Indian Journal of Ophthalmology

CURRENT OPHTHALMOLOGY
Year : 1993  |  Volume : 41  |  Issue : 4  |  Page : 153--171

The biology of cataract. The Hyderabad cataract research group

D Balasubramanian1, Aashish K Bansal2, Surendra Basti2, KS Bhatt3, JS Murthy4, C Mohan Rao1,  
1 Centre for Cellular and Molecular Biology, Hyderabad, India
2 L.V.Prasad Eye Institute, Hyderabad, India
3 National Institute of Nutrition, Hyderabad, India
4 Department of Genetics, Osmania University, Hyderabad, India

Correspondence Address:
D Balasubramanian
Centre for Cellular and Molecular Biology, Hyderabad 500 007
India




How to cite this article:
Balasubramanian D, Bansal AK, Basti S, Bhatt K S, Murthy J S, Rao C M. The biology of cataract. The Hyderabad cataract research group.Indian J Ophthalmol 1993;41:153-171


How to cite this URL:
Balasubramanian D, Bansal AK, Basti S, Bhatt K S, Murthy J S, Rao C M. The biology of cataract. The Hyderabad cataract research group. Indian J Ophthalmol [serial online] 1993 [cited 2023 Sep 26 ];41:153-171
Available from: https://journals.lww.com/ijo/pages/default.aspx/text.asp?1993/41/4/153/25600


Full Text

Cataract is the most common cause of blindness. It is estimated that there are about 45 million blind people in the world and more than a third of them are blind due to cataract. In India alone, cataract ac�counts for over 80% of the cases of blindness. Cataract is one of the most ancient diseases known to man, which is so since it is an age- related disorder. It is for this reason that there is no medical solution or cure for this affliction. Many of the approaches that have been taken to mitigate the problem have thus been revolving around preventive measures, and towards delaying its onset or progression. Consider�able research has been done on the multifarious aspects of this disease. Important leads have come from studies on the epidemiological, nutritional, photochemical and genetic aspects of cataract. In addition, the role of behavioural habits such as smoking, alcohol intake, or drug addiction have also been investigated. This review attempts to provide an overview of the developments that have occurred in our understanding of cataract and to present the current status of research in all these areas. It has become clear in recent years that it is vital to pursue a multi-disciplinary approach to better understand the problem involving collabora�tion between the basic scientists and the clinicians. We highlight below the several facets of the cataract problem and the efforts being made towards containing it.

 I. EPIDEMIOLOGY OF CATARACT



Despite the existence of cataract surgery for thousands of years and despite it being an easily curable affliction, it continues to remain a major cause of blindness.

Epidemiological studies have increased our knowledge of cataract in many ways : in estimating the magnitude of the problem, in determining its prevalence and incidence in different regions, and in identifying the various risk factors in the development of cataract.

Different views have been expressed in the litera�ture regarding the criteria of diagnosing cataract. While some investigators include any opacity in the lens in the definition of cataract irrespective of its size, loca�tion, and effect on vision, others include only those lens opacities associated with decreased visual acuity, glare and contrast sensitivity. We conform to the latter view. Opacities which do not impair vision should be called lenticular opacities and not cataract because lens opacities begin to occur in increasing degrees even in normal individuals as they age and such opacities are mostly peripheral and do not cause any visual impairment. Moreover, there is no convincing evidence that these progress to cause visual impairment. This view is highlighted in a study by Sasaki et al [1] wherein it was seen that 63% of a Japanese population in the age group of 50 to 59 years had cataract including early senile changes; 43% of this age group had cataract including incipient cataractous changes but only 0.9% of this age group had a visual acuity of 6/9 or worse. Further, only 4% of those in their sixties and only 14% of those in their seventies had a visual acuity of 6/9 or worse. Apparently, many of those with early senile changes could have excellent vision even 20 years later.

 THE MAGNITUDE OF THE PROBLEM



During the past fifteen years, a number of cross�sectional surveys have provided data on prevalence of cataract, which indicate that cataract is by far the commonest cause of blindness and visual disability worldwide. [2][3][4][5][6][7][8][9][10][11][12] Cataract can include cases developmental in origin, or secondary to trauma, systemic diseases, drugs and age-related factors. Senile or age-related cataract is responsible for more than 80% of all cataracts. [13] According to the World Health Organisation, there are about 42 million blind people in the world; of which 17 million (40%) are blind due to cataract [14][15][16]sub and about 13 million of these are in developing countries. [17] In India alone, 4 million people turn blind due to cataract every year. [18]

Cataract being an age-related disorder, it is but natu�ral that its incidence increases as longevity increases. For example, in the West, the incidence of cataract in people over 50 years is 15%, while in developing countries it is about 40%. [19]sub With the rapid increase in older population worldwide, it is predicted that there will be 40 million people blind from cataract by the year 2025. [20]

By far, the only available treatment for cataract is surgical removal of the lens. Although quite effective, it has its share of risks and limitations. Moreover, it entails great economic burden on the meagre medical resources of developing countries. Also, the increasing incidence of cataract has widened the gap between the number of patients requiring surgery and cataract surgeons, thus making it difficult to cope with the problem. For instance, in Nepal, only 35% of cataract patients receive surgery, [21] while it is not astonishing that even in countries like England cataract patients are wait listed for surgery for a period of 4 years. [22] In India, the scenario is even more depressing with a gigantic backlog of more than 22 million cataract cases (1990 statistics). To cope with this, and with the ever increasing number of cataract patients, we would need to operate 5 million cases per year for the next 10 years as against the present rate of 1.2 million surgeries per year. [23]

These limitations of cataract surgery have stimulated experimental cataract research in animals, laboratory, and epidemiological studies to determine the incidence, prevalence, and risk factors for the development of cataract so as to focus on the preventive aspects of cataract.

 PREVALENCE AND INCIDENCE



While "prevalence" gives us the total number of people that have cataract in a population at a given time, "incidence" indicates the number of new cases that occur over a given period.

There are only a handful of studies in the litera�ture citing the incidence of cataract. Minassian and Mehra have discussed the very high incidence of cataract in India. [18] In this study, the incidence of blindness was shown to rise with age, with a steep rise after the age of fifty years [Table 1]. They have estimated that four million Indians become blind due to cataract every year.

Another index that has been used to define the problem of cataract is the incidence of cataract extraction. The incidence of cataract extraction increases with age and is more among the Oriental people than among Europeans. [24]

In contrast, there are many studies on the prevalence of cataract, and these studies show cataract to be more prevalent in the third world countries than in the West.

Chaterjee et al determined the prevalence of cataract in five different regions of northern India, ranging from dry hot plains to the mountains in the Himalayan region. [25] It was seen that the overall prevalence was lower in the mountains than in the plains, apparently indicating that people inhabiting the plains develop cataract ten years earlier than those inhabiting the mountains. A similar study conducted in Nepal also showed higher prevalence of cataract in the plains (4.2%) than in the mountains (1.9%). [3]

Another investigation carried out in Framingham, Massachusetts investigated the prevalence of four major diseases, namely, cataract, glaucoma, diabetic retinopathy, and macular degeneration. [12] The subjects ranged in age from 52 to 85 years. The definition of cataract included lens opacities with visual acuity of 6/9 or worse, or aphakia. The prevalence of cataract was found to be greater than the other three diseases put together. Prevalence of both early and late lens changes increased rapidly with age and was more in females. Nuclear opacities were the most commonly diagnosed change and the propor�tion of lenses with more than one region opacified increased with age. [26] Similar results were obtained by Gibson et al in England [27] and Martinez et al. in New Zealand. [28] Another survey, known as the Health and Nutrition Examination Survey (HANES), was carried out in the USA during 1971-72. The prevalence of cataract was found to be higher in this study as compared to that in the Framingham study, though less degree of opacification was scored as cataract [29] It was noticed that cataract was more prevalant among the black population as compared to the whites. [24]

Another study was done on an Indian population in Punjab, taking a visual acuity of 6/18 or worse with lenticular opacity, as criteria for the diagnosis of cataract. [30] This study showed a steep rise in the prevalence of cataract after 40 years of age. Comparison of this with the Framingham study shows that cataract is much more prevalent in Punjab and occurs at least 15 years earlier here than in Massachusetts [Figure 1].

 RISK FACTORS



Various risk factors have been identified in the pathogenesis of senile cataracts. Apart from ageing, genetic factors, nutrition, diabetes mellitus, trace metals, ultravoilet radiation, and smoking have been impli�cated as significant risk factors in the causation of cata�ract. There has been controversy on the advisability of classifying the cataract patients into morphological groups, such as, nuclear, subcapsular or cortical for studying the risk factors. Most case-control studies have been on pooled cataracts. This approach has been strongly criticized by some authors on the basis that different morphological types have different risk fac�tors. However, most authors agree that categorizing senile cataract into morphological types is pointless as most of the cataracts are of mixed type, each cataract patient may have several risk factors, and moreover any single risk factor may be associated with differ�ent morphological types. [24]

In the ensuing paragraphs, we review the epidemio�logical evidence of role on the various risk factors for the formation of senile cataract. As the term senile cataract implies, the major risk factor for its development is age, which unfortunately is not preventable. What is not known is that whether age is only a risk factor or a definitive causative agent for cataract formation. Heredity, does seem to play a role in cataracto�genesis, though it does not appear to exert a dominant genetic effect. We, therefore, review the more significant risk factors involved in cataract formation.

 SUNLIGHT



Almost 70 years ago, Duke-Elder had opined that the fundamental cause of cataract in all its forms may be traced to the incidence of radiant energy directly on the lens itself. [31] During the past decade some evidence has accumulated implicating UV light as a factor in cataractogenesis. We discuss the photochem�ical aspects of this matter in some detail in later sections.

Support for the sunlight hypothesis has come from studies done in Nepali China, [4] United States [32] and Australia. [33] These studies compared the prevalence of cataract in different geographical and climatic regions. Data from the HANES survey have shown higher ratio of cataract to non-cataractous diseases in areas with high numbers of annual sunlight hours [32] In Australia, people inhabiting areas of higher UV irradiation were shown to have higher prevalence and early onset of age- related cataract . [33] Similarly, in Nepal, cataract prevalence was 3.8 times higher in areas with an average of 12 hours of daily sunlight exposure compared to areas with only 7 hours of exposure. [34] Interestingly, examining outdoor labourers in various areas of India, Wright found that cataract was more common in cloudier areas. [35] The reason could well be that the pupil opens more in cloudy conditions than in bright light to admit more radiation into the lens. This could lead to increased ultraviolet radiation falling on the lens.

Factually water vapour in the clouds filters visible and infrared radiation but not ultraviolet rays.

Although these studies suggest sunlight as a risk factor, the statistical rigour in several of these has been low. However, since each one of us is exposed to sunlight throughout life, the public health impact of even a weak risk could well be large in terms of the number of cataract cases caused by sunlight. [13]

 DIARRHOEA / DEHYDRATIONAL CRISIS



The first epidemiological study to investigate the role of diarrhoea in cataractogenesis was done by Minasssian et al in Raipur, India. [36] One hundred and sixty matched pairs of cataract cases and controls were questioned for any episodes of life-threatening diarrhoea (severe enough to render the patient in bed for at least three days). It was seen that one episode of severe diarrhoea was 4.1 times more likely to cause cataract than in the control group. The risk rose to 21% with two or more episodes of diarrhoea and was still higher in those with histories of both severe diarrhoea and heatstroke. These data suggested that 36% of cataracts in people aged less than 70 years could be attributed to severe diarrhoea. The attributable risk increased to 40% if episodes of dehydration due to heatstroke were included. These observations were reinforced by a later methodologically distinct case- control study in Orissa, which again showed an attributable 38% risk. [37]

Two other case control studies in India have shown more equivocal results. The India-US case-control study of age-related cataract found no association between diarrhoeal disease and cataracts. [38] However, they employed a less vigorous definition of severe diarrhoea - a history of diarrhoea that required pa�tients to stay in bed for more than a day. Bhatnagar et al in Southern India found a relative risk of 1.3, applying the same definition of diarrhoea as in the Raipur and Orissa studies. [39] [Figure 2] graphically shows the results of various studies conducted so far.

Harding [24] summarizes the possible connection between diarrhoea and cataract in molecular and cellular terms. Diarrhoea leads to malnutrition, acidosis, dehydration and associated osmotic imbalances, and high levels of urea in the body which could (a) lead to osmotic imbalance, and (b) accumulation of cyanate which would adversely affect the glutathione levels, and also carbamylate and thus alter the structure and composition of the lens proteins leading to their loss of solubility.

 NUTRITION



Animal studies and in vitro investigations have shown that nutritional deficiencies are associated with cataract. These nutrients include riboflavin, total protein, amino acids, vitamin E, vitamin C, selenium, calcium, zinc and others. However, corroborating evidence for human cataract is little. (We discuss the role of nutrition in cataract in greater detail in Section V). A recent review concludes that there is no convincing evidence that nutritional supplements can affect develop�ment and progression of age-related cataracts in healthy people . [40]However, another study published recently shows that regular intake of multivitamin supplement decreases the risk for all types of cataracts. [41]

Chaterjee et al found a higher prevalence of cataract in Punjab, associated with consumption of diets low in total protein. [30] Their study has shown that low�protein diet may account for as much as 40% of the excess prevalance in Punjab as compared to Framing�ham. [13]sub The role of nutrition in cataract formation in developing countries is perhaps closely linked with diarrhoea and poverty, all of which are closely inter�related. We discuss this in greater detail in section V.

 SMOKING



The role of smoking in cataractogenesis has been highlighted in various studies . [42][43][44][45] In these case� control, cross-sectional, and prospective studies, current smokers have been shown at a consistent two to three fold increased risk of cataract. Also, evidence is accumulating showing that smokers who quit smok�ing can drastically reduce their elevated risk to that of non-smokers. In one such study, [42] significantly increased risk of pure nuclear opacities was associated with cigarette smoking. The increase in smoking dose was associated with increasing severity of nuclear opacities and the effect of smoking was most striking in those less than 80 years old. The mechanism by which smoking might damage the nucleus is becom�ing clearer with some of the ongoing studies in our group. The role of reactive oxygen species generated in the inhaled smoke is clear. In addition, aromatic compounds present in the inhaled smoke oxidatively modify lenticular components. The smoke constituents have been seen to alter the membrane transport of some cations, and also to induce epithelial cell division.

 DIABETES



Diabetes has been associated with cataract since long. Evidently, direct in vivo and in vitro experimental studies suggest that diabetes is a cause of cataract.

Earlier epidemiological studies as reviewed by Caird have shown that diabetes causes a more rapid maturation but may not trigger initiation of cataract.46 However, currently, most investigators are of the view that initiation and maturation of cataract are not totally different processes .24 The proportion of cataract patients with diabetes has been found to range from 8.7 to 21% which is considerably greater than the prevalence in general population, which shows a high risk of cataract associated with diabetes.[24]

Interestingly, various epidemiological studies on cataract show that the relative risk of cataract in diabetics decreases with age. [Table 2]This phenomenon has been explained by two effects: first, the excess mortality associated with diabetics decreases their number in older population and second, other causes for cataract become more common which dilute the effect of diabetes alone . [24]

Another interesting data from the Edinburgh study have shown cataract patients to have higher blood glucose levels than the controls even when diabetic cases were withdrawn from the analysis.[47] Another report has shown that 44% of the cataract patients had abnormal glucose tolerance curve 48 Thus, it may well be that glucose per se may be responsible for many a cataract rather than diabetes alone. The ability of sugars to covalently modify lens proteins, crosslink and insolubilize them, has been well studied, and our study in this area highlights the molecular events involved . [49]

Two other defects in carbohydrate metabolism have been associated with cataract in recent studies: deficiencies of glucose-6-phosphate dehydrogenase50 in red blood cells and of galactose - 1 - phosphate uridyltransferase.[51]

 OTHER RISK FACTORS



Apart from the above mentioned significant risk factors, a number of other risk factors have been implicated in cataractogenesis. These include glaucoma, myopia, alcohol, and hypertension. These factors seem to be of more importance for the industrialised world. However, their public health implications in the developing world cannot be ruled out.

Clearly, the tremendous burden of blindness due to cataract remains a major challenge for eye care professionals with public health perspective. Surgical treatment of cataract imposes great economic burden on the state and the backlog is perhaps too big to be handled by surgery alone. Alternatively, preventive ophthalmology offers us another approach to tackle the problem by seeking to identify factors that might modify the onset or progression of cataract. If such a factor is identified which simply delays the onset of cataract by a period of 10 years, the number of cataract surgeries would drastically decrease by 45% or more. [20]

 II. CLASSIFICATION OF CATARACT



Many classification schemes have been proposed for cataract. These are based on the time of development, etiology, location within the lens, colour, texture, shape, and degree of opacification. Such classification systems find application in clinical practice and also in epidemiologic and interventional studies.

 CLINICAL CLASSIFICATION OF CATARACT



Clinically, cataract may be classified based on:

(a) the morphological characteristics of the cataract such as its location, size, and appearance; and

(b) the etiology of the cataract.

The various morphological types of cataract [52] are illustrated in [Figure 3]. Each morphological variety may be caused by different conditions and cause typical symptoms." These are summarized in [Table 3]. Based on the etiology, cataracts can be classified into four broad categories, namely:

(i) Congenital and developmental cataracts

This group [54] includes cataracts seen at birth or in childhood and is caused due to genetic factors, as a part of syndromes, developmental abnormalities, metabolic abnormalities, and intrauterine infections.

(ii) Senile cataracts

This group includes cataracts that occur as part of the normal ageing process.

(iii) Acquired cataracts [55]

Cataracts secondary to trauma, toxins and metabolic disturbances are included in this group. [53]sub

(iv) Secondary (complicated) cataracts [55]

These are cataracts that are the result of inflam�matory, degenerative, or ischaemic ocular disease. The various causes for Acquired and Secondary Cataracts are mentioned in [Table 4].

 USE OF CLASSIFICATION SYSTEMS IN CLINICAL RESEARCH



The etiologic and morphologic classification systems are not suitable for cross-sectional and longitudinal research studies since they do not quantify the degrees of opacity. Other classification systems [56],[57] have been proposed but are however, observer biased since parameters measured are subjective and the sub groups broad, making these unsuitable for documentation in clinical research studies.

The more recent classification systems [58],[59],[60],[61],[62],[63],[64],[65],[66] have sought to be sensitive to the detection of occurrence and progression of lens opacities. Of these, the lens opacities classification systems. [58],[59],[60] (LOCS) proposed by Chylack et al is the one most often used. LOCS Version II [59]sub has been extensively tested in clinical research studies [67]sub and found to be reliable and reproducible. [68][,69]

The LOCS III system uses a set of colour photo�graphs as standards for comparison. The following features are graded:

(a) Cortical cataract (Cl-C5)

(b) Nuclear Opalescence (NO1-NO6)

(c) Nuclear Colour (NCI-NC6)

(d) Posterior Subcapsular Cataract (P1-P5)

[Figure 4] illustrates the various standard photo�graphs used in LOCS III. This system can be used to classify cataracts at the slit lamp or to grade photo�graphs taken on high speed film (Kodak Hi speed Ektachrome, Rochester, NY) with the Retroillumina�tion (Neitz CTR, Kowa optimed, Torrance, Calif) and colour slit-lamp camera (Zeiss, Zeiss Oberkochem/ Wacrtt, West Germany).

The classification systems that use standard photographs for comparison, for example the LOCS or the Oxford System [61] are significantly better than the previous systems, but they do have a subjective element in them. The focus today, hence, is to develop systems that are more objective. Methods that use computerized image analysis of photographs [70] have been introduced recently and aim at eliminating observer bias completely.

 III. GENETICS OF CATARACTS



The study of genetics of eye disorders has always been in the forefront and has given rise to several new results and concepts in the understanding of genetics of man. Congenital cataracts and colour blindness are among the first human disorders to be studied -genetically. Colour blindness happens to be the first condition assigned to a chromosome (X-chromosome), and colour blindness and anaphakia form the first pair of linked genes known in man. Congenital cataracts were among the first serious genetic conditions to be treated effectively and the possibility of therapy seems to have stimulated the study of hereditary aspects of diseases after the discovery of Mendel's Laws. The first assignment of human disease gene to an autosome is also that of congenital cataract (Zonular pulverulent cataract) to chromosome 1. The concept of anti�oncogene (oncogene suppressor) has also arisen from Retinoblastoma. [71] More recently, the first human disease gene assigned to a chromosome exclusively by using DNA marker studies appears to be the autosomal dominant Retinitis Pigmentosa. [72]

Apart from the leads that the study of genetics of ophthalmic conditions has provided, it assumes importance from its relevance to prevention and management of these conditions. Genetic counselling has become common in the routine of physicians and geneticists that an understanding of the genetics of a disease has become a prerequisite. Many conditions exhibiting disorders of the eye can be prenatally diagnosed today [for example, all chromosomal disorders; many metabolic disorders such as galacto�semia, glycogen storage diseases, amino acid disorders such as phenylketonuria, maple syrup urine disease, blood disorders such as hemophelias, hemolytic anemias thalassemias, muscle disorders such as myotonic dystrophy, Duchenne muscular dystrophy, lipoprotein disorders such as hypercholesterolaemia, and so on. [73] These can be effectively managed through prenatal diagnosis and genetic counselling. Several inherited conditions can be managed through therapeu�tic measures (e.g., albinism, marfan syndrome, galacto�saemia, phenylketonuria, maple syrup urine disease, Wilson's disease, glycogen storage disease, beta thala�ssemia, familial hypercholesterolaemia). Possibilities for gene replacement therapy are also increasing gradu�ally. Some such conditions of ophthalmic interest are: Lesch-Nyhan Syndrome, Hemophelia, and Leucocyte adhesion deficiency. The studies published in the November 1993 issue of Archives of Ophthalmology foresees substantial prospects for ocular gene therapy, and has devoted great attention to mapping of the genes associated with some eye diseases. Understanding the genetics of these conditions, their frequency of occurrence, and epidemiology, and maintaining proper records is of paramount importance today.

Keeping these aspects in mind, we present a brief review of the genetics of cataracts and highlight current knowledge on the location of some of these genes.

 MODES OF INHERITANCE



There are several etiological factors, such as intrauterine infections, drugs, radiations, endocrine and metabolic disturbances and diseases that lead to opacities of the lens. But these are to be carefully distinguished from the hereditary types. A crude estimate puts 25% of all cataracts as hereditary. Hereditary cataracts may occur independently or in association with other ocular anomalies, each with a hereditary base. Also, there are several inherited syndromes and diseases associated with cataract formation. Detailed descriptions of inherited types of cataracts are covered in classical texts. [74],[75],[76],[77] A more recent presentation by McKusick [78] lists 24 types of inherited cataracts by their morphological features and modes of inheritance [Table 5]. The important features and variations exhibited by these types are:

(i) age : Opacities can occur at variable ages (example, type 10);

(ii) expression : the size, shape, intensity, and distribu�tion of opacities may show wide variation;

(iii) syntenny : different types of cataracts may occur in the same individual or family (example, types 9 and 11);

(iv) genetic heterogeneity : same type of cataract may be inherited in different modes (example, nuclear cataract, in types 11, 17, 20; posterior polar cataract in types 5 and 9; anterior polar cataract in types I and 11); and

(v) anticipation : appearance of opacities at progre�sively earlier ages in subsequent generations (example, type 11).

In addition to the types in [Table 5], several new types of cataracts could go unreported or wrongly identified unless investigators are alert in noticing and identifying them and tracing the family pedigree. This is amply illustrated in our study of a family with a history of congenital cataract with sutural opacities, apparently a new type of inherited cataract hitherto unreported [79] Our patient, a boy, reported with congenital cataract, information provided by family members on the occurrence of cataract in the family suggested that it could be of an autosomal recessive type, in view of wide spread consanguinity in the family. Slit-lamp examination of some affected indivi�duals revealed zonular opacities, which are, however, inherited as dominant cataracts. Further careful examina�tion of all affected and unaffected individuals including the grand parental generation revealed additional individuals with the zonular opacities but with normal vision. Sutural opacities were seen in all af�fected individuals, which lead us to identify a new type of dominant cataract. Our case underscores the importance of careful examination of the lens for opacities and of all members of a family and noting the pedigree for correct identification of a cataract, and determining its mode of inheritance.

 MAPPING THE GENES FOR CATARACTS



Several techniques have been developed to map genes located on chromosomes but four important methods have been used in mapping genes for cataracts when the location of a marker gene is known. These are:

(i) use of family data for estimating recombination fraction () between the two loci,

(ii) use of chromosomal markers such as deletions and translocations,

(iii) use of somatic cell hybrids in case of genes that express at cellular level (example, enzyme markers) and

(iv) use of DNA markers, such as restriction fragment length polymorphism (RFLP) and microsatellite markers. The method of analysing family data, necessary in particular for methods (ii) and (iv) above, requires that there be segregation for both recombinant and parental genotypes in the progeny, and also that at least one parent be double heterzygote for the disease and marker gene loci. In addition, the phase of linkage as coupling or repulsion needs to be known. The probability of the genotype (or haplotype) combinations at the two loci of all individuals in the family is found under the assumption of a certain recombination fraction 0 and is compared with the probability of the genotype combinations of the family under the assumption of no linkage. For this comparison one finds the LOD SCORE (LS) as

Probability of the family under certain recombination 0

LS = log

Probability of the family under no linkage (0 = 1/2)

If LS is greater than 2 for a family, it is taken as indicative of linkage between the two loci. 0 values from different families are pooled to strengthen the evidence for assessing the linkage. A recombination fraction so estimated will be used to calculate the map distance i.e. the physical distance between the loci on the chromosome and expressed in centimorgans (cM).

[Table 6] presents a list of Lataract genes which have been mapped so far using different methods mentioned above. Clearly, many more genes for cataracts remain to be mapped.

 IV. PHOTOCHEMICAL ETIOLOGY OF CATARACT



Our perception of vision is derived from the image that is formed on the retina. The cornea and the lens act as a composite lens system to produce the image. It is likely therefore that these organs suffer damage through the continuous incidence of light. Fortunately, the cornea is able to withstand this insult due to its turnover mechanisms. But the lens has no such opportunity and hence damage accumulates here, eventually leading to lens opacification. Such a possi�bility was first described by Duke-Elder more than a half century ago. [80] It was 10 years later that Rohrsch�neider experimentally verified this [81] and Bachem pro�duced the action spectrum, [82] both in animal models. Since then there have been several studies implicating the role of light in the etiology of cataract. Nordmann has shown as early as 1962 that radiation leads to cataracts. [83]sub Exposure to intense light from electrical�arc welding is also shown to be associated with high incidence of cataract. [84] Pitts et al have reviewed the literature till 1977, relating to the effect of ultraviolet (UV) light on the eye and concluded that exposure to UV light enhances formation of cataract.SS These early observations have established the phenomenological connection between light and cataract.

Numerous investigations have been made into the photochemical and photophysical features of crystall�ins, the proteins that are the major constituents of the lens. Interestingly, all aspects of human cataracts such as increased UV-visible absorption, non-tryptophan fluorescence, accumulation of kynurenines, or protein cross-linking can be experimentally produced by exposure of the lens to UV light.

Light-mediated damage can only occur due to the presence of light absorbing chromophores. Proteins have the following major chromophores; peptide bonds that absorb below 220 nm, cysteine (cys) 235 nm, histidine (his) 240 nm, phenylalanine (phe) 254 nm, tyrosine (tyr) 275 nm, and tryptophan (trp) around 290 nm. Sunlight that reaches the earth is made up of visible (750-400 nm), ultraviolet A (UV- A, 400-320 nm) and UV-B (320-280 nm) radiations. Since the cornea filters of much of light below 295 nm, the major chromo�phore that is left to absorb light in the lens is trypto�phan, and to a limited extent tyrosine. Most of the report that follows is thus centred around the photo�chemistry of these two amino acids and of crystallins themselves.

 PHOTOCHEMISTRY OF AROMATIC AMINO ACIDS



Exposure of tryptophan to UV radiation, in aqueous solutions, produces several photoproducts [86] along with the generation of free radicals. [87],[88]

Conventional stationary and laser flash photolysis studies of trp in the 280 nm region have shown that the initial photoproducts are: the triplet state 3trp, the radical cation trp+,and the neutral radical trp*. [89],[90]

The primary product of tryptophan photolysis is N-formylkynurenine (NFK) which is also formed enzymatically in the human lens from tryptophan and subsequently converted to kynurenine, 3-hydro�xykynurenine, and hydroxykynurenine glucoside. [91]

Some of the metabolic or photo-oxidation products of tryptophan might act as photosensitizers in the lens. In the presence of oxygen they are capable of generating active species of oxygen such as singlet oxygen( 1sub 0 2 ), superoxide (02), hydrogen peroxide (H 2 0 2 )and hydroxyl radical (OH -sub ). [92][93][94][95] In the photosensitization phenomenon, the sensitizer molecule is promoted to its excited singlet state by the absorption of light; the process of intersystem crossing then takes the system to the longer lived triplet state. From the triplet state of the sensitizer, there are two major mechanisms which can lead to oxidation of substrate molecules. The type I or direct reaction pathway is a redox reaction of the triplet sensitizer involving either electron transfer or proton abstraction from the substrate by the sensitizer, with the production of active oxygen species such as O2 -sub H 2 0 2 , and the OH. - These radicals can rapidly react with nearby substrates and cause covalent modifications. In the type II reaction, the triplet sensitizer transfers its excited state energy not to the substrate but to ground state molecular oxygen, producing the highly reactive singlet oxygen (O 1sub ) 2 , which can then react with and oxidize the substrate. [96],[97]

Tyrosine is also susceptible to photochemical modifications. Garcia et al have isolated bityrosine from cataractous lenses. [98] The identification was based on correspondence with synthetic bityrosine with respect to chromatography, fluorescence and ultraviolet and mass spectra. However, neither van Haard et al [99]sub nor McNamara and Augusteyn [100] could find bityrosine in the lens. Guptasarma and Balasubramanian have shown that interaction of active oxygen species with crystallins does not lead to production of bityrosine, while direct photolysis of crystallins produces small amounts of intramolecular bityrosine in all the three crystallins. Based on the absorption characteristics and availability of oxygen in the lens, they argued, how�ever, that probability of bitryrosine formation in the lens is rather low. [101]

Other than these aminoacids, phe, his, and cys side chains are also known to undergo photochemical modification, though to a far smaller extent.

From the foregoing it can be seen that light inter�acts with trp and tyr and can produce variety of compounds such as N- formylkynurenine, kynuren�ine, 3-hydroxykynurenine, and anthranilic acid. Some of these compounds absorb light in the visible region and hence can decrease lens transmission. These compounds can also produce reactive oxygen species which can cause further damage to the lens. Fortunately, some of these compounds may absorb light and dissipate the energy to the surroundings without causing any photodamage. [102],[103] Luthra and Bala-subramanian have shown that 3-hydroxykynu�renine and 3- hydroxyanthranilic acid may act as antioxidants in the lens. [114]

 PHOTOCHEMISTRY OF CRYSTALLINS



All the three major crystallins, namely, Alpha-, beta-, and gamma-crystallins, undergo photochemical modification. Upon exposure to UV light, alpha�crystallin solutions do not show any change in transmis�sion properties, while beta-crystalline show yellow colouration and insolubilization, gamma-crystallin precipitates quickly forming a turbid solution . [105][106]

The secondary and tertiary structure of alpha�crystallin do not undergo any major changes upon exposure to UV light, [107] while beta- and gama�crystallins show conformational changes. There have been several studies on the photochemical aspects of crystallins. [108],[109],[110],[111],[112],[113],[114],[115],[116] Rao et al have shown that delta� crystallin from chick lenses retains its secondary structure, while completely losing its tertiary structure upon similar exposure. [117] Balasubramanian et al have shown that singlet oxygen induced oxidation of tryptophan or tyrosine alone is not sufficient to cause protein cross-links. They have demonstrated the participation of histidine in the case of singlet oxygen induced cross-linking. [95] In a similar study with OH- radicals, Guptasarma et al have demonstrated the participation of histidine and lysine in the cross�linkage. [118] However, it is important to recognize that cross-linking of proteins need not necessarily lead to precipitation. Protein solubility depends largely on the nature of the exposed surfaces. Any modification which leads to increase in surface hydrophobicity or decreased hydrophilicity will decrease protein solubility. Photo�chemical changes can lead to such modifications with or without cross-linking.

 PHOTOCHEMICAL ASPECTS OF INTACT LENSES



The lens is probably the only organ where the cellular concentration of proteins can be as high as 500 mg/ml. Because of this high concentration and the resulting molecular proximity, intermolecular interactions and organization would be expected to have a role in maintaining lenticular transparency, and its loss in cataract. Thus a study of the intact lens, preserving all its condensed phase features, would be of interest. Intact lens fluorescence spectra were recorded by Lerman et all [119] and laser induced loss of trypto�phan fluorescence was observed by Borkman et al. [120] Rao et al [117] have used a solid sample holder with a geometrical design to minimize artifacts in fluorescence measurements and also studied lenses from various species. This study revealed some supramolecular features that are not observed in earlier solution studies.

Specifically, it showed that intermolecular energy transfer occurs from tryptophan to N-formylkynu�renine (NFK) in the intact lens; NFK, the suspected photodynamic cross-linker, also appears to be photodegraded. In addition, UV exposure leads to changes in lens packing. [117] The photoinduced packing alteration has been studied further by measuring the Red Edge Excitation Shifts (REES). [121] The magnitude of REES observed for normal lens is different from that seen in a photodamaged lens. Photochemical damage leads to further decrease in fragmental mobility of tryptophan residues in the lens. [121] This parameter, REES thus appears to be a potential tool to monitor the state of the lens.

Since photochemical damage is largely oxidative in nature, one would expect that concentration of the reducing agents in the lens may alter its photo�vulnerability. Indeed, an intact lens study by Rao and Zigler has shown that high levels of reduced nucleo�tides offer protection against photochemical damage. [122] The lens has several pigments that fluorescence, and UV exposure only increases this number. Studying such a multiflorophore system by conventional fluorescence spectroscopy is difficult. Synchronous scanning facilitates analysis of several fluorophores in normal, photodamaged, and cataractous lenses. [123]

These intact lens spectral studies have shown that trp residues of crystallins are buried in hydrophobic pockets and possess limited freedom of molecular mobility. Exposure to UV light leads to a loss of trp fluorescence due to photochemical conversion of trp to NFK, and a change in mobility features. In the intact lens, light absorbed by trp can be transferred to NFK, which perhaps gets degraded or loses its energy to its surroundings. NFK which is thought to be a potential photodynamic agent, itself gets photolysed yielding further products.

Atleast five different fluorophores are present in intact lenses, abundance of each depends on the age of the lens and geographical location (environmental, light, and heat factors).

 EFFECT OF UV EXPOSURE ON THE LENS METABOLISM



Other than the photochemical features discussed above, there have been several studies to investigate the metabolic changes in the lens upon exposure to UV light. Jose and Yielding have shown that UV exposure results in unscheduled DNA synthesis in lens epithelial cells. [124] UV light is shown to alter protein synthesis as well. For example, in a recent study with cultured rabbit lens epithelial cells, UV exposure resulted in induction of a 32-kD protein and loss of a 26-kD protein, the identity of which is not yet certain. Also, the enzyme levels altered significantly. Recently, Kojima has shown that there is a regional variation in the fructose-l,6-bisphosphate aldolase activity in UV�exposed lenses. [125] Amino acid uptake is also affected by UV exposure; leucine uptake is inhibited by about 47% in cultured human lenses. [126 ] This can adversely affect the protein synthesis in lenticular cells. DNA damage through UV radiation is of course a distinct possibility, and this should occur in the lens epithe�lium. Such damage would also affect lens metabolism.

 SUNLIGHT, CATARACT, AND PROTECTION



Clearly, UV light can lead to or enhance the process of lens opacification. The UV light, in some parts of the world, is enough to act as a factor in lens coloura�tion and opacification. Further, Drugs such as psoralen [127]sub and methoxsalen [128] used with UV-A to treat psoriasis can also enhance lens opacification.

Hiller et al have carried out a multivariate logistic risk analysis on the data obtained from over 2000 persons and concluded, inter alia, that cataracts were positively associated with increasing UV-B counts, latitude, and sunlight hours. [129] A study of about 850 watermen working at the Chesapeake Bay has also shown an association between sunlight (UV-B) and cataract. Analysis of these data suggest that wearing spectacles might protect the eye from UV-B exposure. [130],[131] Based on a study of persons above 60 years of age, Wojno et al have concluded that the group wearing spectacles showed significantly less sclerotic nuclear changes as compared to the group that never wore spectacles. [132]

 V. ROLE OF NUTRITION



Our knowledge on nutritional cataracts is mostly confined to animal experimentation. Deficiencies of tryptophan, valine, phenylalanine and histidine have been implicated in cataract formation [133],134] Tryptophan deficiency-induced cataract has consistently been docu�mented. [135] However, the plasma tryptophan levels in cataract subjects were not always affected [136][137][138] Early work on riboflavin deficient animals demonstrated opacities of lens. [139][140][141] Derangement in protein metabolism (synthesis) and redox cycle have been suggested to be the biochemical mechanisms in tryptophan and riboflavin deficiencies induced experi�mental cataracts, respectively. [141],[143] Cataracts have also been produced in experimental animals on a diet either low in folic acid or deficient in vitamin E. [133] In these cases, vitamin deficiencies were maternal and lenticular opacities were in their embryos.

Despite evidences from animal experimentation and from worldwide occurrence of cataract in humans, there is, at present, no conclusive evidence demonstrating the damaging effect of malnutrition on human lens. However, current evidence points to the role of sugar (high), proteins (low), tryptophan (oxidative photo�products), calcium (hyper- as well as hypo-calcaemic conditions), selenium (deficiency or excessive intake) and lowered intake of antioxidants (riboflavin, vitamin C, vitamin E, and beta-carotene (pro-vitamin A) in human cataract formation. [142],[144][145][146].

High levels of sugars such as D-glucose, D-galac�tose, D-xylose,and L-arabinose could adversely affect the normal metabolism of the lens. The reduction of sugars to corresponding polyhydric alcohols by the enzyme, aldose reductase is the basis for the forma�tion of cataracts related to abnormalities in sugar metabolism. The reduced sugar accumulates in the cell, resulting in osmotic disequilibrium and consequently increases net influx of water, swelling, membrane leakiness, and cation imbalance. Altered levels of oxidant scavangers accompanied by altered oxidant stress are also seen. [147],[148] Cataract is very common in persons with galactosaemia, an autosomal recessive condition wherein there is deficiency of the enzyme, galactose�1-phosphate uridyltransferase involved in the conver�sion of galactose to glucose. [149 ] In such condition, Galactose-l-phosphate accumulates in the lens. Likewise, Deficiency of galactokinase, the enzyme catalysing the first step of galactose metabolism, also produces cataracts similar to those in transferase deficiency. [150] However, the activities of galactokinase in erythrocytes and transferase in blood samples from senile cataract patients were observed to be normal. [151] As known for many years, diabetic patients are prone to develop cataract [152] [Table 2]. The rate of development of cataract is directly related to degree of hyperglycaemia and therefore to the concentration of glucose in the aqueous humour.

The eye as a whole, and the lens in particular, is well protected against the adverse affects of protein deficiency. Although cataract has not been observed in animals on low-protein diet, except in pigs that survived for more than one year on a protein-free diet, it accelerates when galactose is included in the diet. [133],[153] In the case of humans, an association between cataract and low intake of protein has been observed in Punjab, India [145] In yet another study by the Indo-US group, high level of protein intake was observed to be protective for posterior subcapsular, nuclear, and mixed types of cataract. [38] Cataract patients with low body mass index (undernourished) were observed to have increased proportions of insoluble proteins in lens as compared to patients with high body mass index (well�nourished), while total proteins remained unchanged, suggesting increased insolubilisation of protein. [136] Further studies suggested that poor nutritional status of cataract patients accelerates protein insolubilisation in the lens, a common observation in most types of human and experimentally induced animal cataracts. [114] Malnutrition has been observed to be an important cause of cataract in several other countries including Italy and Israel, and among the blacks of the United States and aborigines of Australia (see Section I above). Thus, patients with higher nutritional levels appear to have less risk of cataract formation.

Earlier work carried out at the National Institute of Nutrition has suggested a protective role for some micronutrients such as riboflavin, zinc, and copper against cataract formation. [137],[151],[155] Biochemical evidence for the association between galactosaemia and ribo�flavin deficiency in cataract patients has been noted. [156]

A comparative study on the biochemical assessment of vitamin B status (as measured by enzyme activa�tion coefficient values) in cataract patients and control subjects showed that while riboflavin status was poor in cataract patients (nearly 81% of cataract patients as compared to 12.5% in age- match and socio�economically-matched controls), both groups displayed evidence of inadequacies for thiamine and pyridoxine. [151] Clinical and biochemical inadequacy of riboflavin and pyridoxine is widely prevalent in the Indian popula�tion [157] and increased incidence of riboflavin deficiency is particularly found among the elderly. The impact of diminished dietary supply of riboflavin on lens transparency is influenced by a variety of factors including absorption of the vitamin, efficiency of its conversion to the active derivative, turnover of the enzyme glutathione reductase and its cofactor in the lens, and level of peroxidative challenge. Lower activity of glutathione reductase, which requires riboflavin as FAO for its activity, was observed in cortical cataracts as compared to normal lenses. This enzyme is necessary for the maintenance of the cellular pool of reduced glutathione (GSH), which serves as a reduc�tant to convert hydrogen peroxide to water and to prevent formation of protein disulfides leading to molecular aggregation and cataract formation. For instance, about 36% of the cataract patients monitored in a study in Alabama, USA, exhibited glutathione reductase activity, suggestive of riboflavin deficiency. [156]

High values of antioxidant index (determined by dietary intake of riboflavin, vitamin C, vitamin E, and carotene) are seen to be associated with low risk of cortical, nuclear, and mixed cataract. [158] In another study, however, Jacques et a1 [159] did not find an association between cataract and antioxidant index including erythrocyte superoxide dismutase and glutathione peroxidase. Very recent findings from nutrition inter�vention trials carried out in north central China by Sperduto et a1 [160] revealed lower prevalence of age�related nuclear cataracts in persons receiving either multivitamin/mineral or riboflavin/ niacin supplements as compared with persons not receiving these. As mentioned earlier, the lens is under constant oxida�tive stress from reactive species of oxygen. These species can damage the lens cellular membrane and macromolecules, as well as enzymes involved in energy production and membrane transport. With ageing, enzymatic and nonenzymatic antioxidant capabilities change. The excessive free radical attack implicated in the development of cataract can be protected by dietary intake of micronu trients with antioxidant capabilities. Naturally occurring antioxidants of potential importance include vitamins, riboflavin, ascorbic acid, tocopherol, carotenoids, and glutathione.

Ascorbic acid appears to be one of the most effec�tive antioxidants. Its higher concentration in the aqueous humour of diurnal animals relative to that of noctur�nal animals suggests that ascorbic acid protects the eye against solar radiation. Ascorbic acid absorbs UV light and is an efficient water-soluble reductant, react�ing with active species of oxygen. Although scorbu�tics are not known to get cataracts, scorbutic guinea pigs fed on high galactose diet develop cataract more rapidly than ascorbate supplemented animals.[161] Supplementation of guinea pig diets with ascorbic acid appears to decrease UV induced damage to the lens proteins. Several epidemiological studies have suggested an association between protection against cataract and levels of ascorbate in diet, plasma, or tissue. [162] Subjects with lowest ascorbate status were more likely to develop posterior subcapsular cataract than those with higher vitamin status.[163] Ascorbic acid levels were found to be low in brown cataract.[163]

It has been noted that ascorbic acid can also act as a prooxidant.[164]sub This happens when the overall oxi�dant system of the lens exceeds the capacity of the antioxidant system or when ability to maintain ascorbic acid in the reduced state is lost. During these conditions ascorbate can generate free radicals. The reactions could be light-induced or a result of metal�catalysed oxidation. Ascorbic acid can react with lens crystallins and cause non-disulfide covalent cross-linking and insolubilisation of lens proteins.

Tocopherol is reported to be effective in delaying a variety of experimentally induced cataracts in ani�mals [135],[165 ] Persons consuming tocopherol supplements (400 IU/day) were found to have about 30% less risk of developing cataract as compared to those without supplementation. [166]

Copper and zinc are required for the catalytic activity of the metalo-protein, superoxide dismutase which plays an important role in the removal of toxic superoxide anion. Senile cataracts were found to have low levels of zinc and high levels of copper.[167] Plasma levels of zinc and copper are significantly low in cataract patients.[137] Trace element analysis of diets consumed by Indians has revealed the inadequacy of copper and zinc as compared to recommended daily intakes. [168] Thus copper and zinc inadequacy might play an important contributory role in cataract risk. Selenium has been reported in all eye tissues including lens.[146] Selenium is an integral part of the enzyme, glutathione peroxi�dase which destroys peroxides derived from unsatu�rated fatty acids. Rats are susceptible to the formation of selenite cataract.[169] However, there is no evidence that selenium is a cause of cataract in humans.

It appears possible that in cataract the oxidant�antioxidant equilibrium is shifted towards oxidant stress and there might be an increased demand for antioxi�dant micronutrients (vitamins and trace metals) and enzymes concerned with meeting such oxidant stress. [145],[170][171][172] Evidence relating to the risk of senile cataract and micronutrients, particularly riboflavin (especially in early stages of cataractogenesis), ascor�bic acid (with caution, since oxidative biproducts of this vitamin form protein cross-links in the lens), carote�noids, and tocopherol, suggests that intake of antioxi�dant micronutrient supplements reduce the risk of cataract. Well controlled clinical intervention trials are desirable for future research in this area. In the absence of such corroborative data, a diet consisting of a variety of fruits and vegetables (rich sources of antioxidants) every day may be recommended.

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