Kjer's optic neuropathy

Dominant optic atrophy, or dominant optic atrophy, Kjer's type, is an autosomally inherited disease that affects the optic nerves, causing reduced visual acuity and blindness beginning in childhood. This condition is due to mitochondrial dysfunction mediating the death of optic nerve fibers. Dominant optic atrophy was first described clinically by Batten in 1896 and named Kjer’s optic neuropathy in 1959 after Danish ophthalmologist Poul Kjer, 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) aside from glaucoma, it is often misdiagnosed.

Synonyms
Dominant optic atrophy is also known as autosomal dominant optic atrophy, Kjer type; Kjer optic atrophy; or, Kjer's autosomal dominant optic atrophy.

Clinical presentation
Dominant optic atrophy usually affects both eyes roughly symmetrically in a slowly progressive pattern of vision loss beginning in childhood. Vision testing will reveal scotomas (areas of impaired visual acuity) in the central visual fields with peripheral vision sparing and impaired color vision (color blindness). Visual acuity loss varies 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. In rare cases, vision loss is more severe.

Characteristic changes of the fundus evident on examination is temporal pallor (indicating atrophy) of the optic disc and in its end stage, excavation of the optic disc, as is also seen in Leber hereditary optic neuropathy and normal tension glaucoma.

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. First signs of Kjer's typically present between 4–6 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.

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.

Incidence and inheritance
The incidence of dominant optic atrophy has been estimated to be 1:50000 with prevalence as high as 1:10000 in the Danish population (Votruba, 1998). Dominant optic atrophy is inherited in an autosomal dominant manner. That is, a heterozygous patient with the disease has a 50% chance of passing on the disease to offspring, assuming his/her partner does not have the disease. Males and females are affected at the same rate. Although Kjer's has a high penetrance (98%), severity and progression of DOA are extremely variable even within the same family.

Pathophysiology
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 OPA1 gene found on chromosome 3, region q28-qter. Also, 5 other chromosomal genes are described 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. Although the mechanism of action of the OPA1 gene product is unknown, it is likely involved in stabilization of mitochondrial membrane complexes. OPA1 has been implicated in the fusion of mitochondrial inner membranes during mitochondrial fusion events, indicating that a mitochondrial fusion dysfunction may be important in the development of OPA1 related optic atrophy. Mitochondria are subcellular structures that generate and transform energy from metabolism into discrete usable units (ATP) for the cell’s functions (See oxidative phosphorylation, electron transport chain). Retinal ganglion cells (neurons), which make up the optic nerve, have a high energy demand and are particularly sensitive to mitochondrial dysfunction. This is especially the case for smaller and less myelinated neurons such as those found in the papillomacular bundle of the retina, which transmit information corresponding to the central visual field.

Dominant optic atrophy demonstrates genetic heterogeneity, which is where a single disease can be caused by various genetic defects at different loci. Over 60 different mutations of the OPA1 gene causing Kjer's have been reported.

Mutations at the OPA1 gene are also associated with normal tension glaucoma (OMIM 606657) and deafness (OMIM 125250).

Management
Currently there is no effective therapy for dominant optic atrophy, and consequently, these patients are simply 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.