Chapter 46 Inherited macular dystrophies
The inherited macular dystrophies are characterized by bilateral central visual loss and symmetrical macular abnormalities. Most present in the first two decades of life with a wide range of clinical, electrophysiological, psychophysical, and histological findings. The molecular basis of inherited macular disease is now well understood, providing insights into the pathogenesis (Table 46.1).
We review pediatric macular dystrophies and not those that present later, such as Sorsby’s fundus dystrophy, dominant drusen, and adult vitelliform macular dystrophy. Systemic disorders with macular dystrophy will be discussed in Chapters 45 and 62.
Stargardt’s macular dystrophy (STGD) is the most common inherited macular dystrophy with a prevalence of 1 in 10 000; it is inherited as an autosomal recessive trait. Most cases present with central visual loss in early teens. There is typically macular atrophy with yellow-white flecks at the level of the retinal pigment epithelium (RPE) at the posterior pole (Fig. 46.1). The flecks may be “fish-shaped” (pisciform), round, oval, or semilunar. The oval area of macular atrophy may, in the early stages, have a “beaten bronze” appearance (see Fig. 46.1). However, there may be no evidence of flecks at presentation, with the only abnormality being macular atrophy; but usually flecks develop over time. Fundus flavimaculatus (FFM) is when the retinal flecks occur without macular atrophy. STGD and FFM are caused by mutations in the same gene; both patterns may be seen in the same family. Most patients who present with FFM develop macular atrophy.
In both STGD and FFM, fluorescein angiography classically reveals a dark or masked choroid (Fig. 46.2) in the early phase. This is due to excess lipofuscin accumulation in the RPE, which obscures fluorescence from choroidal capillaries. The retinal flecks appear hypofluorescent on FFA early in their evolution, but later they appear hyperfluorescent due to RPE atrophy. Autofluorescence (AF) imaging, using the intrinsic fluorescence from lipofuscin in the RPE, has superseded FFA in confirming the diagnosis. The abnormal accumulation of lipofuscin, the presence of active and resorbed flecks, and RPE atrophy are characteristic on fundus AF imaging.1 (Fig. 46.3). In children with normal fundoscopy and visual loss from macular dysfunction, FFA is still helpful; a subtle window defect in the central macula or a dark choroid helps confirm the diagnosis.
Fig. 46.3 Stargardt’s disease. Characteristic appearance on fundus autofluorescence imaging showing abnormal accumulation of lipofuscin, the presence of active and resorbed flecks, and RPE atrophy. Color fundus photographs (above) are shown for comparison.
Electrophysiological abnormalities in STGD are variable. An abnormal electro-oculogram (EOG), suggestive of generalized RPE dysfunction, is common. The pattern electroretinogram (PERG) and focal ERG are usually abolished or markedly reduced, suggesting macular dysfunction. The full-field ERG may be normal at diagnosis (group 1) or suggest widespread retinal dysfunction (group 2 or 3):1
These groups are not explained by differences in age of onset or duration of disease; these electrophysiological groups may represent different phenotypic subtypes and thereby be helpful in informing prognosis. Patients in group 1 have better visual acuity, more restricted distribution of flecks, and macular atrophy; those in group 3 have the worst visual acuity, more widespread flecks, and macular atrophy is universal.
Mutations in the gene ABCA4 underlie STGD/FFM, and have also been implicated in retinitis pigmentosa (RP) and cone−rod dystrophy. ABCA4 encodes a transmembrane rim protein in the outer segment discs of rod and cone photoreceptors involved in transport of retinoids from photoreceptor to RPE. Failure of this transport results in deposition of a lipofuscin fluorophore, A2E (N-retinylidene-N-retinylethanolamine), in the RPE,2 which is deleterious to the RPE and leads to secondary photoreceptor degeneration.
More than 500 sequence variations in ABCA4 have been reported, demonstrating the high allelic heterogeneity and highlighting the difficulties in assigning disease-causing status to sequence variants detected when screening such a large (50 exons) and polymorphic gene. Nonsense mutations with a major effect on the encoded protein can be confidently predicted to be disease-causing. A major problem occurs with missense mutations since sequence variants are common in controls; therefore, establishing pathogenicity may be problematic. Direct evidence of pathogenicity can only be established by functional analysis of the encoded mutant protein. The most common ABCA4 mutation seen in STGD is Gly1961Glu; Ala1038Val is also seen frequently.
Correlation between the type and combination of ABCA4 mutations with the severity of the phenotype is often possible.3 For example, biallelic null mutations usually lead to a cone−rod dystrophy phenotype rather than STGD. Variable retinal phenotypes within families may be explained by different combinations of ABCA4 mutations segregating within a single family; it is likely that other modifier genes or environmental factors may also influence intra-familial variability.
Accumulation of lipofuscin-related products in the RPE, such as A2E, occurs in STGD and in ABCA4 knockout mice (abca4−/−), resulting in free radical generation, release of pro-apoptotic mitochondrial proteins, and lysosomal dysfunction.2 This leads to RPE dysfunction and cell death and subsequent photoreceptor cell loss.
A2E synthesis can be reduced by raising abca4−/− mice in total darkness, and is increased by feeding the mice supplemental vitamin A. It seems reasonable to advise STGD patients to avoid vitamin A supplementation and to wear ultraviolet light-blocking sunglasses. We also recommend an antioxidant rich diet which slows photoreceptor cell death in animal models of retinal dystrophies. Affected children may be helped by low vision aids and educational support.
There is a 1% risk of an affected individual having an affected child (higher if the partner is a close relative). The carrier frequency of STGD is 1 in 50; there is a 1 in 50 chance that an asymptomatic partner carries a disease-associated sequence change in ABCA4.
New therapeutic interventions for STGD include drugs that target the ATP dependent transport mechanism thereby augmenting ABCA4-related retinoid transport, or slow the visual cycle, reducing the production of A2E. Directly inhibiting the toxic effects of A2E may prove more effective. Pharmacological agents aimed at these three targets have been developed and are likely to progress to a human clinical trial in the near future.2,4 Such agents may also be helpful in other macular degenerations associated with lipofuscin accumulation, such as Best’s disease.
Other interventions include gene supplementation (www.clinicaltrials.gov), and cell-based or stem cell-based strategies aimed at providing supportive growth factors or RPE/photoreceptors for transplantation, respectively. It is likely that cell/stem cell-based clinical trials will be undertaken soon.
Compared to the recessive disorder, individuals with autosomal dominant (AD) STGD-like dystrophy have a milder phenotype with good vision and minimal color vision defects. Individuals usually present in the first or second decades with visual loss which may precede retinal changes. Temporal optic disc pallor may precede retinal findings. The “dark choroid” sign on fluorescein angiography is uncommon in the dominant form. Histopathological findings are similar to autosomal recessive STGD, with widespread accumulation of lipofuscin throughout the RPE.
Inheritance patterns may distinguish the two forms of STGD but pseudodominance is a confounding factor − the carrier frequency of autosomal recessive STGD is sufficiently common (1 in 50) for an affected individual to have an asymptomatic partner carrying a disease-associated sequence change in ABCA4. Pseudodominance is also common in consanguineous families.
Two chromosomal loci have been identified: 6q14 (STGD3) and 4p (STGD4). Two mutations, a 5-bp deletion and two 1-bp deletions separated by four nucleotides, in the gene ELOVL4 have been associated with STGD3 and other macular dystrophies, including pattern dystrophy. ELOVL4 is expressed in rod and cone photoreceptor inner segments and may be involved in retinal fatty acid metabolism.
A missense mutation, p.Arg373Cys, in PROM1 co-segregates with disease in STGD4. PROML1 encodes human prominin 1 which has a role in outer segment disc formation and maintenance. The same PROM1 missense mutation, p.Arg373Cys, occurs in patients with an early-onset autosomal dominant “bull’s-eye” macular dystrophy (MCDR2).
Onset is from the end of the first to the sixth decade, most presenting with reading difficulties.5 RPE mottling in younger subjects progresses to a bull’s-eye maculopathy (BEM) and, later, macular atrophy. Some patients have typical features of RP (see Chapter 44). Patients have a mild to moderate reduction in visual acuity, except when associated with RP where markedly reduced central vision is common.
Best’s disease (BD) is an autosomal dominantly inherited macular dystrophy with a round or oval yellow subretinal macular deposit that is highly autofluorescent on AF imaging (Fig. 46.5). Although most gene carriers show a reduced light rise on EOG, the retinal phenotype is variable. Some gene carriers have a completely normal fundus. The phenotype is classified into five stages (Table 46.2):
Stage II: classical “egg yolk” macular lesion (Fig. 46.6A). FFA shows a corresponding area of blocked choroidal fluorescence (Fig. 46.6B). This appearance is usually seen during the first or second decades, often with near normal visual acuity.