Stargardt disease

Stargardt disease is the most common inherited single gene retinal disease. 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. Stargardt disease is the most common inherited single gene retinal disease. 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. Presentation usually occurs in childhood or adolescence, though there is no upper age limit for presentation. The main symptom is loss of visual acuity, uncorrectable with glasses. This is manifest as the loss of the ability to see fine details when reading or seeing distant objects. Symptoms typically develop before age 20 (median age of onset: ~17 years old), and include: wavy vision, blind spots, blurriness, loss of depth perception, sensitivity to glare, impaired colour vision, 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. Peripheral vision is usually less affected than fine, central (foveal) vision. 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. The carrier frequency in the general population of ABCA4 alleles is 5 to 10%. 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). 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 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) 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. These investigations may be followed by genetic testing but this is not essential until treatment is available. Fluorescein angiography is used less often than in the past. At present there is no treatment. However, ophthalmologists recommend measures that could slow the rate of progression of the disease. There are no prospective clinical trials to support the 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 ultra violet light, avoiding foods rich in Vitamin A with the hope of lowering lipofuscin accumulation and maintaining good general health and diet.