Cataracts have multiple causes but are often associated with breakdown of the lens microarchitecture,^7–9 possibly including vacuole formation, which can cause large fluctuations in density resulting in light scattering. In addition, light scattering and opacity occur if there is a significant amount of high-molecular-weight protein aggregates of 1000 Å or more.^10,11 The short-range ordered packing of the crystallins is important in this regard. For transparency, crystallins must exist in a homogeneous phase. The physical basis of lens transparency can be complex and has been reviewed elsewhere.^3,10–12

Hereditary cataract may be inherited as autosomal dominant (most common), autosomal recessive, or X-linked trait. Phenotypically identical cataracts can result from mutations at different genetic loci and may have different inheritance patterns, whereas phenotypically variable cataracts can be found in a single large family.¹⁵ Linkage analysis is a powerful tool to sort out the different genetic loci that can cause human cataracts. Linkage studies emphasize the genetic heterogeneity of autosomal dominant congenital cataracts. Although the number of known cataract loci has increased dramatically in the last few years, it has been estimated that there are as many as 30 loci that can cause autosomal dominant cataracts in humans.¹⁶ Obviously, much work remains to be done in understanding inherited congenital cataracts.

The human lens is first anatomically visible at 3 to 4 weeks of gestation.¹⁹ The surface ectoderm over the eye field thickens into the lens placode, then invaginates toward the developing optic cup, forming the lens pit. The lens pit closes and the resulting lens vesicle pinches off from the surface ectoderm.¹⁹ By the seventh week of development, cells forming the posterior layer of the optic vesicle begin to elongate and fill in the vesicle, losing their nuclei. These become the primary fiber cells forming the embryonic lens nucleus.¹⁹ The remaining cells form the cuboidal anterior epithelium; some of them will divide, move laterally along the lens capsule, and differentiate into secondary fibers²⁰ (Fig. 1). Although developmental control of lens differentiation is not yet well understood, Pax-6, Rx, and several additional growth factors seem important for lens development.^21–25 Mutations in Pax-6 are associated with aniridia, which is often accompanied by cataracts.²⁶ Six3, a vertebrate homologue of the Drosophila sine-oculis gene, can induce lens formation as well,²⁷ and targeted deletion of Sox1 results in microphthalmia and cataract with failure of lens fiber cells to elongate.²⁸ Pitx3, a member of the RIEG/Ptx gene family, is expressed in the developing lens vesicle.²⁹ A hereditary congenital cataract, associated in some cases with the developmental abnormality anterior segment mesenchymal dysgenesis, can result from mutations in the PITX3 gene.¹⁴

The lens has a single layer of anterior epithelial cells overlying the fiber cells wrapped onion-like around the lens nucleus.³⁰ Cell division occurs in the germinative zone just anterior to the equator, and the cells then move laterally toward the equator, where the anterior epithelial cells begin to form secondary fibers. Both the anterior epithelial cells and fiber cells contain large amounts of crystallins. The anterior epithelial cells of the lens are connected by gap junctions,³¹ allowing exchange of low-molecular-weight metabolites and ions, but have few or no tight junctions (zonula occludens) that would seal the extracellular spaces to low-molecular-weight proteins and ions.^32,33 Ultrastructurally, anterior cuboidal epithelial cells are rich in organelles and contain large amounts of actin, myosin, vimentin, microtubules, spectrin, and α-actinin, which should stabilize them during accommodation.^34–36 Differentiating lens fiber cells lose their organelles, including the mitochondria, Golgi bodies, and both rough and smooth endoplasmic reticulum. As the cells elongate, they move toward the lens nucleus. There is little extracellular space between the fiber cells, which have many interdigi-tations.^20,30 Adjacent fiber cells are connected by many junctional complexes, allowing intercellular passage of metabolites.^35,36

The major soluble components of fiber cells are the lens crystallins, which make up about 90% of the water-soluble protein, and cytoskeletal components, including actin, myosin, vimentin, α-actinin, and microtubules.³⁷ During this process, it seems clear that transcriptional control plays a significant role in the differential synthesis of lens crystallins.³⁸ The distributions of the β-crystallins in chickens^39,40 and the β- and β-crystallins in rats^41,42 provide examples of the spatial and temporal control of crystallin gene expression during lens development.

Defined by age at onset, a congenital or infantile cataract is visible in the first year of life, a juvenile cataract occurs in the first decade of life, a presenile cataract occurs before the age of 45 years, and the so-called senile or age-related cataract occurs thereafter. The age of onset of a cataract does not necessarily indicate its cause. Congenital cataracts may be hereditary or secondary to a noxious intrauterine event. Cataracts associated with a systemic or genetic disease may not occur until the second or third decade (e.g., cataracts associated with retinitis pigmentosa). Even age-related cataract, thought to be due to multiple insults accumulated over many years, have a genetic component, making certain persons more vulnerable to the environmental insults.

Several classification systems have been developed based on the anatomic location of the opacity. In an attempt to deal with congenital cataract, Merin⁴³ proposed a system based on morphologic classification: the cataract is classified as total (mature or complete), polar (anterior or posterior), zonular (nuclear, lamellar, sutural), and capsular or membranous.

Because, as discussed above, lens development follows a well-documented timed sequence, the location of a lens opacity provides information about the time at which the pathologic process intervened, thereby helping to determine the cause. Nuclear opacities from the most central region outward denote cataract formation occurring at the time of the development of that portion of the involved lens nucleus—embryonic (first 3 months), fetal (third to eighth month), infantile (after birth), or adult. Because the lens fibers are laid down constantly throughout life, lens opacities that develop postnatally present as cortical opacities or appear just beneath the posterior lens capsule as subcapsular opacities—for example, cataracts caused by topical steroid drugs and radiation.

Polar opacities involve either the anterior or posterior pole of the lens and may include the posterior subcapsular lens cortex extending to the lens capsule (Fig. 2). Posterior subcapsular cataracts can also occur secondary to a variety of insults. Although they have been associated with proliferation of dysplastic bladder-like fiber cells called Wedl cells, at least some posterior subcapsular cataracts appear to be due to abnormalities of the posterior fiber ends.⁴⁴ When both anterior and posterior poles are involved, the term bipolar is used. Isolated anterior polar cataracts are usually small, bilateral, and nonprogressive and do not impair vision. They may be inherited as an autosomal dominant trait⁴⁵ or may be associated with microphthalmos, persistent pupillary membrane, or anterior lenticonus. Posterior polar cataracts also may be inherited as a dominant trait⁴⁶ or may be sporadic and unilateral; they can be associated with abnormalities of the posterior capsule, including lentiglobus or lenticonus, or with remnants of the tunica vasculosa. Although usually stable over time, they may progress and can be associated with capsular fragility.

Nuclear cataracts show opacities in the fetal or fetal and embryonic lens nucleus (Fig. 3). They can show a wide variation in severity, from dense opaci-ties involving the entire nucleus to pulverulent (or dusty-appearing) cataracts involving only the central nucleus or discrete layers (see below).

Lamellar cataracts (see Fig. 3) affect lens fibers that are formed at the same time, resulting in a shell-like opacity at the level at which the fibers were laid down at the time of the presumed insult. They are the most common type of congenital cataract and may be inherited in a dominant fashion.^47–52 Some cataracts have associated arcuate opacities in the cortex called cortical riders.

Sutural or stellate cataracts (Fig. 4) affect the regions of the fetal nucleus on which the ends (or feet) of the lens fibers converge, called the Y sutures. These are visible by slit-lamp biomicroscopy as an upright Y anteriorly and an inverted Y posteriorly, even in normal lenses. Theories of cataract development⁵³ suggest that abnormalities in lens fiber development or maturation may predispose to cataract development later in life. This is supported by examples in animals (the Philly mouse) and in humans (gyrate atrophy).⁵⁴ Sutural cataracts can also be inherited as autosomal dominant traits.⁴⁷ Cerulean or blue dot cataracts are characterized by numerous small bluish opacities in the cortical and nuclear areas of the lens.⁵²

Mature or total cataracts may represent a late stage of any of the above types of cataract, in which the entire lens is opacified (Fig. 5). Membranous cataracts result from resorption of lens proteins, often from a traumatized lens, with resulting fusion of the anterior and posterior lens capsules to form a dense white membrane. They usually cause severe loss of vision.

LENS CRYSTALLINS

Crystallins can be defined as proteins that are found in high concentration in the lens. They make up more than 90% of the water-soluble lens protein and fulfill a critical structural role for transparency and refraction.¹⁸ Classically, the ubiquitous crystallins, found in all species, can be separated into three soluble and one insoluble fraction.⁵⁵ The soluble fractions are the α-, β-, and γ-crystallins, found in all vertebrate lenses. In the mature human lens α-crystallins make up 40%, β-crystallins 35%, and γ-crystallins 25% of total crystallin protein. The β- and γ-crystallins show sequence and tertiary structure homology and form the βγ-superfamily (see below).

α-CRYSTALLINS

The α-crystallins are products of two similar genes, αA- and αB-crystallin. The sequences of human αA- and αB-crystallins are 57% identical,^56–58 with αA-crystallin containing 173 and αB-crystallin 175 residues; both have a predominantly β-sheet structure.⁵⁹ Native α-crystallins exist in the lens as globular complexes ranging from 300 to 1200 kDa. Currently, the most favored structural⁶⁰ model proposes that the α-crystallin aggregate behaves as a protein micelle.^61,62 It can be shown that αA and αB occupy equivalent and dynamic positions in the aggregate, with subunit exchange occurring easily.^62–65 Cryoelectron microscopy has shown that recombinant αB-crystallin has a hollow central core surrounded by a protein shell with variable monomer packing.⁶⁶ Although αA-, αB-, and even αA_ins-crystallins appear to occupy equivalent positions in the α-crystallin aggregate,^62,63 they are expressed in different tissues, have radically different effects in knockout mice,^67,68 and differ in their phosphorylation,^69,70 structural properties,⁷¹ and chaperone functions,⁷¹ suggesting that each fulfills a unique role in the lens.

Both αA- and αB-crystallin can function as molecular chaperones in that they can protect both β- and γ-crystallins and enzymes from thermal aggregation. However, they do not cycle these proteins in the manner of true chaperones.^72,73 The chaperone function of the α-crystallins probably serves to protect lens proteins from denaturing with age and could explain their presence in nonlenticular tissues. It involves the C-terminal domain of the protein,⁷⁴ which participates in structural transitions resulting in the appropriate placement of hydrophobic surfaces in a multimeric molten globular state.⁷⁵ The chaperone function of the α-crystallins should serve to protect against cataractogenesis by reducing the aggregation of partially denatured proteins that accumulate in the lens during aging. αB-Crystallin and to a lesser extent αA-crystallin are expressed in tissues outside the lens.⁷⁶ Thus, the α-crystallins are similar to enzyme-crystallins and may have important metabolic functions in the lens and other tissues.

Mutant or absent α-crystallins have been associated with inherited cataracts. An autosomal dominant congenital zonular nuclear cataract that can progress to include cortical and posterior subcapsular opacities in adults maps to the αA-crystallin region on chromosome 21q22.3 (Table 1).⁷⁷ These are associated with a sequence change in αA-crystallin substituting a cysteine for an arginine (R120C), which is invariant in α-crystallins in mammals, chickens, and frogs. This results in αA-crystallin with an irregular structure and defective chaperone-like function.^77a When this arginine is changed to glycine in αB-crystallin (R120G), it forms large aggregates with desmin in smooth muscle cells, causing a severe myopathy associated with cataracts.⁷⁸ This is reminiscent of the behavior of αB-crystallin in αA-crystallin knockout mice,⁶⁷ whereas αB-crystallin knockout mice develop a late-onset fatal myopathy without cataracts.⁶⁸

TABLE 1. Chromosomal Location of Human Ubiquitous Crystallin Genes

βγ-CRYSTALLINS

The β- and γ-crystallins are antigenically distinct but are members of a related βγ-crystallin superfamily, as determined by sequence conservation of 30%⁷⁹ and conserved tertiary structure of their central globular domains.^80,81 They differ with respect to their developmental expression and association of the β- but not the γ-crystallins into macromolecular complexes.

γ-CRYSTALLINS

The γ-crystallins have molecular weights of about 21 kDa and show the highest symmetry of any crystallized protein, which may contribute to their high stability in the lens. The structures of γB-, γD-, γE-, and γF-crystallin have been determined and are very similar.^82–85 The amino acids of the core domains are arranged into four repeated segments called Greek key motifs. Each Greek key motif consists of an extremely stable, torqued β-pleated sheet resembling the characteristic pattern found on classical Greek pottery.⁸² The first and second motifs are in the N-terminal domain, and the third and fourth motifs are in the C-terminal domain of the protein.

The γ-crystallins accumulate specifically in the lens fibers and are the predominant crystallins in the lens nucleus, which maintains the highest protein concentration and is the least hydrated section of the lens. Thus, γ-crystallins appear especially adapted for high-density molecular packing.⁸⁴ γ-Crystallins can be subdivided into two groups: γABC- and γDEF-crystallins.^86,87 Proteins in the latter group have higher critical temperatures for phase separation and are largely responsible for the occurrence of the “cold cataract,”⁸⁸ a reversible opacity that occurs on cooling of the lens.⁸⁵ βγ-Crystallins appear distantly related to protein S, a sporulation-specific protein of the bacteria Myxococcus xanthus, to spherulin 3a of the slime mold Physarum polycephalum,⁸⁹ to CRBG-GEOCY of the sponge Geodia cydonium,⁹⁰ and to A1M1, a tumor suppressor gene.⁹¹ These microbial proteins can be induced by physiologic stresses such as osmotic stress,⁸⁹ providing a functional parallel to the α-crystallins and some taxon-specific crystallins (see below).

γS-crystallin (formerly called βS-) represents a link between the β- and γ-crystallins.^92–95 Many physical and chemical properties of the γS protein resemble those of β-crystallins.^96,97 γS-Crystallin is also expressed later in development than the other γ-crystallins, especially in the adult, when expression of other γ-crystallins is low or has ceased,⁹⁸ and is expressed in birds and reptiles.^99,100 However, in contrast to the β-crystallins and like the other γ-crystallins, γS-crystallin exists in solution as a monomeric protein. It is especially important that the gene structure of γS-crystallin has three exons,^93,94 making it similar to the other γ-crystallins and distinctly different from the β-crystallins, which are encoded by genes with six exons.^18,81 However, although most γ-crystallin genes are clustered on chromosome 2, the γS-crystallin gene is found alone on chromosome 3 (see Table 1).

The Coppock-like cataract, an autosomal dominant pulverulent nuclear or nuclear lamellar cataract, is associated with a T4P mutation in γC-crystallin,¹⁰¹ whereas another autosomal dominant nuclear or nuclear lamellar cataract of severity varying from asymptomatic pulverulent to a total cataract with blindness is associated with a 5-base insertion in the first Greek key motif.¹⁰² A fetal nuclear needle-like aculeiform cataract is associated with an R58H mutation in γD-crystallin,¹⁰¹ and a dominant cataract first appearing in the first year of life progressing to total cataract in childhood is associated with an R14C mutation on the surface of γD-crystallin. An interesting congenital cataract consisting of crystallized γD-crystallin in lens fiber cells results from an R36S mutation in this molecule.¹⁰³ The last two cataracts suggest that cataracts can result not only from mutations affecting the stability and tertiary structure of γ-crystallins but also from surface changes affecting their association.

β-CRYSTALLINS

β-Crystallins are divided into two groups, with the acidic (βA2-, βA1/A3-, and βA4-) crystallins having lower isoelectric points than the basic (βB1-, βB2-, and βB3-) crystallins,⁸¹ although the isoelectric points of both are slightly above neutral. Each β-crystallin protein is encoded by a separate gene, except for the βA3- and βA1-polypeptides, which can originate from separate AUG translation initiation codons on the same mRNA.¹⁸ The β-crystallin polypeptides range from about 23 to 32 kDa. Amino acid sequences of the globular domains of the β-crystallins are about 45% to 60% identical with each other and about 30% identical with sequences of β-crystallins.^18,104,105 The N- and C-terminal arms are much less well conserved than the globular core, usually showing about 30% sequence similarity to the arms of orthologous β-crystallins.^104–106 Basic β-crystallins have both N- and C-terminal arms, whereas acidic β-crystallins have only N-terminal arms. The β-crystallins may undergo post-translational modification, including proteolytic cleavage of βB1,¹⁰⁷ phosphorylation of βB2 and βB3,^108,109 and glycosylation of βB1.¹¹⁰

In a fashion similar to the α-crystallins, both the β- and γ-crystallins have been shown to be expressed in nonlens tissue. β-Crystallin mRNAs and peptides have been detected in a variety of nonlens tissues, including chicken retina, cornea, brain, and kidney,¹¹¹ and mouse^112,113 and cat^112,114 retina. γ- and βA4-Crystallins were detected in nonlens tissues in Xenopus development,^115,116 bovine cornea, and mouse retina.¹¹⁷ Nonlens expression of the βγcrystallins suggests that they might have nonrefractive functions similar to the α-crystallins. Although this is unclear, βB2-crystallin does appear to have autokinase activity.¹¹⁴

Mutations in β-crystallins have also been implicated in human cataracts.¹¹⁸ A locus for nuclear lamellar cataracts with sutural opacities has been mapped to chromosome 17q11-q12 (see Table 1)¹¹⁹ and is associated with a splice mutation in the third exon of βA3A1-crystallin.¹²⁰ This is predicted to cause truncation of the mutant βA3-crystallin after the first two Greek key motifs, essentially leaving the amino terminal arm and the two Greek key motifs of the carboxy domain. Autosomal dominant congenital cataracts in a second family map to a wide but overlapping region of chromosome 17.¹²¹ Autosomal dominant congenital cerulean cataracts show linkage with markers on chromosome 22q and are associated with a chain termination mutation in βB2-crystallin at the beginning of exon 6, which would result in absence of the fourth Greek key motif.¹²²

TAXON-SPECIFIC CRYSTALLINS

Taxon-specific crystallins, also called enzyme-crystallins, are proteins that occur in the lens at a high concentration (usually 10% or more of the protein) but are present in only one, or more generally a few, species.¹⁸ Many taxon-specific crystallins appear to have arisen by a process called gene-sharing in which a single gene product acquires an additional function without duplication, often retaining its original function in nonlens tissues.^123–126 When a single gene product is used for two separate functions, it becomes subject to double evolutionary selection. In gene sharing, a mutation in a regulatory sequence resulting in a change in gene expression may lead to a new function for the encoded protein without gene duplication and while it maintains its original function. Gene duplication and specialization of function for one or both proteins may occur later, as appears to have happened with the α- and δ-crystallins.¹²⁵

Proteins that serve as taxon-specific crystallins in other organisms are expressed in humans, but it remains unclear whether they function as crystallins or whether mutations in this interesting group of proteins would cause cataracts. For example, the locus for the CCV (Volkmann) cataract, which has variable progressive central and zonular nuclear and sutural morphology, maps to a region of chromosome 1p34-p36 including τ-crystallin,⁴⁷ although that gene is not expressed at high levels in the human lens. Recent reviews of enzyme-crystallins are available.¹²⁶

MEMBRANE PROTEINS

Approximately 2% of lens proteins with a wide range of molecular masses, ranging from 10 to more than 250 kDa, are associated with membranes. They include cytoskeletal components, such as N-cadherin, a 135-kDa intrinsic membrane protein that may be involved in cell-cell adhesion.¹²⁷ Neural cell adhesion molecule 2 (NCAM 2) has been implicated in cell adhesion and contributes to the appropriate arrangement of gap junctions in developing lens fiber cells.¹²⁸ The calpactins are extrinsic membrane proteins attached to the membrane through calcium and are probably involved in membrane-cytoskeleton interactions.^35,36 Other membrane proteins are enzymes such as glyceraldehyde 3-phosphate dehydrogenase and other glycolytic enzymes on the endoplasmic reticulum¹²⁹ and a variety of ATPases. There are also intrinsic membrane proteins specific to lens fiber cells whose functions remain unknown—for example, a 17- to 19-kDa protein.¹³⁰ Several membrane proteins have been implicated in cataracts, either in humans or natural or engineered animal models.

The most abundant membrane protein of the lens is intrinsic membrane protein 26 (MP26, MIP). It is a lens-specific single polypeptide with a molecular mass of 28,200 kDa (263 residues) that makes up about 50% of the lens membrane protein.^35,36,131 MP26 is a member of the aquaporin (AQP) family, members of which transport small molecules such as water and glycerol.^132,133 The AQP1 monomer is composed of six membrane-spanning, tilted α-helices that form a barrel that encloses a water-selective channel.¹³⁴ The genes for both AQP2 and MP26 are on chromosome 12q13.¹³⁵ Circular dichroism studies show that about half of MP26 is an α-helix. The deduced amino acid sequence¹³⁶ and known tetramer structure of MP26137 have allowed construction of a model suggesting that MP26 forms α-helical coils that traverse the membrane six times, similar to AQP1. The C- and N-terminals are both on the cytoplasmic side, consistent with a possible role for MP26 as a junctional protein.¹³⁷

Electron microscopic immunocytochemistry suggests that MP26 occurs in junctional complexes of lens fiber cell plasma membranes but not in the anterior lens epithelia or nonlens cell membranes.^138,139 It is found in thin (11 to 13 nm) junctions in single membranes as well as between cells, suggesting that it may form channels to the extracellular space rather than intercellular channels, as do the connexins. MP26 also forms channels permeable to ions and other small molecules in liposomes and artificial membrane systems.^140–143 MP26 may bind calmodulin.¹⁴⁴ It is a substrate of endogenous protein kinase,^137,145 raising the possibility that metabolic control of its structure has functional significance. In addition, MP26 is palmitoylated, as is its degradation product MP22.¹⁴⁶ A locus for autosomal dominant cataracts has been mapped to chromosome 12q12-14.1 near the MIP gene.¹⁴⁷

GAP JUNCTION PROTEINS

Because the lens is avascular, it must depend on intercellular junctions for nutrition and cell-to-cell communication. The thick, 16- to 17-nm junctions may be the lens equivalent of the gap junctions found in other tissues, containing connexins in homomeric or heteromeric combinations.¹⁴⁸ Lens junctions contain the intrinsic membrane protein connexin 50, also called gap membrane channel protein alpha-8 (Gja8) or MP70. A member of the connexin family,^{138,148–150} connexin 50 is most prevalent in outer cortical fibers, where it undergoes age-related degradation to MP38, which continues in functional gap junctions.¹⁵¹ It is also phosphorylated by a specific membrane-associated kinase.^152,153 Connexin 50, connexin 37, and connexin 40 are all encoded by genes consisting of a single exon on chromosome 1q21.1.^154,155

Aberrations in two connexins have been implicated in inherited human cataract. The autosomal dominant lamellar (central pulverulent) cataract originally described by Nettleship and Ogilvie in 1906¹⁵⁶ was linked to the Duffy locus on chromosome 1q21-q25 by Renwick and Lawler.⁴⁸ It is associated with a C→T transition in codon 88 of connexin 50 (GJA8),¹⁵⁷ resulting in substitution of a serine for a highly conserved proline residue. A zonular pulverulent cataract has been localized to chromosome 13 near the connexin 46 (gap junction α3) gene.⁵⁰ It was shown to be associated with an A→G transition at nucleotide 188 of this gene, resulting in a nonconservative N63S substitution in the first extracellular loop (E1), which mediates intermembrane coupling of connexin hexamers to form gap junction channels.¹⁵⁸ A second family with punctate cataracts mapping to the same region were shown to have a C inserted at nucleotide 1137, resulting in a frameshift with substitution of 87 aberrant and apparently random amino acids for the 31 amino acids of the normal carboxy terminus. Disruption of connexins 46 and 50 is predicted to result in defects in membrane targeting and junctional permeability. Absence of or mutations similar to those described here in connexin 46 and connexin 50 have been associated with cataracts in mice.^159,160

CYTOSKELETAL PROTEINS

Many cytoskeletal proteins found in the lens, including actin, ankyrin, myosin, vimentin, spectrin, and α-actinin, are also found in other tissues. It is likely that a complex network of proteins immediately below the cell membrane similar to that in erythrocytes¹⁶¹ helps to remodel and control the shapes of differentiating fiber cells of the lens cortex. Microtubules containing α- and β-tubulins are arrayed lengthwise in the peripheral cytoplasm in cortical fiber cells and are rare in nuclear fiber cells and epithelial cells.¹⁶² Microtubules may maintain the elongated shape of fiber cells and may be involved in nuclear migration in dividing lens epithelial cells.¹⁶³

Actin filaments, which are closely associated with lens cell membranes,^164,165 may effect accommodation.^30,166,167 Lens microfilaments, also called thin filaments, contain nonmuscle β- and γ-actins.¹⁶⁸ These actin filaments may interact with intercellular junctions.^169,170 Tropomodulin and α-actinin also interact with actin in microfilaments, especially in elongating cortical fibers.^171,172

Vimentin usually occurs in mesenchymally derived cells but also forms the intermediate filament in lens epithelia.¹⁷³ These 10-nm filaments, which can be highly phosphorylated,¹⁷⁴ can occur as extrinsic membrane proteins but are more commonly found in the cytoplasm.³⁴ Although expressed primarily in lens epithelial cells, some vimentin is also expressed in superficial cortical cells. Deeper in the lens cortex, vimentin-containing filaments are replaced by filaments containing CP49.¹⁷⁵ Vimentin expression increases approximately threefold during embryonic chicken lens development and then decreases after hatching.^176,177 Glial fibrillary acidic protein (GFAP), an intermediate filament protein usually seen in cells of neuroectodermal origin, is also expressed in lens anterior epithelial cells and disappears on differentiation to fiber cells.^178,179 Although the developmental patterns of vimentin and GFAP suggest that their disappearance is related to fiber cell differentiation, their specific roles remain unknown.^180,181 The beaded filament consisting of a 7- to 9-nm backbone filament with 12- to 15-nm globular protein particles spaced along it³⁵ appears to be unique to the lens.³⁷ The central filament contains CP-115 (also called filensin), and the globular beads contain CP-115 as well as CP-49 (also called phakinin).^180,182,183 Both of these proteins are highly divergent members of the intermediate filament family.¹⁸⁴ As mentioned above, beaded filaments appear in the differentiating fiber cells as vimentin-containing intermediate filaments disappear.¹⁷⁵ This is discussed in detail in several excellent reviews of lens membrane and cytoskeletal proteins and their biochemistry.^34,185,186

α-Crystallins appear to function in the assembly, maintenance, and remodeling of the cytoskeleton. By themselves, CP-49 and CP-115 copolymerize in vitro to form 10-nm fibers similar to intermediate filaments.^182,187 However, when they assemble in the presence of α-crystallin, a structure similar to a lenslike beaded chain is formed.¹⁸⁷ In addition, α-crystallins inhibit the in vitro assembly of both GFAP and vimentin in an ATP-dependent manner,¹⁸⁸ shifting these proteins from formed filaments to the soluble pool. Finally, both α-crystallin knockout mice and human mutations suggest that interactions between α-crystallins and the cytoskeleton are important for both muscle and lens function.

TABLE 2. Mapped Mendelian Cataract Loci and Mutations

TABLE 3. Inherited Syndromes Associated with Cataracts

Cataracts also occur in association with a variety of multiple malformation syndromes (see Table 3). In some cases, this association appears truly to be the result of pleiotropic effects of a single gene; in others, the cataracts appear to be secondary to pathology occurring primarily in the retina or ciliary body. These cataracts can also be accompanied by additional lens pathology such as microphakia, coloboma, or abnormal positioning of the lens. As might be expected, cataracts are frequently associated with diseases resulting in marked involvement of the retina, choroid, or portions of anterior chamber structures. In addition, cataracts frequently occur with skin diseases such as epidermal dystrophies and a variety of bone and cartilage dysplasias. Inherited syndromes and diseases with which cataracts are associated are summarized in Table 3. Many of these diseases have been extensively studied or mapped, especially on the X chromosome.

ABNORMALITIES OF LENS SIZE, SHAPE, AND POSITION

Coloboma of the lens is a congenital anomaly showing an asymmetry of the lens with a peripheral flattening of indentation and loss of zonules, usually in the 6 o'clock position. It may be associated with coloboma of the uvea (choroid, ciliary body, iris). Colobomas are not uncommonly associated with cataracts and can be seen in Stickler and Marfan syndromes.^310,311 Microspherophakia describes a small spherical lens that because of its shape produces a high lenticular myopia. Frequently these lenses are subluxated and displaced into the anterior chamber, resulting in a pupillary block (obstruction of the pupil by the lens). This in turn causes an acute onset of elevated intraocular pressure. Cataract is a common complication. Microspherophakia is a component of the Weill-Marchesani syndrome, a rare syndrome also associated with short stature, brachycephaly, prognathism, and peg-shaped teeth.³¹²

Lentiglobus and lenticonus are abnormalities of the shape of the lens. Lentiglobus refers to spherical bulging, usually of the anterior surface, and lenticonus refers to conical changes, usually of the posterior surface. Both lentiglobus and lenticonus create a central thickening resulting in high myopia. Posterior lentiglobus most frequently occurs as a unilateral condition and frequently is associated with a localized lens opacity. Anterior lenticonus occurs in about 25% of patients with Alport syndrome and is thus found more frequently than cataracts.³¹³

Abnormal lens position can occur with weakened, stretched, or broken zonules, resulting in a partial dislocation or subluxation. This frequently presents clinically as iridodonesis (tremulous iris movement), astigmatism, and occasionally monocular diplopia. It can be complicated by pupillary block (see above), chorioretinal damage, or an ocular inflammatory (uveitic) response. Genetic diseases associated with subluxation of the lens include Marfan syndrome,³¹⁴ in which the lens is usually dislocated up and outward, and homocystinuria,³¹⁵ in which the lens is usually dislocated downward. Lens dislocation can also occur in the Weill-Marchesani syndrome,³¹⁶ Lowe syndrome,²⁹⁹ and other rare conditions, such as sulfite oxidase deficiency³¹⁷ and some forms of primordial dwarfism. Marfan syndrome, Weill-Marchesani syndrome, and autosomal dominant ectopia lentis can be caused by a defect in the fibrillin gene on chromosome 15q21.1.^316,318

Cataracts may be visualized in a variety of ways. When viewed with a handlight, a cataract may appear as a white pupillary opacity (leukocoria). Direct ophthalmoscopy is useful to evaluate the effect on visual function, following the principle that if the examiner can see the optic nerve and macula, the patient can probably see out. One can visualize a lens opacity silhouetted in the red reflex using either direct or retroillumination. The definitive description of a lens opacity depends on a slitlamp biomicroscopic examination through a widely dilated pupil, allowing for direct illumination and retroillumination with appropriate magnification to visualize the lens opacity and define its clinical features. Photographs are useful to document the features and progression of the cataract, especially in a research setting.

DIFFERENTIAL DIAGNOSIS AND DIAGNOSTIC TESTS

The differential diagnosis of a hereditary congenital cataract includes the following:

  {*} Prenatal causes, including virus or other infectious disease. Rubella directly involves the lens; other infectious agents (toxoplasmosis, mumps, measles, influenza, chickenpox, herpes simplex, herpes zoster, cytomegalovirus, and echovirus type 3) result in ocular inflammation (uveitis). These can be screened for by TORCH titers.
  {*} Developmental abnormalities associated with prematurity. These may be associated with low birth weight, birth anoxia, or central nervous system involvement leading to seizures, cerebral palsy or hemiplegia, and retinopathy of prematurity.
  {*} Perinatal or postnatal problems such as hyperglycemia and hypocalcemia can cause cataracts. These are associated with signs of diabetes and tetany, respectively, and can be screened for by serum chemistries.
  {*} Association with other ocular abnormalities, including anterior chamber abnormalities (e.g., Reiger syndrome or anomaly), primary hyperplastic vitreous, aniridia, retinopathies such as retinal dysplasia, Norrie disease, and microphthalmia.
  {*} Association with multisystem syndromes may be suggested by the clinical examination, chromosome analysis, and specific blood and urine chemistries, determined by which syndromes are suspected.

Studies begun in kittens³²¹ and extended to nonhuman primates^322,323 show that unequal input into cortical neurons as a result of unilateral form deprivation results in more severe visual deficits than does bilateral deprivation. Thus, ophthalmic surgeons generally consider a unilateral dense congenital cataract to be a surgical emergency; bilateral dense cataracts can be scheduled in a more routine fashion. Usual practice suggests that limited dense cataracts can be operated on successfully in the first weeks of life; bilateral cataracts can be operated on successfully up to 3 months of age. With prompt surgery, the visual prognosis is better for bilateral than unilateral cases, and for less dense cataracts than total opacities. When congenital cataracts are associated with other ocular abnormalities or systemic disease, a poorer visual outcome often results.^323–325 Communication between clinicians, therapists, and teachers and counseling of patients are very important in the treatment of young cataract patients and their families.³²⁶

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