Best’s Vitelliform Macular Dystrophy – Genetic Advances In Research And Treatment Essay, Research Paper

Introduction & Overview

In 1905 Dr. Best first described a condition affecting the macular region of the retina (located in the eye). The retina and its component photoreceptor cells are essential to vision as they convert light into electrical impulses and then transfer these impulses to the brain via the optic nerve. The macula is the central part of the retina responsible for fine visual detail and color perception.

The term macular degeneration refers to a group of disorders that affect the central portion of the retina and, as a result, the center of the field of vision. The most common forms of this disease usually affect patients over the age of 65 and are collectively the most frequent cause of legal blindness in developed countries.

BMD is an autosomal dominant disorder. With such genetic conditions it is likely that there would be several affected individuals in successive generations but BMD can be erratic and may miss a generation.

Although the age of onset of BMD can vary, it is usually diagnosed during childhood or adolescence. In the initial stages, a bright yellow cyst (fluid-filled sac) forms under the retinal pigment epithelium (RPE) beneath the macula. Upon examination, the cyst looks like a sunny-side-up egg. Despite the presence of the cyst, visual acuity may remain normal or near normal (between 20/30 and 20/50) for many years. Peripheral (side) vision usually remains unaffected.

In many individuals with BMD, the cyst eventually ruptures. Fluid and yellow deposits from the ruptured cyst spread throughout the macula. At this point the macula has a scrambled egg appearance. Once the cyst ruptures, the macula and the underlying RPE begin to atrophy causing further vision loss. As a result, central vision tends to deteriorate to about 20/100 late in life. However, BMD disease does not always affect both eyes equally. Many individuals retain useful central vision in one eye with a visual acuity of about 20/40 in the lesser affected eye.

In some cases, BMD does not progress far enough to cause significant central vision loss. However, retinal specialists can still detect the disease using sophisticated diagnostic tests that measure the function of the RPE and the retina. Individuals with BMD are also often farsighted. Although the farsightedness can be corrected with glasses, the other vision-affecting symptoms currently remain untreatable.

Phenotypic Expression of BMD

BMD is an autosomal dominant disease with a juvenile age of onset. BMD is diagnosed by its unique electrophysiologic symptoms, a depressed EOG (light peak to dark trough ratio *1.5) in the absence of an altered electroretinogram

The inside of the eye is lined by three layers of tissue, each critical for normal vision. The innermost layer (the one first struck by the light that enters the eye) is known as the retina and consists of a complex network of nervous tissue. Some of the cells in this layer (the photoreceptors) convert light into an electrical signal that is then amplified and processed by other cells before being sent to the brain via the optic nerve.

The central part of the retina–the macula–has a number of special structural features that allow images focused on it to be seen with very high resolution. (See Appendix 1) The middle layer is a one-cell-thick sheet known as the retinal pigment epithelium, or RPE. The RPE provides metabolic support for the photoreceptor cells and also removes old bits of cellular debris from the tips of the photoreceptor cells as they renew themselves. The layer farthest from the incoming light is a rich network of blood vessels known as the choroid. These vessels supply oxygen and nutrients to the retinal pigment epithelium and photoreceptor cells and carry away waste products.

In macular degeneration, clumps of yellowish cellular debris–possibly of retinal origin–gradually accumulate within and beneath the retinal pigment epithelium. These deposits are visible to the clinician looking inside the eye as small yellow dots known as drusen (singular: druse). (See Appendix 2) With the passage of time, patches of retinal pigment epithelial cells may die, resulting in bare spots known as geographic atrophy.

When the support functions of the RPE are lost, the photoreceptor cells overlying the areas of geographic atrophy cannot function and the vision from this patch of retina is lost. If these patches become large and involve the very center of the macula (the fovea), the individual’s visual acuity can fall to the point that he or she is considered legally blind. This atrophic phase of macular degeneration is sometimes referred to as “dry” macular degeneration.

In approximately 10 percent of patients with macular degeneration, the injury to the retinal pigment epithelium stimulates the choroidal blood vessels to grow up into the RPE and retina–seemingly in an attempt to heal the defects in these layers. This reparative response is very similar to those that occur elsewhere in the body in response to injury–such as scar formation after a cut on the skin. Unfortunately, the retina is such a complex and highly ordered tissue that the in-growth of these new blood vessels causes more visual loss than the original degenerative process. In fact, although only 10 percent of patients develop new blood vessels, this complication is responsible for most of the legal blindness associated with macular degeneration. The vascular phase of macular degeneration is sometimes called “wet” macular degeneration.

Because the new blood vessels (also known as choroidal neovascular membranes) can be so damaging, a wide variety of treatments have been tried to arrest their growth. By far the most successful to date has been the use of laser light to cauterize the blood vessels. Unfortunately, laser treatment has a number of significant drawbacks including a high recurrence rate, laser injury to the retina, and an inability to treat the majority of patients affected with neovascular membranes (because the lesions are too large or ill-defined when discovered).

Causes of Macular Degeneration

Physicians have wondered about the causes of macular degeneration for over a century. In the late 1800s, when doctors first began looking into eyes with ophthalmoscopes, they believed that the drusen they observed represented some type of infection, or at least inflammation, of the choroid. Even today, there is some evidence to suggest that the body’s immune system plays a role in the development of some forms of macular degeneration, especially the development of neovascularization.

An important group of possible causes of macular degeneration is mildly abnormal genes. It has been recognized for over a century that some forms of macular degeneration run in families. During the past 25 years, increasing evidence has been gathered to suggest that a significant fraction of macular degeneration has a hereditary basis.

This has important implications for understanding macular degeneration at the molecular level, as well as for designing improved treatments for the disease. When a disease like macular degeneration is caused by a dominant gene, a number of family members may be similarly affected. Such families can be studied by modern molecular genetic methods in ways that allow the causative gene to be identified.

Do not plaguerize my paper.

In the past 10 years, the chromosomal locations of at least 10 genes that cause macular-degenerationlike conditions have been identified, and three of the genes have actually been identified. Unfortunately, none of these three genes causes a measurable fraction of typical late-onset macular degeneration, but the disease mechanisms are similar enough to the latter condition that scientists can already begin developing animal models of macular degeneration based on these genes to use in new treatment research.

The genetic approach is particularly appealing because if a genetic predisposition to macular degeneration can be identified, it raises the possibility that individuals can be tested for the predisposition early in life, and given some sort of treatment that will delay or prevent the onset of the macular disease. Such treatment has the potential to be safer, simpler, cheaper (and hence more widely available) than some of the other experimental treatments currently under development.

Areas of Promising Research

Since the majority of severe visual loss is caused by abnormal blood vessels growing beneath the retina, a massive effort is underway to identify methods of arresting this process. Any breakthrough in this area could be of immediate benefit to thousands of patients with macular degeneration. Strategies under investigation at this time include the use of drugs, growth factors, anti-growth factors, surgery, and radiation. All these strategies are designed to retard new blood vessel growth without significantly damaging the overlying retina (as occurs with conventional laser treatment).

In 2001, the mainstays of therapy for patients with macular degeneration include daily monitoring of the integrity of their central vision (usually by viewing a simple printed grid) as well as periodic visits to their eye doctor. Both of these strategies are designed to identify treatable new blood vessel membranes as early as possible. When such a growth is suspected, it is confirmed by an angiographic procedure. If the membrane has characteristics that have been shown to be favorable for treatment, laser photocoagulation is applied by an ophthalmologist who has had special training in the technique.

Patients who lose vision despite treatment, or who lose vision from atrophic disease, can often be significantly helped by a thorough low-vision-rehabilitation program. Such a program is administered by an optometrist or ophthalmologist with special training in low vision and consists of a number of integrated parts ranging from counseling to the prescription of special glasses, magnifiers and even electronic devices.

Mapping and Sequencing of BMD Gene

Many important human genes, including those causing diseases, cannot be easily studied with standard techniques of molecular biology, like cloning and sequencing. For most genetic diseases information concerning the gene function are not available and the biochemical basis of the pathogenetic mechanism of the disease is often limited. These obstacles hinder the progress of genetic studies with standard procedures. These difficulties can be overcome through the genetic linkage analysis. This paper has been plaguerized. It was obtained at With this technique, the first step towards the identification of the gene is its chromosomal localization. The linkage analysis allows the identification of chromosomal localization of the disease-associated gene without having any hypothesis on its pathogenetic mechanism. Once the disease-gene is localized on a specific chromosomal region, the application of traditional techniques like positional cloning or the progressive closing in of the candidate gene, will lead to its identification

The BMD disease gene (VMD2) has been localized to chromosome 11q12-q13.1 within an approximately 1.4 Mbp interval between markers at D11S1765 and uteroglobin (UGB). This region has been cloned in overlapping yeast artificial chromosomes (YACs) and P1 artificial chromosomes (PACs) as a prerequisite for the construction of a gene map of the BMD locus. This report was downloaded from the Internet ( A comprehensive characterization of these genes is required to identify possible candidates for the disease gene and consequently to isolate the defective gene by analyzing BMD patients for mutational changes.

To identify the gene defect, genetic linkage mapping was performed and has positioned the BMD locus to an approximately 1-2 cM interval in 11q12-13.1. The closest flanking markers are D11S1765 proximally and UGB distally. The entire interval has been cloned into overlapping YAC and PAC clones together covering approximately 1.4 Mbp. The contig (sequence of overlapping clones) provides the basis for the generation of a comprehensive transcript map from the BMD locus. In pursuit of this goal, researchers are currently using two strategies including the fine mapping of known genes and ESTs and direct tissue-specific cDNA selection. This report has been plaguerized. Thus far, another 14 novel transcripts have been added to the 6 genes (CD5, PGA, DDB1, FEN1, FTH1 and VMD2) localized within the minimal BMD region. In addition, researchers have determined their expression pattern in various human tissues including the retina and RPE. Several transcripts were identified that reveal an expression profile conceivable with an involvement of these genes in the pathogenesis of BMD. Their further characterization and mutational analysis in BMD patients is currently under way.

VMD2 encodes a previously unknown protein designated bestrophin. Although mutations in VMD2 in individuals with age-related macular dystrophy (AMD) are rare, mutations have been reported in up to 1.5% of individuals with AMD. Bestrophin is predicted to be a 585-aa protein with an approximate mass of 68 kDa.

Based on Northern blotting and in situ hybridization data, bestrophin is predominantly expressed in the RPE. Bestrophin shares homology with the Caenorhabditis elegans RFP gene family, named for the presence of a conserved arginine (R), phenylalanine (F), and proline (P) amino acid sequence motif. However, the function of the RFP genes is unknown. Computer-assisted structural analysis predicts that bestrophin is a transmembrane protein with four membrane-spanning ALPHA (insert greek symbol) helical domains, although a less likely five-transmembrane domain model recently has been proposed. There are no obvious targeting signals present in the amino acid sequence that would provide clues to its subcellular localization, and based on the four-transmembrane domain model, bestrophin has no obvious sites for posttranslational modifications such as N-glycosylation.

Implications for Treatment and Prevention

Knowledge of a disease-gene allows in principle for gene therapy. One of the advantages of the gene therapy is that it does not require a detailed understanding of the function of the gene or of its product. It is enough to deliver the normal gene or its products in the appropriate ocular tissue. This report was written by Heather Dineen-Porter and copied by the student who has submitted it to you. Unfortunately, for many diseases of the dominant autosomic form the benefit is limited. In these cases, the comprehension of the gene function is critical for the development of an effective therapy. The isolation of the disease-gene may allow the identification of the protein and its function, thus providing the biochemical basis of the disease. Consequently, this kind of study can lead to new therapeutic approaches.

The genetic bases of macular dystrophies and of some subgroups of age-related macular degeneration could be related, on the basis of their similarity. It is possible that mutations, different or less severe, in the same gene causing early onset diseases, could be involved in a significant number of cases of age-related macular degeneration. A better understanding of macular dystrophies could therefore provide a genetic model of age-related macular degeneration pathogenesis. Were we to find specific mutations in macular dystrophies which are also associated with a subgroup of age-related macular degeneration, the pathogenetic mechanism could be investigated by using cellular cultures or transgenic animals. The progress already achieved and that researchers hope to attain in the field of molecular genetics will contribute increasingly to improve the management of patients affected by hereditary degenerative diseases. The risk of disease onset could thus diminish through prevention or adequate treatment.


Appendix 1

Layers of the Retina

A light micrograph llustrates the three main layers involved in macular degeneration. The neurosensory retina is shaded in blue, the retinal pigment epithelium in yellow, and the choroid in pink. The blood vessels in the choroid have been filled with red.


Appendix 2

Comparison of Normal and BMD Retinas



Find the info yourselves you lazy bastards.

Anyone thinking of simply copying this and handing it in, this will only work if your professor will reasonably believe that you would have been able to find the data sources referred to in the paper. This paper has been circulated at genetics and biology conventions around Canada and the US, as well as submitted via email to several professors at various institutions for their comments.

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