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Stargardt disease: for patients


Overview

Stargardt disease (STGD) or Stargardt macular dystrophy, is the most common form of inherited macular degeneration, affecting 1 in 8,000 to 10,000 individuals overall.[1,2] It is caused by mutations in the ABCA4 gene and results in progressive vision loss. The condition can occur at any age but most patients usually experience symptoms between adolescence and young adulthood (early 20s), and less frequently around middle-age onwards. The age of onset and the rate of disease progression differ significantly among patients, depending on the type of mutation in the ABCA4 gene.[3] Generally, patients with earlier onset of symptoms are more severely affected and have a faster rate of visual decline.[4-7]

The macula is a specialised area in the retina responsible for detailed, sharp central vision and colour perception. In STGD, the light-sensing photoreceptors and the supporting retinal pigment epithelium (RPE) in the macula are primarily affected. As a result, patients may notice initially that their central vision is less sharp/focused, having difficulties in recognising colours and possibly blind spots (known as scotoma) appearing in the centre of their vision.

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The condition

Symptoms

Patients with STGD may experience some or all of the following symptoms during the course of their condition:

  • Blurry vision/reduced visual sharpness (visual acuity) is usually one of the earliest symptoms. This may cause difficulty in reading, distinguishing facial features or watching the TV
  • Difficulty in distinguishing colours
  • Blind spots in the centre of vision
  • Distortion of vision with objects appearing wavy (known medically as metamorphopsia)
  • Light sensitivity (also known as photophobia)
How metamorphopsia looks from a patient's perspective. A pair of hands playing the piano. The piano keys appear distorted, along with the notes above the keys.
A patient’s perspective of metamorphopsia (B) compared to normal (A)

Central vision loss tends to worsen over time as larger areas of the macula are damaged, which can be quite debilitating for patients as our central vision is crucial for most tasks. However, the severity of visual loss and the rate of decline are highly variable. Overall, an earlier age of onset is usually associated with a poorer visual prognosis while those who only start experiencing symptoms in later life tend to have relatively preserved central vision till later in the disease course.[4-7]

Nevertheless, patients often maintain their navigational abilities and are able to move around as the peripheral retina, and consequently their peripheral (side) vision remain largely unaffected. However, some patients do experience visual loss in their peripheral vision as certain mutations in the ABCA4 gene can cause cone-rod dystrophy instead.

A person driving a car with normal peripheral vision is able to see the girl in a red dress on the left. If the driver has a loss of peripheral vision, the same girl is not noticeable.
Peripheral vision loss

Cause

STGD is mainly caused by mutations in the ABCA4 gene. The gene provides information for the production of a protein that removes a toxic by-product called A2E from the photoreceptors. A2E is normally ingested by the supporting RPE cells to maintain photoreceptor health. If this protein is not functioning properly or absent, A2E builds up to form a fatty waste product known as lipofuscin in and around the macula.[8] The RPE cells become overwhelmed, resulting in subsequent photoreceptor damage and thus visual impairment.

How is it diagnosed?

An ophthalmologist is able to diagnose Stargardt disease based on symptoms and clinical evaluation of the retina to identify the characteristic yellowish flecks in or around the macula, which signify the lipofuscin deposits. Often, patients also undergo other more specialised tests so that the ophthalmologist can assess the retina in more detail and determine the level of visual function. These additional tests include:

  • Colour vision testing
  • Visual field testing for the detection of blind spots. Patients are asked to press a button when they detect flashing lights and a map of their visual field is created
  • Optical coherence tomography (OCT), a camera that allows detailed visualisation of all the retinal layers and reveal abnormalities in the retinal structure if present
  • Autofluorescence imaging (FAF) is another camera that can help identify lipofuscin deposits and areas of photoreceptor damage
  • Electroretinogram (ERG) is an electrodiagnostic test to assess the overall function of the photoreceptor cells in the retina and macula
Photograph of a patient's retina with Stargardt disease. There are dull-yellowish linear deposits scattered around a small area of the macula, surrounding an area of retinal degeneration, which appears dark grey.
Retinal photograph of a patient with Stargardt disease (A). When the macula section is enlarged (B), dull-yellowish deposits are seen, surrounding an area of photoreceptor degeneration (atrophy). The deposits are called flecks and constitute a hallmark of the condition

Genetic testing can help confirm the diagnosis by identifying mutations in the ABCA4 gene.

How is it inherited?

1) Autosomal recessive (AR) inheritance

This is the most common inheritance pattern for STGD as two faulty copies of the ABCA4 gene are required to cause the condition. Both parents are usually unaffected carriers (only carrying one faulty gene copy) while the patient inherits one faulty copy from each parent.  

This means that every newborn has the following risks regardless of gender:

  • 25% chance of being affected by STGD
  • 25% chance of being unaffected and not a carrier
  • 50% chance of being a carrier with no symptoms
If the mother has 1 copy of the faulty gene in her X chromosome (a carrier) while the father is unaffected, there is 50% chance that a daughter is a carrier and a 50% chance that a son is affected by the condition.
Autosomal recessive inheritance

If you or your child are affected by STGD, it is advisable to see a genetic counsellor to obtain more information and advice on inheritance and family planning options.

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Treatment

Is there any treatment?

1) Supportive visual measures

There is currently no treatment available for STGD but researchers are exploring various approaches, some of which have entered clinical trials. In the meantime, treatment is focused on alleviating symptoms and optimising remaining sight. These include:

  • Regular monitoring of visual function and prescribing glasses (if required)
  • Patching treatment may be required if a “lazy” eye is detected in children (usually involves patching of the better seeing eye)
  • Referral to low vision services
  • Utilising visual aids and assistive technology to improve quality of life
  • Having a healthy diet consisting of fresh fruits and green leafy vegetables
  • Using blue light screen protectors on mobile devices or computer screens*
  • Wearing hats/UV protected sunglasses and placing sunlight diffusers at the back window of cars

*Current available evidence shows that blue light emitted from screens do not damage the retina but it can disrupt our sleep cycle. The screen protectors are used as a precautionary measure.

2) Optimisation of development

As vision is important in normal childhood development and education, children with visual impairment due to STGD should be referred to developmental paediatricians and advisory teaching services for children/adolescents with visual impairment (e.g. sensory support services within local authority). This will enable provisions to be made within the educational and home settings so that the child can reach his/her developmental potential and develop skills to achieve independence.

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Current research in Stargardt disease

1) Drug therapies

Several drugs capable of reducing excessive lipofuscin build-up in the macula are currently being investigated[9]:

  • Emixustat– An oral medication that reduces lipofuscin production by slowing down the chemical process that transforms light into electrical signals in the retina (known as the visual cycle); A phase 3 clinical trial is currently underway (SeaSTAR, NCT 03772665)
  • ALK-001— A modified vitamin A which does not transform into A2E and lipofuscin as easily as normal Vitamin A during the visual cycle; It is currently subject to a phase 2 clinical trial (NCT 02402660)
  • Avacincaptad pegol (Zimura)—Lipofuscin can induce inflammation and cause premature cell death.[10,11] Zimura is a drug administered through intravitreal injections (a commonly performed outpatient procedure worldwide) to reduce the inflammatory effect of lipofuscin; The safety and efficacy of this treatment is currently being tested in a phase 2 clinical trial (NCT 03364153)
  • Omega-3 fatty acid (fish oil) supplement— Omega-3 is another anti-inflammatory agent where its effect on the progression of STGD has been examined in three trials, two of which have reported outcomes (NCT 00060749, NCT 00420602). No clear visual benefit was observed in the completed studies[12,13] while the other trial is still ongoing (MADEOS, NCT 03297515)
  • Soraprazan—An oral medication normally used to treat indigestion, was discovered that it can also remove lipofuscin from the RPE cells in animal studies[14]; A phase 2 trial is currently underway in the European Union (EU) to assess its safety and effectiveness

Related links

Injection of a drug into the clear jelly (vitreous) of the eye.
Intravitreal injection

2) Gene therapy

Gene therapy aims to halt retinal degeneration by replacing the mutated gene with a normal healthy copy. This enables the affected cells to regain some of their function and produce functioning proteins. A healthy copy of the ABCA4 gene is accommodated into a harmless virus, which is then injected into the retina. This way, the affected retinal cells will have maximum exposure to the viruses containing the normal ABCA4 gene.

The normal gene copy is packaged into a harmless virus, which is then injected below the retina through surgery. This allows maximum exposure of the photoreceptors to the injected therapy
Sub-retinal injection of gene therapy

Interest in gene therapy research has intensified in recent times after the approval of Luxturna for the treatment of Leber Congenital Amaurosis (LCA) caused by mutations in the RPE65 gene. There are many ongoing gene therapy trials for other forms of inherited retinal dystrophies but research in STGD has not reached the same stage yet. This is because the large size of the ABCA4 gene exceeds the carrying capacity of the most commonly used virus in gene therapy, the adeno-associated virus (AAV). However, Professor Robert MacLaren, a leading expert in the field of gene therapy research, recently made a statement that his team at the University of Oxford might have found a way to mitigate this obstacle by splitting the gene into two smaller parts and recombining them upon injection into the retina.

Another harmless virus called lentivirus, which has a larger cargo capacity than AAV and thus able to accommodate the ABCA4 gene, has been tested in a phase 1/2 clinical trial (StarGen NCT 01367444) which has unfortunately been terminated prematurely as the trial sponsor decided to cease product development. Only 22 patients were treated before the trial was suspended and the study results at 1 year after treatment showed that the treatment was safe with no clear evidence of visual improvement. Again, the small number of patients involved in this trial precludes a definite conclusion being made regarding its effectiveness on vision.

2) Stem cell based therapies

Another potential treatment for STGD are stem cell-basedtherapies. Stem cells are “immortal” cells with the ability to multiply indefinitely and transform into any type of cell in the human body, including the RPE cells. By transplanting these cells into the macula, it is hoped that the newly developed RPE cells can replace those that are damaged by the disease process.

Two phase 1/2 clinical trials were conducted in the US and UK to examine the safety of human stem cell transplantation in STGD patients. The studies demonstrated that stem cell transplantation into the eye is a safe procedure but visual improvement was highly variable.[15,16] Almost half of the treated patients in the US trial experienced improvement in their visual acuity in the first year after surgery. However, the same result was not observed in the UK study. Due to the small number of patients involved in both trials, a definite conclusion regarding its effectiveness cannot be drawn.

The scientific summaries of both trials are listed here:

Related links

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Practical advice

Living with Stargardt disease

Patients are still able to lead independent lives through maximising their available vision and having access to social support. Here are some ideas:

  • Attending the low vision clinic which provides access to low vision specialists, Eye Clinic Liaison Officers (ECLOs), visual aids and visual rehabilitation services
  • Utilising visual aids and assistive technology that may improve quality of life
  • Getting in touch with the local education authority for access to qualified teachers for children with visual impairment (QTVI) and special educational needs co-ordinator (SENCO)
  • Registering your child as sight impaired (SI) or severely sight impaired (SSI) if eligible for access to social support and financial concessions
  • Getting in touch with national or local charities for advice and peer support

Related links

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Referral to a specialist centre

If you are based in the UK and would like to be seen in the nearest specialist centre for your eye condition, either to receive a more comprehensive genetic management or just to find out more about current research, you can approach your GP to make a referral or alternatively arrange for a private appointment. 

More information can be found in our “How to see a genetic eye specialist?” page.  

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Further information and support

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A patient’s perspective

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References

  1.  Blacharski P. Fundus flavimaculatus. Retinal dystrophies and degenerations. 1988:135-159
  2.  Rahman N, Georgiou M, Khan KN, Michaelides M. Macular dystrophies: clinical and imaging features, molecular genetics and therapeutic options. Br J Ophthalmol. 2019
  3.  Cremers FPM, Lee W, Collin RWJ, Allikmets R. Clinical spectrum, genetic complexity and therapeutic approaches for retinal disease caused by ABCA4 mutations. Prog Retin Eye Res. 2020:100861
  4.  Lambertus S, van Huet RA, Bax NM, et al. Early-onset stargardt disease: phenotypic and genotypic characteristics. Ophthalmology. 2015;122(2):335-344
  5.  Fujinami K, Zernant J, Chana RK, et al. Clinical and molecular characteristics of childhood-onset Stargardt disease. Ophthalmology. 2015;122(2):326-334
  6.  Lambertus S, Lindner M, Bax NM, et al. Progression of Late-Onset Stargardt Disease. Invest Ophthalmol Vis Sci. 2016;57(13):5186-5191
  7.  Fujinami K, Sergouniotis PI, Davidson AE, et al. Clinical and molecular analysis of Stargardt disease with preserved foveal structure and function. Am J Ophthalmol. 2013;156(3):487-501.e481
  8.  Weng J, Mata NL, Azarian SM, Tzekov RT, Birch DG, Travis GH. Insights into the function of Rim protein in photoreceptors and etiology of Stargardt’s disease from the phenotype in abcr knockout mice. Cell. 1999;98(1):13-23
  9.  Lu LJ, Liu J, Adelman RA. Novel therapeutics for Stargardt disease. Graefe’s Archive for Clinical and Experimental Ophthalmology. 2017;255(6):1057-1062
  10.  Zhou J, Jang YP, Kim SR, Sparrow JR. Complement activation by photooxidation products of A2E, a lipofuscin constituent of the retinal pigment epithelium. Proc Natl Acad Sci U S A. 2006;103(44):16182-16187
  11.  Berchuck JE, Yang P, Toimil BA, Ma Z, Baciu P, Jaffe GJ. All-trans-retinal sensitizes human RPE cells to alternative complement pathway-induced cell death. Invest Ophthalmol Vis Sci. 2013;54(4):2669-2677
  12.  Choi R, Gorusupudi A, Bernstein PS. Long-term follow-up of autosomal dominant Stargardt macular dystrophy (STGD3) subjects enrolled in a fish oil supplement interventional trial. Ophthalmic Genet. 2018;39(3):307-313
  13.  MacDonald IM, Sieving PA. Investigation of the effect of dietary docosahexaenoic acid (DHA) supplementation on macular function in subjects with autosomal recessive Stargardt macular dystrophy. Ophthalmic Genetics. 2018;39(4):477-486
  14.  Fang Y, Tschulakow A, Tikhonovich M, et al. Preclinical results of a new pharmacological therapy approach for Stargardt disease and dry age-related macular degeneration. Investigative Ophthalmology & Visual Science. 2017;58(8):256-256
  15.  Schwartz SD, Regillo CD, Lam BL, et al. Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt’s macular dystrophy: follow-up of two open-label phase 1/2 studies. Lancet. 2015;385(9967):509-516
  16.  Mehat MS, Sundaram V, Ripamonti C, et al. Transplantation of Human Embryonic Stem Cell-Derived Retinal Pigment Epithelial Cells in Macular Degeneration. Ophthalmology. 2018;125(11):1765-1775

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Updated on November 30, 2020
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