by Dan Roberts
(Updated May 25, 2011)
Stargardt disease (also known as fundus flavimaculatus and Stargardt macular dystrophy) is the most common form of inherited juvenile macular degeneration. Inherited as an autosomal recessive trait, it is a severe form of MD that begins in late childhood, leading to legal blindness. Stargardt disease is symptomatically similar to age-related macular degeneration, and it affects approximately one in 10,000 children.
Stargardt disease is usually diagnosed in individuals under the age of twenty, when decreased central vision is first noticed. It causes a progressive loss of central vision and, in the early stages, patients may have good visual acuity, but they may experience difficulty with reading and seeing in dim lighting. Other common symptoms of Stargardt disease include blurriness and distortion. On examination, the ophthalmological findings vary significantly with the progression of the disease. In fundus photos, patients with early Stargardt disease appear to have simple macular degeneration. Children with the disease typically begin experiencing dark adaptation problems and central vision loss between six and twelve years of age, but symptoms may also first appear in adulthood.
As the disease progresses, lipid rich deposits accumulate in the retinal pigment epithelium (RPE) layer beneath the macula. This “lipofuscin” appears as yellowish-tinted flecks. The RPE is a layer of cells that lies between the retina and the choroid, where it serves the purpose of nourishing the photoreceptor cells. In advanced Stargardt disease, the buildup of lipofuscin causes atrophy of the macula and the underlying RPE. The progression of vision loss is variable and can start with a visual acuity of 20/40 and decrease rapidly (especially in children) to 20/200 (legal blindness). By age 50, approximately 50% of all of those studied in clinical trials had visual acuities of 20/200 to 20/400. In late stages of this disease, there may also be color vision impairment.
Stargardt disease is almost always inherited as an autosomal recessive disorder, with only ten percent of cases resulting from a dominant mode of inheritance. Autosomal recessive means that both parents are carriers, having one gene for the disease paired with one normal gene. As a consequence, each of their children has a 25 percent chance of inheriting the two copies of the Stargardt gene (one from each parent) needed to cause the disease. Carriers are unaffected because they have only one copy. At this time, it is impossible to determine who is a carrier for Stargardt disease until after an affected child is diagnosed.
In 1997, researchers isolated the gene for Stargardt disease. The ABCA4 gene produces a protein involved in energy transport to and from photoreceptor cells in the retina. Mutations in the ABCA4 gene, which cause Stargardt disease, produce a dysfunctional protein that cannot perform its transport function. As a result, photoreceptor cells degenerate, and vision loss occurs. One of nineteen mutations in the gene (causing deletions and substitutions of amino acids) has been identified to cause Stargardt disease. The non-functional ABCA4 protein permits the accumulation of yellow fatty material to accumulate in the retina. This material causes flecks and, ultimately, loss of vision. Further research is needed to find out how the mutated ABCA4 genes affect the biochemistry of the retina and lead to vision loss.
This discovery allows researchers to study the underlying biochemical interactions that result from mutations in this gene. Understanding how genetic mutations lead to retinal degeneration is critical for the development of experimental therapies.
Current research also shows that patients with Stargardt disease could slow its progression by wearing UV-protective sunglasses and avoiding exposure to bright light. Researchers have observed that mice which had a mutation of the ABCA4 gene, and which were reared in dark environments had virtually no lipofuscin deposits.
The disease is often misdiagnosed, or not diagnosed in the first few years of onset, and this could be the result of little evidence being found during eye examinations. The discovery of the Stargardt gene could help in a test for the direct diagnosis of the disease. It is possible that the effect of this newly discovered gene may not be limited only to juvenile MD, in that it could also aid in the search for causes for age-related macular degeneration, the leading cause of vision loss in people over age 65.
Currently, there is no effective treatment for Stargardt disease, but having the genetic “instruction manual” may assist in developing new strategies for therapy. Also, Advanced Cell Technology announced in November 2010 that the FDA approved injection of human embryonic stem cells into the eyes of 12 patients affected by the disease. The study began recruiting subjects in 2011, and promising results have been reported, most recently in ACT’s preliminary report published in January 2012.
Other promising research is gene therapy, which was been approved for Phase I/IIa trials in March 2011. The work is based upon research led by Columbia geneticist Rando Allikmets, who discovered the Stargardt gene in 1997. Together with Oxford BioMedica, Allikmets uses an EIAV-based vector to add a normal ABCA4 gene to the eye.
Until treatments are developed, it is important that the learning and working environment be adapted for people with Stargardt disease. Appropriate low vision aids and lighting are two important considerations for helping both children and adults to function as normally as possible.
Foundation Fighting Blindness
Robert Hammer, B. Optom.
Janet S. Sunness, M.D.