Hereditary Optic Atrophy

Hereditary optic atrophy is a group of inherited disorders that damage the optic nerve, causing progressive vision loss that typically begins in childhood or adolescence and affects both eyes.

Table of contents

• What is Hereditary Optic Atrophy?
• Main Types of Hereditary Optic Atrophy
• Causes and Inheritance Patterns
• Symptoms and Warning Signs
• How is it Diagnosed?
• Treatment and Management
• Living with the Condition

What is Hereditary Optic Atrophy?

Hereditary optic atrophy, also called hereditary optic neuropathy, refers to a group of genetic conditions that cause damage to the optic nerve, the nerve that carries visual signals from your eye to your brain^[1]. The word “atrophy” means to waste away or deteriorate. When the optic nerve deteriorates, it loses its ability to transmit these important visual signals, leading to vision loss^[2].

These disorders typically show up in childhood or adolescence, though they can appear at any age. Vision loss affects both eyes and is usually permanent^[1]. The damage happens because of genetic defects that particularly affect special cells called retinal ganglion cells, which are located in the inner layer of the retina at the back of the eye. These cells and their extensions form the optic nerve^[4].

Hereditary optic neuropathy, Inherited optic atrophy

Main Types of Hereditary Optic Atrophy

The two most common forms of hereditary optic atrophy are dominant optic atrophy and Leber hereditary optic neuropathy. While both cause vision loss through optic nerve damage, they differ in how they are inherited and how quickly vision loss occurs^[1].

Dominant Optic Atrophy

Dominant optic atrophy is believed to be the most common of the hereditary optic neuropathies, affecting approximately 1 in 10,000 to 1 in 50,000 people^[1]. In the United Kingdom, it’s estimated to affect about 1 in 25,000 individuals^[16]. This form is also known as autosomal dominant optic atrophy or Kjer type optic atrophy^[5].

Vision loss in dominant optic atrophy often begins in the first decade of life, though it can be detected later^[1]. The condition causes gradual, slowly progressive vision loss over years to decades. Most patients experience a narrowing of their field of vision, creating what is called tunnel vision^[5]. The severity varies widely, even among affected members of the same family, ranging from nearly normal vision to complete blindness^[5].

Leber Hereditary Optic Neuropathy

Leber hereditary optic neuropathy is a rare genetic disease that affects approximately 1 in 25,000 to 1 in 50,000 people, with about 2,000 people affected in England^[7]. Vision loss typically begins between ages 15 and 35, though it can occur anywhere from age 1 to 80 years^[1].

In Leber hereditary optic neuropathy, vision loss is fairly rapid, occurring over weeks to several months^[6]. Painless central vision loss usually starts in one eye and is followed weeks to months later by loss in the other eye, though both eyes can be affected simultaneously^[1]. Most patients lose vision and develop worse than 20/200 visual acuity, which is considered legally blind^[1].

Most cases of Leber hereditary optic neuropathy occur in males, with approximately 80% to 90% of affected individuals being male^[7].

Causes and Inheritance Patterns

Hereditary optic atrophies are caused by genetic defects, but the specific genes involved differ between types. Both forms affect structures called mitochondria, which are the energy-producing centers inside cells^[1].

Genetic Basis of Dominant Optic Atrophy

About 75% of cases of dominant optic atrophy are caused by mutations in a gene called OPA1^[5]. This gene provides instructions for making a protein found within mitochondria that plays a key role in organizing their shape and structure, in controlled cell death, and in energy production^[5]. A smaller number of cases are caused by mutations in another gene called OPA3^[5].

Dominant optic atrophy is inherited in an autosomal dominant pattern. This means only one copy of the altered gene is needed to cause the disorder^[5]. If either parent has the disease, each child has a 50% chance of developing it^[6]. In some cases, the mutation is new and occurs in people with no family history of the disorder^[5].

Genetic Basis of Leber Hereditary Optic Neuropathy

Leber hereditary optic neuropathy involves abnormalities in mitochondrial DNA, which is genetic material found within mitochondria that is separate from the DNA in the cell’s nucleus^[1]. About 90% of cases are due to one of three specific mutations that affect parts of the energy production system in mitochondria^[8].

This condition is inherited through the mother only, because mitochondria and their DNA are passed from mother to child. All children of a woman with the abnormality inherit the abnormality, but only females can pass it on to their children^[1]. Affected men cannot pass the disease to their children^[6].

Symptoms and Warning Signs

The main symptom of hereditary optic atrophy is vision loss, but the pattern and additional symptoms differ between the two main types^[1].

Vision-Related Symptoms

In dominant optic atrophy, vision loss is very gradual, progressing over years to decades^[6]. People typically experience blurry vision in both eyes that gradually worsens over time. They often develop a blind spot in the center of their vision and experience a progressive narrowing of their field of vision^[5]. Problems with color vision are common, particularly difficulty distinguishing shades of blue and yellow^[1].

In Leber hereditary optic neuropathy, vision loss is much more rapid, occurring over weeks to several months^[6]. Central vision becomes blurry or a blind spot develops in the middle of the field of vision. The loss is painless and typically affects one eye first, then the other^[7].

When doctors examine the eyes of people with hereditary optic atrophy, they can see that the optic disc (the visible part of the optic nerve at the back of the eye) appears abnormally pale. This paleness is related to changes in blood flow in the optic nerve^[2].

Additional Symptoms

Most people with dominant optic atrophy have no other health problems beyond vision loss. However, rarely, some people may also experience involuntary eye movements called nystagmus, hearing loss, or both^[1]. About 20% of patients develop what is called “dominant optic atrophy plus syndrome,” which can include hearing loss, numbness, muscle weakness, muscle stiffness, and balance difficulties^[16].

Some patients with Leber hereditary optic neuropathy have additional symptoms beyond vision loss. Rarely, they may develop problems with heart rhythm, tremors, loss of ankle reflexes, involuntary muscle contractions, muscle stiffness, or symptoms similar to multiple sclerosis^[1]. These additional symptoms are sometimes called “Leber plus”^[7].

How is it Diagnosed?

Diagnosis of hereditary optic atrophy begins with a thorough eye examination by an eye care specialist^[1].

Clinical Evaluation

During the examination, the doctor will ask about symptoms, medical history, and family history of vision problems. They will test visual sharpness, peripheral vision (side vision), and color vision. Using an instrument called an ophthalmoscope, the doctor will look at the back of the eye to examine the optic nerve^[2]. In hereditary optic atrophy, the optic disc appears pale compared to normal^[1].

Specialized Testing

Several specialized tests may be used to confirm the diagnosis and assess the extent of damage. These include optical coherence tomography (a detailed imaging test of the retina), visual field tests to map areas of vision loss, and imaging scans such as MRI to look for other possible causes^[2].

Genetic Testing

If hereditary optic atrophy is suspected based on the clinical examination, molecular genetic testing can be performed to confirm many of the mutations responsible for both dominant optic atrophy and Leber hereditary optic neuropathy^[1]. However, test results can be falsely negative because not all mutations can be detected by current testing methods^[1].

For Leber hereditary optic neuropathy, testing focuses on identifying the three most common mitochondrial DNA mutations. For dominant optic atrophy, testing looks for mutations in the OPA1 gene and, in some cases, the OPA3 gene^[4].

People suspected of having Leber hereditary optic neuropathy may also undergo electrocardiography to check their heart function, as some patients can develop heart rhythm problems^[6].

Treatment and Management

Currently, there is no treatment that can reverse hereditary optic atrophy once it has developed. The optic nerve damage is usually permanent^[1]. However, treatment approaches focus on slowing progression, managing symptoms, and helping people adapt to vision loss^[8].

Medical Management

For Leber hereditary optic neuropathy, a medication called idebenone has shown some benefit. It is a quinone analog that helps bypass the defective part of the mitochondrial energy production system, which can enhance energy supply to cells and support recovery of retinal ganglion cells during the acute phase of the disease^[9]. Idebenone is currently the only clinically proven drug for treating Leber hereditary optic neuropathy, though results have been modest and the treatment is expensive^[9].

No effective medical treatment is available for dominant optic atrophy, though new treatments are being studied^[1].

Lifestyle Recommendations

Limiting alcohol consumption and avoiding tobacco products may help slow the rate of vision loss, as both alcohol and tobacco can affect mitochondria^[6].

Supportive Care

Since the vision loss is permanent, much of the care focuses on helping people make the most of their remaining vision. Low-vision aids such as magnifiers, large-print devices, and talking watches can help people with significant vision loss^[1]. Optical devices, tinted lenses, and other assistive technologies may improve daily function^[2].

People who develop additional health problems such as hearing loss, heart rhythm abnormalities, or neurological symptoms should be referred to appropriate specialists for management^[6].

Emerging Treatments

Researchers are actively studying new treatment approaches. These include gene therapy aimed at halting the degeneration of retinal ganglion cells, cell-based therapies to replace damaged cells, and various neuroprotective strategies to rescue cells from death^[8]. While some early results are promising, these treatments are still in research stages and not yet widely available^[9].

Living with the Condition

Living with hereditary optic atrophy requires adaptation and support. Children with vision loss may need special assistance at school, including personalized learning plans created by education specialists, school teachers, and low vision specialists^[22]. Special tools and accommodations can help children learn more effectively despite their vision challenges.

For people with vision loss in only one eye, protecting the good eye by wearing safety glasses is very important^[2].

Genetic counseling should be considered for affected individuals and their families. A genetic counselor can explain inheritance patterns, discuss the chances of passing the condition to children, and provide information about family planning options^[6].

Registration for vision impairment services may provide access to additional support and resources^[2]. Organizations dedicated to supporting people with vision loss can offer practical advice, emotional support, and connections to others living with similar conditions.

The major complication of hereditary optic atrophy is progressive loss of vision, which can lead to legal blindness. However, with appropriate support and adaptive strategies, many people with hereditary optic atrophy can maintain independence and quality of life^[2].