Macular abnormalities are seen in a number of hereditary disorders. The abnormality can be associated with a hereditary systemic disease (eg, the cherry-red spot in GM2 gangliosidosis type I) or can reflect a primary retinal disorder, such as Stargardt disease or Best disease. Only primary retinal disorders are discussed here.
Stargardt disease (juvenile macular degeneration) is the most common hereditary macular dystrophy. Inheritance is usually autosomal recessive; in rare cases, it is autosomal dominant. Most cases are caused by mutations in the retina-specific adenosine triphosphate–binding transporter gene (ABCA4). Children with Stargardt disease usually present between ages 8 and 15 years with a decrease in vision, photophobia, or color vision abnormalities. The condition is bilateral, symmetric, and progressive; visual acuity levels off at approximately 20/50–20/200.
The disease often progresses through stages. Initially, the fundus appears normal even when vision is decreased, and the condition may be misdiagnosed as functional vision loss. The first ophthalmoscopic changes observed are loss of foveal reflex, followed by development of a characteristic macular bull’s-eye atrophy surrounded by round or pisciform yellowish flecks, which develop in the posterior pole at the level of the RPE. If the flecks are scattered throughout the fundus, the condition may be referred to as fundus flavimaculatus. Before the flecks develop, the macula often appears atrophic due to diseased RPE, inducing a peculiar light-reflecting quality resembling that of beaten bronze (Figs 25-14, 25-15).
Figure 25-14 Stargardt disease. Macular atrophy, pisciform yellow-white flecks, and a beaten-bronze appearance. Note the peripapillary sparing of retina.
(Courtesy of Marc T. Mathias, MD.)
The “dark choroid” sign on fluorescein angiography is distinctive but is not present in all patients. This phenomenon is due to the accumulation of lipofuscin within the RPE, which blocks the choroidal fluorescence. Fluorescein angiography has been largely replaced by fundus autofluorescence (FAF) testing for the confirmation of Stargardt disease. FAF reveals both increased autofluorescence due to lipofuscin accumulation in the RPE and reduced autofluorescence in areas of RPE atrophy and photoreceptor loss (see Fig 25-15C, D). OCT imaging of the macula can reveal lipofuscin accumulation in the RPE and photoreceptor loss.
Results of visual field testing may be normal in the early stages of the disease. Disease progression will result in a central scotoma.
ERG results are often normal in the early stages of Stargardt disease. Stargardt disease can be associated with a progressive cone–rod dystrophy that has a much worse visual prognosis and an extinguished ERG.
Detection of ABCA4 mutations via genetic testing may be diagnostic.
Gene therapy for Stargardt disease has been used in animal models and is being studied in phase 1/2a clinical trials in humans.
Classic Best disease, or juvenile-onset vitelliform macular dystrophy (VMD), is an autosomal dominant retinal disorder with variable penetrance and expressivity. The condition is caused by mutations in the BEST1 gene on chromosome 11, which encodes for the protein bestrophin. Patients usually present asymptomatically in childhood with the classic retinal appearance, or later in life with decrease in vision.
Figure 25-15 Fundus photographs from a patient with Stargardt disease. The right eye (A) and left eye (B) demonstrate classic pisciform yellow-white flecks throughout the macula, with mottling of the central retinal pigment epithelium (RPE). Corresponding right (C) and left (D) fundus autofluorescence (FAF) images reveal mottled hypo- and hyperautofluorescence with hyperautofluorescent flecks (corresponding to the pisciform flecks) and a bull’s-eye maculopathy, greater in the left eye than in the right eye.
(Courtesy of Marc T. Mathias, MD.)
Over the last decade, a rare, distinct phenotype—autosomal dominant vitreoretinochoroidopathy (ADVIRC)—has been recognized. ADVIRC results from exon-skipping mutation in BEST1. A separate, distinct phenotype caused by biallelic null mutations in BEST1 also exists. The various phenotypes caused by heterozygous or biallelic mutations of BEST1 are collectively termed bestrophinopathies.
Pasquay C, Wang LF, Lorenz B, Preising MN. Bestrophin 1—phenotypes and functional aspects in bestrophinopathies. Ophthalmic Genet. 2015;36(3):193–212.
The retina may appear normal at first, but between 4 and 10 years of age, the “egg yolk,” or vitelliform, stage begins (Fig 25-16). A yellow-orange cystlike structure is seen, usually in the macula; however, the lesion may occur elsewhere, and occasionally there are multiple lesions. The lesions are usually 1.5–5.0 disc diameters in size. The egg yolk–like appearance is associated with good central vision.
Figure 25-16 Best disease, “egg yolk” stage.
(Courtesy of Joseph Morales, CRA, COA. Cover image for Ophthalmology Retina [Sept/Oct 2017 issue].)
With time, the cystic material may become granular, giving rise to the “scrambled egg” stage. At this stage, central vision usually remains good, with visual acuity roughly 20/30. The cyst may rupture and become partially resorbed; a pseudohypopyon may form from cystic contents. Choroidal neovascular membranes (CNVMs) and pigment epithelial detachments (PEDs) develop in 20% of patients (Fig 25-17A). Subretinal hemorrhage may occur, and visual acuity may deteriorate to 20/100 or worse. FAF reveals central macular hyperautofluorescence due to vitelliform material (Fig 25-17B). Fluorescein angiography reveals central macular hyperfluorescence due to staining of the vitelliform material as well as late leakage from a CNVM, if present (Fig 25-17C, D). Spectral-domain OCT (SD-OCT) imaging can further illustrate the central macular abnormalities (Fig 25-17E, F).
The EOG is usually abnormal in affected patients and carriers. This disorder is one of the few in which the EOG is abnormal and the ERG is normal. BEST1 gene mutations are found in 60%–83% of affected patients. Carriers can be identified by the presence of an abnormal EOG with a normal retina or a BEST1 gene mutation.
Meunier I, Sénéchal A, Dhaenens CM, et al. Systematic screening for BEST1 and PRPH2 in juvenile and adult vitelliform macular dystrophies: a rationale for molecular analysis. Ophthalmology. 2011;118(6):1130–1136.
No treatment is indicated unless subretinal neovascularization occurs.
Excerpted from BCSC 2020-2021 series: Section 10 - Glaucoma. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.