This is the most common type of JMD. Symptoms typically develop in childhood or teen years. However a variant of Stargardt's disease, called fundus flavimaculatus, has the same symptoms, but they do not become manifest until early adulthood. Symptoms include decline in visual acuity, drusen spots on the macula and scarring of the macula. Stargardt's disease has an autosomal recessive pattern of inheritance.
The gene responsible for Stargardt's disease and fundus flavimaculatus is called abcr (recently renamed abca4). The gene encodes a protein which functions in ATP-dependent transport of "spent" retinol from outer disc segments of the light-sensing rods and cones of the retina. The spent retinol is a result of the light-sensing photoreaction in the discs. The transport protein is located at the rim of the discs, so was named rim protein.
Many mutant forms of the abcr gene have been found. Many seem to have no adverse consequences, while some apparently cause Stargardt's disease and others cause the late-developing variant, fundus flavimaculatus. In addition to causing these retinal disorders, other mutations in the abcr gene cause a disorder called rod-cone dystrophy, and still other mutations in the same abcr gene cause an autosomal type of retinitis pigmentosa.
In a large multinational study involving over 1,000 individuals with AMD, and a similar number without the disease, two mutations in the abcr gene were 3-fold and 5-fold more frequent in the group with AMD. This finding suggests that certain mutations in abcr increase the likelihood of AMD.
Best's vitelliform retinal dystrophy
This disorder is the second most common JMD. It is usually a relatively mild form of macular degeneration. Its most distinctive symptom is an "egg yolk" large drusen spot on the macula at an early stage, which later breaks up into "scrambled egg" drusen The degree to which central vision is impaired, and the age of onset of symptoms, varies greatly, even among members of the same family. Some people with the gene may never experience a noticeable decline of central vision.
Best's disease has an autosomal dominant pattern of inheritance, but with highly variable expressivity. The gene responsible, called VMD2, has been mapped, cloned and sequenced. The protein encoded by the gene has been named bestrophin, but its function is unknown. Using recombinant DNA techniques the protein was produced in quantities adequate for raising antibody proteins in mice. The antibodies were used to determine the location of bestrophin. It was found concentrated on the cell membrane of the retinal pigment epithelium (RPE), which is a layer of cells at the back of the retina.
Some mutations in VMD2 are associated with early, childhood onset of symptoms, while other mutations are associated with onset in adulthood.
People who carry the bestrophin gene do not have an enhanced probability of developing AMD.
Doyne's honeycomb retinal dystrophy
This disorder has symptoms quite similar to those of AMD: drusen on the macula and at the edge of the optic nerve head, macular scarring, and neovascularization in late stages, with progressive loss of central vision. Symptoms typically arise during the fourth or fifth decade of life.
Doyne's disease has an autosomal dominant pattern of inheritance. The responsible gene has been mapped, cloned and sequenced. Based on sequence similarities, it has been given the name EGF-containing fibrillin-like extracellular matrix protein, abbreviated as EFEMP1. The protein, whose function is not yet known, is found behind the retinal pigment epithelium (RPE).
Malattia levintinese has one distinctive symptom: drusen distributed radially on the macula. In all other respects, it closely resembles Doyne's disease and ARM. When the responsible gene was mapped, it was found to have the same location as the EFEMP1 gene, i.e. the one which causes Doyne's disease. Consequently, malattia levintinese is now thought to be a variant of Doyne's disease.
Sorsby's fundus dystrophy
Symptoms of Sorsby's disease typically arise during middle age. This disorder is characterized by heavy accumulations of drusen and lipofuscin at Bruch's membrane behind the RPE. RPE cells die and neovascularization may occur.
This disorder has an autosomal dominant pattern of inheritance. The gene responsible has been mapped, cloned and sequenced. The protein encoded by the gene has been identified as belonging to a class of proteins known as tissue inhibitor of metalloproteinase-3, abbreviated TIMP-3.
The TIMP-3 protein has been shown to normally be produced by RPE and deposited at Bruch's membrane, which separates the retina from the choroid and the blood vessels therein, behind the retina. Individuals with Sorsby's disease appear to overproduce a faulty version of the TIMP-3 protein.
Individuals carrying a mutant TIMP-3 gene do not have an increased probability of developing AMD.
Autosomal dominant hemorrhagic macular dystrophy
This disorder closely resembles Sorsby's disease, except that it does not involve a mutation in the TIMP-3 gene.
Prospects for Prevention and Treatment
Progress is being rapidly made in understanding how specific mutations in specific genes cause the various forms of JMD. We can expect several benefits from this greatly improved understanding of these disorders.
Molecular genetic screening tests can be set up to determine if children of people with a JMD inherit the responsible gene. As preventive treatments are developed, they can be employed to minimize the impact of the faulty gene on vision.
It is likely that researchers will try to invent ways to minimize the adverse impact of genes which cause JMDs. For example, drugs may be developed which either inhibit synthesis of faulty TIMP-3 protein, or which interfere with its harmful effect. Such drugs might prevent Sorsby's disease symptoms. Unfortunately, because Sorsby's disease is quite rare, it is unlikely that a drug company would consider it a commercial opportunity. However, there is evidence that people with AMD also overproduce TIMP-3, so such drugs may have commercial possibilities as treatments for AMD, if it can be shown that excess TIMP-3 is a cause of damage in AMD.
It may one day be possible to introduce into specific cells, such as RPE, DNA containing a "good" version of a JMD-causing gene, and thereby enable the cells to perform the function properly. However, this possibility is still a long way off in the future. In the case of autosomal dominant JMD-causing genes, perhaps a method can be devised to specifically inactivate the faulty copy, thereby letting the good copy in the gene pair take over.