Stargardt disease

Stargardt disease, or fundus flavimaculatus, is the most frequent form of inherited juvenile macular degeneration. Stargardt causes progressive vision loss usually to the point of legal blindness. Several genes are associated with the disorder. Symptoms, mainly central vision loss, typically develop before age 20 (median age of onset: ~17 years old), and also include wavy vision, blind spots, blurriness, impaired color vision, and difficulty adapting to dim lighting (dark adaptation delays).

Stargardt 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, with age of onset which can be as early as ~6 years of age. The main symptom of Stargardt disease is loss of visual acuity, uncorrectable with glasses, which progresses and frequently stabilizes between 20/200 and 20/400.^[2] Other symptoms include wavy vision, blind spots (scotomata), blurriness, impaired color vision, and difficulty adapting to dim lighting (delayed dark adaptation).^[3][4] The disease sometimes 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, along with sparing of the area surrounding the optic disc (peripapillary sparing).^[1] Techniques such as fundus autofluorescence (FAF),^[6] Optical Coherence Tomography (OCT), or less frequently fluorescein angiography, can detect early signs before they are visible ophthalmoscopically.

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 causes malfunction of the ATP-binding cassette transporter (ABCA4) protein of the visual phototransduction cycle. Defective ABCA4 leads to improper shuttling of vitamin A throughout the retina, and accelerated formation of toxic vitamin A dimers (also known as bisretinoids), and associated degradation byproducts. Vitamin A dimers and other byproducts are widely accepted as the cause of STGD1. As such, slowing the formation of vitamin A dimers might lead to a treatment for Stargardt. When vitamin A dimers and byproducts damage the retinal cells, fluorescent granules called lipofuscin in the retinal pigmented epithelium of the retina^[7] appear, as a reflecting such damage.

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,^[8] gene therapy, or pharmacotherapy.

The Argus retinal prosthesis was successfully fitted to a 67-year-old women in Italy at the Careggi Hospital in Florence by Professor Stanislao Rizzo in 2016. The patient had a very advanced stage of Stargardt’s disease, and a total absence of peripheral and central visual fields.^[9]

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.^[10] Some patients, usually those with the late onset form, can maintain excellent visual acuities for extended periods, and are therefore able to perform tasks such as 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.

Regarding cell therapy, Advanced Cell Technology,^[11] now called Ocata Therapeutics, has completed Phase I/II multicenter clinical trial using retinal cells derived from human embryonic stem cells (hESCs) to treat patients with Stargardt. 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.^[12] In October 2014, the results of the Phase I/II clinical trial were published in the Lancet.^[13] 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 derived from HIV 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, a modified vitamin A which is delivered orally as a once-a-day pill. ALK-001^[14] prevents the formation of toxic vitamin A dimers in the eye without affecting the body's vitamin A supply. ALK-001 has shown efficacy in mice models of Stargardt disease, with preclinical data replicated by two academic groups in the USA and Europe. ALK-001 has completed a phase 1 clinical trial and is currently running a Phase 2 multicenter, double-masked, placebo-controlled clinical trial.^[15]

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

Research at the preclinical (animal) stage include a new compound that can remove lipofuscin from retinal pigment epithelial cells.^[16] 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.^[17]

History

The disease was first reported in 1909 by Karl Stargardt, a German ophthalmologist.^[18][19]

In 1997, it was discovered that mutations in the ABCA4 gene cause Stargardt disease. Vitamin A dimers and byproducts are thought to cause Stargardt disease, as they poison the retinal cells, leading to retinal cells death, 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