CASE REPORT
A 69-year-old female patient complained of progressive vision loss. Her parents were first cousins. The patient had been a smoker for 15 years. She had a past medical history of hyperlipidemia and hypothyroidism.
Upon a comprehensive ophthalmic evaluation, the patient was found to have the best corrected visual acuity of counting fingers at 5’ and 3’ in the right and left eyes, respectively.
Retinoscopy showed a refraction of –1.00 + 0.50×70 and –2.00 + 1.00×5 in the right and left eyes, respectively. The patient had pale optic discs with extensive deep atrophy of the central macula, epithelial pigment hyperplasia, and other areas of multifocal atrophy in the right eye.
In addition, the patient had macular atrophy in the left eye. In the patient’s fundus autofluorescence (FAF) imaging, there was evidence of central hypo autofluorescence of the macula, with diffuse outward centrifugal extension from its center to its periphery.
Macular optical coherence tomography (OCT) determined that the average macular thickness was 191 µm and 193 µm in the right and left eyes, respectively. Macular volume was 6.9 mm3 and 7.0 mm3 in the right and left eyes, respectively. No macular edema, cysts, or subretinal fluid was found in either eye.
A visual field test revealed that the patient had mean deviations of –23.75 dB and –24.56 dB in the right and left eyes, respectively. Pattern standard deviations were +3.69 dB and +4.69 dB in the right and left eyes.
The results of a full-field electroretinogram (ERG) showed a normal rod response and decreased cone response, bilaterally. For these reasons, a clinical diagnosis of Stargardt disease was made.
DISEASE
Stargardt disease (STGD) is the most common childhood recessively inherited macular dystrophy. The condition has a genetic basis due to mutations in the ABCA4 gene, on chromosome 1, which encodes a retinal transporter protein; it results from the accumulation of visual cycle kinetics-derived byproducts in the retinal pigmented epithelium (RPE) with secondary photoreceptor dysfunction and death.
The most common symptom of Stargardt disease is a slow loss of central vision in both eyes. Some people lose their central vision more quickly than others.
Other symptoms may include:
- Gray, black, or hazy spots in the center of your vision
- Sensitivity to light
- Needing more time for your eyes to adjust between light and dark places
- Color blindness
Some people with Stargardt disease may also lose their side (peripheral) vision.
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From Choroida — the team behind this siteMANAGEMENT
Stargardt disease remains an incurable condition. Current therapeutic options include photoprotection and low-vision aids. Pharmacological slow-down of the visual cycle, gene therapy, and other treatment options aim to prevent lipofuscin accumulation and represent prospects of long-term visual rescue.
Unbound all-trans-retinal induces photo-oxidative damage to the unusually sensitive ABCA4, further compromising its function. Given that Stargardt patients already have impaired ABCA4 function and increased levels of all-trans-retinal trapped inside their photoreceptors, it is logical to think that these patients would be extremely sensitive to light exposure.
Furthermore, it has been demonstrated that di-retinoid-pyridinium-ethanolamine (A2E) does not accumulate in the RPE of abca4 knockout mice kept in total darkness. Thus, Stargardt patients should be advised to avoid direct sunlight exposure. Ultraviolet-blocking sunglasses are a useful option.
Vitamin A supplementation has been regarded as a therapeutic option for certain retinal degenerative conditions such as retinitis pigmentosa.
However, recent data suggests that in ABCA4-mediated disease, vitamin A supplementation accelerates the accumulation of lipofuscin pigments in the RPE. Long-term vitamin supplementation increases the formation of vitamin A dimers which favor lipofuscin synthesis and deposition.
Therefore, Stargardt patients should avoid vitamin A supplementation. In contrast, long-term administration of deuterium-enriched vitamin A (i.e. C20-D3-vitamin-A), may have a beneficial effect since this compound prevented vitamin A dimerization in the murine model of Stargardt disease.
Isotretinoin has reportedly been capable of dampening A2E deposition in the RPE of abca4 knockout mice. Considerable side effects associated with chronic intake of isotretinoin prevent its chronic use in humans.
Stargardt disease is a preferred target for gene replacement therapy. Like in Leber Congenital Amaurosis (LCA), from which the most astonishing results of human ocular gene therapy have been obtained, the replacement of the mutant ABCA4 gene by its wild-type counterpart may produce positive results, as those observed in RPE65 gene trials.
Given Stargardt is a retinal degeneration, the identification of viable photoreceptors plays a central role in the selection of patients amenable to gene therapy. Thus, retinal imaging is essential to assess photoreceptor viability, when selecting patients for gene therapy.
High-definition OCT and Adaptive Optics technology enhance lateral resolution in retinal images up to 3-4μm, allowing the visualization of individual photoreceptors.
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From Choroida — the team behind this siteREFERENCES
- Boyd K, Janigian RH. Juvenile Macular Degeneration. American Academy of Ophthalmology. EyeSmart® Eye health.
- Boyd K, Vemulakonda GA. Stargardt Disease. American Academy of Ophthalmology. EyeSmart® Eye health.
- Cremers FPM, Lee W, Collin RWJ, Allikmets R. Clinical spectrum, genetic complexity and therapeutic approaches for retinal disease caused by ABCA4 mutations. Prog Retin Eye Res. 2020 Nov;79:100861. doi: 10.1016/j.preteyeres.2020.100861. Epub 2020 Apr 9. PMID: 32278709; PMCID: PMC7544654.
Test yourself
A few questions straight from this article.
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How is Stargardt disease characterised in terms of inheritance and age group?
Stargardt disease (STGD) is the most common recessively inherited macular dystrophy of childhood. -
Mutations in which gene cause Stargardt disease?
Stargardt disease has a genetic basis in mutations of the ABCA4 gene on chromosome 1, and gene therapy aims to replace mutant ABCA4 with its wild-type counterpart. -
What is the underlying pathological process in Stargardt disease?
Byproducts of the visual cycle accumulate in the retinal pigment epithelium, causing secondary photoreceptor dysfunction and death. -
What is the most common symptom of Stargardt disease?
The commonest symptom is slow bilateral central vision loss; others include central grey or hazy spots, light sensitivity, slow light-dark adaptation and colour blindness. -
Which full-field ERG pattern supported the clinical diagnosis of Stargardt disease in the article's 69-year-old patient?
Full-field ERG showed normal rod and decreased cone responses bilaterally, alongside macular atrophy and central macular hypoautofluorescence on FAF. -
Why should patients with Stargardt disease be advised to avoid direct sunlight?
Unbound all-trans-retinal causes photo-oxidative damage to ABCA4, and A2E did not accumulate in abca4 knockout mice kept in darkness; UV-blocking sunglasses are a useful option. -
Unlike in retinitis pigmentosa, why should vitamin A supplementation be avoided in Stargardt disease?
In ABCA4 disease, long-term vitamin A increases vitamin A dimers that favour lipofuscin synthesis and deposition in the RPE. -
Why may deuterium-enriched vitamin A (C20-D3-vitamin A) benefit Stargardt disease?
Deuterium-enriched vitamin A prevented vitamin A dimerization in a murine Stargardt model, so its long-term use may be beneficial. -
Why is isotretinoin not used chronically for Stargardt disease despite dampening A2E deposition in knockout mice?
Isotretinoin reduced A2E deposition in the RPE of abca4 knockout mice, but its considerable side effects prevent chronic use in humans. -
What plays a central role in selecting Stargardt patients for gene replacement therapy?
As a retinal degeneration, STGD needs viable photoreceptors for gene therapy; high-definition OCT and adaptive optics resolve down to 3-4 μm and can show individual photoreceptors.
