Stargardt Disease Overview
Stargardt disease (SGD) is the most frequent childhood recessively inherited macular dystrophy. Most patients present with central visual loss in the early teenage years and ophthalmoscopy classically shows macular atrophy with yellowish “pisciform” subretinal flecks at the posterior pole due to lipofuscin deposition (▶ Fig. 23.1). When the flecks extend throughout the retina, the disease is called fundus flavimaculatus. The estimated prevalence is 1 per 10,000 individuals. SGD is caused by mutations in the ABCA4 gene.
Fig. 23.1 Stargardt disease. (a) Fundus picture of a patient with Stargardt disease showing posterior pole subretinal yellow flecks, associated with mild macular atrophy. (b) Silent choroid sign on fluorescein angiography in a patient with Stargardt disease due to a mutation in ABCA4. (c) Fundus autofluorescence in a patient with Stargardt disease revealing multiple hyperfluorescent lesions (corresponding with subretinal flecks) and macular hypo-autofluorescence (corresponding with atrophy).
SGD results from the accumulation of lipofuscin in the retinal pigment epithelium (RPE) with secondary photoreceptor dysfunction and subsequent death. ABCA4 encodes a transmembrane protein that is localized specifically to the retina. It is found in the disc membranes in cone and rod outer segments, where it participates in the retinoid cycle through which 11-cis-retinal recycles, and returns the photoreceptor to its dark adapted state, enabling further phototransduction. It is thought that ABCA4 works as a “flippase” that transports N-retinylidene-phosphatidylethanolamine across the disc membranes. When ABCA4 activity drops, there is progressive accumulation of A2E in the RPE as lipofuscin deposits. This is the histological hallmark of SGD. In SGD, lipofuscin can be accumulated up to five times above normal values. This produces a negative effect on the RPE function and survival, altering the cell membrane architecture and inducing apoptosis. Loss of RPE leads to secondary photoreceptor degeneration and, consequently, loss of vision.
SGD most commonly presents with bilateral central visual loss, color vision abnormalities, central scotomas, and slow dark adaptation with or without photophobia. Some patients may enjoy normal or only mildly reduced visual acuity despite a very abnormal retinal appearance. Eventually these patients usually experience further central vision loss. Generally, initial vision deterioration is otherwise rapidly progressive, but its age of onset is highly variable. Few patients deteriorate as far as to counting finger or hand motion. Visual prognosis is dependent on age of disease onset: patients who present with significantly compromised vision earlier have worst outcomes.
There is a particular form of SGD called childhood-onset, early-onset, or juvenile SGD. These patients tend to develop early severe visual acuity loss (usually worse than 20/40), before 10 years old, markedly compromised retinal function on electroretinogram (ERG) with generalized rod and cone system dysfunction, and rapid progression of RPE atrophy, from mild to severe findings in approximately 12 years. Approximately half of these patients have a diagnostic delay, which averages 3 years. Individuals with adult-onset SGD are more likely to retain useful visual acuity for longer and show milder retinal dysfunction at diagnosis. At presentation, 30% have flecks and 3% have a normal looking retina.
Paradoxically, fundus examination can be normal early in the course of disease, even when patients already have visual complaints. Later on, pigment mottling, a “beaten bronze” appearance of the macula, macular atrophy, fundus flecks, or even bull’s eye maculopathy may arise. Flecks are typically “pisciform,” round, amorphous, or dotlike yellow-white lesions. Their distribution may change with time. The number of flecks does not have a good correlation with the visual loss.
Patients with SGD can develop eccentric fixation. Furthermore, ABCA4-related disorders tend to spare the structure and function of the parapapillary retina, demonstrated by fundus autofluorescence and optical coherence tomography (OCT). This area can become a preferred retinal locus of fixation in up to one-third of patients.
It should be noted that SGD and fundus flavimaculatus differ in significant aspects. Individuals with fundus flavimaculatus often have a later disease onset and slower visual deterioration. Therefore, fundus flavimaculatus is often a milder condition with the macula less involved, and because of it, generally results in a better visual acuity than SGD.
Current treatment options include photoprotection and low-vision aids as needed. Patients may benefit from ultraviolet-blocking sunglasses. Vitamin A should be avoided as supplementation increases the lipofuscin accumulation in the RPE. The role of compounds that decreases lipofuscin deposits, such as deuterium-enriched vitamin A or isotretinoin, is under investigation, as are stem cell therapy and gene therapy.
23.2 ABCA4 Retinopathies Overview
Other ABCA4-related phenotypes present as a spectrum that includes age-related macular degeneration (AMD), macular atrophy without flecks, bull’s eye maculopathy, autosomal recessive (AR) CORD, and AR RP. Some overlap or intermediate forms can also be seen with different progression rates during the course of the conditions. In addition, different presentations may converge to the same end stage, characterized by diffuse atrophy. Symptoms may vary as well. For example, photoaversion may be seen in isolated cone dysfunction syndromes, while nyctalopia develops more frequently in patients with RP and cone–rod dystrophy (CORD). There are, however, clues that can suggest ABCA4. For instance, if an RP phenotype shows severe pigmentary changes in the macula or posterior pole atrophy as opposed to mild peripheral disease, ABCA4 can be suspected. In addition, silent choroid on angiography can be seen in RP and CORD due to ABCA4 pathogenic variants. It is estimated that 30 to 50% of CORD is due to ABCA4 mutations.
23.3 Stargardt Disease Molecular Genetics
ABCA4 (chr 1p22.1) is a large gene that comprises 50 exons and has great allelic heterogeneity, with over 800 disease-associated variants described, most of which are missense mutations. The most frequent ABCA4 pathogenic variations account for only approximately 10% of patients. There are ethnic group-specific ABCA4 alleles demonstrating founder effects in different regions (e.g., T1428M allele in Japan). The carrier frequency for ABCA4 mutations is relatively high, usually 4 to 5% of the general population, although it can be higher in some populations. The estimated prevalence of ABCA4 mutations in AR CORD ranges from 30 to 60%. Later-onset SGD is seen in patients with missense mutations that do not affect functional domains of ABCA4, resulting in milder mutant alleles and leaving some ABCA4 activity. For early-onset SGD, the prevalence of ABCA4 mutations can be as high as 90%. Deep intronic mutations have also been described in ABCA4opathies. Full sequencing of ABCA4 coding and intronic sequences in individuals with SGD find two disease-associated alleles in 65 to 75% of patients, one mutation in 15 to 20% of individuals, and no mutations in approximately 15%. Most nonsense mutations are associated with classic SGD, whereas mutations found in patients with fundus flavimaculatus and late-onset SGD are usually missense mutations. It is not uncommon to find two or more mutations on the same ABCA4 allele, creating a mutation number greater than 2. Familial segregation analysis is therefore crucial to determine pathogenicity and determine if the patient truly has biallelic mutations (in trans) as opposed to two mutations on the same allele (in cis).
Some phenotype–genotype correlations are noted for specific mutations. The G1961E ABCA4 allele contributes to central macular changes rather than generalized retinal dysfunction, and is a cause of bull’s eye maculopathy in either the homozygous or the compound heterozygous state. The c.2588G>C allele is associated with typical SGD instead of “early-onset” SGD (this allele is seen in up to 4% of patients with early-onset SGD vs. 30% of individuals with classic SGD). Loss of peripapillary sparing is likely associated with the more deleterious mutations of the ABCA4 gene.
23.4 ABCA4 Retinopathies Molecular Genetics
Different combinations of affected ABCA4 alleles are predicted to result in distinct phenotypes, in a spectrum of retinal manifestations of which severity is inversely proportional to the residual ABCA4 activity. ABCA4 has been described in the pathogenesis of AMD (ABCA4 polymorphisms), CORD (residual ABCA4 activity), and retinitis pigmentosa (full null alleles). Even within families, the same ABCA4 allelic combinations can produce diverse phenotypes. It has been described that heterozygotes for the G1961E and D2177N ABCA4 alleles have an increased risk of developing AMD. However, co-segregation studies in families with AMD have failed to establish a direct correlation between the condition and ABCA4 variations.
23.5 Stargardt Disease Differential Diagnosis
23.5.1 Autosomal Dominant (AD) Stargardt Disease (STGD4, OMIM 603786)
Stargardt’s-like disease with AD inheritance pattern has been described in families with heterozygous mutations in the PROM1 gene (4p). Patients typically have a bull’s eye maculopathy. These patients may be indistinguishable from classic SGD, although central vision loss with significant outer nuclear atrophy in the context of an AD pattern of inheritance is the key factor.
23.5.2 Stargardt Like Macular Dystrophy (STGD3, OMIM 600110)
Stargardt like macular disease with AD inheritance pattern has been described in families with heterozygous mutations in the ELOVL4 gene (6q14.1). Affected individuals have normal visual acuity in early childhood but start decreasing between the ages of 5 and 23 years. Flecks are present early in most cases. Central atrophy develops in later stages, with visual acuity decreasing to 20/200 or worse in all affected individuals by adulthood. Intravenous fluorescein angiography (IVFA) does not show a silent or dark choroid sign.
23.5.3 Malattia Leventinese and Doyne Honeycomb Retinal Dystrophy (OMIM 126600)
These two AD diseases due to mutation in EFEMP1 (2p16.1) are characterized by yellow-white drusenoid deposits that accumulate beneath the RPE. Drusen are seen typically in the second and third decades of life, although there are reports of earlier onset (15 years old). Drusen tend to be bilateral, elongated, and with radial distribution. Drusen are more regular in shape and can extend beyond the arcade and nasal to the disc, which are uncommon in SGD. RPE and macular atrophy develop later.
23.5.4 Kandori’s Flecked Retina (OMIM 228990)
This AR rare condition is characterized by irregular flecks, with variability in size and tendency to confluence, distributed in the equator or midperiphery. The macula is spared. The genetic basis remains unknown.
23.5.5 Familial Benign Fleck Retina (228980)
This is an AR condition associated with a pattern of diffuse, yellow-white, flecklike lesions extending to the far periphery of the retina but sparing the fovea. These individuals are asymptomatic and electrophysiology is normal. It is caused by biallelic mutation in the PLA2G5 gene (1p36). Hyaline deposits occur along the cuticular layer of Bruch’s membrane, looking as multiple deep yellowish white lesions of variable size and shape.
23.5.6 Sorsby’s Fundus Dystrophy (OMIM 136900)
This is an AD retinal dystrophy characterized by loss of central vision as a result of macular disease by the fourth to fifth decade of life. Peripheral visual loss develops later. It is usually manifest at the age of approximately 40 years, beginning as a macular lesion showing edema, hemorrhage, and exudates; the latter may be confused with lipofuscin. Atrophy with pigmentation and extension peripherally occurs later, with sclerotic choroidal vessels. It is associated with mutations in TIMP3 (22q12.3).
23.5.7 Pattern Macular Dystrophy (OMIM 169150)
Patterned dystrophies of RPE refer to a heterogeneous group of macular disorders, defined by an abnormal macular accumulation of lipofuscin. Three main patterns have been reported: reticular dystrophy, macroreticular (“spider-shaped”) dystrophy, and butterfly dystrophy. It is caused by heterozygous mutation in the RDS–peripherin gene (PRPH2; 6p21). It is frequently manifest by the age of 40 years.
23.5.8 Age-Related Macular Degeneration (OMIM 603705)
Because of drusen, and geographic atrophy in the macula, ARMD can be confused with SGD. The age of onset is typically much later than classic SGD but may coincide with late-onset SGD. ARMD is the most common cause of acquired visual impairment in the elderly. Mild forms of ARMD are seen in 30% of those who are 75 years and older, and advanced stages occur in about 7% of individuals in this age group. ARMD is considered a complex phenotype and therefore, genetic testing still is not recommended. Multiple pathogenic variants have been associated with AMD (CFH, CFB, ABCA4, TIMP3, BEST1, and EFEMP1 genes) and might suggest AMD is a polygenic disease, resulting from the presence of disease variants in multiple different genes.
23.5.9 Basal Laminar Drusen (OMIM 126700)
This term refers to an early adult-onset drusen phenotype that presents with a pattern of uniform small yellow subretinal nodules randomly scattered in the macula. Some authors consider it to be part of a spectrum of disease that includes ARMD. On IVFA, a typical “stars in the sky” appearance may be seen. CFH gene mutation may be associated with this condition.
23.5.10 Central Areolar Choroidal Atrophy (OMIM 215500)
Patients present a well-defined area of atrophy of the RPE and choriocapillaris in the center of the macula. It is usually diagnosed at the age of 40 to 60 years. It is an AR condition, associated with a mutation in the PRPH2 gene (6p21.2-p12.3). Flecks are not present and the choroid is only affected under the geographic lesion.
23.5.11 Kjellin Syndrome (OMIM 270700)
Spastic paraplegia-15 is a neurodegenerative disorder defined by progressive spasticity primarily affecting the lower limbs, associated with mental retardation, hearing and visual defects, and thin corpus callosum. It is an AR disorder caused by biallelic mutations in the gene ZFYVE26 (14q24.1). SPG11 mutations (15q21.1) can also cause Kjellin syndrome. Retinal findings include macular atrophy and posterior pole flecks. The systemic associations easily differentiate it from SGD.
23.5.12 Fundus Albipunctatus (OMIM 136880)
This flecked retina disorder is characterized by discrete uniform white dots over the entire fundus with greatest density in the midperiphery and less macular involvement. It presents with nyctalopia. Scotopic full-field (ff) ERG typically improves after dark adaptation. It is associated with mutations in RDH5 or RLBP1 (▶ Fig. 23.2).
Fig. 23.2 Fundus albipunctata in a patient with discrete uniform white dots in the midperiphery and no macular involvement.
(The image is provided courtesy of Sergio Zacharias, MD, and René Moya, MD.)