Our genes and proteins are encoded in our DNA; they determine such traits as physical beauty and mental prowess that make us unique as individuals, but they also contain information which negatively influences our lifelong ocular and systemic health. Genetic disorders are caused by mutations in our genes, which modify the resulting proteins. These mutations may occur spontaneously in an individual or are inherited through the parental chromosomes. They may manifest in the heterozygous state (be present on one chromosome, either paternal or maternal) or in the homozygous state (affecting both alleles). A mutation that is manifest in the heterozygous state leads to a dominant disorder, whereas mutations that manifest in the homozygous state are referred to as autosomal recessive. X-linked conditions differ from autosomal types in that women are unaffected or only mildly affected carriers and affected persons are usually male. Other disorders may require the additive effect of mutations in several genes in order to become manifest or require an environmental component; they are then referred to as polygenic or multifactorial. Some 6,000 human genetic diseases are known and about 1/3rd of these are purely ocular or have ocular manifestations.
Since the DNA sequence of the Human Genome has been completed we know that there are about 20,000 genes in man, but the number of described diseases is significantly smaller. This discrepancy may be in part due to mutations that are lethal and we never see their effect, or due to genes that are redundant, so that mutations will not become clinically manifest. Disease development may require mutations in multiple genes, reducing the significance of each individual gene.
Human genes may be large, their information complex and their mutations may lead to more than one disease. Inversely, mutations in more than one gene may lead to similar diseases (phenotypes). For example, the existence of more than 200 genes, which lead to retinitis pigmentosa have been recognized. Mutations in several of these genes may lead to macular degeneration or night blindness or to the most severe of the inherited retinal diseases: Leber congenital amaurosis.
A person’s genome consists of two such double strands, a maternal and a paternal, organized as chromosomes, each containing three billion base pairs.
For any established or suspected genetic eye disease a thorough ophthalmologic examination is required to confirm the diagnosis. The genetic workup will include constructing a pedigree to show the genetic relationships and medical histories in a family. From this pedigree, patterns of transmission of familial disorders may emerge. This, in turn, will further refine the diagnosis of a genetic disorder and allow risk assessment for family members. A chromosomal analysis or a molecular analysis in search of gene mutations may specify the subtype of disease.
A large number of hereditary eye disorders has been identified: these include conditions limited to the eye as well as heritable and complex syndromes with ocular manifestations. Congenital cataracts (those present at birth) and retinal degenerations rank high among the many genetic causes of blindness. Approximately one out of 250 infants is born with a cataract; others develop cataracts later, often in association with another underlying genetic disorder. Among the heritable retinal degenerations is a group of eye disorders called retinitis pigmentosa (RP), which affects an estimated one in 5,000 people in the United States. Onset of symptoms in RP occurs commonly during the first two decades of life, with progressive deterioration that may lead to severe vision loss by the fourth and fifth decades. The severity of the disorder varies according to subtype, and can be transmitted by either of the two autosomal modes or in X-linked fashion. The clinical appearance of the retina and natural history of the disease may vary by gene involved and type of mutation. Many common eye conditions recur within families although the patterns of transmission may not be clear-cut. The most common form of glaucoma (increased pressure in the eye), also referred to as primary open angle glaucoma, affects worldwide about 68 Million individuals over age 40 years. The recurrence risk for first-degree relatives of affected persons ranges from 5% to 16%. Strabismus, or crossed eyes, is another commonly inherited condition. Recurrence risks for this condition have been estimated at 15% for a subsequent child. If a parent of a child with strabismus is also affected, the recurrence risk for subsequent children is reported as 40%.
Due to the medical implications of genetic disorders for family members as well as for the affected individual, counseling is an important part of managing genetic diseases. Advice of recurrence risks is particularly crucial for couples wishing to have more children. The cost of sequencing individual genomes is rapidly decreasing and we may soon be able to change a recurrence risk figure from a probability estimate to a “yes” or “no” for a given person at a reasonable cost. Exact determination of carrier status may provide assurance that the couple is not at risk for affected children or it may alert them to the need for prenatal diagnostic evaluation and follow-up. Genetic counseling is also important because genetic disorders often put emotional stress on the family. Assurance that the parents of children diagnosed with genetic disorders are not at fault may lighten their emotional burden.
Periodic screening of individuals at-risk may lead to prevention of blindness through early diagnosis and treatment. The negative outcome of genetic diseases may not be inevitable: we may be able to predict increased risks of developing a retinal detachment and can be alert to early findings and the need for curative care.
The most effective way to combat genetic disorders is through medical research. Research in the molecular and cell biology of the ocular structures promises more effective management of heritable eye disorders and provides hope for therapy and cure for genetic eye diseases. Due to the technological breakthroughs in these scientific disciplines, major strides have been made worldwide in gaining understanding and developing treatment methods for genetic eye disorders.
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