The commonest cause of visual impairment globally is cataract, which is defined as opacity or loss of transparency within the crystalline lens, leading to reduced vision (Figure 32.1). This occurs when the refractive index of the lens varies over distances similar to the wavelength of light (Delaye and Tardieu, 1983). The causes of cataract are many and varied but include changes in lens cell architecture or in its protein constituents. For example, light scattering can result from aggregates in the size range of 100 nm or greater.
About 37 million people worldwide are blind and over 160 million visually impaired (Resnikoff et al., 2004). The proportion of the population with severe visual impairment rises steeply with age, but the causes differ between continents and countries, varying from 0.1-0.2% in industrialized countries to over 1% in sub-Saharan Africa (Resnikoff et al., 2004). About 90% of the world's blind live in developing countries, where the major cause of blindness is cataract. Globally, cataract accounts for 48% of all blindness, almost four times more than any other disorder. There is no known means of cataract prevention but in industrialized countries, cataract removal is a relatively simple and successful operation. The prevalence in a middle class white United Kingdom (UK) population was 49% of
Figure 32.1 Anatomical features of the human eye. (a) Human eye showing the main anatomical features referred to in the text. The visual axis is the line connecting the object of fixation and the fovea, so that light is neither reflected nor refracted. This differs from the optic axis, which passes through the centre of the cornea and lens, which are rarely co-axial. The limits of the macula lutea are shown (arrows) flanking the fovea, the region of highest visual acuity
Figure 32.1 Anatomical features of the human eye. (a) Human eye showing the main anatomical features referred to in the text. The visual axis is the line connecting the object of fixation and the fovea, so that light is neither reflected nor refracted. This differs from the optic axis, which passes through the centre of the cornea and lens, which are rarely co-axial. The limits of the macula lutea are shown (arrows) flanking the fovea, the region of highest visual acuity those in the age range 75-84 years, rising to 71% of those over age 85 years, with slightly higher rates in females than males (Reidy et al., 1998). In the UK, it is the commonest surgical operation, with over 160000 extractions per year compared with a global figure of about 10 million per year. As a result of treatment, cataract-related blindness is declining in many countries, despite their increasingly elderly populations.
There are three main types of cataract: nuclear, cortical and posterior subcapsular. These do not readily correspond to distinct etiological groups, although nuclear cataracts are the most common form of age-related cataract, followed by cortical cataracts, which are most common in those under age 75 years. Besides age, one of the major risk factors for cataract is exposure to ultraviolet B light, which has been proposed to explain about 10% of cortical cataracts in some populations. In one study, a doubling of exposure to UV light increased the risk of cortical cataract by 60% (Taylor et al., 1998). The lens is vulnerable to damage from solar radiation, which generates reactive oxygen species and may lead to protein cross-linking and aggregation, lipid peroxidation and DNA damage, all of which can lead to cell death (Hejtmancik et al., 2001). The lens has powerful antioxidants and repair capacity but these defences are insufficient to prevent age-associated change. Oxidation of lens proteins is closely associated with cataract formation (Hejtmancik et al., 2001) but there is only weak or conflicting evidence for protection by antioxidant nutrients.
Other risk factors for cataract include cigarette smoking, which may account for as much 16-17% of nuclear cataract in some populations, diabetes mellitus, hypertension, obesity, corticosteroids, female gender and conditions such as uveitis, degenerative disorders of the retina, myopia, ocular trauma and surgery (Congdon and Taylor, 2003).
Recently, evidence has been presented for genetic influences in age-related cataract. Population-based studies show two- to threefold relative risks of cataract for those with an affected first-degree relative, although this does not distinguish between shared environmental and genetic factors. Twin studies suggest that the greater similarity of identical versus non-identical twins for both nuclear and cortical cataracts cannot be due to common environment but rather is due to both heritable and non-shared environmental differences (Hammond et al., 2000; 2001). A large twin study of 506 female twin pairs from the UK population, aged 50-79 years, showed that the heritability of age-related nuclear cataract was 0.48, only slightly lower than for cortical cataract (0.53-0.58) (Hammond et al., 2000). Age accounted for 38% of the variance in nuclear cataract, genetic variation for 48%, while unique
(strictly, the centre of the fovea (foveola) shows maximum acuity). (redrawn from remort.wz.cz/retina/II/images/ DRAWEYE.png). (b) Drainage of aqueous humor, which is formed by the ciliary body, into the trabecular meshwork. Drainage abnormalities are implicated in glaucoma (redrawn from www.ahaf.org/glaucoma/about/ aqueousflowBorder.jpg). (c) Normal human retinal fundus photograph showing the macula lutea, the small pigmented spot at the centre of the posterior retina, which is damaged in age-related macular degeneration. The term macula commonly refers to the area of central retina (area centralis) lying between the superior and inferior temporal retinal arteries (vascular arcades). The underlying retinal pigment epithelium and Bruch's membrane are not seen. (d) Human retinal fundus photograph from a patient with age-related macular degeneration (AMD) showing abnormal extracellular deposits or drusen, one of the clinical hallmarks of AMD, in the macular region. (e) Schematic diagram of sub-RPE deposits in age-related macular degeneration (AMD). Macular cone and rod photoreceptors are shown inter-digitating with the villous extensions of the underlying retinal pigment epithelium (RPE), Bruch's membrane and choroidal blood vessels. A single extracellular deposit or druse is shown between RPE and Bruch's membrane. See text for further details. Image from Johnson and Anderson (2004) N Engl J Med 351, 320-2.
environmental factors explained only 14% of the variance (Hammond et al., 2000). These estimates were based on the higher correlation (r) for the presence of nuclear cataract within identical (monozygotic, MZ) twins (r=0.90) compared with non-identical (dizygotic, DZ) twins (r = 0.57). The high correlation within DZ twins suggests the importance of shared environmental factors, including age.
In age-related cortical cataract, genetic factors showing either additive (0-20% of variance) or dominance (38-53% of variance) effects contributed about half (53-58%) of the variance and unique (non-shared) environment explained 26-37% of the variance, the remainder being due to age (Hammond et al., 2001). These studies illustrate the value of the ''perfect natural experiment" in which MZ and DZ twin pairs are compared to elucidate the relative importance of genetic and environmental sources of variability (Martin et al., 1997).
Racial differences in cataract prevalence have also been reported. The odds of African-Americans having cortical cataracts are four times greater than for Whites living in the same community (West et al., 1998). However, both nuclear (odds ratio 2.1) and posterior subcapsular (odds ratio 2.5) cataracts are more common in Caucasians (West et al., 1998). Indians who have moved to the UK and share similar exposure to solar radiation also have a higher prevalence of cataract than the native British population, although dietary and other environmental factors cannot be excluded.
A large number of genes have been implicated in congenital cataract, which accounts for about one-tenth of childhood blindness worldwide. There are over 150 mostly syndromic disorders associated with human congenital cataract listed in the Online Mendelian Inheritance in Man (OMIM) catalogue (www.ncbi.nlm.nih.gov/omim). A smaller number are associated with isolated (non-syndromic) congenital cataract. Specifically, about 30 congenital cataract genes have been mapped, 15 of which have been identified (Table 32.1). Many of these genes have corresponding mutations among the approximately 40 cataract genes in the laboratory mouse (Graw, 2004). The prevalence of congenital cataract is about 1 in 3000 and one-third to one-half have a genetic basis (Graw, 2004). A common genetic cause of congenital cataract is mutation in one or other of the genes producing stable, water-soluble lens crystallins, which account for almost 90% of lens proteins and are essential for lens transparency. Maintaining the solubility of crystallins is critical for lens transparency, and point mutations which only alter their solubility, rather than their structure, are capable of causing cataract (Hejtmancik and Kantorow, 2004). Other genetic causes include mutations in gap junction proteins, water channels, membrane transporters, cytoskeletal proteins and transcription factors (Table 32.1) (Hejtmancik and Kantorow, 2004; Reddy et al., 2004). Mutations in most of these genes cause autosomal dominant forms of congenital cataract.
It has been suggested that more subtle mutations affecting some of the same congenital cataract genes could influence susceptibility to age-related cataract, although this remains to be demonstrated (Hejtmancik and Kantorow, 2004). It is known that crystallins are subject to a wide variety of post-translational modifications which increase with age, including proteolysis, oxidation of sulphydryl groups, deamidation of asparagine and glutamine residues, phosphorylation, non-enzymatic glycosyl-ation and other changes (Hejtmancik et al., 2001). Maintaining their solubility and transparency throughout life is therefore a challenge and subtle genetic changes could contribute to insolubility. a-Crystallins are known to bind and help maintain the solubility of age-modified bg-crystallins, which reduces light scattering. However, a-crystallins do not renature their binding partners, so that the resultant complexes increase in size and deplete the available soluble crystallins so that light scattering does occur (Reddy et al., 2004). A number of congenital cataract genes have been implicated in juvenile or progressive forms of cataract. Juvenile cataracts can result from
Table 32.1. Genes associated with monogenic forms of congenital cataract (see text)
Protein function (mutations)
Membrane transport proteins
Transcription factors MAF 16q23.2
Subunit of a-crystallin, which has small heat shock protein and chaperone activity
(-35% of lens crystallins) (R116C, R49C (dominant) and W9X (recessive)) Subunit of a-crystallin, which has small heat shock protein and chaperone activity
(-35% of lens crystallins) (Frameshift, R120G) p-crystallin subunit, the most abundant water-soluble protein in the lens (Splice site) Subunit of p-crystallin, the most abundant water-soluble protein in the lens (-55% of lens crystallins) (G220X) Subunit of p-crystallin, the most abundant water-soluble protein in the lens (-55% of lens crystallins) (Q155X) Subunit of g-crystallin; abundant water-soluble lens protein; similar in structure to p-crystallin (-10% of lens crystallins) (T5P, insertion) Subunit of g-crystallin; abundant water-soluble lens protein; similar in structure to p-crystallin (-10% of lens crystallins) (T5P, insertion)
Component of low resistance gap junction channels between lens fibre cells; necessary for flow of ions and metabolites between cells (S88P, E48K, I247M) Component of low resistance gap junction channels between lens fibre cells; necessary for flow of ions and metabolites between cells (N63S, Frameshift, P187L) Member of aquaporin family; mediates rapid flow of water across membranes; abundant membrane protein in lens fibre cells (T138R, E134G)
A component of beaded filaments, a cytoskeletal structure restricted to lens fibre cells (R287W, delE233)
Basic leucine zipper transcription factor which binds MAF responsive elements in in the promoters of PITX3 and crystallin genes (R288P) Paired class of homeodomain transcription factor (S13N)
Heat shock transcription factor; regulates small and large heat shock proteins (A20D, I87V, L115P, R120C)
Second most abundant protein of the lens fibre cell membrane; function unknown (F105V, recessive)
mutation in the BFSP2 gene and progressive juvenile cataracts can occur with mutations in the gC- crystallin and aquaporin 0 (MIP) genes (Conley et al., 2000; Francis et al., 2000; Ren et al., 2000). Age-related cataract, defined as onset after the age of 40 years (Hejtmancik and Kantorow, 2004), can be caused by a number of rare monogenic disorders. Galactokinase (GALKI) is one of three genes implicated in galactosemia, all of which can cause congenital cataracts. Mild mutations in GALK1 result in age-related cataract, as a result of galactitol accumulation, which causes osmotic swelling of lens fibre cells. For example, the Osaka variant (Ala198Val) of galactokinase, which is found exclusively in Japanese and other eastern populations, is present in 8% of Japanese with age-associated cataract compared with 4% of the general population (P<0.02)(0kano et al., 2001). Diabetes mellitus is a known risk factor for cataract, which here also results from polyol accumulation. Hyperglycemia results in greatly increased glucose uptake in tissues where uptake is independent of insulin, including lens, retina, kidney and peripheral nerves (Harding, 1991). As a result, the glucose flux through the polyol pathway is increased tenfold. The excess glucose is reduced by aldose reductase to sorbitol, which accumulates and becomes hydrated in lens fibres and epithelium, leading to osmotic stress, a major factor in diabetic cataract. Susceptibility to diabetic cataract has been associated with a specific polymorphism upstream of the aldose reductase gene (Lee et al., 2001), although this remains to be replicated. Finally, common variation in the glutathione-S-transferase gene has been associated with age-related cataract but this has not been consistently replicated (Hejtmancik and Kantorow, 2004).
The aim of identifying individual genes associated with age-related cataract in families has recently been furthered by a genome-wide linkage scan (Iyengar et al., 2004). A series of 224 sib pairs, each with quantitative scores reflecting the extent of cortical cataract was analysed for linkage to microsatellite markers. This identified two chromosomal regions (1p35, 6p12-q12) showing significant evidence for linkage. The most significant linked region, on chromosome 6, contained about 267 genes, posing a formidable problem for gene identification (Iyengar et al., 2004). These findings remain to be replicated, so that the identification of age-related cataract genes remains at an early stage, with much still to be learnt.
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