Autosomal dominant optic atrophy and cataract is an eye disorder that is characterized by impaired vision. Most affected individuals have decreased sharpness of vision (visual acuity) from birth, while others begin to experience vision problems in early childhood or later. In affected individuals, both eyes are usually affected equally. However, the severity of the vision loss varies widely, even among affected members of the same family, ranging from nearly normal vision to complete blindness.

Several abnormalities contribute to impaired vision in people with autosomal dominant optic atrophy and cataract. In the early stages of the condition, affected individuals experience a progressive loss of certain cells within the retina, which is a specialized light-sensitive tissue that lines the back of the eye. The loss of these cells (known as retinal ganglion cells) is followed by the degeneration (atrophy) of the nerves that relay visual information from the eyes to the brain (optic nerves), which contributes to vision loss. Atrophy of these nerves causes an abnormally pale appearance (pallor) of the optic nerves, which can be seen only during an eye examination. Most people with this disorder also have clouding of the lenses of the eyes (cataracts). This eye abnormality can develop anytime but typically appears in childhood. Other common eye problems in autosomal dominant optic atrophy and cataract include involuntary movements of the eyes (nystagmus), or problems with color vision (color vision deficiency) that make it difficult or impossible to distinguish between shades of blue and green.

Some people with autosomal dominant optic atrophy and cataract develop disturbances in the function of other nerves (neuropathy) besides the optic nerves. These disturbances can lead to problems with balance and coordination (cerebellar ataxia), an unsteady style of walking (gait), prickling or tingling sensations (paresthesias) in the arms and legs, progressive muscle stiffness (spasticity), or rhythmic shaking (tremors). In some cases, affected individuals have hearing loss caused by abnormalities of the inner ear (sensorineural deafness).

Autosomal dominant optic atrophy and cataract is caused by mutations in a gene called OPA3. The protein produced from this gene is made in cells and tissues throughout the body. The OPA3 protein is found within mitochondria, which are the energy-producing centers of cells. While the exact function of the protein is unknown, it is thought to play a role in the organization of the shape and structure of the mitochondria and in controlled cell death (apoptosis).

Mutations in the OPA3 gene lead to abnormal mitochondrial function. The mitochondria become misshapen and disorganized and have reduced energy-producing capabilities. Cells that contain these poorly functioning mitochondria seem to be more susceptible to apoptosis. In particular, affected cells that have high energy demands, such as retinal ganglion cells, are likely to die prematurely. Specialized extensions of retinal ganglion cells, called axons, form the optic nerves, so when retinal ganglion cells die, the optic nerves atrophy and cannot transmit visual information to the brain. Together, these effects reduce vision in affected individuals. It is likely that nerve cells in other parts of the body are similarly affected by dysfunctional mitochondria, resulting in the signs and symptoms of neuropathy in individuals with autosomal dominant optic atrophy and cataract. It is unclear how OPA3 gene mutations lead to cataracts and other eye problems that can occur in autosomal dominant optic atrophy and cataracts.

Normal Function

The OPA3 gene provides instructions for making a protein whose exact function is unknown. The OPA3 protein is found in structures called mitochondria, which are the energy-producing centers of cells. The OPA3 protein is thought to play a role in the organization of the shape and structure of the mitochondria and in controlled cell death (apoptosis).

Health Conditions Related to Genetic Changes

Autosomal dominant optic atrophy and cataract

At least four mutations in the OPA3 gene have been found to cause autosomal dominant optic atrophy and cataract. This condition causes slowly worsening vision in both eyes that often begins at birth. The severity of the vision loss varies widely, even among affected members of the same family. People with this condition have degeneration (atrophy) of the optic nerves, which carry information from the eyes to the brain, and clouding of the lenses of the eyes (cataracts). Some affected individuals have additional features such as hearing loss or movement problems.

Mutations in the OPA3 gene that cause autosomal dominant optic atrophy and cataract occur in one copy of the gene in each cell. A mutation that has been found in multiple people with autosomal dominant optic atrophy and cataract results in the production of a protein with the building block (amino acid) glutamine replaced with the amino acid glutamic acid at position 105 (written as Gln105Glu or Q105E).

This and other OPA3 gene mutations that cause autosomal dominant optic atrophy and cataract lead to abnormal mitochondrial function. The mitochondria become misshapen and disorganized and have reduced energy-producing capabilities. Cells that contain these poorly functioning mitochondria seem to be more susceptible to apoptosis, particularly those with high energy demands, such as a type in the eye called retinal ganglion cells. Specialized extensions of retinal ganglion cells, called axons, form the optic nerves, so when retinal ganglion cells die, the optic nerves atrophy and cannot transmit visual information to the brain. Loss of retinal ganglion cells and optic nerve atrophy contribute to vision impairment in people with autosomal dominant optic atrophy and cataracts. It is likely that nerve cells in other parts of the body are similarly affected by dysfunctional mitochondria, resulting in movement problems and hearing loss in some individuals with this condition.

Costeff syndrome

At least five mutations in the OPA3 gene have been found to cause Costeff syndrome. This condition is characterized by vision loss due to optic nerve atrophy, delayed development, and movement problems. Costeff syndrome is caused by mutations in both copies of the OPA3 gene in each cell, leading to a complete loss of OPA3 protein function. An OPA3 gene mutation that causes Costeff syndrome in the Iraqi Jewish population (written as 143-1G>C) alters the way the OPA3 gene's instructions are put together to make the protein, which results in a lack of functional protein. Cells without any functional OPA3 protein have abnormally shaped mitochondria with reduced energy-producing capabilities. Nerve cells in the brain and retinal ganglion cells that make up optic nerves have high energy demands and may be particularly dependent on energy production in the mitochondria for survival. It is likely that dysfunctional mitochondria and reduced energy production result in the death of these cell types more readily than other cell types.

Other Names for This Gene

• FLJ22187
• FLJ25932
• MGA3
• MGC75494
• OPA3 protein
• OPA3_HUMAN
• optic atrophy 3 (autosomal recessive, with chorea and spastic paraplegia)

Genomic Location

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

In most cases, an affected person has one parent with the condition.

Autosomal dominant optic atrophy and cataract is one form of autosomal dominant optic atrophy, a group of conditions that are estimated to affect 1 in 30,000 people worldwide, and approximately 1 in 10,000 people in Denmark. A form of optic atrophy called optic atrophy type 1 accounts for most cases, while autosomal dominant optic atrophy and cataract is thought to represent only a few percent of autosomal dominant optic atrophy cases.