Stargardt Disease

What is Stargardt disease?

Stargardt disease is an inherited disorder of the retina – the tissue at the back of the eye that senses light. The disease typically causes vision loss during childhood or adolescence, although in some forms, vision loss may not be noticed until later in adulthood. It is rare for people with the disease to become completely blind. For most people, vision loss progresses slowly over time to 20/200 or worse. (Normal vision is 20/20).

Stargardt disease is also called Stargardt macular dystrophy, juvenile macular degeneration, or fundus flavimaculatus. The disease causes progressive damage — or degeneration — of the macula, which is a small area in the center of the retina that is responsible for sharp, straight-ahead vision. Stargardt disease is one of several genetic disorders that cause macular degeneration. Experts estimate that 1 in 8-10 thousand people have Stargardt disease.

What are the symptoms of Stargardt disease?

The most common symptom of Stargardt disease is variable, often slow loss of central vision in both eyes. People with the disease might notice gray, black, or hazy spots in the center of their vision, or that it takes longer than usual for their eyes to adjust when moving from light to dark environments. Their eyes may be more sensitive to bright light. Some people also develop color blindness later in the disease.

The progression of symptoms in Stargardt disease is different for each person. People with an earlier onset of disease tend to have more rapid vision loss. Vision loss may decrease slowly at first, then worsen rapidly until it levels off. Most people with Stargardt disease will end up with 20/200 vision or worse. People with Stargardt disease may also begin to lose some of their peripheral (side) vision as they get older.

What causes Stargardt disease?

The retina contains light-sensing cells called photoreceptors. There are two types of photoreceptors: rods and cones. Together, rod and cones detect light and convert it into electrical signals, which are then “seen” by the brain. Rods are found in the outer retina and help us see in dim and dark lighting. Cones are found in the macula and help us see fine visual detail and color. Both cones and rods die away in Stargardt disease, but for unclear reasons, cones are more strongly affected in most cases.

You may have heard about the importance of vitamin A-rich foods in maintaining healthy vision. That’s because vitamin A is needed to make key light-sensitive molecules inside photoreceptors. Unfortunately, this manufacturing process can lead to harmful vitamin A byproducts — which turn out to play a key role in Stargardt disease.

Mutations in a gene called ABCA4 are the most common cause of Stargardt disease. This gene makes a protein that normally clears away vitamin A byproducts inside photoreceptors. Cells that lack the ABCA4 protein accumulate clumps of lipofuscin, a fatty substance that forms yellowish flecks. As the clumps of lipofuscin increase in and around the macula, central vision becomes impaired. Eventually, these fatty deposits lead to the death of photoreceptors and vision becomes further impaired.

Mutations in the ABCA4 gene are also associated with other retinal dystrophies including cone dystrophy, cone-rod dystrophy, and retinitis pigmentosa, a severe form of retinal degeneration.

How is Stargardt disease inherited?

Genes are bundled together on structures called chromosomes. One copy of each chromosome is passed by a parent at conception through egg and sperm cells. The X and Y chromosomes, known as sex chromosomes, determine whether a person is born female (XX) or male (XY) and also carry other non-sex traits.

In autosomal recessive inheritance, it takes two copies of the mutant gene to give rise to the disease. An individual who has one copy of a recessive gene mutation is known as a carrier. When two carriers have a child, there is a:

• 1 in 4 chance of having a child with the disease,
• 1 in 2 chance of having a child who is a carrier,
• 1 in 4 chance of having a child who neither has the disease nor is a carrier.

In autosomal dominant inheritance, it takes just one copy of the mutant gene to bring about the disease. When an affected parent with one dominant gene mutation has a child, there is a 1 in 2 chance that a child will inherit the disease.

Autosomal recessive mutations in the ABCA4 gene account for about 95 percent of Stargardt disease. The other five percent of cases are caused by rarer mutations in different genes that play a role in lipofuscin function. Some of these mutations are autosomal dominant.

How is Stargardt disease diagnosed?

An eye care professional can make a positive diagnosis of Stargardt disease by examining the retina. Lipofuscin deposits can be seen as yellowish flecks in the macula. The flecks are irregular in shape and usually extend outward from the macula in a ring-like pattern. The number, size, color, and appearance of these flecks are widely variable.

A standard eye chart and other tests may be used to assess symptoms of vision loss in Stargardt disease, including:

• Visual field testing. Visual fields testing attempts to measure distribution and sensitivity of field of vision. Multiple methods are available for testing; none is painful and most share a requirement for the patient to indicate ability to see a stimulus / target. This process results in a map of the person’s visual field, and can point to a loss of central vision or peripheral vision.
• Color Testing: There are several tests that can be used to detect loss of color vision, which can occur late in Stargardt disease. Three tests are often used to get additional information: fundus photography combined with autofluorescence, electroretinography, and optical coherence tomography.
• A fundus photo is a picture of the retina. These photos may reveal the presence of lipofuscin deposits. In fundus autofluorescence (FAF), a special filter is used to detect lipofuscin. Lipofuscin is naturally fluorescent (it glows in the dark) when a specific wavelength of light is shined into the eye. This test can detect lipofuscin that might not be visible with standard fundus photography, making it possible to diagnose Stargardt disease earlier.
• Electroretinography (ERG) measures the electrical response of rods and cones to light. During the test, an electrode is placed on the cornea and light is flashed into the eye. The electrical responses are viewed and recorded on a monitor. Abnormal patterns of light response suggest the presence of Stargardt disease or other diseases that involve retinal degeneration.
• Optical coherence tomography (OCT) is a scanning device that works a little like ultrasound. While ultrasound captures images by bouncing sound waves off of living tissues, OCT does it with light waves. The patient places his or her head on a chin rest while invisible, near-infrared light is focused on the retina. Because the eye is designed to allow light in, it’s possible to get detailed pictures deep within the retina. These pictures are then analyzed for any abnormalities in the thickness of the retinal layers, which could indicate retinal degeneration. OCT is sometimes combined with infrared scanning laser ophthalmoscope (ISLO) to provide additional surface images of the retina.

How is Stargardt disease treated?

Currently, there is no treatment for Stargardt disease. Some ophthalmologists encourage people with Stargardt disease to wear dark glasses and hats when out in bright light to reduce the buildup of lipofuscin. Cigarette smoking and second hand smoke should be avoided. Animal studies suggest that high-dose vitamin A may increase lipofuscin accumulation and potentially accelerate vision loss. Therefore, supplements containing more than the recommended daily allowance of vitamin A should be avoided, or taken only under a doctor’s supervision. There is no need to worry about getting too much vitamin A through food.

A number of services and devices can help people with Stargardt disease carry out daily activities and maintain their independence. Low-vision aids can be helpful for many daily tasks and range from simple hand-held lenses to electronic devices such as electronic reading machines or closed circuit video magnification systems. Because many people with Stargardt disease will become visually disabled by their 20s, the disease can have a significant emotional impact. Work, socializing, driving and other activities that may have come easily in the past are likely to become challenging. So counseling and occupational therapies often need to be part of the treatment plan.

What research is being done?

Over the past several decades, researchers have identified hundreds of genes that contribute to inherited eye diseases, including Stargardt disease. This information has led to better diagnostic tests, and is providing insight into possible treatments.

Scientists are also working to find new mutations in the ABCA4 gene, and in other genes, that might contribute to Stargardt disease. NEI’s National Ophthalmic Disease Genotyping and Phenotyping Network (eyeGENE^®) is an important resource for these efforts. The eyeGENE network gives patients access to genetic studies and clinical trials, while giving researchers access to patient DNA samples and clinical information.

Many studies continue to explore the biology and genetics of Stargardt disease, and of macular degeneration more generally. For example, NEI is conducting a natural history study of Stargardt and other ABCA4-related diseases. The study is following 45 individuals with ABCA4 mutations for five years. The main goals are to better understand the natural course of the disease, to make contact with people who may be interested in future clinical trials, and to collect blood, skin, and DNA samples from those people. These samples can be studied in the lab to explore the mechanisms of Stargardt disease.

Such mechanistic studies can lead to new treatment strategies. One strategy currently under study is to reduce the build-up of lipofuscin and other toxic byproducts in the retina. An NEI-funded group based at Columbia University is working with a synthetic form of vitamin A, called ALK-001, that isn’t readily converted into lipofuscin. In mice and larger animal models, an oral form of ALK-001 slows the formation of lipofuscin deposits. ALK-001 is being tested for safety in healthy volunteers before testing begins on people with Stargardt disease.

A group based at Case Western Reserve University and supported by the NEI Translational Research Program on Therapy for Visual Disorders is taking another approach. The group has tested a panel of drugs already deemed safe by the Food and Drug Administration (FDA) in a mouse model of Stargardt. They found that some FDA-approved drugs can reduce retinal damage in the mice. They are now evaluating chemical compounds with a similar structure to FDA-approved drugs, and exploring different modes of drug delivery.

Gene therapy—that is, repairing or replacing the defective ABCA4 gene—also holds promise for treating Stargardt disease. Gene replacement therapy requires a method for delivering the gene of interest into cells, and for some diseases, the solution has been to package the gene inside a small, harmless virus called the adeno-associated virus (AAV). The ABCA4 gene is too large to fit within this virus. Researchers funded by NEI therefore modified a larger virus from the lentivirus family, and engineered it to carry ABCA4. Tests in the Stargardt mouse model showed that this approach can reduce lipofuscin accumulation. Oxford Biomedica has refined this technology, and licensed it under the name StarGen. Human safety trials of StarGen began in 2011.

Finally, stem cell-based therapies are showing promise for Stargardt disease in clinical trials. Stem cells are immature cells that can generate many mature cells types in the body, including the photoreceptors that die off in Stargardt disease. Human stem cells can be derived from embryonic or adult tissues. Both kinds of cells are being tested in patients with Stargardt disease and age-related macular degeneration (AMD), which is a leading cause of vision loss in the United States.

A U.S. company called Advanced Cell Technology (ACT) is conducting a trial of retinal pigment epithelium (RPE) cells for AMD and Stargardt disease. These cells provide support and nourishment to the retina. The RPE cells under study in the ACT trial are derived from human embryonic stem cells.

Other clinical and laboratory studies are making use of adult cells that have been reprogrammed into stem cells, called induced pluripotent – or iPS – cells. In 2014, Japanese scientists launched the first clinical trial of iPS cells to treat AMD, and indeed the first trial ever of iPS cells. The goal is to coax the iPS cells into making RPE cells. NEI scientists are planning a similar trial and going a step further – by seeding the RPE cells onto a scaffold so that they form a sheet, similar to how they arrange themselves in the eye. NEI scientists also plan to make iPS cells from the skin cells collected in the Stargardt natural history study. These iPS cells could be used to make photoreceptors and RPE cells – for use in potential cell therapies and as a research tool to study how potential drugs will affect these cell types.