Open Access Review Article

J Ocular Biol
November 2015 Vol.:3, Issue:2
© All rights are reserved by El-Sayyad et al.
Journal of

Ocular Biology
Overview of Congenital, Senile
and Metabolic Cataract
Hassan I.H.El-Sayyad1*, Eman HM Bakr1, Heba A.
El-Ghawet1 and Taher M G E El-Desoky2
Faculty of Science, Mansoura University, Mansoura, Egypt
1

Ophthalmic Surgery, Ophthalmic Center, Mansoura University, Egypt

2

Keywords: Cataractous lens, Congenital, Senile cataracts, Genetic

factors, Metabolic pathways *Address for Correspondence
Hassan I El-Sayyad, PhD, Faculty of Science, Mansoura University,
Abstract Mansoura, Egypt, Tel: 0020502254850; E-mail: elsayyad@mans.edu.eg

Opacity of the lens is a major public health problem of unknown Submission: 26 September 2015
causes and impaired vision of a large number of peoples. There are Accepted: 13 October 2015
different forms of cataractous lenses including congenital, senile Published: 02 November 2015
and metabolic associated ones. Although the congenital and senile Copyright: © 2015 El-Sayyad HIH, et al. This is an open access article
cataractous lenses were markedly different in its origin, developmental distributed under the Creative Commons Attribution License, which
aspects and genes involved, the patho-physiological pathways permits unrestricted use, distribution, and reproduction in any medium,
seemed to be similar. The present review summarized the causes of provided the original work is properly cited.
cataractous lenses such as genetic and abnormal conformational Reviewed & Approved by: Dr. Li Wang, Associate Professor of
changes of glycation end products. The alterations of proteins, lipids, Ophthalmology, Cullen Eye Institute, Department of Ophthalmology,
minerals and antioxidants defense were illustrated and discussed. Baylor College of Medicine, USA

Introduction idiopathic [9] and particularly, a cause for unilateral cataract is rarely
The lens is avascular biconvex ellipsoid transparent tissue, present found [10].
in front of the anterior chamber of the eye; just behind the cornea. It Congenital cataracts are of different genetic type, and more than
is an ectodermal organ, developed at the 25th day of gestation. By the 25 loci and genes on different chromosomes are involved in the
second month of intra-uterine growth, the spherical criteria structure disease [11]. Rahi and Dezateux reported a similar genotype in 27%
of the lens is developed with characteristic anterior and posterior pole of children with bilateral congenital cataract [12].
and dorsally outlined by lens epithelium. The lens fibers developed
and matured after birth with subsequent formation of crystalline In age related cataract, many changes have been found to have
protein especially in adult state [1]. occurred in the lens structure which facilitated the opacities of
lens fibres. The epithelia of nuclear, posterior subcapsular, mature,
The cornea is affected by continues light exposure which may be
mixed, hypermature, and black cataracts of male and female patients
reflected in the structure of the lens with age. The lens comprises three
revealed that the 56% superimposed epithelial cells are probably the
main regions; capsule, lens epithelium, and lens fibers. The capsule is
source of increased and altered cell activity. Senile cataract is classified
made up of dense connective tissue. The lens epithelium; lined the
into; mature or immature, nuclear cortical and posterior subcapsular
surface and it comprises a simple cuboidal epithelium. It possesses
cataract [13]. Investigation of 233 cataractous patients, revealed
a vital function by regulating the homeostatic functions allowing the
apparent increased incidence of nuclear, cortical, and posterior
permeability of ions, nutrients, and osmolarity to the aqueous humor.
subcapsular cataract in older patients. These were correlated with
It develops earlier during utero life in the 5th-6th week of gestation
and maintains its normal integrity throughout [2]. The entire body of lower expression of SIRT1 in patients [14].
the lens is composed of concentric layers of tightly backed lens fibers Mechanism of Cataract Formation
interdigitated with each other by a ball and socket. Glucose represents
the primary energy source of the lens tissues [3]. Sodium/potassium Metabolic diseases were found to be associated with the activation
adenosine triphosphatase and calcium adenosine triphosphatase of the sorbitol pathway [15] that enhanced the progress of cataract
promote the osmolarity of the lens fibers [4]. formation. Liberation of free radicals is more common as a result
of these diseases. In vivo and in vitro studies revealed that hydrogen
Damage of the lens fibres lead to the formation of clouding in the peroxide (H2O2) is related to the accumulation of Aβ in the lenses of
lens and scattering of light, the predictor of cataract. It increases with rats and causes lens opacification [16]. The incidence of cataractous
age with a prevalence of about 50% in over 80 years old individuals lenses was markedly increased among patients with metabolic diseases
[5]. There are different forms of cataracts; namely congenital [6] age- such as hypertension [15] and diabetes [17]. Hypertensive patients
related cataract [7] and metabolic cataract [8]. showed significantly higher nitrite levels in their cataractous lenses
Congenital & Senile Cataract were detected in 26 (44.1%) especially that of posterior subcapsular
cataracts [18,19].
Cataract is a clouding of the eye’s natural lens which causes visual
impairment. More than 17 million people are blind due to cataract Moncaster et al. reported increased amyloid accumulation
and 2800 new cases are known throughout the world daily [5]. and supranuclear cataracts in the ocular lenses of patients with
Alzheimer’s disease [20].
Congenital cataract are developed during intra-uterine growth
as a result of environmental and genetic factors and observed after There are different pathways for the formation of cataract (Figure
parturition. Approximately half of all congenital cataracts are 1), they include:

Citation: El-Sayyad HIH, Bakr EHM, El-Ghawet HA, El-Desoky TMGE. Overview of Congenital, Senile and Metabolic Cataract . J Ocular Biol. 2015;3(2):
12.
Citation: El-Sayyad HIH, Bakr EHM, El-Ghawet HA, El-Desoky TMGE. Overview of Congenital, Senile and Metabolic Cataract . J Ocular Biol.
2015;3(2): 12.

ISSN: 2334-2838

Over-expression of aldose reductase also enhanced the expression

of both extracellular signal-regulated kinase (ERK1/2) and c-Jun
N-terminal (JNK1/2), which are involved in apoptosis [34].
In sugar cataracts, the initial swelling brought about by polyol
accumulation leads to an imbalance in the pump-leak equilibrium,
increasing sodium and chlorine content. Genetic mouse cataract
was found to exhibit the imbalance of the pump-leak system which
appeared to be initiated by a deficiency of Na-K ATPase which
facilitates sodium retention and osmotic swelling [35].
Nagai et al. reported a decrease in the activity of Ca2+-ATPase
in the lenses of Shumiya cataract rat (SCR) and Ihara cataract rat
(ICR), which is concurrent with the development of cataract [36].
The expression of cytochrome c oxidase (CCO)-1 mRNA and CCO
activity in UPLR lenses was found to have decreased during cataract
development. Both nitric oxide (NO) and lipid peroxide were
markedly increased in the lenses of UPLR, SCR and ICR with opaque
lenses. Increased liberation of NO may enhance lipid peroxidation
resulting in the inhibition of Ca(2+)-ATPase and elevation in lens
Ca(2+), leading to lens opacification in ICR/f rats.
Glycation end product (AGE): AGE is a non-enzymatic glycation
of lens proteins by reducing sugars (glucose, galactose etc) resulting
in the formation of protein aggregates that precipitate in the lens
Figure 1: Chart illustrates the mechanism of cataract formation. [37,38] and represent a causative factor of damaging lens epithelial
Abbreviations: CE: Corneal Epithelium; CO: Ciliary Organ; E: Endothelium; cells (LECs), the promoter of cataract formation [39]. The receptor
LC: Lens Capsule; LE: Lens Epithelium; LF: Lens Fiber; LN: Lens Nucleus;
St: Stroma.
for advanced glycation end-products (RAGE) and proliferating cell
nuclear agents (PCNA) are over-expressed in old-age and diabetes
which is involved in cataract formation [40,41]. Advanced glycation
Polyol pathway end products (AGEs) including carboxymethyl lysine (CML) was
In diabetic cataractous lens, there was a marked increase of found to be increased in diabetic and senile cataractous lenses [42].
damaging lens epithelium [21] associated with over production of The urea-insoluble fraction, showed the highest levels of AGEs
free radicals and decreased capacity of antioxidant defense system. [43]. Pentosidine, CML, and imidazolone were markedly increased
These were associated with a depletion of the activities of aldose in cataractous lenses [44]. In vitro and in vivo studies revealed
reductase and sorbitol dehydrogenase while G6PD and glutathione AGE induced apparent apoptosis of LECs through enhancement of
system enzyme activities were found to be lower in cataractous lenses accumulation of argpyrimidine and nuclear factor- kappaB (NF-κB).
from diabetes [22]. Aldose Reductase is a key enzyme involved the The ratio of Bax to Bcl-2 protein levels was also increased [39].
reduction of glucose into sugar alcohol sorbitol, which is metabolized
to fructose by sorbitol dehydrogenase. Sorbitol was found to Cataractous lenses were markedly higher in women especially
accumulate in lens cells causing osmolysis, leakage of glutathione, those with diabetes [45]. In cataractous lens of 21-week-old male ZDF
myo-inositol, the generation of free radicals which contributed to rats, increased apoptosis of LECs was correlated with upregulated
diabetic complication such as cataract [23,24]. The enzyme is more expression of iNOS mRNA and protein, causing the accumulation
active in diabetes and implicated in cataractous lenses [25,26]. of glycated proteins in their cytoplasm, meanwhile activated NF-
kappaB was mainly detected within their nuclei [46].
Sugar cataract formation was found to have resulted from
lenticular sorbitol accumulation. In the lens, increase of aldose Genetic Role of Cataract Formation
reductase is contradicted with a decrease of the activity of sorbitol
There are multifactorial agents that contribute in the development
dehydrogenase [27]; it increases the accumulation of sorbitol rapidly
of cataractous lenses as well as between congenital and age-related
than it is converted to fructose [28] which induces apoptosis of
cataracts. Congenital cataract affects childhood, and different
lenticular epithelial cells and subsequent cataracts [29]. Diabetes
intrauterine factors are involved (Figure 2). The genetic incidence
was found to express poly(ADP-ribose) polymerase(PARP) in lens
accounts for 8.3 and 25% cataract. Congenital cataracts may result
[30] which in turn led to NAD+ depletion and energy failure and also
from chromosomal abnormalities such as neurofibromatosis type 2
contributed to necrosis and apoptosis [31].
or homeobox gene PITX3 [47,48] classified congenital abnormalities
Intracellular accumulation of sorbitol is associated with marked into mature, polar (anterior or posterior), zonular (nuclear, or
increase of oxidative stress in the endoplasmic reticulum (ER), the lamellar), and capsular or membranous.
principal site of protein synthesis, it initiates the liberation of free
Zhu et al. attributed the congenital cataract to the mutation
radicals and also involved in the breakdown of lens fibers [32,33].

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2015;3(2): 12.

ISSN: 2334-2838

are affected, age-related cataracts are responsible for blinding 17

million people worldwide [55].
In age related cataract, many changes had been found to have
occurred in the structure of the lens which facilitated the opacities
of lens fibres. Telomerase represents one of the genetic factors. It is
a naturally occurring enzyme that maintains telomeres and prevents
them from shortening during cell division. Telomerase consists of at
least two components: an RNA template (hTR), which binds to the
telomere and a catalytic subunit (hTERT) with reverse transcriptase
activity, which adds a specific DNA sequence to the chromosome ends.
During the formation of cataract, telomeres attained a considerable
atrophy in lens epithelial cells due to increased oxidative stress of the
lens cell membranes and biomolecules [56,57]. Cataractous patients
possessed the presence of a large number of micronuclei (MN) in
their epithelia, manifesting epithelial damage [58].
MicroRNA-125b (miR-125b) is responsible for lens epithelial cell
apoptosis. In vitro studies of miR-125b revealed increased incidence
of human lens epithelial cell apoptosis through assessments of p53. In
age-related cataract, there was an inverse relationship between miR-
125b and p53 expression [59]. Oxidative stress and DNA damage
contributed to the pathogenesis of age-related cataract (ARC) [60].
Oxidative stress represents the main factor responsible for
lenticular cataract. Glutathione-S-transferase (GST) catalyses the
nucleophilic addition of the thiol of GSH to electrophilic acceptors, it
is important for protecting tissues from oxidative damage. In humans,
GSTT1 and GSTM1 deletion genotypes are associated with a variety
Figure 2: Diagrammatic representation the incidence and genetic role in of ophthalmic diseases. The frequency of GSTM1 affected individuals
congenital and senile cataract formation.
was markedly increased in MT cataracts followed by NC, CC and PSC
Abbreviations: CE: Corneal Epithelium; CO: Ciliary Organ; E: Endothelium;
LC: Lens Capsule; LE: Lens Epithelium; LF: Lens Fiber; LN: Lens Nucleus; types [61].
St: Stroma.
Peroxiredoxin 6 (Prdx6) is a new family of antioxidants which
regulates gene expression and function by scavenging reactive oxygen
of connexin 50 of a valine residue with alanine at codon 44 [49]. species and protects lens epithelial cells of rat. Oxidative stress was
In cataract lenses of KO-Dp71 mice and wild-type (wt), Fort et al. found to have contributed in the formation of nuclear or cortical
reported increased incidence of cataracts with subsequent lack of cataract through a decrease of Prdx6 in cataractous lenses especially
Dp71 (dystrophin gene of Duchenne muscular dystrophy) [50]. during aging [62].
Khan et al. observed posterior cortical lenticular opacities with Nuclear transcriptional factor, NF-E2-related factor 2 (Nrf2),
over-expression of a novel missense mutation in KCNJ13 in 12-year- plays an integral role against oxidative stresses by promoting 20
old Saudi Arabian girl with nystagmus [51]. different antioxidative enzymes. Kelch-like ECH associated protein
CF1/b mouse strain (an outbred colony) reared at Osaka 1 (Keap1) targets and binds to Nrf2 for proteosomal degradation.
Prefecture University was found to develop cataracts at 14 d old in the Palsamy et al. detected significant levels of demethylated DNA in
form of vacuolated lens epithelial cells, swollen lens fibers, pyknotic the Keap1 promoter in the diabetic cataractous lenses [63]. Human
nuclei, and vacuolation of the lens cortex. Cataractous lens was lens epithelial cell lines (HLECs) treated with a demethylation agent,
found to result from autosomal recessive mutation genes in mouse 5-aza-2’deoxycytidine (5-Aza), showed 10-fold higher levels of Keap1
chromosome 16 between D16Mit5 and D16Mit92 and between mRNA, 3-fold increased levels of Keap1 protein, which enhanced the
D16Mit92 and D16Mit201 [52]. liberation of free radicals and increased cell death. Decreased Nrf2
activity depleted the transcription of many antioxidant enzyme genes
Lens syntaxin 3 gene interfered with lens protein structure and altered the redox-balance towards lens oxidation. During aging-
and function. Mutation of this gene results in the development of related cataract, there was a considerable reduction of protein and
autosomal recessive congenital cataract [53]. Inherited forms of gene expression level of nuclear transcriptional factor, NF-E2-related
cataract are characterized by mutation in the gene of cation channel factor 2 (Nrf2) in lenses. Over-expressed Keap1 protein is responsible
and member-3 (TRPM3, melastatin-2). Genome-wide linkage for decreasing Nrf2 by proteasomal degradation, thereby suppressing
analysis mapped the ocular disease locus to the pericentric region of
Nrf2-dependent stress protection. Therefore, decreased activity of
human chromosome 9 [54].
Nrf2 restrained the transcription of its downstream antioxidant
Although congenital cataracts may alter vision; sparse individuals enzyme and led to the failure of the antioxidant system; ultimately

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2015;3(2): 12.

ISSN: 2334-2838

leading to the formation of ARCs [64,65].

In experimental animals, different pathways are involved.
Transgenic mice were found to express ectopic Col4a3 and Col4a4
genes in the lens which have the capability of activating IRE1,
ATF6, and PERK associated with the expansion of the endoplasmic
reticulum and attenuated protein translation. These were associated
with damaging lens epithelium and accumulate terminally unfolded
proteins [66]. Following the study of three mice lens epithelial cells
(LECs) 17EM15, 21EM15 and αTN4, Terrell et al. reported that the
expressed genes Foxe3, Pax6, Anxa4 and Mcm4 were up-regulated
in lens epithelial cell lines (LEC), compared to lens fiber cells [67].
All the three LECs exhibited down-regulation of fiber cell-expressed
genes Crybb1, Mip and Prox1 as well as over-expressed cataract-
associated genes, such as Dkk3, Epha2, Hsf4, Jag1, Mab21l1, Meis1,
Pknox1, Pou2f1, Sfrp1, Sparc, Tdrd7 and Trpm3.
Lipid and Cataracts
Lipids are of functional importance to lens. About 172 lipid species
were identified mainly as sphingomyelins, phosphatidylcholines,
and phosphatidylethanolamines. Also, 20 phosphatidylcholines,
6 phosphatidylethanolamines, and 4 phosphatidic acids were also
detected [68]. The lens transmit light through thousands of cellular
membranes rich in phospholipids especially dihydrosphingomyelin.
Most of the lipids are associated with proteins. Sphingolipids
represent 60% of human lens and represents the main integral part
in its transparency. Lens glycolipids are composed of 4-sphingenine
(sphingosine) to which carbohydrates are bound [69] and represents
1% of the total human lens lipid but are of valuable importance for Figure 3: Diagrammatic representation the role of lipids in senile cataract
formation.
differentiation of lens epithelial cells to lens fibers [70].
Abbreviations: CE: Corneal Epithelium; CO: Ciliary Organ; E: Endothelium;
Lipids represent the main structural components of the lens LC: Lens Capsule; LE: Lens Epithelium; LF: Lens Fiber; LN: Lens Nucleus;
St: Stroma.
membranes and have profound effect on its fluidity. Cataractous lens
involves protein aggregation as a result of losing stability in protein
conformation. Age-related changes in lipid composition could be a cataractous lens when compared with marked depletion of oleic acid,
contributing factor for altered protein-lipid interaction leading to linolenic acid and docosahexaenoic acid [76].
protein aggregation and cataract formation [71]. The lens membranes Huang et al. detected increased amount of sphingolipids
exhibited three distinct lipids such as the bulk, nuclear, and trapped (dihydrosphingomyelin and sphingomyelin) compared with
lipid domain. The cholesterol bilayer was detected in the cortical and apparent depletion of glycerolipids (phosphatidylcholine and two
nuclear lens lipid membranes, and missing in the intact membranes. phosphatidylethanolamine) in cataractous lens [77].
The amount of lipids combine proteins was increased in the nuclear
than in cortical membranes facilitating rigidity of nuclear membranes Lipid peroxidation (LPO) is a pathogenic factor in cataract. It
and increasing permeability in the cortical ones [72]. includes diene conjugates, lipid hydroperoxides, oxy-derivatives of
phospholipid fatty acids and present in the lipid moieties of aqueous
Cataractous lenses were found to exhibit membrane derangement, humour and lenses of senile patients [73]. Plasma membranes of the
widespread of vacuoles and clusters of highly undulating membranes. ocular lens are rich in fiber junctions which in turn have 20-40% of
Damage of the lens fiber cell membranes impairs vision and interferes total lipid content compared with that of the total plasma membrane.
with light-scattering which causes lens opacity. Phospholipid In the bovine nucleus, the cholesterol/phospholipid molar ratio was
molecules modified by oxygen accumulate in the lipid bilayer, they markedly increased in the fiber junctional-enriched membrane than
have been found to change their geometry and impair lipid-lipid and in the total plasma membrane, suggesting a special association of
protein-lipid interactions in the lenticular fiber membranes [73]. cholesterol with bovine nuclear fiber junctions [78]. In cataractous
Human cataractous lenses contain the long chain base glycolipids human lenses, the ratio of cholesterol to phospholipid (Chol/PL)
(C18a sphingosine (sphinganine). The major fatty acids were C160, attained a considerable increase in lens membranes.
C24:l and C24:0, and monounsaturated fatty acids accounted for 40-
55% the total fatty acids [74]. Siddique et al. reported alterations of Exposure of membranes isolated from transparent human
phospholipid and protein moieties in lens fibers, disrupting function lenses to the free radical generator were found to produce 7 alpha-
and leading to cataract formation (Figure 3) [75]. hydroxycholesterol (6%), 7 beta-hydroxycholesterol (19%), 5 alpha,
6 alpha-epoxycholestanol (1%) and 7-ketocholesterol (74%) as
The content of palmitic acid showed apparent increase in

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Citation: El-Sayyad HIH, Bakr EHM, El-Ghawet HA, El-Desoky TMGE. Overview of Congenital, Senile and Metabolic Cataract . J Ocular Biol.
2015;3(2): 12.

ISSN: 2334-2838

major oxidation products. Cataractous lenses possessed moderate metabolism, protein synthesis and degradation [88].
amounts of 7 beta-hydroxycholesterol, 7-ketocholesterol, 5 alpha,
In old age, there is a marked disruption of lens disulphide protein
6 alpha-epoxycholestanol, 20 alpha-hydroxycholesterol and
aggregates and conformation which is unique to cataract. In cataracts,
25-hydroxycholesterol compared with no-detectable amounts in
60% of the methionine is bounded to the lens membrane. Most of the
clear lenses [79]. Studies have shown that cholesterol contributes
disulfide amino acids bind with glutathione to form α-crystallin via
to the impermeability of oxygen across the lens membranes [80].
oxidative changes [89]. Homozygous alpha alanine-cysteine mutant
Maintaining low levels of oxygen is important to the lens to prevent
mice, possessed apparent characteristic loss of cytological structure of
oxidation and cataract formation. One of the main function of the
lens epithelial and fiber cells such as actin filaments and mitochondria
mitochondria, present in the epithelium and outer cortical fibers [81]
(alpha, beta, and gamma classes) [90]. Alpha-A crystallin represents
is to degrade oxygen [82]. The cholesterol-related impermeability
the major protein of the lens and is composed of a mixture of cysteine
of the membranes to oxygen may help to keep oxygen in the outer
sulfhydryl and half-cysteine disulfide groups. Oxidation of cysteine
regions of the lens long enough for the mitochondria to degrade it.
sulfhydryl groups may be involved in opacification of lens [91].
The etiology of lipids in cataract formation led Deeley et al.
Crystallins are categorized in three forms α, β, and γ. The
to investigate the variation of eye lipid contents in humans and
β-crystallins remain the most elusive form due to their greater
experimental animals [83]. The authors found that the most
number of subunits and possible oligomer formations and changes
abundant phospholipids in all the lenses examined were choline-
during aging. Deamidation of β-crystallins occurred during aging in
containing phospholipids. Human lens showed wide variations
cataractous lenses and α-crystallin chaperone impaired the cataractous
of lens lipid components compared with rat, mouse, sheep, cow,
changes [92]. The cysteine is characterized by having disulfide bond
pig and chicken. Sixty six percent (66%) of the total phospholipid
with the low molecular weight thiol in the lens. The appearance of
in Homo sapiens was sphingomyelin (dihydrosphingomyelins).
gamma-Glu-Cys may be coincident with biochemical abnormalities
The abundant glycerophospholipids in human lenses were
preceding cataract formation. This protein modification may result
phosphatidylethanolamines and phosphatidylserines. Experimental
from changes in the GSH biosynthetic pathway within the lens
and domestic animals showed abundant phosphatidylcholines in their
[93,94]. In cataractous patients with or without diabetes, there were
lenses. Several neutral and acidic glycosphingolipids were observed
marked aggregations of two types, soluble and insoluble proteins.
in rat lens epithelia, cortex and nucleus. Immunohistochemical
Higher levels of m-Tyr, o-Tyr, DOPA and Phe/protein ratio were
staining revealed apparent concentration of gangliosides GM3 and
GM1 in the anterior lens epithelial cells and the cortex, with gradual
decrease toward the lens nucleus. GD3 appeared more intense in the
lens nucleus than in epithelial cells [84]. Adult rat lens were found
to have a complex ganglioside consisting of six major components
identified as GM3, GD3, GD1a, GD1b, GT1b, and GQ1b based on
their reactivity to anti-GM1. The relative concentration of GT3
in total gangliosides of the eye lens was highest among neural and
extra-neural tissues examined. Administration of streptozotocin to
rats caused a severe reduction in the GD3 content in the eye lenses
within three days prior to other gangliosides alterations [85]. Emory
mouse cataracts undergo protein oxidation by the formation of
hydrazone with 2, 4-dinitrophenyl hydrazine. The lipid oxidation
was observed from a depletion of oleic acid and over-expression of
ketoacids [86]. The relative and absolute amount of sphingolipids,
including dihydrosphingomyelin and sphingomyelin, increased with
age parallel with the development of cataractous lenses. Increased
membrane stiffness led to light-scattering, reduced calcium pump
activity, altered protein-lipid interactions, and decreased fiber cell
elongation [77].
Protein and Cataracts
The lens protein attained nearly 33% of its net weight. Crystallins
are the main protein components in the lens reaching up to 90% of total
soluble protein. Other proteins form the cytoskeletal and membrane
structure such as actin, filensin and spectrin, transporters and channel
proteins and junctional proteins. There are three distinct forms of
crystallins; α-, β- and γ-crystallins. α- and β-crystallins are present in Figure 4: Diagrammatic representation the role of protein in senile cataract
oligomers, compared with the monomer form of γ-crystallin [87]. In formation.
adults, the nucleus represents the major part of the lens. The nucleus Abbreviations: CE: Corneal Epithelium; CO: Ciliary Organ; E: Endothelium;
LC: Lens Capsule; LE: Lens Epithelium; LF: Lens Fiber; LN: Lens Nucleus;
is concerned with cell communication and many enzymes involved in St: Stroma.

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2015;3(2): 12.

ISSN: 2334-2838

markedly detected in cataract formation (Figure 4) [95]. the vitamin C concentration. Upon oxidation, vitamin C was found
to have combined with glucose to form protein glycation. The lens
Opacification of the ICR/f mutant lenses was found to be
vitamin C concentration significantly decreased with cataract severity,
accompanied by changes in crystallin structure and composition,
especially in severe brown cataracts. The peptide tryptophan content
including several deletions of the N-terminals of beta-crystallins and
was stable but the tryptophan to tyrosine ratio decreased and was
low molecular weight alpha-crystallins [96].
highly correlated to the ascorbic acid concentration [109]. Taurine
Cataractous lens proteins exhibited apparent decrease in gamma-, and total protein were detected in cataractous lenses and involved in
betaB1-, betaA3-, and betaA4-crystallin content, accompanied with altering the structural integrity and permeability of lens membrane to
some increase in alpha-crystallin (or its aggregate). Higher molecular protein and amino acids [110]. Taurine showed antioxidant capacity
weight proteins were also observed in the form of cross-linked dimers and was markedly depleted in diabetic cataract. The culture of lenses
(43 to 55 kDa) of beta-crystallins [97]. Deletions of the N-terminals in high glucose medium increased the weight and opacity of the
of beta-crystallins and low molecular weight alpha-crystallins were lenses due to increase of carbonylated protein level, and decrease of
detected in cataractous ICR/f mutant lenses [96]. Aggregation of glutathione (GSH) content [111].
chromophores and insoluble crystallin led to the formation of a
brown nuclear cataract while cortical type resulted from impairing of
Minerals and Cataract
membrane permeability and altered enzyme function [88]. Sodium & potassium
Linetsky et al. stated that ascorbic acid, but not glucose, fructose, Electrolyte balance is of vital importance to the lens transparency
ribose or erythrulose, facilitated the aggregation and glycation of calf in mammals including humans. Its permeability depends on different
lens crystallins [98]. Dipeptidyl peptidase III was markedly increased ion channels such as potassium, sodium, chloride, and calcium
in cataractous lens to an apparent 45.5-fold over that of the original channels. The ions may move across a number of electrical silent system
aqueous extract [99]. There are two forms of cataractous lenses, one such as Na+ /H+, Na+ /Ca2+ HCO3-/Cl- exchange mechanisms as well
with a low internal sodium and calcium content which behaves in a as active transporters such as Na-K-ATPase [112,113]. Na, K-ATPase
manner similar to normal lenses. Elevated level of sodium ion was activity plays an important role in maintaining the functional activity
found to be involved in alterations of amino acid accumulation, in lens. Two apparent roles of the enzyme activity were observed more
however calcium ions seem to play a critical role in the disturbance of in the epithelium than in the lens fibers. During aging, oxidation and
lens protein synthesis [100]. Water-insoluble, high molecular weight glycation of lens fibers may decrease Na, K-ATPase activity which is
protein represents the major component of human nuclear cataracts markedly detected in the nuclear region [114,115]. There is a close
[101]. association between abnormal elevation of lens sodium and the
AGEs formation resulted from oxidation reaction between opacification of the human lens cortex [116]. Aging has also led to
reducing sugars and protein which caused lens opacification. Diabetes alteration of Na/K permeability toward the center of the lens as well
showed more glycation in patients suffering from diabetes compared as impairing the functional activity of the Na-K-ATPase to hydrolyze
with non-diabetic. Pyrraline is an advanced Maillard reaction formed adenosine triphosphate [117]. Increasing extracellular K+ was found
by oxidation of glucose with lysine residues on proteins. This reaction to depolarize the lens potential, reducing and reversing the magnitude
involves an intermediate metabolite, 3-deoxyglucosone which is of the net current densities around the lens [118].
markedly increased in diabetic lenses [38,102]. There are two forms of cataractous lenses, one with a low internal
Lens proteins possessed the higher levels of dideoxyosones sodium and calcium content behaving in a similar manner to normal
(DDOs): intermediates in the synthesis of advanced glycation lenses, and the other with high sodium and calcium contents which
endproducts (AGEs), such as pentosidine and glucosepane [103]. showed a markedly reduced ability to accumulate amino acid and
Deamidation of glutamine and asparagine residues was observed in synthesized low molecular weight protein. Sodium ion was found
older lenses [104]. to be involved in alterations of amino acid accumulation, however
calcium ions seems to play a critical role in the disturbance of lens
One of the possible roles of inducing lenticular diabetic cataract is
protein synthesis and also protein-protein interaction [119].
the capability of glycated proteins producing reactive oxygen species
(ROS), which oxidized tryptophan (Trp) into kynurenines [105,106]. Magnesium
There were marked differences in the amounts of oxindolealanine
Magnesium represents one of the main elements in regulating
(OIA, tryptophan oxidation product) in the nucleus versus the cortex
the lens function. It maintains the function of more than 350 enzymes
in human cataractous lenses [107]. Lenticular levels of Indoleamine
by regulating the intracellular ionic environment of the body ATPase.
2, 3-dioxygenase (IDO) activity, IDO mRNA, IFN-gamma mRNA,
Its deficiency led to impairments of ATPase functions leading to
oxidize tryptophan (Trp) and kynurenic acid (KYNA) increased
marked increased of intracellular calcium and sodium and decrease
significantly in 60 days diabetic rats [106]. Histidinoalanine and
intracellular potassium concentration and development of cataract.
lanthionine were the most abundant dehydroalanine crosslinks in
Consequently, magnesium deficiency has also contributed to the
both water-soluble and -insoluble lens proteins in cataractous lenses
increase of oxidative stress and inducible NOS stimulation that can
of Indian patients [108].
initiate the progress of cataract, glaucoma and diabetic retinopathy
Another view of cataract formation is believed to have resulted [120,121].
from a decrease in the antioxidant defense of the lens, particularly
Zinc

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2015;3(2): 12.

ISSN: 2334-2838

Zinc plays an integral role in maintaining normal ocular function. cell structures [134]. Abnormal metabolism of Zn, Cu and Fe may
The zinc content of human lenses was significantly elevated in mature be influenced in diabetic complications [134], especially Cu which
cataracts compared to cortico-nuclear cataracts. The increase of the reached a high peak in the blood of diabetic patients [135] compared
lens zinc content was markedly increased with the change in lens with low peak of zinc [136,137] and iron [138].
coloration from light to dark brown colouration. Diabetic patients
Iron was found to have contributed in ocular diseases, including
were found to show both increased zinc and iron contents in the lens.
glaucoma, cataract, AMD, and intraocular hemorrhage [139].
Zinc and iron were markedly increased in cataractous lenses [122]. Numerous genes encoding proteins involved in iron transport and
Lens opacification in diabetic patient was found to possess homeostasis are promoted by hypoxia inducible factor. Low oxygen
increased level of Cu content than Zn and Fe content [123]. Patients level was found to stimulate the lens epithelial cells (LEC) to trap the
with either pseudoexfoliative or senile cataract showed increased cytosolic iron and increased the risk of iron inducing the formation of
serum level of both iron and copper [124]. reactive oxygen species (ROS) and oxidative cell damage [140].

α-Crystallin, is a member of the small heat shock protein Diabetic cataractous lenses of rats were found to possess increased
family present in the mammalian lens. The stability of α-crystallin level of Zn and Fe and decreased level of K [141]. In senile cataractous
is increased in the presence of Zn(2+). H79, H107 and H115 of αA- lenses, Fe, Al, Zn and Ca levels were markedly increased. The calcium/
crystallin and H104, H111 and H119 of αB-crystallin are identified phosphorous ratio was 50 times (1:0.02) greater than in clear lenses
as the Zn(2+) binding residues [125]. Development of lens opacities [142]. Senile cataractous lenses were found to possess elevated level of
was associated with lack of copper-zinc superoxide dismutase which nickel and iron with concomitant depletion of chromium, manganese
participated in an antioxidant capacity [126]. and aluminum, the promoter of cataract formation [143]. Li et al.
detected degenerated lens fibers in nuclear cataract associated with
There is a close association between mineral and antioxidant
aggregation of gamma-crystallin in lens fibers lacking actin filaments
defense. Cataractous lens possessed a decrease of Cu/Zn- and Mn-
and increased calcium concentration of homozygous mutant mouse
SOD activity and Cu/Zn-SOD transcript. The decrease of superoxide
[144].
dismutase activity in cataractous lenses was associated with the
decreased level of mRNA transcripts and their protein expression Calcium
[127].
Calcium plays a great role in large numbers of cellular regulatory
Iron pathways. The transmembrane influx of Ca(2+) through Ca(v)
channels has contributed to the biological function of human lens
Iron (Fe) is an essential trace element for ocular homeostasis.
epithelium [145].
It was found to play a great role in regulating L-cystine uptake and
consequently promoting the activity of aconitase in production of Ca(2+)-ATPase activity was approximately 50% less in membranes
glutathione in lens epithelium and retinal pigmented epithelium prepared from cataractous lenses in comparison to clear lenses [146].
that led to elevation of the antioxidative capacity against oxidative Marian et al. reported that the increased calcium concentration in
stress [128]. During the development of lens epithelial cells into cataractous lens was attributed to the increase of calcium-ATPase
lens fiber, both ferritin H and L chains were altered with increase expression in its plasma membrane [147]. Activation of Ca-dependent
in the mass of lens fiber [129]. Iron pathway may occurred through enzymes may cause irreversible breakdown of structural proteins and
different mechanisms; (i) iron is actively transmitted from the retina apparent cell death of lens cells [148].
to the aqueous humor by a ferroportin/ferroxidase-mediated process
Excessive levels of Ca2+ in human lenses with cortical cataract
through Müller cells, (ii) binding of iron with vitreal transferrin and
have been found to play a major role in the opacification process. Ca2
then diffusing towards the lens, (iii) Incorporation of iron/ transferrin
attained 10,000 fold increase in human aqueous humour inwardly
complex with lens extracellular space and infiltrated into the
directed gradient across the plasma membrane and these are needed
epithelial-fiber interface, (iv) iron/transferrin complex is endocytosed
to maintain reduction. Both Na/Ca2 exchanger (NCX) and plasma
by epithelial cells and drained with the aqueous humor into systemic
membrane Ca2-ATPase (PMCA) actively remove Ca2 from the
blood circulation for recycling [130].
cells, whereas in endoplasmic reticulum, the Ca2-ATPase (SERCA)
Transferrin and Fe concentrations were found to be increased in the facilitated the storage of Ca++. Adenosine triphosphatase was found to
intraocular fluids during inflammation and pathological conditions. be more active in lens epithelial cells compared with that of NCX in
There was a close relationship between the amount of Fe-transferrin fiber cells. Activation of these channels may lead to a rapid increase
and development of cataractous lenses [131]. The ferritin levels in the in pathological calcium overload which facilitates the formation of
cataractous lens nuclei appeared to be markedly increased than that of cataract [149]. Plasma membrane calcium ATPase (PMCA) mRNA
the cortex due to the presence of ferritin within an insoluble protein and protein levels attained a considerable higher level in cataractous
fraction of the homogenized lenses. Both nuclei and cortices showed lens which might be a compensatory mechanism to overcome
heavily redox-active metals staining [132]. Hyperferritinemia cataract increased intracellular calcium levels [147]. Chen et al. observed ATP-
formation was found to result from a mutation in the L-ferritin gene binding cassette protein (ABCA3) in human lens capsule, choroid-
(C33T) which interferes with function of the L-ferritin transcript in retinal pigment epithelium and retinal pigment epithelial cells [150].
an RNA gel shift assay [133]. Mutation of ABCA3 protein was found to be associated with cataract-
microcornea syndrome.
Cu and Fe lacking a non protein-binding condition, initiate the
liberation of reactive oxygen species, thereby affecting tissue and Lenticular copper, lead, cadmium and calcium levels were

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Citation: El-Sayyad HIH, Bakr EHM, El-Ghawet HA, El-Desoky TMGE. Overview of Congenital, Senile and Metabolic Cataract . J Ocular Biol.
2015;3(2): 12.

ISSN: 2334-2838

markedly increased in cataractous human lenses especially in superoxide dismutase and glutathione peroxidase in the nuclear
males. Cataract formation in diabetic patients possessed a higher cataract of human, calf, rabbit and rat lenses [165]. Cataract formation
concentration of copper which coincides with copper-containing is believed to be attributed to oxidative stress and reduction of the
superoxide dismutase and liberation of free radicals. Increased copper antioxidant defense, especially vitamin C concentration. Vitamin C
ions were attributed to its release from copper-containing enzymes was found to initiate glucose to protein glycation. Lens vitamin C
affected by oxidative stress of hyperglycaemia and free radicals [151]. concentration attained marked depletion in severe brown cataracts
(88 mumol/100 g lens in mild cataracts, and 50 mumol/100 g in dark
Maintenance of calcium homeostasis is important for the clarity
brown lenses) [109].
of the lens. Ca(2+)-ATPase play a great role for the removal of cytosolic
calcium, either across the plasma membrane or through intracellular There was a detected reduction of the blood antioxidant redox
organelles such as the endoplasmic reticulum. The activity of Ca(2+)- chain and increase of thiobarbituric acid was found to be indicator
ATPase reached approximately 50% in membranes prepared from of cataractous lenses in diabetic [166] and senile cataractous patients
nuclear subcapsular, nuclear and brunescent cataracts [146]. [167-169]. Jain and Bulakh confirmed similar findings of depletion
in glutathione peroxidase and increase of thiobarbituric acid in
The lenticular Ca2+ was found to be maintained by either plasma
cataractous lenses [170].
membrane Ca2+ pumps [152], or plasma membrane Na+:Ca2+
exchangers [153], and endoplasmic reticulum Ca2+ pumps [152]. Lipid peroxidation (LPO) represent the main cause of cataract
Cataractous lenses as a result of increased calcium concentration formation, initiated by enhanced production of oxygen free radicals
were observed in 14 out of 406 affected human lenses [154]. Odeigah in the eye fluids and tissues and inhibited antioxidant enzymatic
and Patmore detected epithelial hyperplasia in cataractous lens of and non-enzymatic defenses of the lens. The LPO products (diene
HY-1 genotype chick lenses and attributed it to the increased calcium conjugates, lipid hydroperoxides) and end products of fluorescent
binding capacity and elevated sialic acid [155]. Kuck and Kuck LPO were markedly detected in the aqueous humor samples of
mentioned that mouse cataract was different from human senile cataractous patients [171]. Lipid peroxidation led to degradation of
cataracts due to invariable accumulation of calcium depending on the the double bonds of unsaturated membrane hydrocarbon and altered
severity of cataract formation [156]. the carbonyl and phosphate-oxygen sites of the fiber cell membranes
[172]. These oxidative damages initiated in the absence of antioxidant
Cataractous lenses possessed abnormal intracellular ionic
defense [173].
environment associated with increased levels of calcium (Ca2+),
sodium (Na+), magnesium (Mg2+) and potassium (K+), Mg2+ deficiency The formation of cataract is believed to have resulted from an
was found to enhances nitrous oxide production via inducible nitric oxidative insult which decreases the antioxidant defense of the lens,
oxide synthase in the lens and accelerate the progression of lens especially vitamin C. The lens vitamin C concentration significantly
opacification [157,158]. Increased calcium ions in cataract [159], may decreased with cataract severity, but mostly in severe brown cataracts
activate calpain and transglutaminase, the markers of cataracts [160]. [109].
Lenticular cataracts were found to exhibit abnormal intracellular The authors finally concluded that both congenital and senile
ions including increased level of calcium and sodium and depletion cataractous lenses resulted from multifactorial agents included
of magnesium and potassium. These were associated with a decrease genetic, biochemical transformations and alterations in antioxidant
of ATP and adenosine triphosphatase activity as well as increase of defences
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