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"Macular degeneration" is a catch-all term for a number of different disorders that have a
common end result: the light-sensing cells of the central region of the retina - the macula - malfunction and eventually die, with gradual decline and loss of central vision, while
peripheral vision is retained. Most cases of macular degeneration are isolated, individual, occurrences, mostly in people over age 60. These types are called Age Related Macular
Degeneration (AMD). Much more rarely, younger people, including infants and young children, develop macular degeneration, and they do so in clusters within families, because their
disorders are inherited, caused by mutated genes. These types of macular degeneration are collectively called Juvenile Macular Degeneration (JMD). The major types of JMD are: Stargardt's disease
Best's vitelliform macular dystrophy
Doyne's honeycomb retinal dystrophy
Sorsby's fundus dystrophy
Malattia levintinese
Fundus flavimaculatus
Autosomal dominant hemorrhagic macular dystrophy
Stargardt's disease
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.
Early detection
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.
Specific treatments
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. Gene therapies
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.
Technical Details
Drusen
The precise nature of
drusen has not yet been determined. It is a yellowish-white fatty substance, which appears as small spots on the macula or elsewhere on the retina. Some drusen spots are described as
soft, while others are described as hard, but these terms are based on looking at them, not touching them.
Drusen is thought to be a waste product of the recycling of constituents
of the light-sensing reactions which occur in the rod and cone cells of the retina. However, its chemical composition, structure and origin remain to be determined. Lipofuscin
Abnormal retinas sometimes have a deposit behind the RPE which
has a green autofluorescence. That is, it fluoresces without being stained with a fluorescent dye. This material is called lipofuscin. Recently, a toxic component of lipofuscin,
a metabolic derivative of retinol, has been identified. It is known as A2E. Apparently, if the system for recycling spent retinol is not working properly, it gets diverted to
become part of lipofuscin, which accumulates and may poison nearby cells in the retina. ATP
Adenosine-5'-triphosphate is the full chemical name of ATP. It is the main medium of energy exchange in living things. When a
reaction requires energy to drive it, that energy is usually provided, directly or indirectly, by ATP. When energy-rich molecules like starch or sugar are broken down, the energy is
captured in ATP so that it can be used elsewhere.
Living things have transport mechanisms for moving selected molecules across membranes, e.g. from outside a cell to inside, or
vice versa. Many of those reactions are driven by energy from ATP. Retinitis pigmentosa
Mutations in several different genes can cause a decline of peripheral vision and night vision. All of those disorders are called
"retinitis pigmentosa". The peripheral region of the retina is rich in rods, which provide our night vision and peripheral vision. These light sensing cells gradually die in
cases of retinitis pigmentosa. Thus these disorders are similar to macular degeneration, except that macular degeneration affects the cone-rich center of the retina, while retinitis
pigmentosa affects the rod-rich periphery of the retina. Retinol
The light-sensing cells of the retina consist of rods, which can adapt to a
very wide range of light intensities, enabling us to see in dim or bright light, but do not distinguish colors; and cones, which respond to colors. Three different sets of cones
exist, which respond to red, green or blue light. Each rod or cone has a stack of disc-shaped structures which contain a pigment-protein complex called rhodopsin. The rhodopsins in
the various types of rod or cone each respond preferentially to a different part of the visible light spectrum. The pigment part of rhodopsin is retinal, which is made from vitamin A.
When light is absorbed by a rhodopsin, a photoreaction occurs which converts the retinal to retinol, initiates an electrical signal along a connected nerve cell, and causes the
structure containing the rhodopsin molecule within the disc segment to break down. The breakdown products are exported from the rod or cone to the retinal pigment epithelium where it
is recycled in preparation for reuse in a future light-sensing event. Antibody
Higher vertebrates have immune systems which respond to foreign substances by synthesizing proteins which bind specifically to the foreign
substance. These proteins are called antibodies. They occur in the globulin fraction of blood proteins, so are also called immunoglobulins.Researchers use specific antibodies
as reagents to detect, determine concentration, and determine location of the substance with which the specific antibody reacts. To determine location within a cell or tissue, a
distinctive stain of some sort is devised which binds to the specific antibody without interfering with its binding to the foreign substance. Genetic Terms and Concepts
Inheritance Patterns
It had long been known that JMDs have distinctive
patterns of occurrence within families. That is, they appeared to be inherited disorders, each type presumably caused by a faulty version, a mutation, of a particular gene. In the
last few years, thanks to the power of research tools of modern molecular genetics, the faulty genes responsible for most types of JMD have been identified, and their mechanisms of
action are currently under intensive investigation.Inherited traits are classified as being dominant or recessive. We each inherit two copies of each gene, one from our mother and
one from our father. A dominant trait is one which is inherited from only one parent, because the presence of one faulty copy of a gene, inherited from one parent, is dominant
over the presence of a normal copy of that gene inherited from the other parent. If, however, the inherited trait is recessive, two faulty copies of a gene have to be inherited, one
from each parent, because a single normal copy of the gene is dominant over a single faulty copy of the gene. Some forms of JMD exhibit dominant inheritance, while others exhibit
recessive inheritance. In humans, genes are distributed along 23 chromosome pairs, one member of each pair inherited from each parent. One chromosome pair consists of the
sex-determining chromosomes, denoted X and Y. Females have an XX pair, and males have an XY pair. Egg and sperm cells each carry only one chromosome of the sex-determiing pair. All of
a woman's eggs carry an X chromosome, while half of a man's sperm carry an X chromosome and half carry a Y chromosome. If the fertilizing sperm carries an X chromosome, the fertilized
egg will have an XX pair, so the offspring will be female, while if the sperm carries a Y chromosome, the fertilized egg will have an XY pair, so the offspring will be male. Most of
the genes in the Y chromosome are turned off, so a single faulty copy of a gene in the X chromosome will behave in a male as if it is dominant, even if it is recessive in the presence
of a normal copy of that gene, i.e. in a female with two X chromosomes, one of which has a normal copy of the gene. Some inherited traits are much more frequent in males. They are
called sex-linked, and are determined by genes on the sex-determining XY pair. A particular type of retinitis pigmentosa is inherited in a sex-linked manner. None of the known types
of JMD is sex-linked. The other 22 chromosome types, i.e. those which are not sex-determining chromosomes, are called autosomes. Some JMDs are inherited as if caused by
an autosomal dominant gene, while others are inherited as if caused by an autosomal recessive gene.
Molecular Genetic Terms
Each gene is located at a specific position on a specific chromosome. A gene is said to be
"mapped" when its position on a chromosome has been determined.
The gene is actually a segment of DNA. Segments of DNA can be isolated and copied. A gene is said to have
been "cloned" when the DNA segment containing it has been isolated and copied thousands of times, making enough to do structural analysis.The DNA of a gene contains a
unique sequence of four units called nucleotides, whose names are abbreviated by A, T,G anc C. A gene is said to have been sequenced when the exact order of A's, T's, G's and C's in
the gene have been determined. Genes typically have a sequence several hundred to several thousand nucleotides long.
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