Dominant optic atrophy
Encyclopedia
Dominant optic atrophy, or dominant optic atrophy, Kjer's type, is an autosomally inherited disease that affects the optic nerve
s, 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.
beginning in childhood. Vision testing will reveal scotoma
s (areas of impaired visual acuity) in the central visual field
s 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.
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.
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 myelin
ated 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).
Optic nerve
The optic nerve, also called cranial nerve 2, transmits visual information from the retina to the brain. Derived from the embryonic retinal ganglion cell, a diverticulum located in the diencephalon, the optic nerve doesn't regenerate after transection.-Anatomy:The optic nerve is the second of...
s, causing reduced visual acuity
Visual acuity
Visual acuity is acuteness or clearness of vision, which is dependent on the sharpness of the retinal focus within the eye and the sensitivity of the interpretative faculty of the brain....
and blindness
Blindness
Blindness is the condition of lacking visual perception due to physiological or neurological factors.Various scales have been developed to describe the extent of vision loss and define 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
Glaucoma
Glaucoma is an eye disorder in which the optic nerve suffers damage, permanently damaging vision in the affected eye and progressing to complete blindness if untreated. It is often, but not always, associated with increased pressure of the fluid in the eye...
, 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 lossVision loss
Vision loss or visual loss is the absence of vision where it existed before, which can happen either acutely or chronically .-Ranges of vision loss:...
beginning in childhood. Vision testing will reveal scotoma
Scotoma
A scotoma is an area of partial alteration in one's field of vision consisting of a partially diminished or entirely degenerated visual acuity which is surrounded by a field of normal - or relatively well-preserved - vision.Every normal mammalian eye has a scotoma in its field of vision, usually...
s (areas of impaired visual acuity) in the central visual field
Visual field
The term visual field is sometimes used as a synonym to field of view, though they do not designate the same thing. The visual field is the "spatial array of visual sensations available to observation in introspectionist psychological experiments", while 'field of view' "refers to the physical...
s with peripheral vision sparing and impaired color vision (color blindness
Color blindness
Color blindness or color vision deficiency is the inability or decreased ability to see color, or perceive color differences, under lighting conditions when color vision is not normally impaired...
). Visual acuity
Visual acuity
Visual acuity is acuteness or clearness of vision, which is dependent on the sharpness of the retinal focus within the eye and the sensitivity of the interpretative faculty of the brain....
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
Fundus (eye)
The fundus of the eye is the interior surface of the eye, opposite the lens, and includes the retina, optic disc, macula and fovea, and posterior pole. The fundus can be viewed with an ophthalmoscope. The term may also be inclusive of Bruch's membrane and the choroid.The color of the fundus varies...
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
Glaucoma
Glaucoma is an eye disorder in which the optic nerve suffers damage, permanently damaging vision in the affected eye and progressing to complete blindness if untreated. It is often, but not always, associated with increased pressure of the fluid in the eye...
.
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 incidenceIncidence (epidemiology)
Incidence is a measure of the risk of developing some new condition within a specified period of time. Although sometimes loosely expressed simply as the number of new cases during some time period, it is better expressed as a proportion or a rate with a denominator.Incidence proportion is the...
of dominant optic atrophy has been estimated to be 1:50000 with prevalence
Prevalence
In epidemiology, the prevalence of a health-related state in a statistical population is defined as the total number of cases of the risk factor in the population at a given time, or the total number of cases in the population, divided by the number of individuals in the population...
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
Penetrance
Penetrance in genetics is the proportion of individuals carrying a particular variant of a gene that also express an associated trait . In medical genetics, the penetrance of a disease-causing mutation is the proportion of individuals with the mutation who exhibit clinical symptoms...
(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 mutationMutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
of the OPA1 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
found on chromosome
Chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
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
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
into discrete usable units (ATP
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
) for the cell’s functions (See oxidative phosphorylation
Oxidative phosphorylation
Oxidative phosphorylation is a metabolic pathway that uses energy released by the oxidation of nutrients to produce adenosine triphosphate . Although the many forms of life on earth use a range of different nutrients, almost all aerobic organisms carry out oxidative phosphorylation to produce ATP,...
, electron transport chain
Electron transport chain
An electron transport chain couples electron transfer between an electron donor and an electron acceptor with the transfer of H+ ions across a membrane. The resulting electrochemical proton gradient is used to generate chemical energy in the form of adenosine triphosphate...
). 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 myelin
Myelin
Myelin is a dielectric material that forms a layer, the myelin sheath, usually around only the axon of a neuron. It is essential for the proper functioning of the nervous system. Myelin is an outgrowth of a type of glial cell. The production of the myelin sheath is called myelination...
ated neurons such as those found in the papillomacular bundle of the retina
Retina
The vertebrate retina is a light-sensitive tissue lining the inner surface of the eye. The optics of the eye create an image of the visual world on the retina, which serves much the same function as the film in a camera. Light striking the retina initiates a cascade of chemical and electrical...
, which transmit information corresponding to the central visual field
Visual field
The term visual field is sometimes used as a synonym to field of view, though they do not designate the same thing. The visual field is the "spatial array of visual sensations available to observation in introspectionist psychological experiments", while 'field of view' "refers to the physical...
.
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).