Stargardt disease is the most common inherited single-gene retinal disease.[1] It usually has an autosomal recessive inheritance caused by mutations in the ABCA4 gene. Rarely it has an autosomal dominant inheritance due to defects with ELOVL4 or PROM1 genes. It is characterised by macular degeneration that begins in childhood, adolescence or adulthood, resulting in progressive loss of vision.[2]
Signs and symptoms
Presentation usually occurs in childhood or adolescence, though there is no upper age limit for presentation and late onset is possible. The main symptom is loss of visual acuity, uncorrectable with glasses. This manifests as the lack of the ability to see fine details when reading or viewing distant objects. Symptoms typically develop before age 20 (median age of onset: ~17 years old),[3] and include: wavy vision, blind spots, blurriness, loss of depth perception, sensitivity to glare, impaired colour vision,[3] and difficulty adapting to dim lighting (delayed dark adaptation). There is a wide variation between individuals in the symptoms experienced as well as the rate of deterioration in vision. Vision loss can be attributed to buildup of byproducts of vitamin A in photoreceptor cells and Peripheral vision is usually less affected than fine, central (foveal) vision.[citation needed]
Genetics
Historically from Stargardt’s first description of his eponymous disease until recently, the diagnosis was based on looking at the phenotype using examination and investigation of the eye. Since the advent of genetic testing, the picture has become more complex. What was thought to be one disease is, in fact, probably at least three different diseases, each related to a different genetic change. Therefore it is currently a little confusing to define what Stargardt's disease is. It is certainly caused by defects in the ABCA4 gene, but whether changes to other genes such as PROM1 or ELOVL4, or missense mutations play a role remains to be seen.[citation needed]
The carrier frequency in the general population of ABCA4 alleles is 5 to 10%.[4] Different combinations of ABCA4 genes will result in widely different age of onset and retinal pathology. The severity of the disease is inversely proportional to ABCA4 function and it is thought that ABCA4 related disease has a role to play in other diseases such as retinitis pigmentosa, cone-rod dystrophies and age-related macular degeneration (AMD).[5]
- STGD1: By far the most common form of Stargardt disease is the recessive form caused by mutations in the ABCA4 gene.[6]
- STGD4: A rare dominant defect in the PROM1 gene.[7][5]
- STGD3: A rare dominant form of Stargardt disease caused by mutations in the ELOVL4 gene.
- Late-onset Stargardt disease is associated with missense mutations outside known functional domains of ABCA4.[5]
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[8] 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)[9]
Diagnosis
Diagnosis is firstly clinical through history and examination usually with a Slit-lamp. If characteristic features are found the investigations undertaken will depend on locally available equipment and may include Scanning laser ophthalmoscopy which highlights areas of autofluorescence which are associated with retinal pathology. Spectral-domain optical coherence tomography, electroretinography and microperimetry are also useful for diagnostic and prognostic purposes. Fluorescein angiography is used less often than in the past. These investigations may be followed by genetic testing in order to avoid misdiagnosis. Other diseases may have overlapping phenotypic features with Stargardt Disease and the disease itself has multiple variants. In one study 35% of patients diagnosed with Stargardt Disease through physical ophthalmic examination were found to be misdiagnosed when subsequent genetic testing was done.[10] Genetic testing can be utilized to ensure an proper diagnosis for which the correct treatment can be applied.
Treatment
At present there is no treatment for Stargardt Disease. However, ophthalmologists recommend measures that could slow the rate of progression. There are no prospective clinical trials to support these recommendations, but they are based on scientific understanding of the mechanisms underlying the disease pathology. There are three strategies doctors recommend for potential harm reduction: reducing retinal exposure to damaging ultraviolet light, avoiding excess Vitamin A with the hope of lowering lipofuscin accumulation and maintaining good general health and diet.[citation needed]
Ultra-violet light has more energy and is a more damaging wavelength spectra than visible light. In an effort to mitigate this, some ophthalmologists may recommend that the patient wears a broad-brimmed hat or sunglasses when they are outdoors.[11] Sometimes, doctors also instruct their patients to wear yellow-tinted glasses (which filter out blue light) when indoors and in artificial light or in front of a digital screen.
Certain foods, especially carrots, are rich in vitamin A, but the amount from food is not harmful.[11] Foods with a high vitamin A content are often yellow or orange in color, such as squash, pumpkin, and sweet potato, but some, such as liver, are not. There are supplements on the market with more than a daily allowance of vitamin A that should be avoided, but each individual should discuss this with their doctor.
Smoking, overweight or obesity, and poor diet quality may also contribute to more rapid degeneration. On the other hand, the consumption of oily fish, in a diet similar to that which doctors recommend for age related macular degeneration, can be used to slow the progression of the disease.[citation needed]
Advances in technology have brought devices that help Stargardt patients who are losing their vision maintain their independence. Low-vision aids can range from hand lenses to electronic devices and can allow those losing their vision to be able to carry out daily activities. [11] Some patients may even opt for in-person services.
Prognosis
The long-term prognosis for patients with Stargardt disease is widely variable and depends on the age of onset and genetic alleles. The majority of people will progress to legal blindness.[12] Stargardt disease has no impact on general health and life expectancy is normal.[13] 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.[9]
Epidemiology
A 2017 prospective epidemiologic study which recruited 81 patients with STGD over 12 months reported an incidence of between 1 and 1.28 per 10 000 individuals. The median age of presentation was 27 years (range 5–64 years), most (90%) were symptomatic, with a median visual acuity of Snellen equivalent 20/66.[14]
History
Karl Stargardt (1875–1927) was a German ophthalmologist born in Berlin. He studied medicine at the University of Kiel, qualifying in 1899. He later became head of the Bonn University’s ophthalmology clinic, followed by a post as chair of ophthalmology at the University of Marburg. In 1909 he described 7 patients with a recessively inherited macular dystrophy, now known as Stargardt’s disease.[15][16][17]
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