Pattern Dystrophies

by Wendy Strouse Watt, O.D.
November 2003
Pattern dystrophies are inherited in an autosomal dominant fashion and they involve the Retinal Pigment Epithelium (RPE) and the external macular retina. Pattern dystrophies represent a group of disorders that present in midlife with mild visual disturbances in one or both eyes. Since patients present later in life with this condition, they are often misdiagnosed as having Age-Related Macular Degeneration. Inherited pattern macular dystrophies are not a form of AMD, but they do share many important features with ARMD. These patients present with various patterns of yellow, orange or gray pigment deposits in the macular area.
Autosomal Dominant Inheritance has to do with genes and chromosomes. Genes are the basic unit of inheritance. They provide the instructions for growth and development from the single cell of a fertilized egg into the complex structure of a baby. Many continue to provide instructions for the production of proteins needed for bodily functions throughout a person’s lifetime. Genes are strung together like beads on a string and packaged into individual chromosomes. Chromosomes come in pairs, with one coming from an individual’s mother and the other from the father. One pair of chromosomes is called the sex chromosomes, since they determine the sex of the individual. The other 22 pairs of chromosomes are called autosomes.
Since our chromosomes come in pairs, we have two copies of all of our genes. The two copies in a pair of genes may or may not have the same code. A gene that is expressed regardless of the code in the other gene is said to be dominant. An autosomal dominant gene is one carried on one of the 22 pairs of autosomes. This means that males and females with the gene are equally likely to pass it on to male or female offspring.
A person who has a pattern macular dystrophy has one gene for the pattern dystrophy and one normal gene in one pair of genes. For example, if the father has one gene for the pattern dystrophy and one normal gene and the mother has two normal genes, the mother will always contribute a normal gene from that pair when they have children. There is a 50% chance the father will contribute the pattern dystrophy gene and a 50% chance he will contribute the normal gene.
There can be variation in the expression of a dominant gene even within the same family. In other words, the gene may cause a profound loss of vision for an individual and only a mild to moderate loss for that individual’s child. Another phenomenon that is seen with some dominant genes is non-penetrance. This means that there is no detectable evidence that an individual with a dominant gene has the gene. When the gene is non-penetrant, it appears that the gene has skipped a generation. An example of this would be in a family with many people who have pattern dystrophy, including a child and a grandparent, but the intervening parent who has the same dominant gene for pattern dystrophy, has normal vision. Over the past few years, significant progress has been made in the molecular genetics of inherited macular dystrophies. Genes responsible for dominant and recessive Stargardt’s macular dystrophy, as well as, Best’s disease, have been localized to specific chromosomal regions. The peripherin/RDS gene, when defective, is associated with butterfly-shaped pattern dystrophy.
Based on the pattern of pigment distribution in the macula, this disease has been subdivided into five principle groups:
Group 1: adult-onset foveomacular vitelliform dystrophy.
Group 2: butterfly-shaped pigment dystrophy.
Group 3: reticular dystrophy of the RPE.
Group 4: multifocal pattern dystrophy simulating fundus flavimaculatus.
Group 5: fundus pulverulentus.
Patients with pattern dystrophies may show different patterns between the two eyes. They may even show progression from one pattern to another over several years. Patients can have a pattern dystrophy in just one eye since it may not yet have presented in the fellow eye. The presence of different pattern dystrophies within the same family suggests a common etiologic continuum. Pattern dystrophies of the retinal pigment epithelium, an arrangement of a pattern of dots, lines, or branches, are infrequent fundus abnormalities.
Patients with adult-onset foveomacular vitelliform dystrophy generally present with a solitary yellow subretinal lesion that’s symmetric, round and slightly elevated. It is usually about 1/3 to 1 disc diameter in size (the size of the optic nerve that is visible in the retina). There is often a pigmented spot in the center. Initially, the yellow lesion may develop only in one eye. Most of the vitelliform lesions in this condition are small, but the larger ones can look identical to the “sunny-side-up” stage (looks like an egg sunny-side-up) of Best’s vitelliform macular dystrophy. These can also look quite similar to bilateral serous detachments of the RPE. In differentiating Best’s disease from these adult vitelliform lesions, it is important to remember that the vitelliform lesions in Best’s develop in infancy or early childhood. Also, genetic linkage studies have identified Best’s disease to a different chromosome. Attempts to identify common genetic linkage between Best’s disease and other vitelliform macular dystrophies have been unsuccessful. The prognosis for maintaining good vision is favorable with this type. The elevated foveal lesions generally fade and leave an irregular oval or round area of RPE depigmentation. The lesions generally do not show the sort of disruption and layering of the yellow pigment that is seen with Best’s vitelliform lesions. Choroidal neovascularization may occur, but it is rare.
Patients with a butterfly-shaped pattern dystrophy will have gray or yellow pigment in a well-organized pattern.
With reticular dystrophy, the pattern extends into the periphery and the yellow pigment is highly organized, in a manner resembling the knotted configuration of a fishnet or chicken wire.
Those with multifocal pattern dystrophy simulating fundus flavimaculatus develop a pattern of flecks similar to those of Stargardt’s disease, but these patients do not show angiographic evidence of a dark choroid suggesting a lipofuscin storage disease. The RPE dystrophy is characterized by an X-shaped yellowish macular lesion and numerus flavimaculatus retinal flecks. The condition is bilateral, has a dominant inheritance, and starts in middle age with a slow-developing macular lesion. Visual functions are often minimally disturbed for two or three decades. The association between flaveomacular vitilliform macular dystrophy and vascularized pigment epithelial detachment (PED), supports the hypothesis that flaveomacular vitilliform macular dystrophy may be a different subgroup of age-related macular degeneration with specific genetic predisposition. Adult onset foveomacular vitelliform dystrophy (AOFVD) is considered a subtype of pattern dystrophy. Onset occurs during middle age, with an accumulation of yellow-gray macular deposits in the deeper retinal layers. Electro-oculograms are mildly subnormal or normal. Genetic studies suggest an autosomal dominant inheritance with variable penetrance.
Patients with fundus pulverulentus display prominent, coarse, “punctiform” mottling of the RPE in the macular area. Further testing might include an electro-oculogram (EOG) and fluorescein angiography. Angiography may show hypofluorescence (under fluorescence) from increased pigmentation or hyperfluorescence (over fluorescence) due to RPE atrophy. Patients will infrequently show evidence of choroidal neovascularization. Pattern dystrophy has been associated with pseudoxanthoma elasticum and myotonic dystrophy. The visual prognosis is favorable. Usually, good visual acuity is maintained in this inherited macular disease. However, acute visual loss can be caused by the ingrowth of subretinal new vessels. Therefore, if visual acuity decreases or metamorphopsia (crooked lines and different sized squares on an Amsler Grid) develops in these patients, careful fluorescein or Indocyanine Green angiography is advisable. Management should include photodocumentation, laser intervention (if there is choroidal neovascularization), and genetic counseling. There should be annual follow-up.
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REFERENCES:
Retinal Quiz April 2000 Review of Optometry Mark T. Dunbar, O.D.
Surv Ophthalmol 1995 Jul-Aug;40(1):51-61 Genetic and molecular studies of macular dystrophies: recent developments. Zhang K, Nguyen TH, Crandall A, Donoso LA. Henry and Corinne Bower. Laboratory for Macular Degeneration, Wills Eye Hospital, Philadelphia, Pennsylvania, USA.
Ophtalmologie 1990 Jul-Aug;4(4):372-6 Francois P, Puech B, Turut P. Service d’Exploration Fonctionnelle de la Vision, Lille. Eye 1990;4 ( Pt 1):210-5 Adult vitelliform macular dystrophy. Brecher R, Bird AC. Department of Clinical Ophthalmology, Institute of Ophthalmology, Moorfields Eye Hospital, London.

Foundation Researchers Use Gene Therapy to Restore Retinal Function in an Animal Model of Retinal Degeneration

by Tom Hoglund
July 2000
In the July issue of Nature Genetics, Foundation Fighting Blindness-supported researchers used gene replacement therapy to treat a rodent model of retinal degeneration. This is the first published study to show that gene replacement therapy can restore function to photoreceptor cells. These findings also demonstrate that gene replacement therapy can create missing cellular components when genetic mutations interfere with the development of a photoreceptor cell.
Dr. Gerald Chader, Chief Scientific Officer of The Foundation Fighting Blindness commented, “Previous studies have established ‘proof of principle’ that gene replacement therapy can dramatically slow the loss of photoreceptor cells in animal models with retinal degenerative diseases. However, this study offers the first evidence that gene replacement therapy can also restore retinal function. This study gives us real hope that researchers may be able to develop treatments that restore vision.”
In the study, a team of scientists from London (Dr. Robin Ali and Dr Shomi Bhattacharya from the Foundation’s Research Center at the Institute of Ophthalmology along with Dr. Adrian Thrasher at the Institute of Child Health) tested gene replacement therapy in the rds mouse. This mouse has an autosomal recessive retinal degeneration that results from mutations in the peripherin/rds gene. Using electroretinograms (ERG), a diagnostic tool that measures photoreceptor cell function, ten-week old treated rds mice had significant ERG recordings, indicating a marked improvement in retinal function. Untreated rds mice of the same age have no detectable ERG response.
Peripherin/rds Gene Key to Photoreceptor Cell Structure
The peripherin/rds gene produces a specialized protein that helps to form the outer segment discs of photoreceptor cells. Outer segments are the finger-like structures containing hundreds of light-sensitive discs that absorb light. These discs contain rhodopsin, the visual pigment that begins phototransduction, the process of turning light into an electrical signal. This signal is then relayed to the visual cortex, the part of the brain that interprets visual information. Mutations in the recessive form of the rds mouse prevent the peripherin/rds gene from producing its protein product. As a result, photoreceptor cell outer segments and their light-sensitive discs fail to form. Phototransduction and vision are not possible without these crucial cellular components.
To verify that delivery of the peripherin/rds gene resulted in the development of outer segments, the research team used a sophisticated imaging technology called electron microscopy to examine the structure of treated photoreceptor cells. Photoreceptor cells of treated rds mice were able to generate outer segments containing light-sensitive discs. By contrast, untreated rds mice have no outer segments. Although treated mice had fewer outer segments than normal mice, improvements in gene delivery techniques should allow researchers to treat a greater portion of the retina in the future.
Limits of Gene Replacement Therapy
This study offers “proof of principle” that gene replacement therapy can restore photoreceptor cell function. It also indicates that gene therapy can restore missing photoreceptor cell components that result from genetic mutations. However, it is important to note that gene replacement therapy is not applicable to all retinal degenerative diseases. It is only likely to be applicable to autosomal recessive diseases and some X-linked diseases.
Ribozyme Gene Therapy
For autosomal dominant diseases, ribozyme gene therapy may be applicable. In dominant forms of retinal degeneration, patients have a healthy functioning gene and a gene with a disease-causing mutation. The mutant gene produces a dysfunctional, toxic protein that damages the photoreceptor cell. Ribozymes are molecules containing genetically encoded information that disrupt the mutant gene’s ability to produce the harmful protein. With the diseased gene inactivated, the healthy gene can supply the photoreceptor cell with the needed protein. In previous studies, Foundation researchers have dramatically slowed retinal degeneration in a rodent model with ribozyme therapy.
It is also important to note that treatment with both gene replacement and ribozyme therapy must be administered before photoreceptor cells have died.