual acuity for DOA patients with OPA1 mutation.

Idebenone

works as an antioxidant by shuttling electrons affected by reduced ATP synthesis and defective oxidative

phosphorylation in complex I directly to complex III.

Typically, idebenone is prescribed to be taken three times a

day.

Patients should be monitored for changes in vision by their eye-care professional. Children of patients should be

screened regularly for visual changes related to dominant optic atrophy. Research is underway to further characterize

the disease so that therapies may be developed.

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]

Since November 2018,

has been focusing on fellow patients and their families. They have the

following goals: scientific research, disease awareness, interaction between all parties involved and a trustworthy

place for the patients.

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Incidence

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The

of dominant optic atrophy has been estimated to be 1:50,000 with

as high as 1:10,000 in the

Danish population (Votruba, 1998).