Stargardt Retinal Dystrophy

A 46-year-old man presented for a second opinion from an outside eye doctor for a possible hereditary retinal dystrophy. The patient reported having difficulty seeing for years but could not specify when his poor distance and near visual acuity became truly bothersome. He described looking to the side of central areas of blindness to perceive the details of an object of interest. Upon questioning, the patient said his vision was poor under all circumstances, rather than worse during the day (ie, hemeralopia) or at night (ie, nyctalopia). His medical history was otherwise unremarkable, and he was not taking any medications. The patient did not use tobacco and occasionally consumed alcohol. He had no family history of inherited retinal disease to report.

EXAMINATION FINDINGS

The patient’s UCVA was 20/200 OD and 20/150 OS. The pupils were equal in size, round, and reactive to light, and no afferent pupillary defect was evident. Extraocular motility testing demonstrated a full range of motion in each eye. Confrontation visual field testing showed largely intact peripheral vision and difficulty with central vision. The patient was unable to identify any of the color vision test plates with Hardy-Rand-Rittler color testing in either eye. With a mildly myopic spectacle prescription and noticeable difficulty, he was able to read 20/60 OD and 20/50 OS.

External ocular examination findings were unremarkable. His IOP was 8 mm Hg OD and 8 mm Hg OS with rebound tonometry. The results of a dilated fundus examination of the posterior pole were consistent with suspected hereditary retinal dystrophy (Figures 1 and 2). OCT of the posterior pole showed extensive loss of overall retinal structure, particularly the photoreceptors and retinal pigment epithelium (RPE) in each eye (Figure 3).

The patient provided a buccal sample for genetic testing. Approximately 10 weeks later, the results confirmed a mutation of the ABCA4 gene, supporting a diagnosis of Stargardt disease. He was counseled on the current lack of treatment options. A low vision consultation was highly recommended, but the patient declined. He was asked to return for follow-up in 1 year.

DISCUSSION

Genetics

Stargardt disease is the most common inherited macular dystrophy in both children and adults.^1,2 First described by Karl Stargardt in 1909,^2,3 the disease classically has an autosomal recessive inheritance pattern, but a high degree of heterogeneity in both patient genetics and clinical findings results in a large spectrum of clinical presentations.^1-3 The ABCA4 gene is believed to encode 2,273 amino acid proteins,³ and more than 900 different sequence variations in this gene have been described in Stargardt disease.¹ This could explain the high heterogeneity noted.³ Autosomal dominant Stargardt-like diseases have been reported that are associated with lesser degrees of vision loss.^2,3

Generally speaking, vision loss due to Stargardt disease is bilateral and occurs between 6 and 20 years of age.^2,3 Visual acuity often plateaus at approximately 20/200 with the development of central scotomas.^2,3 Yellowish pisciform (ie, fishtail) or round flecks of lipofuscin appear in the macula within the RPE and may eventually spread to the midperipheral retina.^2,3 As the disease progresses, pigmentary changes and lipofuscin deposits often build up in the macula, leading to extensive macular atrophy.³ In the earliest disease stages, however, the retina either has a normal appearance or only the foveal reflex is absent.³

Lipofuscin is the pathologic molecule most commonly found and associated with the damage noted in Stargardt disease.³ This intracellular waste product is indigestible and resistant to lysosomal enzymatic degradation.³ In healthy individuals, the ABCA4 gene encodes a transporter protein in the photoreceptors and RPE layers.^3,4 Among patients with Stargardt disease, the ABCA4 gene causes the transporter protein function to decrease or fail.^3,4 The resultant buildup of lipofuscin causes photoreceptor degeneration (primarily of the outer segments) and RPE degeneration, leading to the clinical findings associated with the disease.^3,4 Lipofuscin levels among patients with Stargardt disease have been found to be 2- to 5-times higher than in age-matched controls.³

Diagnosis

Diagnostic testing for Stargardt disease includes a comprehensive dilated examination, visual field testing, color vision testing, retinal photography (ie, color and fundus autofluorescence [FAF]), OCT, fluorescein angiography, ocular electrophysiology (ie, full-field and multifocal eletroretinograms), adaptive optics, and genetic testing.^1-3 OCT imaging often provides strong evidence of structural changes correlating with functional vision loss.²

The main OCT findings are retinal thinning; outer nuclear layer, photoreceptor, and RPE loss; and increased choroidal reflectivity.² FAF testing helps identify lipofuscin by exploiting its autofluorescent properties.¹ Fluorescein angiography, however, has fallen out of favor among eye care providers for the diagnosis of Stargardt disease because the aforementioned tests are less invasive and have shown a similar level of accuracy.¹

Terminology

There is some confusion regarding proper terminology for the condition.³ Generally, fundus flavimaculatus is used in the peer-reviewed literature to describe the disease when it begins later in life, with flecks scattered throughout the fundus, and the patient’s visual acuity is relatively preserved.³ The term Stargardt disease is typically reserved for patients who lose vision during their first or second decade of life and experience more severe visual degradation, with macular degeneration and flecks confined to the posterior pole.³

Because both fundus flavimaculatus and Stargardt disease are caused by mutations in the ABCA4 gene,^2-4 differentiating between the terms and conditions may be a moot point unless treatment options are developed that make it clinically important. Clinical trials of gene replacement therapy, stem cell therapy, and pharmacologics are underway.^1,4 At present, patient care is limited to diagnosis, genetic testing and counseling, and efforts to maximize the patient’s visual function with spectacle correction and/or a low vision consultation.

ARM FOR SUCCESS

At some point during their careers, eye care providers are likely to encounter patients with Stargardt disease. Providers’ awareness of the condition’s pathophysiology and diagnostic testing options is key to maximizing patient care and outcomes.

A low vision consultation and/or devices can benefit most individuals who have an inherited retinal disease. Even when patients decline the offer of a low vision consultation, their awareness that these services exist allows them to explore the option at a later date if they decide it’s in their best interest to do so.