What is Stargardt Disease?
“Macular dystrophy” is the term traditionally used to describe a group of inheritable eye disorders that cause abnormalities in the retina, the part of the eye that senses light. The most common type of this in young people is called Stargardt disease type 1 (STGD1). This disease was first identified in 1909 by a German eye specialist named Karl Stargardt. He noticed it in seven family members who all had a specific type of macular dystrophy, characterized by yellow-white fish-shaped spots in the eye.
Stargardt disease is a genetic condition where a waste product, lipofuscin, builds up in the retina. This disease varies a lot in terms of when it starts and how quickly it progresses. People with this disease usually start experiencing worsening vision in their teens or early adulthood. Because the disease can manifest differently in different people, diagnosing STGD1 can be challenging. Studies about the progression of this disease have helped us understand more about it and how it changes over time, using various methods of examining the eye’s structure and function.
As of May 2023, several possible treatments for Stargardt disease are being studied, but none have been approved for use by the United States Food and Drug Administration (US-FDA) yet.
What Causes Stargardt Disease?
Stargardt disease (STGD) is a type of eye disorder that typically appears during childhood or adolescence. It’s named after the scientist who first documented it and is sometimes known as juvenile macular degeneration. This disease comes from inheriting specific changes in genes – a type of inheritance called an autosomal recessive trait.
One of the main genes involved is ABCA4. This gene is, let’s say, a very complex blueprint with many parts. The ABCA4 gene is linked to other eye diseases as well, such as cone-rod dystrophy 3, retinitis pigmentosa 19, and age-related macular degeneration 2. When something goes wrong in the ABCA4 gene, it can lead to various diseases affecting the retina (the part of the eye that senses light and helps send images to your brain).
These errors in the ABCA4 gene can result in various eye conditions, depending on how severe the error is. Less severe issues might cause diseases like bull’s eye maculopathy or cone-rod dystrophy, while more drastic errors might lead to conditions like retinitis pigmentosa – which is one of the most severe, as it can all but remove the functionality of ABCA4, resulting in significant vision loss.
There are similar eye disorders sharing traits with Stargardt’s disease but come from changes in different genes. These disorders are typically passed down in families differently than STGD and are hence known as “Stargardt-like” diseases. These include STGD2, STGD3, and STGD4.
STGD2 can come from a mutation in the ELOVL4 gene. Patients with STGD3 typically do not show certain symptoms, such as a darkened choroid (the layer behind the retina), common in STGD1.
Changes to the ELOVL4 gene can also lead to completely different disorders – not directly related to vision, such as developmental disorders involving the brain and skin.
STGD4, on the other hand, occurs due to changes in the PROM1 gene. This gene can also cause disorders like macular dystrophy and cone-rod dystrophy. In particularly severe cases, if there are additional mutations in the ABCA4 gene, the disease can be more drastic.
Various other genes can cause eye diseases with symptoms similar to Stargardt disease, but they usually lack the defining features of Stargardt disease.
Risk Factors and Frequency for Stargardt Disease
Stargardt disease is the most common cause of a condition known as juvenile macular dystrophy. However, it isn’t very common overall. In the United States, about 10 to 12.5 people out of every 100,000 have Stargardt disease. The disease is even less frequent in other countries. For example, it is estimated that only around 0.110 to 0.128 per 100,000 people develop the condition each year in the United Kingdom. Similarly, in the Netherlands, each year about 1.67 to 1.95 people out of every million are diagnosed with Stargardt disease. In 2018, the number of people living with Stargardt disease in the Netherlands was between 1 in 22,000 and 1 in 19,000.
Signs and Symptoms of Stargardt Disease
STGD1, also known as Stargardt disease, is a condition that often causes a gradual, painless loss of central vision in both eyes. Those affected can have visual acuity that ranges from 20/20 to 20/400. Other symptoms might include central blind spots (central scotoma), trouble adjusting to low light (delayed dark adaptation), sensitivity to light (photosensitivity), seeing flashes of light (photopsia), and disturbances in color perception. Usually, both men and women can get this condition, which often starts in childhood and can also occur in early adulthood. Generally, if symptoms begin at a younger age, the vision loss can be more severe. It’s also worth noting that differences in the disease, known as “phenotypic heterogeneity,” can lead to variations in the age of onset, severity, visual acuity, among other things.
- Gradual, painless loss of central vision
- Central blind spots (central scotoma)
- Trouble adjusting to low light (delayed dark adaptation)
- Sensitivity to light (photosensitivity)
- Seeing flashes of light (photopsia)
- Disturbances in color perception
The eye condition is often associated with certain changes in the eye, including, flecks, macular atrophy, and peripapillary sparing. Flecks are yellowish-white round or fish-tail-shaped lesions of varying sizes located within the RPE. They tend to develop from the macular region and may progress towards the mid-periphery but usually spare the far periphery. The macula, the part of the eye responsible for central vision, is usually affected early in the disease. However, these changes can vary and may range from a small region of central macular atrophy to atrophy beyond the vascular arcades. Another key feature is the sparing of the area around the optic nerve head (peripapillary sparing) in people with this disease, whereas in certain similar conditions, this region may not be spared.
There are different variations of the disease as well, including a milder version that may present later in life (around 35 to 45 years) and has a better prognosis due to preservation of the fovea, the central part of the macula. This variation is known as foveal-sparing Stargardt disease (FS-STGD1). These cases can sometimes be mistakenly diagnosed as age-related macular degeneration.
Testing for Stargardt Disease
Several imaging tests allow doctors to inspect the retina, the light-sensitive layer at the back of your eye, and monitor the advancement of any disease that might affect it. The importance of these imaging techniques is highlighted in childhood-onset STGD1 (also known as Stargardt’s disease), where nearly one-fourth of patients showed no visible damage to the retina upon initial diagnosis. In some cases, patients can be misdiagnosed and exposed to unnecessary procedures. Multimodal imaging, however, can help diagnose the disease early, track its progression and measure the effectiveness of treatment.
Advancements in molecular and genetic therapies specifically designed for the ABCA4 gene, which is responsible for Stargardt’s disease, offer potential relief for early-stage patients.
Color fundus photography is one such imaging technique that can help doctors monitor changes to the retina and evaluate the extent of the disease. The Fishman classification uses color fundus photographs to determine the severity of the disease based on different symptoms. These range from initial pigmentary changes in the macula (the part of the retina responsible for sharp, central vision) to extensive atrophy (or damage) covering the entire retina.
Researchers Lambertus and Carr further categorized the disease based on the appearance of the retina into 4 groups, helping doctors better understand the disease and devise suitable treatment plans.
Other imaging techniques like Fundus fluorescein angiography and optical coherence tomography can help identify specific symptoms of the disease, such as appearance of “dark choroids” (the blood vessels in the eye) or thinning of outer retinal layers.
Methods like OCT-angiography, Fundus autofluorescence, Adaptive optics scanning laser ophthalmoscopy, Visual field, and Microperimetry offer further insights into areas of the retina that are deteriorating. For example, these tests can reveal reduced vessel densities, the presence of choroidal neovascular membrane (a rare and late symptom), areas with increased spacing between photo-receptor cells, central visual field loss, and varying degrees of reduced sensitivity in the macula.
Finally, visual electrophysiology and genetic testing can aid in diagnosing STGD1 and tracking its progression. Genetic testing is critical since alterations in the ABCA4 gene can result in a variety of disease manifestations, and it can offer predictions about the disease course, as well as facilitate in genetic counselling and preconception planning.
Treatment Options for Stargardt Disease
Currently, the U.S. Food and Drug Administration (FDA) has not recommended any specific treatment to prevent or reverse the visual loss in patients with Stargardt Disease 1 (STGD1), a genetic eye disorder that causes vision loss. However, to slow down the progress of the disease and help those experiencing vision loss, there are several measures patients can take.
Protecting your eyes from sunlight can help delay the disease’s progression. Using low-vision aids, like magnifying glasses, can improve daily activities, especially for those who’ve experienced vision field loss. Proper eyeglasses or contacts should be prescribed to correct vision issues. In addition, smoking is harmful in general but particularly detrimental for eye health, so avoiding it is advised. If the disease results in choroidal neovascularization (CNVM), abnormal blood vessel growth under the retina, the preferred treatment method is injections into the eye to inhibit a growth factor (VEGF).
Numerous ongoing clinical trials are exploring new treatment approaches for STGD1. Some studies are focusing on drugs that might reduce lipofuscin, a pigment buildup associated with numerous retinal conditions. These drugs either slow down an enzyme’s activity that is critical for vision or disrupt a protein called retinol-binding protein 4 (RBP4) that carries vitamin A to and from the cells.
One such drug, emixustat hydrochloride (ACU-4429), slows an enzyme’s activity, leading to less production of a toxic by-product called A2E. It is currently in the clinical trial phase, assessing its safety and dosage levels.
ALK-001, a form of vitamin A, is another drug being tested. It slows down the rate of harmful buildup in cells. In studies on animal models, it showed promising results with no adverse effects, and a clinical trial is testing its safety and dosage in humans.
Fenretinide is a synthetic derivative of vitamin A that blocks vitamin A’s pathway and results in its excretion via urine. This action may reduce the worsening of geographic atrophy, a severe form of dry age-related macular degeneration, and prevent the initiation of CNVM. However, its long-term safety is uncertain due to potentially hazardous effects observed in animals.
While Vitamin A dietary supplements are often avoided in STGD1, more research is needed to definitively say whether they’re beneficial or harmful to the disease progression.
Gene therapy is another active research area aiming at introducing a healthy gene to produce a sufficient amount of the transporter protein in the cells of the eye, ultimately stopping the disease from progressing. The challenge is the delivery method of the large gene, but recent developments in techniques using viral or non-viral delivering systems show potential in overcoming this issue.
Stem-cell therapy, which aims to generate new healthy cells, is also being explored as a potential treatment method.
It is also important for patients with STGD1 to receive genetic counseling. Understanding the genetics of disease can give insights into the disease’s likely progression and outcomes; STGD1 is known to be an autosomal recessive trait (passed on from both parents), while other forms STGD3 and STGD4 are autosomal dominant (inherited from one parent).
What else can Stargardt Disease be?
There are several inherited eye conditions that can look similar to Stargardt Disease (STGD1). It’s crucial to correctly identify STGD1 from these other conditions as it can affect prognosis, any associated systemic disorders, and the genetic advice given.
The following conditions often get mistaken for STGD1:
- Pattern Dystrophy (PD): It’s a dominant genetic condition that usually has mild or no vision loss from the second to fifth decade of life. While it might appear similar to STGD1, it does have some differences, such as a higher rate of vision-deteriorating blood vessel growth (CNVM).
- Autosomal Dominant Stargardt-like Macular Dystrophies: These are variants linked to the ELOVL4 (STGD2 or STGD3) and the PROM1 (STGD4) genes.
- Batten Disease/Juvenile Neuronal Ceroid Lipofuscinosis: It’s a rare metabolic disorder where faulty processing of storage in lysosomes lead to cell death in both the retina and the brain. It’s usually a rapidly progressing disease and patients have a life expectancy of 20 to 30 years. If a young patient initially diagnosed with severe STGD1 shows rapid disease progression, this condition might be considered.
- Maternally Inherited Diabetes and Deafness (MIDD) or Other Mitochondrial Diseases: Patients with these medical conditions often show symptoms in their third to seventh decade of life. Common symptoms include pigmentary changes at the macula, areas of RPE atrophy, and fleck-like deposits.
- Age-Related Macular Degeneration: This can mimic late-onset STGD1 as the specks may be mistaken for drusens (tiny yellow or white deposits in the retina). However, a careful examination can differentiate the two.
- Pentosan Polysulfate Maculopathy: Linked to the use of pentosan for treating bladder condition interstitial cystitis. However, it doesn’t necessarily spare the peripapillary region.
Being able to differentiate between these conditions helps ensure accurate diagnosis and subsequent treatment.
What to expect with Stargardt Disease
This condition often leads to legal blindness due to the loss of central vision, but peripheral vision usually stays intact. The prognosis differs greatly from person to person and largely depends on when the disease begins. Typically, patients who show symptoms early on face tougher outcomes. Their vision could deteriorate quickly, accompanied by progressive damage to the retina, and in some cases, this could evolve into severe chorioretinal atrophy (or the wasting away of the retina and underlying tissue). Hence, patients with this kind of severe disease progression usually have a poor outlook.
Rapid-onset chorioretinopathy (ROC), which is a specific type of the disease characterized by quick development, has its own unique set of symptoms. Patients who develop the disease later in life generally maintain good vision even as they age. Overall, this disease does not usually affect the patient’s overall health or life span.
Possible Complications When Diagnosed with Stargardt Disease
The complications that come with STGD1, a type of genetic eye disorder, are several:
- Subretinal fibrosis: This is a condition where minor trauma to the eye can lead to thickening and scarring under the retina, as well as increased growth of the cells in the retina (RPE Hypertrophy). This damage may be caused by the premature release of a substance called lipofuscin, which disrupts the normal function of the retina. Some researchers have suggested that even small amounts of microtrauma can trigger this condition. Because of this, people with STGD1 are often advised to protect their eyes, especially during activities like sports.
- Choroidal neovascular membrane: This is a rare late stage complication of STGD1 characterized by new, abnormal blood vessels growing under the retina.
- Legal blindness: Many patients with STGD1 unfortunately develop severe vision loss, classified as legal blindness, as they get older.
Preventing Stargardt Disease
Teaching patients about their condition and providing advice is crucial for handling this disease. It’s important to have a discussion about how they are feeling emotionally and make sure they understand that the disease may get worse over time. As a result, their vision might start to deteriorate, making daily activities more challenging.
Let them know about devices designed to help people with low vision, which can make it easier for them to carry out their day-to-day tasks. It is also recommended for patients to have their eyes checked by a specialist and to receive genetic counseling. This will help them understand the likelihood of their children acquiring the same disease in the future.
