61 Dominant Drusen

D , extracellular deposits that accumulate below the retinal pigment epithelium on Bruch’s membrane.7 “Hard” drusen, including basal laminar drusen and cuticular drusen, represent focal thickening of Bruch’s membrane or the basal membrane underlying the retinal pigment epithelium (RPE). “Soft” drusen are usually larger (small RPE detachments) and carry a higher risk of degenerative changes.37 Although drusen are located in the posterior pole, they are biomarkers of a more diffuse disease process that is complex and at least partly genetically determined. Drusen are usually a hallmark of a progressive macular degeneration process, and their formation parallels changes in Bruch’s membrane and the RPE. The deposits seen in dominant drusen are distinguished from those seen in Stargardt’s disease, Best disease, or other “flecked” retinopathies. These pathologies can be characterized on the basis of clinical and pathophysiological findings. These conditions will not be discussed in this chapter, nor will optic nerve drusen, also a distinct entity. Drusen are usually seen in the aging eye but can be seen as early as the first decade, especially when a hereditary pattern is documented. These changes are usually not associated with any systemic findings, although drusen can be documented in conditions such as mesangiocapillary glomerulonephritis type II.11

The nature of drusen

Although drusen are widely accepted as the hallmark of agerelated macular degeneration,52 their composition and the mechanism of their formation are not understood.7 The nature of drusen appears to be partly environmentally determined and partly genetically determined. Histochemical and immunoctytochemical studies have shown that drusen contain a variety of lipids, polysaccharides, and glycoaminoglyans, and over 20 drusen-related proteins have been identified.1,2,7,22,31,35,38,41 The nature of drusen is being further elucidated through various approaches.7

Dominant drusen

The term dominant drusen refers to a genetically heterogeneous group of disorders of autosomal-dominant inheritance. Individuals affected with this genetically determined type of deposits are at 50% risk of transmitting the related genetic defect. The penetrance of dominant drusen is not

always complete, which implies that despite carrying a causal genetic defect, the retina may look normal even late in life. This often challenges the recognition of the inheritance or heritability pattern.8 The appearance and distribution of the drusen can be variable within and between families.8,46 The deposits are usually located in the posterior pole. In dominant drusen, they are also often seen nasal to and/or very close to the optic nerve (figure 61.1). Inherited drusen are usually bilateral and symmetric and tend to appear earlier in life than age-related sporadic drusen. They may appear decades before any symptoms. Other than these observations, there is no specific clinical or pathological clue to distinguish the heritable drusen from the sporadic nonhereditary variant.18,51

In some instances, a specific pattern of distribution may be recognized, leading to the diagnosis of Sorsby’s fundus dystrophy,27,48,59–61 Doyne’s honeycomb dystrophy,9,45 malattia Leventinese,17 or Hutchinson-Tay choroiditis.28 When no specific pattern is recognized, the pathology is simply referred to as dominant drusen (figure 61.2).

Dominantly inherited drusen models have been studied genetically in an attempt to elucidate the basis of the more commonly observed sporadic cases. Although dominant drusen were long thought to constitute one entity,8 this was disproved by recent molecular studies showing the genetic heterogeneity of these deposits. At least four disease gene loci have been identified,26,34,47,73 and three genes have been characterized: peripherin/RDS (RDS), tissue inhibitor of metalloproteinase 3 (TIMP-3), and EGF-containing fibulinlike extracellular matrix protein 1 (EFEMP1).47,63,73 The genetic heterogeneity of drusen implies that the pathophysiological mechanisms that lead to their formation are also varied. This may explain the range of psychophysical and electrophysiological findings that have been documented. Further molecular characterization of drusen should assist in understanding the electrophysiological changes observed. The study of dominant drusen is useful to define the changes that are related to drusen per se, as in those cases, changes related to the aging of the retina are less of a confounding factor.

Functional changes associated with dominant drusen

Functional changes of the retina associated with drusen, although somewhat controversial, are usually minimal

F 61.1 Fundus photography of peripapillary drusen in a case of “aborted” malattia Leventinese.

except for decrease in central visual acuity, contrast sensitivity, and color vision. Progression of the disease is usually associated with the development of central scotoma and changes in dark adaptation. The variability in the psychophysical and electrophysiological abnormalities that have been documented in the literature may reflect not only the various pathophysiological events that are involved, but also the evolving sophistication of the testing techniques available. Full-field electroretinograms (ERGs) are typically normal in drusen, although subnormal recordings have been documented.37 No electrophysiological criteria can currently differentiate patients with familial drusen from those with nonfamilial drusen.18 The standardization of testing procedures (http://www.iscev.org/standards) and the use of newer recent techniques such as the multifocal ERG should provide useful information in the near future.2

E -O Electro-oculography of small cohorts of patients who are affected with dominant drusen shows normal value in all cases.16,65 This suggests that dominant drusen are primarily not a diffuse disease of the RPE. This contrasts with previously documented abnormal electro-oculogram (EOG) reports from patients with fundus flavimaculatus and supports the hypothesis that drusen are functionally and pathophysiologically distinct from flecks.37 Studies of patients affected with nonexudative age-related macular degeneration (AMD) provide different results, 20% of patients having abnormal EOG recording, especially in soft drusen.18,72 The size of the area of retina that is involved at the time of testing as well as the recording technique used may be confounding factors.

E Subnormal ERG recordings have been documented in several patients with dominant drusen and nonexudative AMD, in which decreases of both rod and cone function have been documented.18,43,72 Changes in amplitudes can precede changes in implicit times.72 Recent studies showed that the cone b-wave implicit time was prolonged in at least two subtypes of hereditary drusen: malattia Leventinese and codon 172-RDS–related maculopathy.21 This variability in results partly reflects differences in recording technique and the control populations that were used. When drusen of the elderly are assessed, a decrease in darkadapted retinal sensitivity is measured in the central retina in the area of drusen as well as the nondrusen area.54,65 This sensitivity loss appears to reflect a diffuse retinal disease process and disruption of rod-mediated kinetic parameters of dark adaptation in early nonexudative AMD.44 These observations support the hypothesis that the presence of drusen in the posterior pole reflects a diffuse retinal disease process.

In AMD patients with a variable amount of soft drusen, retinal cone-mediated flicker sensitivity losses can be detected with the focal ERG as a function of flicker modulation depth. Early lesions have been associated with reduced response gain and phase delays, with normal thresholds.15,54 In patients with early nonexudative AMD, the focal ERG changes parallel the extent and severity of fundus lesions. However, a functional impairment of outer macular layers detected by focal ERG losses could precede morphological changes that are typical of more advanced disease.14 In more recent evaluations of AMD populations, it was found that the amplitude of the oscillatory potential OP2 was significantly reduced in addition to the abnormal photopic responses compared with an age-matched control group.72

Significant abnormalities in the foveal amplitude and the foveal latency of multifocal ERG (MERG) can also be detected in pre-AMD or early AMD eyes as well as in the asymptomatic controlateral eyes, suggesting MERG as a sensitive tool in detecting early foveal abnormalities in AMD. By using the concentric configuration, the foveal amplitude of pre-AMD or early AMD eyes was significantly suppressed when compared with the age-matched control group, and their average latency was longer in the fovea than in outer rings and significantly prolonged when compared with the normal control group. Similar changes in amplitude and latency were also observed in the asymptomatic fellow eyes.36

Genetic influences

Several studies have shown that the genetic predisposition of drusen is now accepted to be a major risk factor for the development of macular degeneration.25,33,40,55,57,58 This is especially true when there is a large number (>20) of small hard drusen and large (≥125 micron) soft drusen24 or when drusen are seen nasal to the disc.8 These findings should

F 61.2 Clinical range of dominant drusen. Fundus photography of a 37-year-old female with Sorsby’s fundus dystrophy (A), a 40-year-old with dominant macular drusen with no pattern (B) (courtesy of Dr. J. Hopkins), a 43-year-old male affected with fine

prompt the examination of family members, as the diagnosis of dominant drusen may influence counseling and management. Three specific genetic models of dominant drusen for which the gene has been identified are discussed below.

Specific genetic models

TIMP-3–R D More than 50 years ago, Sorsby et al.60 described a dominantly inherited fundus dystrophy

radial drusen (malattia Leventinese) (C), and a 39-year-old male affected with Doyne’s honeycomb dystrophy (D). Note the coarse macular and peripapillary deposits. (Courtesy of Dr. William Pearce.)

with onset of central visual loss between the fifth and sixth decades, leading eventually to the loss of ambulatory vision in the mid-seventies. Early ophthalmoscopic changes can be seen during the third decade (see figure 61.2A) and may take the form of either discrete drusenlike deposits or a confluent yellow deposit at the level of the retinal pigment epithelium.27,48 Confluent thickening of Bruch’s membrane may be difficult to identify by ophthalmoscopy alone but was suggested as a possible barrier to diffusion of nutrients to the

photoreceptors.61 The first sign of the disease can be the delay in choriocapillaris filling on fluorescein angiography, usually confined to the posterior pole in the young individuals. The most obvious clinical change is the drusenlike deposits seen along the arcades and nasal to the optic disk rather than at the central macula. These deposits are associated with the subsequent development of geographic atrophy or neovascularization.27,48,61 Drusen are very infrequently centered over the fovea, making the distinction between Sorsby’s fundus dystrophy (SFD) and other forms of age-related and genetically determined drusen relatively straightforward. Night blindness is an early symptom that is usually not correlated with an abnormal full-field ERG.56 Photoreceptor dysfunction has been documented in some severe cases,4,30,54 but the EOG is usually normal. Steinmetz et al.61 and Jacobson et al.29 proposed a testable hypothesis that thickening of Bruch’s membrane caused night blindness by blocking the passage of vitamin A from the choriocapillaris to the photoreceptors. This was confirmed by the reversal of psychophysical and electrophysiological abnormalities following high-dose vitamin A supplementation (50,000 IU/d).29

Sorsby’s fundus dystrophy was mapped to chromosome 22q,74 and point mutations in the TIMP-3 gene were subsequently identified in affected members of unrelated SFD pedigrees.73 These mutations are found to disrupt the functional properties of the mature protein; they are not seen in the normal population and most probably are disease causing. The role of TIMP-3 is being elucidated, and it is thought to play a role in the degradation process of Bruch’s membrane78 and as an inhibitor of angiogenesis.49 The recent development of the Sorsby mouse model should contribute to a better understanding of the mechanisms that underlie this disease.75

C 172 RDS–R D A very wide range of phenotype, including that of drusen, result from mutations in the RDS/peripherin gene.3,42,47,50,62,76 For example, mutations in codon 172, especially the Arg172Trp mutation, cause a highly penetrant, progressive form of macular degeneration with subtle dominant drusen47,77 (figures 61.3, 61.4B, and 61.4D). Even though the disease can be detected early by ophthalmoscopy in the asymptomatic adolescent, severe visual loss does not occur before the fifth decade. The early stage is characterized by the presence of bilateral and symmetric macular drusen with no specific pattern of distribution (see figures 61.4B and 61.4D). In later stages, it resembles atrophic AMD except when the chorioretinal atrophy extends to the optic nerve head. In most affected cases, the macular changes are bilateral and symmetric, and the optic disk and periphery remain uninvolved.

Although the product of the RDS/peripherin gene is a photoreceptor-specific glycoprotein detected exclusively in the outer segment of rods and cones,6,67–69 these individuals do not complain of nyctalopia and do not have constricted visual fields. The primary symptoms include early-onset photophobia and difficulty in dark adaptation as early as the second decade. This has been reflected in abnormal colorcontrast sensitivity and reduced pattern and cone ERG in some cases.77 Visual acuity and retinal function changes are first noted around the third decade, when the cone and in some cases rod amplitudes were mildly altered before the b-wave implicit time. Overall, the full-field retinal function remains remarkably preserved until the late stages of the disease. In general, cone and rod thresholds are elevated, and color-contrast sensitivities are absent in the central visual field.77 Cone ERGs are usually diminished in amplitudes and delayed. Peripherally, the scotopic sensitivities

F 61.3 Fluorescein angiography of early and late stage of codon 172 RDS–related maculopathy. A, Intravenous fluorescein angiography (IVFA) of a 31-year-old male affected with a Arg172Trp-related maculopathy, B, IVFA of a 60-year-old male

relative with the same Arg172Trp mutations. Their respective fundus photography and electrophysiology are shown in figures 61.4B and 61.4D.

remain normal until late, as does the recovery to bleach.77 Rod ERGs also usually remain normal until very late in the disease, around the sixth or seventh decade. At that time, some ERG recordings have showed subnormal function of both the cone and rod systems, resembling cone-rod degeneration.21,26 Codon 172-RDS–related maculopathy is characterized by a relatively continuous decrease of central vision starting during the third decade of life, in contrast with EFEMP1-related maculopathy (see below), in which visual acuity is retained until the fifth decade.21 EOGs were shown to be normal with Arden ratios ranging between 170% and 220%.

On evaluation by static perimetry, the areas of elevated threshold and absolute scotomas corresponded closely to the extension of the macular changes. Static and dynamic perimetry would not show peripheral field constriction.47

EFEMP1-R D The first convincing evidence of dominantly inherited drusen was provided by Doyne in 1899.9 Histopathological examination of one of Doyne’s patients5,70 revealed the abnormalities to be hyaline thickenings of Bruch’s membrane. Klainguti, Wagner, and Forni later fully characterized this condition and demonstrated its autosomal-dominant inheritance.17,32,71 This disorder has been referred to as malattia Leventinese, after the origin of the Swiss affected individuals. Malattia Leventinese shows clinical overlap and a shared molecular background with Doyne’s honeycomb dystrophy and the radial drusen maculopathy of Gass.19 Although it was originally recognized in Switzerland, families affected with autosomal-dominant radial drusen have been identified throughout the world, including Czechoslovakia,10,64 Australia, Japan, and the United States.10,20

As suspected by Deutman, Doyne’s honeycomb dystrophy and mallatia Leventinese are allelic variants due to a mutation in EFEMP1.8 Families that are affected with malattia Leventinese and radial drusen maculopathy were mapped to chromosome 2p16-21,26 and the disease-causing gene (EFEMP1) was identified through the analysis of additional families, including some affected with the Doyne’s honeycomb dystrophy phenotype.63 The same mutation, Arg345Trp, was seen in all families that were studied, producing the malattia Leventinese, radial drusen, and Doyne’s honeycomb dystrophy phenotypes.39 Drusen are genetically heterogeneous, as EFEMP1 is not associated with sporadic drusen,53 and there appears to be a radial drusen family without a EFEMP1 mutation.66 No EFEMP1 mutations have been identified in patients affected with AMD.63

EFEMP1 is predicted to be an extracellular matrix protein but is otherwise completely uncharacterized. Mutant EFEMP1 is misfolded and secreted inefficiently and is retained within cells. In normal eyes, EFEMP1 is not present at the site of drusen formation. In eyes that are affected with

malattia Leventinese, EFEMP1 accumulated within the retinal pigment epithelial cells and between the RPE and drusen, not being a major component of drusen. In AMD eyes, EFEMP1 is found to accumulate beneath the RPE overlaying the drusen.38

The malattia Leventinese phenotype is characterized by an early-onset radial distribution of basal laminar type of drusen in the macular and peripapillary area (see figure 61.4A). The nasal retina is also frequently involved. The disease is progressive, the drusen increasing in size and number with age and some developing dense pigmentation. In the early and end stages of the disease, the radial pattern of distribution of the drusen may be difficult to detect without fluorescein angiography (see figure 61.4C). When drusen are larger and coarser with virtually no radial pattern of distribution of the drusen, we refer to Doyne’s honeycomb dystrophy (DHRD) (see figure 61.2D). The severity of radial distribution of drusen (basal laminar) that are seen clinically is the main feature that can be used to differentiate between the DHRD and malattia Leventinese phenotypes. In either case, the deposits are characterized by abnormal autofluorescence patterns and an EFEMP1 mutation. Radial drusen maculopathy, like many autosomaldominant conditions, is characterized by an intrafamilial and interfamilial phenotypic variability that remains unexplained.12 This variability involves the severity, pattern, and progression of the disease. Some molecularly affected patients carry only subtle clinical signs of the disease and fail to show progression. This clinical subtype was identified by Forni in the 1960s as the “aborted form”17 (see figure 61.1). Similarly, the highly variable phenotype suggests that the influence of the EFEMP1 gene may be modulated by other genetic and/or environmental factors.13

Patients usually remain asymptomatic until the fourth decade, when they notice some difficulty in adapting from a brightly lit to a dim lit environment. Some may also develop a variable degree of metamorphopsia, photophobia, and reading difficulty in part owing to the developing paracentral scotomas. The condition relentlessly progresses to a variable degree of visual loss by the fifth decade, which becomes more severe in the sixties and seventies. By the age of 75, most affected individuals are legally blind from the disease. Although considered a rare complication, choroidal neovascularization may be encountered.

Symptomatic visual dysfunction may well precede the stage of retinal atrophy. Patients may complain of reduced central vision, difficulty in adapting to a dimly lit environment, and decreased contrast vision.23 However, most patients with EFEMP1 mutations retain good visual function (0.8–1.0) until the fifth decade, followed by a rapid decrease in the fifth or sixth decade. This contrasts with the RDSrelated maculopathy described earlier, in which the natural history is characterized by a relatively continuous decrease

A

B

F 61.4 Clinical-electrophysiological correlation of different stages of the EFEMP1-related and codon 172 RDS–related maculopathies. A, Fundus photography of a 29-year-old male (early stage) affected with an EFEMP1 maculopathy (left) and the corre-

in visual acuity with increasing age. Rod-driven and conedriven ERG b-wave amplitudes decrease nearly linearly in both conditions in accord with the normal loss of amplitude with increasing age. Implicit times of cone b-waves for EFEMP1-related disease increased more markedly with age when compared to RDS-related disease, in which the values were always prolonged beyond the normal range with a slight increase with age (see figures 61.4A and 61.4C).21,23 The documented change of the rod and cone ERG amplitudes is not different from that related to age.21 Colorcontrast thresholds and both pattern and foveal ERGs show abnormal recordings when tested in adulthood.23 Dark adaptation kinetics can be markedly prolonged when measured in a central location over the confluent deposits, unlike the case when they are measured peripherally to these

sponding full-field ERG recording (right). B, Fundus photography of a 31-year-old male affected with an Arg172Trp-related maculopathy (left) and the corresponding full-field ERG recording (right).

deposits.23 This work highlights the geographic importance of dark adaptation kinetics measurements. In a study of six patients (age range: 34–51 years), a variety of modest ERG changes were observed, which include reduced oscillatory potential and a marginally delayed 30-Hz response cone b-wave. The pattern and focal ERGs were variably reduced in most patients.23

Distinguishing between the different types of dominant drusen based on electrophysiological testing alone is difficult.21 The conflicting reports regarding the functional attributes of various dominantly inherited drusen may reflect the various ages that were tested with respect to the progressive nature of the condition in addition to the genetic heterogeneity of this group of conditions and the different methodologies used through time.

C

D

F 61.4 (continued) C, Fundus photography of a 60-year-old male (late stage) affected with an EFEMP1 maculopathy (left) and the corresponding full-field ERG recording (right). D, Fundus pho-

Summary

The clinical distinction between hereditary and nonhereditary drusen is challenging. Newer electrophysiological techniques that are now available may document retinal dysfunction related to drusen but are not diagnostic of drusen.

The known pathological changes associated with drusen do not significantly alter the electrical properties of the RPE cells.37 Hereditary drusen usually show an early abnormal autofluorescence pattern and correlated abnormal contrast sensitivity, color vision, and cone ERG responses.

At least three early-onset dominant drusen models have led to the identification of a macular degeneration gene. Although these genes are not AMD genes, they are helping the investigation of the pathways involved in age-related

tography of a 60-year-old male affected with an Arg172Trp-related maculopathy (left) and the corresponding full-field ERG recording (right).

macular degeneration. This allowed us to start learning about what AMD genes could look like, where they are expressed, and what they can do. For example, we know that genes that lead to drusen may involve various mechanisms, such as photoreceptors, Bruch’s membrane stability, vitamin A transport, and angiogenesis.

The generation of animal models will facilitate the exploration of the mechanisms underlying phenotype variability. For example, TIMP-3 is present in drusen, and early animal work suggest that TIMP-3 may play a role in the modulation of neovascularization. The knock-in mice display early features of age-related changes in Bruch’s membrane and the RPE that may represent the primary clinical manifestations of SFD. The fact that the night blindness associated with Sorsby fundus dystrophy can be reversed over the short

term with high-dose vitamin A supports the ideas of nutritional manipulation in some cases. Accumulation of EFEMP1 in RPE suggest that misfolding and aberrant accumulation may lead to drusen formation and cellular degeneration. These biological findings combined with the more sophisticated electrophysiological approaches to macular degeneration should provide critical information relating to drusen-related vision loss.

The authors are grateful to Professor Günter Niemeyer, Zurich, for the electrophysiological expertise provided.

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