Many eye diseases are inherited or have familial clustering. It is, therefore, always advisable to enquire about the family history when inter- viewing a patient with an ophthalmological complaint. Some types of inherited eye disease lead to blindness and relatives of patients with such conditions often seek advice concerning their risk of developing the disease. Patients might also consult with a view to prenatal testing, particularly if the disease leads to blindness at a young age.
Recent advances in molecular biology have led to a dramatic increase in our understanding of eye diseases. The discovery and the unravell- ing of the role of numerous ocular disease genes has also helped in our understanding of normal eye development and functioning. Because of the advances made in ophthalmic molecular genetics, we are now able to refer to an inher- ited ocular condition not only by the mode of inheritance, but also to denote the abnormal chromosome, the abnormal gene’s position on the chromosome and its nucleotide sequence.
To date, over 150 different gene defects have been described for retinal conditions alone (www.sph.uth.tmc.edu/retnet/home.htm). For many disorders, we also now know the role the abnormal gene plays in the pathogenesis of the disease, either because it leads to the pro- duction of an abnormally functioning protein or because the gene defect leads to the abnor- mal regulation of nearby or distant genes. Once the abnormal gene product (protein) associated with a disease can be identified, then drugs can
be designed specifically, either to suppress its production or to replace the lost function.
Examples of eye disease that have been mapped out to different chromosomes are shown in Table 23.1.
Several methods are used in molecular biology to link disease to particular gene loci.
Work usually starts by finding and classifying the disease in question in a large family or series of families. Next, the disease chromosome is sought (unless the inheritance pattern is X- linked, then this step can be omitted) and then the position of the gene in question is gradually narrowed down (by the use of linkage analysis followed by chromosome walking). This usually produces a region of the chromosome on which a number of candidate genes are found.
Sequencing of these genes and comparison with normal individuals or animal models usually allows the disease gene to be identified (this can be a very time-consuming operation). Once the sequence of the gene is known, this can be compared on computer databases with similar known genes and the putative structure and function of the disease gene and its product can be determined. The potential of the latter has been greatly improved by the project to sequence the entire human genome.
Eye screening in selected patients at risk of inherited disease might detect important life- threatening conditions, for example familial adenomatous polyposis, retinoblastoma, Marfan’s syndrome, neurofibromatosis and von Hippel Lindau disease.
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Basic Genetic Mechanisms
In order to be able to give advice about the appearance of inherited disease in future gen- erations, it is essential to have a basic knowledge of the mechanism of genetic transmission.
The nucleus of each cell in the body contains 46 chromosomes arranged as 23 pairs. The twenty-third pair comprises the sex chromo- somes (the remainder being known as auto- somes). These sex chromosomes are responsible for the transmission of sex characters but also carry a number of other genes unrelated to sex.
In a woman, the sex chromosomes are the same length but in a man, one is shorter than the other. The shorter one is known as the “Y”
chromosome and the longer one, which is the same as the female sex chromosome, is the “X”
chromosome. When the sperm or ova are formed in the body, the pairs of chromosomes separate and the nuclei of the gametes (i.e., sperm or ova) contain only 23 chromosomes.
When fertilisation occurs, the 23 chromosomes from each gamete reunite as pairs. Genetic material is thus equally provided from each parent. Genes are discoid elements arranged along the length of a chromosome and each one is known to bear special influence on the devel- opment of one or more individual characteris- tics. Genes are arranged in pairs on adjacent chromosomes. The two genes of the pair can be similar (homozygous) or different (heterozy-
gous). If different, one can exert an overriding influence and is said to be dominant. The gene that is overridden is said to be recessive.
Genetic disorders can be divided into three broad groups:
• abnormalities of chromosomes – numerical or structural
• abnormalities of individual genes, which are transmitted to offspring
• abnormalities involving the interplay of multiple genes and the environment.
Pathological genes can carry abnormalities, which are transmitted to the offspring in the same way as (other) normal characteristics.
In a given individual, the abnormal gene can be recessive and masked by the other one of the pair. The individual would thus not appear to have the disease but could transmit it.
There are also some other terms that are important when describing genetic abnorm- alities: penetrance refers to the proportion of individuals who carry the gene and who express the disease, while expressivity refers to the clin- ical spectrum of severity of a particular genetic condition. The four important patterns of inheritance are:
• autosomal recessive
• autosomal dominant
• sex-linked recessive
• mitochondrial inheritance.
Table 23.1. Chromosome mapping for common eye diseases Chromosome Eye disease
1 Leber’s congenital amaurosis, Stargardt’s disease, open-angle glaucoma (type 1A), congenital cataract, retinitis pigmentosa
2 Congenital cataract, iris coloboma aniridia type 1, AR retinitis pigmentosa, congenital glaucoma 3 Usher’s syndrome, AD retinitis pigmentosa
5 Treacher Collins mandibulofacial dysostosis
7p Goldenhar’s syndrome
11 Aniridia type 2 (sporadic aniridia/Wilms tumour), Best’s disease 12 Stickler’s syndrome, congenital cataract
13q Retinoblastoma
17 Neurofibromatosis type 1 (NF1; Von Recklinghausen’s disease) 22q12 Neurofibromatosis type 2 (NF2)
X Chromosome Ocular albinism Juvenile retinoschisis Norrie’s disease Choroideremia Retinitis pigmentosa
(Xq 28) Colour blindness – blue cone, red cone, green cone
Autosomal Recessive Inheritance
If an abnormal recessive gene is paired with another abnormal one on the opposite chromo- some, it will have an effect, but if the opposite gene is normal, the abnormality will not become manifest. Recessive disease in clinical practice usually results from the mating of heterozygous carriers. If the abnormal gene is represented by
“a”, the disease will appear in the individual with genetic configuration “aa” (homozygote) and not with the configuration “aA” (heterozy- gote). When two heterozygotes mate, the likely offspring can be considered as in the diagram (Figure 23.1). If a patient has recessively inher- ited disease, his or her parents are likely to be normal but there might be brothers or sisters with the disease. It is important to enquire whether the parents are blood relatives because this greatly increases the likelihood of trans- mission. If an individual with recessive disease marries someone with the same recessive disease, all the offspring will be affected. If one spouse is a carrier and the other has the disease, there is a risk that 50% of the offspring would
be carriers and 50% would be affected. When a carrier marries a normal individual, 50% of the offspring are carriers. These expected findings could be calculated quite easily using the type of diagram shown in Figure 23.1. Common dis- eases inherited in this manner include sickle- cell disease and cystic fibrosis.
Autosomal Dominant Inheritance
When a gene bearing a defect or disease gives rise to the disease even though the other one of the pair is normal, it is said to be dominant. An affected heterozygote can, therefore, have 50%
of affected children when married to a normal spouse. Of course, if both spouses carry the abnormal dominant gene, all the offspring will be affected. Dominant inheritance can only be shown with certainty if three successive genera- tions show the disease and if about 5% of indiv- iduals are affected. Also, one sex should not be affected more than the other (Figure 23.2).
Examples of this type of inheritance are heredi- tary retinoblastoma and Marfan’s disease.
Aa
PARENTS Aa
A GAMETES
AA CHILDREN
Normal 25%
Normal but carriers 50%
Affected 25%
75% apparently normal
Aa aA aa
a A a
Figure 23.1. Recessive inheritance.
Sex-linked Recessive Inheritance
It has been mentioned already that males have the “XY” configuration of sex chromosomes, whereas females have “XX”. Because of the unpaired nature of much of the male sex chromosomes, some recessive genes can have an effect in males when they do not do so in the female. Certain important eye conditions are carried in this way in pathological genes on the
X chromosome and the pattern of inheritance is termed X-linked recessive. Examples of this type of inheritance are seen in ocular albinism and colour blindness. Retinitis pigmentosa can also show this pattern in some families.
When inheritance is X-linked, only males are affected and there is no father-to-son transmis- sion of the disease. Instead, it is conveyed through a carrier female to the next generation (Figure 23.3).
This description of the three important modes of inheritance should make it apparent
Aa
A
AA PARENTS
GAMETES
CHILDREN AA
Unaffected 50%
Affected 50%
aA aA
A A
a
AA
Figure 23.2. Dominant inheritance.
X PARENTS
X X
XY XX
Normal girl Normal boy Carrier girl Affected boy
Y x XY
GAMETES
CHILDREN
x
x X x Y
Figure 23.3. X-linked inheritance.
that it is possible to predict the likely disease incidence in offspring. It should also be realised that such predictions can only be based on careful and extensive investigation of the family.
Although some eye diseases are known to follow a fixed pattern of inheritance, others, notably retinitis pigmentosa, can be inherited in differ- ent ways in different families. In most large centres, there are now genetic clinics in which time is devoted specifically to the investigation of families and also to the detection of carriers.
Mitochondrial Inheritance
Mitochondria are the only organelles of the cell besides the nucleus that contain their own DNA.
They also have their own machinery for syn- thesising RNA and proteins. Instead of in- dividual chromosomes, mitochondria contain circular DNA similar to bacteria (from which they are thought to be derived). Mitochondrial DNA contains 37 genes, predominately encoding the enzymes necessary for the respiratory chain.
All mitochondria in the zygote are derived from the ovum; therefore, a mother carrying a mito- chondrial DNA mutation will pass it on to all of her children (maternal inheritance) but only her daughters will pass it on to their children. Mito- chondrial DNA mutations are usually manifest clinically in tissues with a high metabolic demand, for example brain, nerve, retina, muscle and renal tubule. Examples of ophthal- mic diseases caused by mitochondrial DNA mutations include Leber’s hereditary optic neu- ropathy, chronic progressive external ophthal- moplegia, maternally inherited diabetes and deafness, and Kearns–Sayre syndrome.
Chromosomal Abnormalities
Microscopic studies of the chromosomes them- selves have revealed that abnormal numbers of chromosomes can be produced by a fault at the
moment of fertilisation. These might be caused by changes in numbers or structure of chromo- somes. Numerical chromosomal changes include the absence of a chromosome (mono- somy), as in Turner’s syndrome, or an additional chromosome (trisomy), as in Down’s syndrome.
Cytogenetic studies have shown that patients with Down’s syndrome have an additional chromosome, which is indistinguishable from chromosome 21. Down’s syndrome is more common in children born to older women and the eye changes include narrow palpebral fissures with a characteristic slant, cataract, high myopia and rather intriguing grey spots on the iris known as Brushfield’s spots. Brushfield’s spots are sometimes seen in otherwise normal individuals. Turner’s syndrome (one missing X chromosome) and Klinefelter’s syndrome (an extra X chromosome) are further examples of disease in which there are known to be abnor- malities of the chromosome, which are visible under the microscope. People with these last two diseases are of interest to the ophthalmol- ogist on account of the abnormal but predic- table manner in which they inherit colour blindness.
Structural abnormalities occur when recom- bination or reconstitution in an altered form follows chromosomal breaks. Such changes can be in the form of deletions, duplication inver- sions, translocations or isochromosomes.
Multifactorial Diseases
These are disorders that arise from an interplay of genetic and environmental influences. The genetic contribution is made up of at least two abnormal genes acting in concert to express a
“dosage-related” type effect, which is signifi- cantly influenced by several environmental factors. This leads to variable phenotypic expression. Examples include diabetes mellitus, some malignancies and perhaps age-related macular degeneration.
