Stargardt disease

Stargardt disease, or fundus flavimaculatus, is an inherited form of juvenile macular degeneration that causes progressive vision loss usually to the point of legal blindness. Several genes are associated with the disorder. Symptoms, mainly vision loss, typically develop before age 20, and also include wavy vision, blind spots, blurriness, impaired color vision, and difficulty adapting to dim lighting.

Stargardt's disease is often used to refer to any juvenile macular dystrophy; however, it properly refers to atrophic macular dystrophy with yellow, poorly-defined flecks surrounding the macula in the retinal pigment epithelium.^[1]

Signs and symptoms

Patients with Stargardt disease usually develop symptoms in the mid-first to the late second decade of life. The main symptom of Stargardt disease is loss of visual acuity, which ranges from 20/50 to 20/200.^[2] Other symptoms include wavy vision, blind spots (scotomata), blurriness, impaired color vision, and difficulty adapting to dim lighting.^[3][4] The disease causes sensitivity to glare; overcast days offer some relief. Vision is most noticeably impaired when the macula (center of retina and focus of vision) is damaged, leaving peripheral vision more intact. Generally, vision loss starts within the first 20 years of life.^[5]

Examination with an ophthalmoscope shows few notable findings in the early stages of the disease. Eventually, however, an oval-shaped atrophy with a horizontal major axis appears in the retinal pigment epithelium, and has the appearance of beaten bronze.^[1] Fluorescein angiograms can show this defect before it is visible ophthalmoscopically, as it produces an area of hyperfluorescence.

Genetics

Stargardt disease is associated with several different genes:

• STGD1: The most common form of Stargardt disease is the recessive form caused by mutations in the ABCA4 gene. It can also be associated with CNGB3.
• STGD3: There is also a rare dominant form of Stargardt disease caused by mutations in the ELOVL4 gene.
• STGD4: Associated with PROM1.

The classification "STGD2" is no longer used.

Pathophysiology

In STGD1, the genetic defect is manifest in the visual phototransduction cycle. The ATP-binding cassette transporter (ABCA4) is defective and leads to rapid formation of toxic vitamin A dimers (also known as bisretinoids), which then build up in fluorescent granules called lipofuscin in the retinal pigmented epithelium of the retina.^[6]

In STGD4, a butterfly pattern of dystrophy is caused by mutations in a gene that encodes a membrane bound protein that is involved in the elongation of very long chain fatty acids (ELOVL4)^[1]

Treatment

Currently, there is no treatment for the disease. However, ophthalmologists recommend wearing sunglasses and hats outdoors and blue-light blocking glasses when exposed to artificial light sources, such as screens and lights.Tobacco smoke and second-hand smoke should be avoided. Animal studies also show that high doses of vitamin A can be detrimental by building up more lipofuscin toxin. Dietary non-supplemental vitamin A intake may not further the disease progression. Clinical trials are being conducted with promising early results. The trials may one day lead to treatments that might halt, and possibly even reverse, the effects of Stargardt disease using stem cell therapy.^[7]

Prognosis

The long-term prognosis for patients with Stargardt disease is widely variable although the majority of people will progress to legal blindness.^[2]

Stargardt disease has no impact on general health and life expectancy is normal.^[8] Some patients have visual acuities as good as 20/25, and are therefore able to perform tasks like reading or driving.^[1]

Epidemiology

STGD1 is the most common form of inherited juvenile macular degeneration with a prevalence of approximately 1 in 10,000 births.^[3]

Research

Treatment modalities currently under clinical investigation include cell therapy, gene therapy and oral therapies. On November 22, 2010, it was announced that Advanced Cell Technology,^[9] now called Ocata Therapeutics, received United States Food and Drug Administration clearance to immediately initiate a Phase I/II multicenter clinical trial using retinal cells derived from human embryonic stem cells (hESCs) to treat patients with Stargardt’s Macular Dystrophy. In September 2011, ACT announced they were beginning the next stage of treatment for SMD, and Dry AMD as the first stage proved to be safe by an independent board of experts.^[10] In March 2013, after treating and collecting data on 18 patients, Advanced Cell was given approval to test its stem cell therapy on patients with 20/100 vision.^[11] In October 2014, the results of the Phase I/II clinical trial were published in the Lancet.^[12]

Gene therapy trials are also on-going. During gene therapy, a working copy of the ABCA4 gene is incorporated in a lentivirus (an inactivated virus which transports the working copy of the gene) and injected into the eye through a subretinal injection. It is hoped that such injection, if performed early enough, could prevent the progression of the disease.

Finally, oral therapies that are being investigated include ALK-001, modified vitamin A delivered orally which prevents the formation of toxic vitamin A dimers in the eye. ALK-001 has completed a phase 1 clinical trials.

ACT, Oxford Biomedica and Alkeus Pharmaceuticals have all received orphan drug designation in the United States for the treatment of Stargardt Disease.

Preclinical research include a new compound that can remove lipofuscin from retinal pigment epithelial cells.^[13] The compound drug has been granted orphan drug designation for the treatment of Stargardt disease by the European Medicines Agency.

Ichor Therapeutics is working on the delivery of a bacterial enzyme to remove A2E for AMD and Stargardt’s macular degeneration.^[14]

History

The disease was discovered in 1909 by Karl Stargardt, a German ophthalmologist.^[15][16]

In 1997, it was discovered that mutations in the ABCA4 gene cause Stargardt disease. The mutations cause the production of a dysfunctional protein that cannot perform energy transport to and from photoreceptor cells in the retina. The photoreceptor cells then degenerate, causing vision loss.^[3]

References

External links

• Stargardt's Disease - from the American Macular Degeneration Foundation
• Stargardt's Disease - from TheRetinaSource
• Stem Cell Research NPR Special Report - from NPR