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Juvenile Macular Degeneration

Macular Degeneration International (MDI) began it’s original mission in 1991 to provide support and information to persons and families affected with Stargardt’s and other forms of juvenile Macular Degeneration. Up to that point it had been difficult for families to find this information because these juvenile macular dystrophies are fairly rare (estimates of between 30,000 and 50,000 total persons in the U.S.). MDI has expanded its help to those around the world with these dystrophies, and now include those with age-related macular degeneration by providing help to thousands of families through it’s programs, journals and conferences.

There are several forms of Macular Degeneration that affect children, teenagers or adults that are known as early onset or juvenile Macular Degeneration. Many of these forms are hereditary and are more accurately called macular dystrophies, instead of degenerations. Degenerations are a more accurate descriptions for the diseases of age related Macular Degeneration, more common in older persons.

These macular dystrophies all have different genetic patterns or ways of inheritance. Some may be passed on in a dominant pattern, others as a recessive pattern and still others as an x-linked trait carried by females and affecting males only. For many with recessive inheritance patterns, it comes often as a surprise because a family might never have known anyone in their family history who was affected. For those of a dominant pattern, it may be quite different as some persons of generation after generation are affected.

Now, let’s investigate more as to the different specific types of early onset forms of macular dystrophies ...STARGARDT MACULAR DYSTROPHY (FUNDUS FLAVIMACULATUS)

Stargardt Macular Dystrophy is the most frequently encountered juvenile onset form of macular dystrophy. This disorder was initially described in 1909 by Karl Stargardt, a German Ophthalmologist.

Persons affected with Stargardt’s first present with the complaint of a decrease in central vision, generally within the first 20 years of life. In some instances, persons may not note visual impairment until their 30's or 40's. Impairment of color vision is generally not noted initially. In the majority of instances, patients do not experience a loss in peripheral vision or night-blindness. However, it has been shown that persons with Stargardt’s have some dark adaptation problems. Once exposed to sunlight, persons with normal vision who enter a dark place need three minutes or so to adapt to the darker environment. However, persons with Stargardt’s disease may take six, eight, ten minutes or longer to adapt to the dark environment.

The diagnosis of Stargardt Macular Dystrophy can often be made by observing characteristic changes that occur within the retina. These involve what has been described as an atrophic or "beaten-bronze" appearance of deterioration to the central portion of the retina that is referred to as the macula.

A characteristic, and often diagnostic feature is the presence of numerous yellowish-white spots that occur within the retina surrounding the atrophic-appearing central macular lesion. These spots or "flecks" can either be sparse or numerous. In certain patients, numerous flecks can be apparent in the absence of or with only minimal atrophic deterioration changes in the macula. Such patients were subsequently referred to as having fundus flavimaculatus, a term first used in 1963 by a European ophthalmologist, Franceschetti. It is now known that Stargardt macular dystrophy and fundus flavimaculatus represent the same genetic disease. Both are transmitted as an autosomal recessive trait. This indicates that both parents, who themselves are normal, carry a defective gene. Together, they can pass on this trait with a risk of 25% for each offspring. Their offspring, in turn, are unlikely to further pass on the trait unless they marry either someone who happens to carry the defective gene or some one who has Stargardt macular dystrophy.

Several electrophysiologic tests, such as an electroretinogram, electro-oculogram, and dark adaptation testing have been used in the diagnosis and follow-up of patients with Stargardt macular dystrophy. It is infrequent that these tests are necessary to make the diagnosis, particularly when the yellow-white fundus flecks are apparent on examination.

A fluorescein angiogram which is a photographic procedure, has been used to confirm the diagnosis in many patients. This test involves the injection of a dye, usually into an arm vein, which then can be photographed as it circulates through the vascular structures of the retina. A phenomenon referred to as the "dark" or "silent" choroid has been observed in the majority of patients with Stargardt macular dystrophy. This observation probably is associated with the accumulation of a waste material, referred to as lipofuscin, that accumulates in the pigment cells throughout the retina in patients with Stargardt macular dystrophy. On the angiogram this accumulation causes this very dark spot resulting in the silent choroid. The accumulation of this material is also likely to be responsible for some of the deterioration of visual cells in the retina, referred to as cones and rods.

The changes observed within the retina, as well as center vision, tend to be more extensive and worsen over time. Most patients with Stargardt disease will experience visual loss of 20/100 to 20/400 often by 30 to 40 years of age. As indicated, peripheral, or side vision tends to remain normal.

Also being studied in this arena are the cell or cells involved in and around the macula. Cell biologists begin to study in what ways the cell is affected because of a specific gene mutation. Also, what type of cell is affected, that is, is it the rods and cone cells, or the layer of cells beneath the rods and cone cells called the RPE cells.

Finally, by learning from what the cell biologists have discovered, and by what the doctors or clinicians have discovered from their patients, a precise story can be developed as to what has gone wrong with this particular degeneration. That is, an educated guess or hypothesis can be put forward as to the cause of this type of Macular Degeneration or dystrophy.

Many patients say, "Will this type of research help me now? There may not be any immediate results from this type of research for the current patient with Macular Degeneration but it is highly important that the researchers understand the cause of Macular Degeneration before they can ultimately figure out the cure.

Some immediate benefit, however, may be in the information gained in order that some types of Macular Degeneration can be explained to families in genetic counseling.

STARGARDT GENE IDENTIFIED

Researchers from the Baylor College of Medicine, the University of Utah, the Howard Hughes Medical Institute at Johns Hopkins University, and the National Cancer Institute all collaborated toward the exciting news of isolating the gene which, when altered or "mutated," causes the recessive form of Stargardt's disease and fundus flavimaculatus.

We at MDl are proud to say we have played a small part in this collaboration. Since 1991, many members of our organization have participated in efforts to isolate this gene for Stargardt's disease. Members from scores of families have shared records of eye examinations, retina photographs, along with an irreplaceable resource, a blood sample, to allow researchers to trace the passage of genes responsible for causing this retinal disorder.

We want to thank the families who have been patient and supportive while this work has been going on for the last 10 years. 'This discovery gives us the first glimpse into how Stargardt's disease attacks the eye," said Dr. Richard Lewis, professor of Ophthalmology at Baylor. "This gene will provide better tools to assist in early diagnosis and a better understanding of the mechanisms and the cause of this disease," Lewis said.

The disease often goes undiagnosed or misdiagnosed in the first few years of onset due to minimal findings during eye examinations. The gene may aid in a test for the direct diagnosis of the disease. It is possible that the gene's effect may not be limited to juvenile macular degeneration, thus this discovery may aid in the search for causes for age-related or adult onset Macular Degeneration, the leading cause of vision loss in people over age 65. (See Age Related in this web site.)

The hunt for the gene began 10 years ago at Baylor College of Medicine when Dr. Richard Lewis, a specialist at Baylor in hereditary disease of the retina, began to collect blood samples from families with Stargardt's disease. Because MDI had a growing number of families affected by Stargardt’s, it helped to recruit many families for this effort. It was already known that Stargardt's and fundus flavimaculatus are caused by a recessive gene determined by a pair of genes, one from each parent. People affected by a recessive trait like Stargardt's disease must have inherited copies of a defective gene from both parents. The parents, who carry just one copy themselves, are normal.

The Baylor researchers, working with Dr. Mark Leppert, geneticist at the University of Utah, began searching for genetic markers that would occur only in patients and carriers. In 1993, a French group found a marker, mapping the gene to a region on chromosome number one.

Baylor and Utah studies continued to try to pinpoint the exact gene by narrowing the marker. "It's like looking for a buried treasure between two palm trees," says Dr. Lewis. ìWe continue digging from each end going towards the middle to find the treasure.î

A surprising turn of events occurred when Dr. Michael Dean of the National Cancer Institute and his group were studying a family of genes known as ABC transporters. They were not working in the area of ophthalmology at all, but they were looking at this transporter problem and where it occurred in diseases throughout the body. Dean stated that recently they had characterized 21 new members of the ABC Super Family of genes and had begun to assign functions to these genes by determining their map locations and their pattern of expression. Many known ABC genes are involved in inherited human diseases. This suggests that some of these new loci will also encode proteins mutated in specific genetic disorders. Here scientists identified one of the 21 human genes specific to the retina (named ABCR for the retina) and its role in the recessive macular dystrophy.

They knew these transporters code for proteins that bound into cell membranes and function as one-way pumps. Most are exporters, meaning that they pump a single type of molecule out of the cell.

The surprise came when this gene being studied mapped to the precise location that the Baylor and Utah groups had described as the site of the Stargardt's gene. Dr. Lewis and James Lupskii from Baylor, collaborating with Dr. Jeremy Nathans from Johns Hopkins University, went to the prior region that was already mapped and found "this new information turned out to be a direct hit," Dr. Lewis said. "It was exciting to see the direct hit, and that the collaboration of several centers was able to quickly find what would have taken a lot longer without their help," he also stated.

More About The Gene

The article published in the March 1997 issue of Nature Genetics describes it further as an ABC Super Family of genes whose products are transmembrane proteins involved in energy dependent transport of a wide spectrum of substances across membranes. In understanding Stargardt's disease, the gene discovery next had to isolate or pinpoint more specific areas of the retina to determine where the problem lies in this eye disorder. Was it in the RPE layer of the retina or was it in the photoreceptor cells?

Stargardt's and fundus flavimaculatus have been characteristically described as an accumulation of lipofuscin-like substance in the retinal pigment epithelium (RPE). This has led to the widely held suggestion that Stargardt's represents an RPE storage disorder.

Interestingly and surprisingly ABCR was not in detectable levels in cone photoreceptors or in the RPE layer. ABCR was, however, localized to rod photoreceptor cells, which implies a highly specific function for this transporter protein. Not detecting ABCR in cone cells suggests that a different gene product may perform a corresponding function in cones.

So what does this mean? The accumulation in the RPE of a lipofuscin-like substance in Stargardt's further suggests that the site of ABCR-mediated transport may be on the apical face of the photoreceptor cell and that this transporter might effect exchange between the RPE and the photoreceptors.Further studies need to be done on this interaction however, based on its sight of expression ABCR might plausibly be involved in either the recycling of fatty acids or the uptake of vitamin E by photoreceptors. Additionally, this study emphasized abnormal photoreceptor function and abnormal accumulation of lipofuscin could result from a number of principal defects:

1. Accelerated turnover of photoreceptor cells.

2. Increased phagocytosis of photoreceptor outer segments.

3.Abnormal photoreceptor membranes or contents rendered indigestible by the RPE.

4. Missing or mutated enzymes capable of digesting photoreceptor proteins or lipids.

5. Failed mechanisms to expel lipofuscin from the cytoplasm of the RPE.

A SPECIAL STUDY ON STARGARDT’S SPEARHEADED BY MDI

A collaborative effort to collect data on persons with Stargardt macular dystrophy was performed by staff of MDI and researchers from Wills Eye Hospital in Philadelphia. The research study was presented as a poster at the May 1998 meeting of ARVO in Florida.

A special thanks to the Macular Disease Foundation of Virginia Beach, Virginia in helping fund the study. Also, a special thanks to :

1 - The Bower Laboratory for Macular Degeneration, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, PA

2 - Macular Degeneration International, Tucson, AZ

3 - ADA Management Services Inc., Philadelphia, PA

Stargardt's Macular Dystrophy - A Patients' Perspective

A. I. Miedziak', MD, T. Perski 2, MA, P.P. Andrews 3 , L.A. Donoso', MD, Ph.D.

This study yielded 244 patients with clinically diagnosed Stargardt Macular Dystrophy, of these 169 or 70% were women and 75 or 30% were men. Of the patients who responded, 196 or 80% were over the age of 21 and 130 of this group or about 53% were employed.

As far as onset of the disease, there were three groups found. The first group approximately 1/3, stated that they started having problems with their vision before the age of 10. Those having problems between the ages of 10 and 20 was also approximately 1/3 and the final third being those who started having vision difficulties after the age of 21.

The great majority of those who responded said that their vision at the time they first noticed there was a problem was at a level of 20/50 vision. Many persons also stated that they noticed a small spot of distortion in their central vision. Some described it as a gray spot, others as a dark spot in the center of their visual field. Many of the young people reported such common problems as difficulty seeing the blackboard at school, and holding books and materials close to their eyes to read. Also, most respondents stated that the problem was in both eyes. For those who are older, the first signs of problems came while driving and reading small print types. As far as their progression of vision loss there were about 8% of persons who said their vision at present reached the level of 20/100 or better, 70% stated their vision was at the 20/200 to 20/400 level and only 10% stated that their vision was worse than 20/400. This was true even for persons who had Stargardt Disease for a long time. From these findings, it may be stated that almost 90% of persons with Stargardt's fall in the level of vision of 20/200 to 20/400. The respondents reported that their vision during the first five years changed from the 20/50 level to the 20/200 to 20/400 level . Although just as many stated that it took longer than five years to reach that level. Some stated that it took ten years, others stated it took 20 years and even longer to reach the 20/200 level.

It was interesting to note that 60% of those who answered the questionnaire had no family history of Stargardt disease on either side of their family. These persons also stated that it took much longer for them to be diagnosed and this group was also more often mis-diagnosed. It is interesting to note that because Stargardt Disease presents a normal looking retina early on in the disease process, and because the age range may be so wide with often no family history, these factors explain why many respondents took longer to be diagnosed, many were told they had a "psychological problem" or "learning disability." It was only until later when the disease process manifested itself to be seen clearly on the retina was the definitive diagnosis able to be made.

It was also interesting to note that those who stated that their vision loss began before age 10 and were of working age, about 60% of those had a job or career. For those who stated that their vision changed after age 21, approximately 70% of those people said that they worked at a career or profession, or were retrained for a different profession after central vision loss. Many of the careers that were listed in the survey fell into the category of social service, counseling and teaching. Researchers are also keeping a comprehensive list of careers and job titles which will be published in future issues for parents and families who may have young children and are interested in what occupations seem best.

It was notable that for persons who were diagnosed after age 21 that over 50% responded to some of the psychological questions by saying they felt a great deal of frustration, sometimes depression, sometimes anger or denial. When persons rated their number 1, number 2, and number 3 frustrations they were quite different for each person. It seemed as though this was an important step, however, in that once a person was able to identify the number 1 frustration for them, they could use their energy to approach and solve this set of problems before going on to number 2. One of the main goals of MDI is to help persons and families get "plugged in" to the many resources that are available to help and to do it quickly. Even persons diagnosed in the 1980's felt they had nowhere to turn and spent many "wasted years" in trying to find answers for their life.

The time between the onset of initial symptoms and a correct diagnosis came within a one year period for 46% of individuals surveyed. Approximately 65% of patients surveyed were correctly diagnosed within the first three visits. But another 26% were originally given a diagnosis other than Stargardt Macular Dystrophy including 8% who were diagnosed with a psychological visual loss. Except for blurred central vision the main two visual problems reported by the studied group included glare 90% and difficulty in adjusting to changes in illumination 64%. Reading print 58%, driving 46%, recognizing faces 36%, computer and detail work 22% and depending on others for transportation 18% were the main daily living activities which were utilized but difficult to perform. The vast majority of evaluated respondents used visual aids - 92%, to enhance their visual performance. Approximately 50% of the population surveyed were able to use or did use public transportation and almost 25% had a valid drivers license. Over 70% had been referred to either their state association for the blind, a low vision center, or MDI for help. The Doctor who diagnosed their condition was only responsible for these sources of referrals in 58% of the cases. Only 50% of those surveyed felt that they were counseled adequately about their condition.

This study suggests that overall, patients with Stargardt Macular Dystrophy can contribute and function well in contemporary society, however, the need for improving diagnosis, referring patients to appropriate services and increased "lack of awareness" of specific needs for this group still persists.

 

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