Genes and Disease - Diseases of the Eye
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For some complex diseases, such as AMD, it is not as clear which genes will protect vision. It also continues to make proteins that inhibit abnormal blood vessel growth, called angiostatin and endostatin, for at least one year after injection.
These proteins were measured in fluid samples taken from inside the eye. Future clinical trials will likely test whether Retinostat can block the growth of harmful blood vessels in patients with wet AMD and diabetic retinopathy. Another gene therapy approach to wet AMD is using a virus to carry a helpful gene into the eye. In a phase I trial, the therapy was safe and appeared to nearly eliminate the need for additional treatments over a one-year period. A second company uses an injection into the eye instead of under the retina using the same virus carrying the sFLT gene, which has the potential to be safer and more convenient.
However, it is likely to be helpful after further research and development. Genetic, biochemical, and cell biology studies have identified a number of potential approaches to treat dry AMD, such as anti-inflammatory, anti-oxidant, anti-cholesterol, and anti-cell-death approaches. Some of these have proven effective in gene therapy studies in mice. A potential downside of gene therapy is that, in most cases, it will not be possible to turn off the therapy once it is delivered into the eye. The cells that receive the therapeutic genes will continue to express them for years.
Therefore, clinical trials are very important to determine the long-term safety of this approach. This content was last updated on: October 24, The information provided here is a public service of the BrightFocus Foundation and should not in any way substitute for personalized advice of a qualified healthcare professional; it is not intended to constitute medical advice. Please consult your physician for personalized medical advice.
BrightFocus Foundation does not endorse any medical product, therapy, or resources mentioned or listed in this article. All medications and supplements should only be taken under medical supervision. Also, although we make every effort to keep the medical information on our website updated, we cannot guarantee that the posted information reflects the most up-to-date research. These articles do not imply an endorsement of BrightFocus by the author or their institution, nor do they imply an endorsement of the institution or author by BrightFocus.
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If you are managing a new diagnosis, we have a Getting Started Guide that will help you understand and manage your disease. Are you a generous person? Your gift can help cure macular degeneration. Donate today. Facebook Twitter Pinterest Email. Print this page. Moreover, the act of performing a genetic test is a tangible sign to patients and their families that their physician imagines that in some way they may be part of a more optimistic future.
If a test result is positive, that result also serves to connect the patient and their family to a very specific part of the research world and allows them to focus their questions and reading on the part of this world that is most relevant to them. A physician's ability to give a patient an accurate prognosis is based on the accuracy and precision of the diagnosis and the availability of accurate historical information from a large number of patients with the same molecular diagnosis in genetic parlance, the genotype-phenotype correlation.
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Imagine the value of knowing that the specific von Hippel-Lindau mutation in your family is almost never associated with renal cell carcinoma 4 or that a year-old woman with the same Leber congenital amaurosis LCA mutation as your 6-month-old daughter is a college professor and has no systemic abnormalities. In both of these situations, a genetic test allows a physician to give a patient or family some very reassuring news that can significantly blunt the negative impact of the clinical diagnosis itself.
At the same time, if the clinical details of these patients are contributed to an Internet-accessible genotype-phenotype database eg, Online Mendelian Inheritance in Man , the very same people who benefit from the existence of such correlative data can also contribute to it. Most physicians realize that a genetic test can allow one to provide more accurate counseling about a disease, but most tend to underestimate the value of this counseling unless they have had specific experience with it. Similarly, most patients affected with an autosomal-recessive disease incorrectly believe that their risk of having an affected child themselves is quite high.
Many types of clinical and basic science research can be fostered by molecular testing of a large number of patients. The identification of suitable subjects for clinical trials and the ability to connect clinical findings to a specific address in the genomic domain has already been mentioned. Performing tests for variations in known genes can also dramatically speed the discovery of new disease genes.
Many clinical entities eg, LCA 5 - 11 and Bardet-Biedl syndrome 12 - 23 are genetically heterogeneous caused by mutations in different genes in different people. As a result, any effort to discover the remaining genes will be 3 to 5 times more likely to succeed if laboratories have access to samples from patients with these diseases who have already been screened for mutations in known genes with negative results. In the broadest sense, a genetic test is any clinical or laboratory maneuver that has the potential to increase or decrease the likelihood that a patient has an inherited disease.
Thus, an abnormal electroretinogram in an asymptomatic year-old child of a parent with autosomal-dominant retinitis pigmentosa is as much a genetic test as a molecular investigation of the rhodopsin, 24 RDS , 25 and RP1 26 - 28 genes of the same patient would be.
The concept illustrated in this example deserves great emphasis: a knowledgeable clinician is arguably the single most important component of the genetic testing process. Laypeople, regulatory agencies,and indeed many physicians often have a much narrower view of a genetic test. They tend to see it as the performance of 1 or more laboratory techniques that result in a black-and-white answer about the presence or absence of a disease-causing mutation. They tend to believe that as the technology gets better and better, the tests will get better and better.
The implication of this view is that the physician's role will eventually be reduced to little more than phlebotomist. In , it may have been true that the rate-limiting steps of genetic testing for rare eye diseases were mostly in the laboratory. However, in , the most rate-limiting steps in the translation of genomic information from the laboratory to the clinic are to inform clinicians about the availability of these tests 29 Table and to educate them about their proper use and interpretation.
There are at least 4 features of a genetic test that are of interest to a clinician and his or her patient: the cost, the turnaround time, the report, and the likelihood that the test will assist in the management of the patient.
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Some of these features are logistically in opposition to one another. That is, if a laboratory takes steps to make the turnaround time of a test very short or the report very detailed and customized, the cost of the test will go up. Similarly, if a laboratory tries to make a test very global so that it evaluates even very unlikely possibilities, the likelihood of a positive result will go up, but the turnaround time and cost of the test will also go up.
If any of these parameters gets too out of balance, it will render the test sufficiently impractical that it will not be widely available,if at all. Experience has shown that none of these 4 test parameters poses an absolute barrier to the use of a test. Many physicians have sent samples to research laboratories even when their turnaround times were measured in years and their written reports were nonexistent. Similarly, some highly motivated families are willing to pay thousands of dollars out of their own pockets for a test,even when the likelihood of a positive result is quite low.
However, the demand for tests performed under these extreme circumstances is very low and will never be sufficient to drive genetic testing to a point where it will be considered standard of care.
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With this in mind, we sampled the opinions of many clinicians and patients across the country and used these opinions to empirically choose a blend of parameters that would make a genetic test maximally attractive. We refer to a test that falls within these empirically determined bounds as a clinically useful test.
These threshold values of the 4 parameters are debatable and will undoubtedly change as technology improves, as more genes are discovered, and as clinicians become more experienced in using these tests to their best advantage. Here, it is sufficient to make the point that clinical skill plays a critical role in the utility of any genetic test and that the favorable balancing of these 4 parameters will be necessary to elevate genetic testing from a futuristic curiosity to the standard of care.
The human genome contains a lot of information. Each person inherits 3 billion nucleotides from each parent, many of which could, if altered, give rise to disease. If one built a model of the human genome out of pennies,with each one representing a single nucleotide, this model would consist of 2 rows of pennies that would circle the globe 1. If all of these pennies had 1 of 4 dates representing the 4 possible nucleotides in DNA , one's task in finding the cause of an autosomal-dominant retinal disease like malattia leventinese 30 or rhodopsin-associated retinitis pigmentosa 24 would be to circle the globe 1.
This task would be complicated by the fact that many variations in the genome do not cause disease and simply represent the normal genetic variation among individuals. In fact, any 2 unrelated human beings will vary from one another at about 1 nucleotide position out of every Thus there are millions of nondisease-causing polymorphisms, which would complicate the search for the true disease-causing mutation in this example.
Fortunately, disease-causing sequence variations are not distributed evenly throughout this large genomic space. Most of them are found in or very near the coding sequences of a gene, thereby limiting the space in which one has to look by at least fold. Of course, once a specific gene or series of genes has been associated with a given clinical entity, the coding sequences of these genes become much likelier locations for disease-causing sequence changes in people with that clinical disease than other places in the genome. Moreover, even within genes, disease-causing mutations are not evenly distributed because certain segments of genes encode protein domains that subserve specific functions.
In many genes, new mutations are more likely to be found near the location of previously identified mutations than they are elsewhere in that gene. Using one's past experience with mutation discovery as a guide for future mutation discovery in the same population is the central idea behind the MDPD Figure 2. With this method, one simply keeps track of all plausible disease-causing sequence variations that are associated with a given clinical entity in a given population and uses this ever-growing experience to fine tune the mutation-hunting strategy.
For example,with a DNA sequence—based mutation detection strategy, one would divide the genes known to cause a specific disease into segments that could be assessed by individual DNA sequencing reactions and then sequence these segments in order of decreasing likelihood of detecting a mutation based on one's past experience in that population. For genetically heterogeneous diseases those caused by different genes in different patients , following the MDPD frequently results in switching back and forth between genes during the assay Figure 2.
For recessive diseases in which 2different disease alleles are expected, the discovery of the first allele causes one to refocus the investigation on that one gene whose segments are also screened in MDPD order , because the discovery of the first allele makes it much more likely that the second allele will lie in that gene than in any other gene in the genome. The MDPD method can dramatically reduce the cost of genetic testing because the most common alleles are detected early in the testing process. In addition, many segments of genes are extremely unlikely to cause disease and in most situations should not be screened at all.
Sequencing the entire coding region of such a gene would increase the cost and the time required for a test with a near zero increase in yield. The primary assumption underlying all clinical genetic testing is that there is a predictable relationship between the presence or absence of certain sequence variations referred to as a patient's genotype and a patient's clinical appearance or disease outcome referred to as the phenotype.
A strong genotype-phenotype correlation has value in both directions.