Macular Dystrophies






Definition


The process of premature retinal cell aging and cell death, generally confined to the macula, in which no clear demonstrable extrinsic cause is evident, and a genetically determined defect is confirmed or implicated.




Key Features





  • Common to have yellowish material within or beneath the retinal pigment epithelium.



  • Loss of macular photoreceptors and retinal pigment epithelial cells causing macular atrophy.



  • Loss of central vision.





Associated Features





  • Neural retinal, retinal pigment epithelial, and choroidal atrophy commonly limited to the macula.



  • Bullseye appearance for some macular dystrophies.



  • Pigment clumps in the posterior pole, midperiphery, or far periphery seen rarely.



  • Optic atrophy, retinal vascular attenuation, macular edema, and choroidal neovascularization seen rarely.





Introduction


The macula is the center of all human vision and is critically unique to our visual function. Its irreducibly complex design requires many unique proteins that allow light to be converted to neuronal impulses (phototransduction). Macular dystrophies are rare genetic disorders that can cause severe central vision loss for the individuals affected. Understanding the genetic causes of these dystrophies allow us to see the various types of clinical abnormalities that arise from specific gene defects in a complex system involved in macular function. Molecular genetics has been instrumental in unlocking the secrets of these mechanisms and has given us a better understanding of the macula. The first retinal degeneration mapped by genetic linkage was one type of X-linked retinitis pigmentosa (XLRP) in 1984. Subsequently, linkage of autosomal dominant retinitis pigmentosa (ADRP) to chromosome 3 was achieved by McWilliams et al. The first macular dystrophy to be mapped was North Carolina macular dystrophy in 1992 by Small and colleagues. Since then there have been many important contributions by numerous groups around the world. There are many online resources to catalog these conditions, including Online Mendelian Inheritance of Man (OMIM, www-ncbi-nlm-nih-gov.easyaccess1.lib.cuhk.edu.hk/omim ), RetNet ( sph.uth.edu/Retnet/ ), and Retina International ( www.retina-international.org/ ).


From a clinical perspective, significant phenotypic variations even within a single family are common, making it imperative to examine as many other family members as possible. For example, differences in phenotypes can represent mutations in different genes, different mutations in the same gene, and/or variability in the genetic background in which a single gene/mutation is expressed. In general most macular dystrophies are autosomal dominant and the appearances of the macular abnormality are severe, but the visual acuity is better than one would expect. The autosomal recessive macular dystrophies tend to have worse visual acuities than one would expect from examination.


In contrast to age-related macular degeneration (AMD), which is a multifactorial and multigenic disease, macular dystrophies are usually thought to be caused primarily by a disruption of a single retinal gene. Table 6.15.1 demonstrates how identification of genetic phenotypes has given us insights into macular dystrophies. Table 6.15.2 categorizes the macular dystrophies by the location of the affected cell/gene.



TABLE 6.15.1

Examples of Cellular Specificity of Macular Dystrophy Genes









































Cellular Location Retinal Dystrophy Chromosome Gene
RPE specific AD Best 11q12.3 VMD2, bestrophin (chloride channel)
AD Sorsby’s macular dystrophy 22q12.3 TIMP3 (tissue inhibitor of metalloproteinase)
Malattia leventinese (Doyne’s honeycomb macular dystrophy) 2p16 EFEMP1 (EGF-containing fibrillin-like extracellular matrix protein 1)
Rod specific AD Stargardt macular dystrophy 6q14 ELOVL4 (photoreceptor-specific elongation of very long chain fatty acids)
Cone specific AD cone dystrophy 6p21.1 GUCA1A (guanylate cyclase activator 1A)
Cone–rod specific AR Stargardt 1p22.1 ABC4 (ATP binding cassette protein found in rods and foveal cones)
AD adult foveal macular dystrophy 6p21.2 RDS/peripherin (cone and rod outer segment glycoprotein in disc membranes for structural integrity)

AD, Autosomal dominant; AR, autosomal recessive; ATP, adenosine triphosphate; EGF, endothelial growth factor; RPE, retinal pigment epithelium.


TABLE 6.15.2

Macular Dystrophies and Example Genes
































































































Disease Name Gene Chromosome Inheritance
Best 1 VMD2 /TU15B 11 AD
Best 2 VMD2L1 19
VMD2L2 1
Stargardt ABCA4 1 AR
Stargardt-like macular dystrophy ELOVL4 6 AD
Pattern dystrophy PRPH2 6 AD
Adult vitelliform
VMD3 IMPG1 6q
VMD 4 IMPG2 3q
VMD 5
Sorsby’s fundus dystrophy TIMP3 22 AD
Dominant drusen EFEMP1 2 AD
North Carolina macular dystrophy AD
NCMD/(Small’s macular dystrophy)
MCDR1 PRDM13 6q
MCDR3 IRX1 5
Enhanced S-cone (Goldmann-Favre) NR2E3 15 AR
Glomerulonephritis type II and drusen

AD, Autosomal dominant; AR, autosomal recessive.


The purpose of this chapter is to highlight the clinical features of some of these macular dystrophies, discuss the pertinent molecular genetics and pathophysiology of these diseases, and correlate the functional consequences of the mutant gene products in the framework of the known anatomy and physiology of the retina and retinal pigment epithelium (RPE). Obviously, every disease cannot be reviewed. However, the intention is to convey certain underlying biological principles that can be extended to understand the molecular pathogenesis of other disease processes.


With the advent of gene therapy, stem cell therapy, artificial vision, and a plethora of new retinal pharmacologicals, proven therapy for these disorders is in the near future. In addition, therapies to halt the progression of choroidal neovascularization have progressed and can benefit some who develop this complication.




Stargardt Disease and Fundus Flavimaculatus


Epidemiology and Pathogenesis


Stargardt disease is the most common macular dystrophy, with an estimated incidence of 1 : 8000–10 000. Stargardt disease is also known as Stargardt macular dystrophy. It usually presents within the first two decades, but the central vision loss may not occur until later in life.


Stargardt disease (STGD1) most commonly is inherited in an autosomal recessive manner caused by various sequence mutations in adenosine triphosphate-binding cassette (ABCA4) gene, which has been localized to chromosome 1p21–22. ABCA4 is a very large gene with more than 900 identified disease-causing mutations. While 60%–70% of these patients have a detectable mutation in the ABCA4 gene, the carrier state is thought to be as frequent as 1 : 20 people. ABCA4 normally encodes for a protein involved in the visual cycle. Lipofuscin buildup in the subretinal space appears to be related to a mutation in ABCA4 and the resulting production of a dysfunctional protein. Lipofuscin is a complex mixture of bisretinoid fluorophores amassed by RPE cells. In the RPE, lipofuscin does not form as a result of oxidative stress, unlike in other cell types. Instead it forms because of a nonenzymatic reaction of vitamin A aldehyde in photoreceptor cells that is transferred to the RPE by the phagocytosis of the photoreceptor outer segments. In recessive Stargardt (STGD1) and ELOV4-related retinal dystrophies (STGD3), the formation of lipofuscin is accelerated, leading to cell death. Carrier parents are unaffected. Interestingly, mutations in this gene can also lead to other retinal diseases such as AMD, retinitis pigmentosa (RP), and autosomal recessive cone–rod dystrophy. These ABCA4 -related dystrophies likely represent a spectrum of phenotypes with overlapping retinal changes, just as Stargardt disease itself exhibits great variability in clinical expression.


In addition to recessive Stargardt disease, there are other rarer forms inherited as dominant rather than recessive traits. Autosomal dominant Stargardt (STGD3) is a rarer form of this condition and is caused by mutations of the ELOVL4 gene, which codes for a photoreceptor-specific membrane-bound protein that plays a role in long chain fatty acid biosynthesis. Several other retinal diseases have been mapped near to ELOVL4, including retinitis pigmentosa, Leber’s congenital amaurosis, cone–rod dystrophy, North Carolina macular dystrophy, early onset dominant drusen, and progressive bifocal chorioretinal atrophy.


Ocular Manifestations and Diagnosis


The phenotypic variation of mutations in the ABCA4 gene presents in many forms as described earlier.


Stargardt disease classically is marked by the accumulation of discrete “pisciform” flecks at the level of the RPE ( Fig. 6.15.1 ). Early in the disease, patients may have few flecks, but they often will develop more macular flecks along with patches of characteristic central atrophy. Fundus flavimaculatus patients have mutations in the same gene but present with pisciform flecks in the peripheral macula and retina sparing the fovea. Therefore, early in the disease, fundus flavimaculatus patients tend to retain their central vision, but later in life they usually develop central macular atrophy, central vision loss, color vision loss, and photophobia. Stargardt patients, on the other hand, develop a macula with a “beaten bronze” appearance caused by atrophic changes in the RPE. In addition, they also often have a “dark” or “silent” choroid on fluorescein angiography that appears as a prominent retinal circulation against hypofluorescent choroid. Although this finding can be helpful in making the diagnosis. only up to one-fourth of patients have a dark choroid. On angiography the pisciform flecks do not stain. Autofluorescence can be helpful in showing the lipofuscin in flecks and atrophic areas, which will show photoreceptor dysfunction ( Fig. 6.15.2 ). The electroretinogram (ERG) is normal early in the disease but may be reduced in more advanced cases. Of note, the ERG findings do not directly correlate with clinical findings. High-resolution optical coherence tomography (OCT) can show atrophic changes in the photoreceptors and RPE, and lipofuscin deposits can be detected within the parafoveal RPE ( Fig. 6.15.3 ). Interestingly, these changes usually precede the occurrence of fundus abnormalities. The OCT can also help with diagnosis and aid in determining the status of the photoreceptor layer in the macula, which is beneficial in the assessment of central vision.




Fig. 6.15.1


Stargardt Disease.



Fig. 6.15.2


Fundus Autofluorescence Clearly Delineates Areas of Central Macular Atrophy in Stargardt Disease, Allowing Accurate Measurements of Atrophy.

Color fundus of the right eye (A) can be compared to autofluorescence of the right (B).





Fig. 6.15.3


Fundus Optical Coherence Tomography Findings Showing Central Retinal Thinning in Stargardt Patient From Photoreceptor and Retinal Pigment Epithelium Cell Loss.


Pathology


Histological studies reveal that Stargardt patients have a buildup of a lipofuscin-like pigment in the RPE. The mouse model (a knockout abcr−/−) of Stargardt disease also has an accumulation of lipofuscin in the RPE. Specifically, the toxic bisretinoid, N-retinylidene-N retinylethanolamine (A2E) protein builds up, suggesting its role in causing the disease.


Treatment, Course, and Outcome


To date there is no known proven treatment for this disease. As ABCA4 plays a role in vitamin A processing in the visual cycle, additional vitamin A is suspected to make the disease worse. Therefore all forms of vitamin A supplements are discouraged for these patients. Polyunsaturated fatty acids such as docosahexaenoic acid (DHA) have been shown to reduce toxicity of A2E and are therefore recommended especially for patients if they are autosomal dominant Stargardt.


Gene therapy has been initiated for Stargardt, specifically a 48-week phase 1/IIa dose escalation study is currently investigating SAR422459 (a lentiviral vector gene therapy carrying the ABCA4 gene) for the treatment of Stargardt. Eligible patients must have two pathogenic ABCA4 gene variants confirmed by segregation analysis of parental samples. ( clinicaltrials.gov/ct2/show/NCT01367444 ). Another clinical trial has been launched using RPE precursor cells derived from embryonic stem cells injected subretinally for patients with Stargardt disease. Retinal pigment epithelial cells derived from human embryonic stem cells (hESC_RPE) are surgically implanted in the submacular space. Saffron, ALK-001 (C20-D3-retinyl acetate), MP-4, and DHA are all being studied in additional clinical trials for Stargardt disease (see clinicaltrials.gov/ ).


Individual members of families with Stargardt disease often display tremendous variability in presentation, course, and outcome. The visual prognosis ranges from 20/5 to 20/200 as determined by the extent of macular atrophy depending mostly on the extent of macular atrophy for both Stargardt and fundus flavimaculatus. Choroidal neovascularization is rare but can worsen the prognosis if it occurs.




Epidemiology and Pathogenesis


Stargardt disease is the most common macular dystrophy, with an estimated incidence of 1 : 8000–10 000. Stargardt disease is also known as Stargardt macular dystrophy. It usually presents within the first two decades, but the central vision loss may not occur until later in life.


Stargardt disease (STGD1) most commonly is inherited in an autosomal recessive manner caused by various sequence mutations in adenosine triphosphate-binding cassette (ABCA4) gene, which has been localized to chromosome 1p21–22. ABCA4 is a very large gene with more than 900 identified disease-causing mutations. While 60%–70% of these patients have a detectable mutation in the ABCA4 gene, the carrier state is thought to be as frequent as 1 : 20 people. ABCA4 normally encodes for a protein involved in the visual cycle. Lipofuscin buildup in the subretinal space appears to be related to a mutation in ABCA4 and the resulting production of a dysfunctional protein. Lipofuscin is a complex mixture of bisretinoid fluorophores amassed by RPE cells. In the RPE, lipofuscin does not form as a result of oxidative stress, unlike in other cell types. Instead it forms because of a nonenzymatic reaction of vitamin A aldehyde in photoreceptor cells that is transferred to the RPE by the phagocytosis of the photoreceptor outer segments. In recessive Stargardt (STGD1) and ELOV4-related retinal dystrophies (STGD3), the formation of lipofuscin is accelerated, leading to cell death. Carrier parents are unaffected. Interestingly, mutations in this gene can also lead to other retinal diseases such as AMD, retinitis pigmentosa (RP), and autosomal recessive cone–rod dystrophy. These ABCA4 -related dystrophies likely represent a spectrum of phenotypes with overlapping retinal changes, just as Stargardt disease itself exhibits great variability in clinical expression.


In addition to recessive Stargardt disease, there are other rarer forms inherited as dominant rather than recessive traits. Autosomal dominant Stargardt (STGD3) is a rarer form of this condition and is caused by mutations of the ELOVL4 gene, which codes for a photoreceptor-specific membrane-bound protein that plays a role in long chain fatty acid biosynthesis. Several other retinal diseases have been mapped near to ELOVL4, including retinitis pigmentosa, Leber’s congenital amaurosis, cone–rod dystrophy, North Carolina macular dystrophy, early onset dominant drusen, and progressive bifocal chorioretinal atrophy.




Ocular Manifestations and Diagnosis


The phenotypic variation of mutations in the ABCA4 gene presents in many forms as described earlier.


Stargardt disease classically is marked by the accumulation of discrete “pisciform” flecks at the level of the RPE ( Fig. 6.15.1 ). Early in the disease, patients may have few flecks, but they often will develop more macular flecks along with patches of characteristic central atrophy. Fundus flavimaculatus patients have mutations in the same gene but present with pisciform flecks in the peripheral macula and retina sparing the fovea. Therefore, early in the disease, fundus flavimaculatus patients tend to retain their central vision, but later in life they usually develop central macular atrophy, central vision loss, color vision loss, and photophobia. Stargardt patients, on the other hand, develop a macula with a “beaten bronze” appearance caused by atrophic changes in the RPE. In addition, they also often have a “dark” or “silent” choroid on fluorescein angiography that appears as a prominent retinal circulation against hypofluorescent choroid. Although this finding can be helpful in making the diagnosis. only up to one-fourth of patients have a dark choroid. On angiography the pisciform flecks do not stain. Autofluorescence can be helpful in showing the lipofuscin in flecks and atrophic areas, which will show photoreceptor dysfunction ( Fig. 6.15.2 ). The electroretinogram (ERG) is normal early in the disease but may be reduced in more advanced cases. Of note, the ERG findings do not directly correlate with clinical findings. High-resolution optical coherence tomography (OCT) can show atrophic changes in the photoreceptors and RPE, and lipofuscin deposits can be detected within the parafoveal RPE ( Fig. 6.15.3 ). Interestingly, these changes usually precede the occurrence of fundus abnormalities. The OCT can also help with diagnosis and aid in determining the status of the photoreceptor layer in the macula, which is beneficial in the assessment of central vision.




Fig. 6.15.1


Stargardt Disease.



Fig. 6.15.2


Fundus Autofluorescence Clearly Delineates Areas of Central Macular Atrophy in Stargardt Disease, Allowing Accurate Measurements of Atrophy.

Color fundus of the right eye (A) can be compared to autofluorescence of the right (B).





Fig. 6.15.3


Fundus Optical Coherence Tomography Findings Showing Central Retinal Thinning in Stargardt Patient From Photoreceptor and Retinal Pigment Epithelium Cell Loss.




Pathology


Histological studies reveal that Stargardt patients have a buildup of a lipofuscin-like pigment in the RPE. The mouse model (a knockout abcr−/−) of Stargardt disease also has an accumulation of lipofuscin in the RPE. Specifically, the toxic bisretinoid, N-retinylidene-N retinylethanolamine (A2E) protein builds up, suggesting its role in causing the disease.




Treatment, Course, and Outcome


To date there is no known proven treatment for this disease. As ABCA4 plays a role in vitamin A processing in the visual cycle, additional vitamin A is suspected to make the disease worse. Therefore all forms of vitamin A supplements are discouraged for these patients. Polyunsaturated fatty acids such as docosahexaenoic acid (DHA) have been shown to reduce toxicity of A2E and are therefore recommended especially for patients if they are autosomal dominant Stargardt.


Gene therapy has been initiated for Stargardt, specifically a 48-week phase 1/IIa dose escalation study is currently investigating SAR422459 (a lentiviral vector gene therapy carrying the ABCA4 gene) for the treatment of Stargardt. Eligible patients must have two pathogenic ABCA4 gene variants confirmed by segregation analysis of parental samples. ( clinicaltrials.gov/ct2/show/NCT01367444 ). Another clinical trial has been launched using RPE precursor cells derived from embryonic stem cells injected subretinally for patients with Stargardt disease. Retinal pigment epithelial cells derived from human embryonic stem cells (hESC_RPE) are surgically implanted in the submacular space. Saffron, ALK-001 (C20-D3-retinyl acetate), MP-4, and DHA are all being studied in additional clinical trials for Stargardt disease (see clinicaltrials.gov/ ).


Individual members of families with Stargardt disease often display tremendous variability in presentation, course, and outcome. The visual prognosis ranges from 20/5 to 20/200 as determined by the extent of macular atrophy depending mostly on the extent of macular atrophy for both Stargardt and fundus flavimaculatus. Choroidal neovascularization is rare but can worsen the prognosis if it occurs.




Vitelliform Macular Dystrophy (Best Disease)


Epidemiology and Pathogenesis


Vitelliform macular dystrophy is an inherited macular dystrophy in which lipofuscin accumulates in the central macula, causing progressive central vision loss. Vitelliform dystrophy can present early in life (described as Best disease), but the onset of symptoms can vary widely. The adult-onset form of vitelliform dystrophy (described later) usually presents in middle age. Best disease is an autosomal dominant macular dystrophy linked to mutations in the bestrophin (VMD2) gene. Like Stargardt, Best patients can be highly variable in clinical phenotype, but is quite rare compared to Stargardt disease. VMD2 encodes for a transmembrane protein, which acts as an ion exchanger. VMD2 is expressed in the RPE cell membrane and appears to be important in the formation of chloride channels. This leads to the accumulation of lipofuscin through mechanisms that are still unclear. Several mutations within the bestrophin gene have been identified and are associated with both classic Best and adult vitelliform-like presentation. Interestingly, some patients with the mutation can be completely free from any clinically observable retinal changes. Incomplete penetrance by clinical exam alone has been well documented, although electro-oculogram (EOG) generally does demonstrate abnormalities. In fact, Best disease expresses a great deal of phenotypic variability even within a single family.


Ocular Manifestations and Diagnosis


Vitelliform dystrophies are characterized by bilateral yellow, yolk-like (vitelliform) macular lesions ( Fig. 6.15.4 ). Although Best disease presents during childhood, adult vitelliform typically presents later in life. In Best, the diameter of the lesion is in the range of 1–5 mm. For Best patients, the lesion will change later in life resulting in macular scarring and atrophy. This may make it more difficult to diagnose later.




Fig. 6.15.4


Best Disease.

Typical vitelliform lesion from an 11-year-old girl.

(Courtesy Ola Sandgren, University Hospital of Umeå, Sweden.)


The stages or evolution of the macular lesions are described as progressing from (1) previtelliform stage to (2) vitelliform stage to the (3) scrambled egg stage with or without hypopyon finally to (4) the atrophic stage. Rarely, the lesions may be multifocal. All Best patients have a light-to-dark (or Arden) ratio of less than 1.5 and often close to 1.1 when tested with the EOG. ERG testing shows only occasionally a reduced C-wave. Therefore this is the only disease with relatively normal ERG results associated with an abnormal EOG. Moreover, OCT findings appear to be very specific ( Fig. 6.15.5 ). In Best disease, the OCT reveals that the vitelliform material appears as a dome-shaped, hyperreflective, and homogenous lesion (see Fig. 6.15.5 ) located below the hyperreflective photoreceptor layer.




Fig. 6.15.5


An 80-Year-Old Patient With Best Disease in the Vitelliruptive Stage (Right Eye) and Atrophic Stage (Left Eye).

Fundus photos (A), red free (B), fluorescein angiogram (C), optical coherence tomography (D), and histology (E). Note optical coherence tomography findings show characteristic hyporeflective subretinal zone consistent with subretinal deposit at this stage.










Pathology


Best patients have an accumulation of lipofuscin-like material throughout the RPE. Unlike with Stargardt disease, despite the accumulation of lipofuscin-like material in the RPE, these patients do not exhibit a dark choroid effect on fluorescein angiography. In addition, Best patients can lose vision from atrophy and scarring in the macula, not from accumulated material in the RPE.


Treatment, Course, and Outcome


Even though the age of onset of Best disease is variable, most patients present in childhood. Best patients usually have good visual acuity when the “yolk” remains intact, but the vision drops when macular atrophy begins. Visual acuity can decrease to the 20/200 range, but most patients will keep enough vision in at least one eye to read and drive. Rarely, Best patients develop choroidal neovascular membranes (CNVs).




Epidemiology and Pathogenesis


Vitelliform macular dystrophy is an inherited macular dystrophy in which lipofuscin accumulates in the central macula, causing progressive central vision loss. Vitelliform dystrophy can present early in life (described as Best disease), but the onset of symptoms can vary widely. The adult-onset form of vitelliform dystrophy (described later) usually presents in middle age. Best disease is an autosomal dominant macular dystrophy linked to mutations in the bestrophin (VMD2) gene. Like Stargardt, Best patients can be highly variable in clinical phenotype, but is quite rare compared to Stargardt disease. VMD2 encodes for a transmembrane protein, which acts as an ion exchanger. VMD2 is expressed in the RPE cell membrane and appears to be important in the formation of chloride channels. This leads to the accumulation of lipofuscin through mechanisms that are still unclear. Several mutations within the bestrophin gene have been identified and are associated with both classic Best and adult vitelliform-like presentation. Interestingly, some patients with the mutation can be completely free from any clinically observable retinal changes. Incomplete penetrance by clinical exam alone has been well documented, although electro-oculogram (EOG) generally does demonstrate abnormalities. In fact, Best disease expresses a great deal of phenotypic variability even within a single family.




Ocular Manifestations and Diagnosis


Vitelliform dystrophies are characterized by bilateral yellow, yolk-like (vitelliform) macular lesions ( Fig. 6.15.4 ). Although Best disease presents during childhood, adult vitelliform typically presents later in life. In Best, the diameter of the lesion is in the range of 1–5 mm. For Best patients, the lesion will change later in life resulting in macular scarring and atrophy. This may make it more difficult to diagnose later.




Fig. 6.15.4


Best Disease.

Typical vitelliform lesion from an 11-year-old girl.

(Courtesy Ola Sandgren, University Hospital of Umeå, Sweden.)


The stages or evolution of the macular lesions are described as progressing from (1) previtelliform stage to (2) vitelliform stage to the (3) scrambled egg stage with or without hypopyon finally to (4) the atrophic stage. Rarely, the lesions may be multifocal. All Best patients have a light-to-dark (or Arden) ratio of less than 1.5 and often close to 1.1 when tested with the EOG. ERG testing shows only occasionally a reduced C-wave. Therefore this is the only disease with relatively normal ERG results associated with an abnormal EOG. Moreover, OCT findings appear to be very specific ( Fig. 6.15.5 ). In Best disease, the OCT reveals that the vitelliform material appears as a dome-shaped, hyperreflective, and homogenous lesion (see Fig. 6.15.5 ) located below the hyperreflective photoreceptor layer.




Fig. 6.15.5


An 80-Year-Old Patient With Best Disease in the Vitelliruptive Stage (Right Eye) and Atrophic Stage (Left Eye).

Fundus photos (A), red free (B), fluorescein angiogram (C), optical coherence tomography (D), and histology (E). Note optical coherence tomography findings show characteristic hyporeflective subretinal zone consistent with subretinal deposit at this stage.












Pathology


Best patients have an accumulation of lipofuscin-like material throughout the RPE. Unlike with Stargardt disease, despite the accumulation of lipofuscin-like material in the RPE, these patients do not exhibit a dark choroid effect on fluorescein angiography. In addition, Best patients can lose vision from atrophy and scarring in the macula, not from accumulated material in the RPE.




Treatment, Course, and Outcome


Even though the age of onset of Best disease is variable, most patients present in childhood. Best patients usually have good visual acuity when the “yolk” remains intact, but the vision drops when macular atrophy begins. Visual acuity can decrease to the 20/200 range, but most patients will keep enough vision in at least one eye to read and drive. Rarely, Best patients develop choroidal neovascular membranes (CNVs).




Adult Vitelliform Macular Dystrophy/ Adult-Onset Foveomacular Dystrophy (Pattern Dystrophy)


Epidemiology and Pathogenesis


Unlike Best disease, the adult-onset form of vitelliform dystrophy usually presents in middle age and typically only causes mild, if any, central vision loss. While these two diseases can be phenotypically similar, the clinical course is highly divergent. While Best is caused by mutations in VMD2, adult vitelliform dystrophy has been associated with mutations of both VMD2 and retinal degeneration slow (RDS, PRPH2 ), but the causative gene cannot be found in most patients with adult vitelliform dystrophy. Interestingly, several mutations within the bestrophin gene have been identified and are associated with both classic Best and adult vitelliform-like presentation. RDS encodes a protein called peripherin. This protein is essential for the normal function of light-sensing (photoreceptor) cells in the retina. How a mutation in RDS only affects the macula and not the remainder of the retina is unclear.


Ocular Manifestations and Diagnosis


Adult vitelliform ( Figs. 6.15.6 ) and Best disease can often appear very similar. While Best presents during childhood, adult vitelliform typically presents later in life. In Best the diameter of the lesion is in the range of 1–5 mm, whereas in adult vitelliform the lesion tends to be smaller ( Fig. 6.15.7 ). Adult vitelliform degenerations include foveomacular dystrophy of Gass, and coalescent, widespread, cuticular drusen that form vitelliform lesions in the macula. Adult vitelliform can be differentiated from Best disease by having a near normal EOG (Arden ratio <1.7), but the multifocal ERG may be reduced. Also the OCT will show the absence of subretinal fluid in adult vitelliform dystrophy ( Fig. 6.15.8 ) but not Best disease.




Fig. 6.15.6


Adult Vitelliform Macular Dystrophy.

(Reproduced with permission from Feist RM, White MF Jr, Skalka H, Stone BM. Choroidal neovascularization in a patient with adult foveomacular dystrophy. Am J Ophthalmol 1994;118:259–60.)



Fig. 6.15.7


Adult Vitelliform Macular Dystrophy.

Color photograph shows the vitelliform deposit in the macula settled inferiorly, and fundus autofluorescence.

(Courtesy Jay S. Duker.)



Fig. 6.15.8


Optical Coherence Tomography Shows the Typical Vitelliform Deposit in the Subretinal Space.

(Courtesy Jay S. Duker.)


Pathology


Adult vitelliform dystrophy patients have damage at the level of the RPE with focal loss of the photoreceptors in the areas of atrophic RPE cells in the fovea. Pigmented material is found between the retina and Bruch’s membrane. OCT images localize the vitelliform lesion to the highly reflective photoreceptor-RPE complex. Interestingly, Gass found no abnormal accumulation of lipofuscin in RPE cells in these patients. Other investigators have found high concentrations of lipofuscin in RPE cells and suggest that this accumulation is responsible for the foveal lesion. Moreover, autofluorescence studies support this hypothesis.


Treatment, Course, and Outcome


Adult vitelliform dystrophy usually presents during the fourth to sixth decade, and visual symptoms are usually metamorphopsia and mildly blurred vision. Rarely, these patients can also develop CNVs. Interestingly, as in Best disease, adult vitelliform dystrophy patients usually only lose significant vision when atrophy and scarring occur. Best disease should be distinguished from adult vitelliform dystrophy, as there are potential genetic implications that require appropriate counseling.




Epidemiology and Pathogenesis


Unlike Best disease, the adult-onset form of vitelliform dystrophy usually presents in middle age and typically only causes mild, if any, central vision loss. While these two diseases can be phenotypically similar, the clinical course is highly divergent. While Best is caused by mutations in VMD2, adult vitelliform dystrophy has been associated with mutations of both VMD2 and retinal degeneration slow (RDS, PRPH2 ), but the causative gene cannot be found in most patients with adult vitelliform dystrophy. Interestingly, several mutations within the bestrophin gene have been identified and are associated with both classic Best and adult vitelliform-like presentation. RDS encodes a protein called peripherin. This protein is essential for the normal function of light-sensing (photoreceptor) cells in the retina. How a mutation in RDS only affects the macula and not the remainder of the retina is unclear.




Ocular Manifestations and Diagnosis


Adult vitelliform ( Figs. 6.15.6 ) and Best disease can often appear very similar. While Best presents during childhood, adult vitelliform typically presents later in life. In Best the diameter of the lesion is in the range of 1–5 mm, whereas in adult vitelliform the lesion tends to be smaller ( Fig. 6.15.7 ). Adult vitelliform degenerations include foveomacular dystrophy of Gass, and coalescent, widespread, cuticular drusen that form vitelliform lesions in the macula. Adult vitelliform can be differentiated from Best disease by having a near normal EOG (Arden ratio <1.7), but the multifocal ERG may be reduced. Also the OCT will show the absence of subretinal fluid in adult vitelliform dystrophy ( Fig. 6.15.8 ) but not Best disease.


Oct 3, 2019 | Posted by in OPHTHALMOLOGY | Comments Off on Macular Dystrophies
Premium Wordpress Themes by UFO Themes