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Duane`s Solution

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Updated 20090401
Chapter 74
Front of Book
↑
Congenital and Inherited Cataracts
[+] Editors
J. Fielding Hejtmancik
[+] Authors
Manuel B. Datiles III
Congenital cataracts are a significant cause of vision loss worldwide, causing approximately one third of blindness in infants. Roughly 8% to 25% of congenital cataracts are
- Disclaimer
hereditary.1,2,3 Cataracts can lead to permanent blindness by interfering with the sharp focus of light on the retina and resulting in failure to establish appropriate visual cortical
synaptic connections with the retina. Prompt diagnosis and treatment can prevent this. Understanding the biology of the lens and the pathophysiology of selected types of cataracts
can yield insight into the process of cataractogenesis in general and provide a framework for the clinical approach to diagnosis and therapy.
- Copyright Notices
[+] Dedications
- Preface—Clinical
Ophthalmology
Cell Biology of Cataracts
- Preface 1990—Foundations of
Clinical Ophthalmology
Transparency
The main functions of the lens are to transmit and focus light on the retina. Although about 80% of total refraction result from the cornea, the lens serves to fine tune the focusing onto
the retina. The human lens is colorless when young, and a gradual increase in yellow pigmentation occurs with age.4 The lens efficiently transmits light with wavelengths from 390 nm
- Preface—Foundations of
Clinical Ophthalmology
to 1,200 nm. This range extends well above the limit of visual perception (approximately 720 nm). Lens transparency results from appropriate architecture of lens cells and tight
- Contacting the Editorial Staff
packing of their proteins, resulting in a constant refractive index over distances approximating the wavelength of light.5,6 As lens proteins are diluted to concentrations below 450 mg/
mL, light scattering actually increases.7,8 In addition, there is a gradual increase in the refractive index of the human lens from the cortex (1.38, 73% to 80% H2O) to the nucleus
- Order & Subscription
(1.41, 68% H2O), where there is an enrichment of tightly packed γ-crystallins.
Information
- Other Lippincott Williams &
Cataracts have multiple causes, but they are often associated with the breakdown of the lens' microarchitecture,9,10,11,12 possibly including vacuole formation, which can cause large
fluctuations in density, resulting in light scattering. In addition, light scattering and opacity will occur if there is a significant amount of high-molecular-weight protein aggregates 1,000 Å
Wilkins Publications
or more in size.13,14 The short-range ordered packing of the crystallins is important in this regard. For transparency, crystallins must exist in a homogeneous phase. The physical
Table of Contents
↑
basis of lens transparency can be complex and has been reviewed elsewhere.5,13,14,15
[-] Duane's Clinical Ophthalmology
Hereditary Cataract
[-] Volume 1
[+] Ocular Motility and
Strabismus
[+] Refraction and Clinical
Optics
Hereditary cataracts are estimated to account for between 8.3% and 25% of congenital cataracts.1,2 The lens alone may be involved, or lens opacities may be associated with other
ocular anomalies such as microphthalmia, aniridia, other anterior chamber developmental anomalies, or retinal degenerations. Cataracts may also be part of multisystem genetic
disorders such as chromosome abnormalities, Lowe syndrome, mitochondrial diseases, or neurofibromatosis type 2. In some cases, this distinction is blurred. Inherited cataracts may
be isolated in some individuals and associated with additional findings in others, as in the developmental abnormality anterior segment mesenchymal dysgenesis, resulting from
abnormalities in the PITX3 gene.16
Hereditary cataracts may be inherited as autosomal-dominant (most frequent), 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.17 Linkage analysis is a powerful tool
http://www.duanessolution.com/pt/re/duanes/bookcontent.01222986-2009_E...vHbRXGvWHFyqcbpG82wZMJHNC2L!1739349167!181195629!8091!-1!1260568801817 (1 of 46)12/11/2009 5:03:48 PM
Duane's Solution
used to sort out the different genetic loci that can cause human cataracts. Linkage studies emphasize the genetic heterogeneity of autosomal-dominant congenital cataracts. The
number of known cataract loci has increased dramatically in the last few years to well over the 30 or so loci predicted to cause autosomal-dominant cataracts in man with no obvious
[-] Diseases of the Lens
[+] Chapter 71A Embryology and Anatomy of
Human Lenses
sign that most loci have been identified. Obviously, much work remains to be done in understanding inherited congenital cataracts.
Lens Development and Cataracts
- Chapter 72 - OPEN
At birth, the human lens weighs about 65 mg. It grows to about 160 mg in the first decade of life and then more slowly to about 250 mg by 90 years of age.18 Proteins may constitute
[+] Chapter 72A -
60% of the total weight of the crystalline lens, much higher than most other tissues.19
Physiology of the Lens
The human lens is first anatomically visible at 3 to 4 weeks of gestation.20 The surface ectoderm over the eye field thickens into the lens placode and then invaginates toward the
[+] Chapter 72B -
developing optic cup, forming the lens pit. The lens pit closes, and the resulting lens vesicle pinches off from the surface ectoderm.20 By the seventh week of development, cells
Pathogenesis of Cataracts
forming the posterior layer of the optic vesicle begin to elongate and fill in the vesicle, loosing their nuclei. These become the primary fiber cells forming the embryonic lens nucleus.20
The remaining cells form the cuboidal anterior epithelium, some of which will divide, move laterally along the lens capsule and differentiate into secondary fibers.21 (Fig. 74.1).
[+] Chapter 72C Nutritional and
Environmental Influences on
Risk for Cataract
Figure 74.1 Development and structure of the crystallin lens. (Adapted from Piatigorsky J:
Lens differentiation in vertebrates: A review of cellular and molecular features.
Differentiation 19:134, 1981.)
[+] Chapter 73 - Cataract:
Clinical Types
[+] Chapter 73A Epidemiologic Aspects of
Age-Related Cataract
[+] Chapter 73B - Clinical
Evaluation of Cataracts
[+] Chapter 74 - Congenital
and Inherited Cataracts
[+] Chapter 75 - Medical
Treatment of Cataract
View Figure
[+] Volume 2
[+] Volume 3
Although developmental control of lens differentiation is not yet well understood, Pax6, Rx, and a number of additional growth factors seem important for lens
development.22,23,24,25,26 Mutations in Pax6 are associated with aniridia, which is often accompanied by cataracts,27 and Pax6 may co-operate with a number of additional factors
[+] Volume 4
including Sox2.()28 Six3, a vertebrate homologue of the Drosophila sine-oculis gene, can induce lens formation as well,29 and targeted deletion of Sox1 results in microphthalmia and
cataract with failure of lens fiber cells to elongate.30 Pitx3, a member of the RIEG/Ptx gene family is expressed in the developing lens vessicle.31 A hereditary congenital cataract
[+] Volume 5
associated in some cases with the developmental abnormality anterior segment mesenchymal dysgenesis, can result from mutations in the PITX3 gene.16
[+] Volume 6
The lens has a single layer of anterior epithelial cells overlaying the fiber cells wrapped onionlike around the lens nucleus.32 Cell division occurs in the germinative zone just anterior
[+] Duane's Foundations of Clinical
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,33 allowing exchange of low-molecular-weight metabolites and ions but
Ophthalmology
have few or no tight junctions (zonula occludens), which would seal the extracellular spaces to low-molecular-weight proteins and ions.34,35 Ultrastructurally, anterior cuboidal
[+] New and Revised Chapters:
Duane's Clinical Ophthalmology
accomodation.36,37,38 Differentiating lens fiber cells loose their organelles, including the mitochondria, Golgi bodies, and both rough and smooth ER. As the cells elongate, they
move toward the lens nucleus. There is little extracellular space between the fiber cells, which have many interdigitations.21,32. Adjacent fiber cells are connected by many junctional
[+] New and Revised Chapters:
Duane's Foundations of Clinical
Ophthalmology
Back of Book
epithelial cells are rich in organelles and contain large amounts of actin, myosin, vimentin, microtubules, spectrin, and α-actinin, which should stabilize them during
↑
complexes, which allow for intercellular passage of metabolites.37,38
The major soluble components of fiber cells are the lens crystallins, which make up approximately 90% of the water-soluble protein, and cytoskeletal components, including actin,
myosin, vimentin, α-actinin, and microtubules.39 During this process, it seems clear that transcriptional control plays a significant role in the differential synthesis of lens crystallins.40
Duane's Solution
The distributions of the β-crystallins in chickens.41,42 and the β- and γ-crystallins in rats.43,44 provide examples of the spatial and temporal control of crystallin gene expression
[+] Resources
during lens development.
[+] Subject Index
Classification of Congenital Cataracts
Characteristics used for diagnostic classification of human cataracts include age of onset, location, size, pattern, number, shape, density, progression, and severity in terms of
interfering with visual acuity or visual function. They can also be categorized by presumed etiology. Roughly one third of congenital cataracts are associated with other disease
syndromes and one-third are inherited, with the remainder being of unclear etiology.
Defined by age at onset, a congenital or infantile cataract is visible within the first year of life, a juvenile cataract occurs within the first decade of life, a presenile cataract occurs before
the age of 45 years, and the so-called senile or age-related cataract, thereafter. The age of onset of a cataract does not necessarily indicate its etiology. 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 cataracts, thought to be due to multiple insults accumulated over many years, have a genetic component, making certain
individuals more vulnerable to the environmental insults.
There are several classification systems that have been developed based on the anatomic location of the opacity. In an attempt to deal with congenital cataract, Merin has proposed a
system based on morphological classification. Accordingly, the cataract is classified as total (mature or complete), polar (anterior or posterior), zonular (nuclear, lamellar, sutural), and
capsular or membranous.45
As discussed earlier, because lens development follows a well-documented timed sequence, the location of a lens opacity provides information about the time at which the
pathological process intervened, thereby aiding in determining the etiology. 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 (Fig. 74.2A) or posterior (Fig. 74.2B) pole of the lens and may include the posterior subcapsular lens cortex (Fig. 2C) extending to the lens
capsule. Posterior subcapsular cataracts can also occur secondarily to a variety of insults. Although they have been associated with proliferation of dysplastic bladderlike fiber cells
called Wedl cells, at least some posterior subcapsular cataracts appear to be due to abnormalities of the posterior fiber ends.46 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
trait,47 or may be associated with microphthalmos, persistent pupillary membrane, or anterior lenticonus. Posterior polar cataracts also may be inherited as a dominant trait.48 or may
be sporadic and unilateral, and they can be associated with abnormalities of the posterior capsule, including lentiglobus or lenticonus or with remnants of the tunica vasculosa.
Although they are usually stable over time, they may progress and can be associated with capsular fragility.
Figure 74.2 Examples of polar cataracts. A. A dense anterior polar cataract visible on slit
lamp examination. Some opacification of the lens nucleus is also visible. B. A dense
posterior polar cataract is visible on slit lamp examination. A smaller anterior polar cataract
is also visible so that this would be termed a bipolar cataract. C. Posterior subcapsular
View Figure
cataract.
Nuclear cataracts show opacities in the fetal or fetal and embryonic lens nucleus (Fig. 74.3A,B). They can show a wide variation in severity, from dense opacities involving the entire
nucleus to pulverulent (or dusty-appearing) cataracts involving only the central nucleus or discrete layers (see later discussion).
Lamellar cataracts (Fig. 74.3C,D) 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.49,50,51,52,53 Some cataracts have associated arcuate opacities
within the cortex called cortical riders.
Duane's Solution
Figure 74.3. Examples of nuclear and lamellar cataracts. A. A dense nuclear cataract. The
macula and optic nerve are obscured by this cataract. B. A punctate nuclear cataract. C. A
multi-lamellar cataract with an anterior polar component. D. A very fine nuclear lamellar
pulverulent cataract viewed by retroillumination. A rider is visible at about 10 o'clock.
View Figure
Sutural or stellate cataracts (Fig. 4A,B) 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 development.54 suggest that abnormalities in lens-fiber
development or maturation may lead to a predisposition to cataract development later in life. This is supported by examples in animals (the Philly mouse) and in humans (gyrate
atrophy).55 Sutural cataracts can also be inherited as autosomal-dominant traits.49 Cerulean, or blue dot cataracts, are characterized by numerous small, bluish opacities in the
cortical and nuclear areas of the lens (Fig. 74.4B).53
Figure 74.4. Examples of sutural or stellate cataracts. A. A sutural cataract with a nuclear
lamellar component B. A sutural cataract with a cortical cerulean or blue dot component.
View Figure
Mature or total cataracts may represent a late stage of any of the above types of cataracts in which the entire lens is opacified (Fig. 74.5A). 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. Other varieties of cataract can usually be described through a combination of the previously mentioned terms, although there are some specialized cataracts that have
unique characteristics, such as the ant's egg cataract (Fig. 74.5B,C), in which a mutation in connexin 46 causes beaded structures to form from the lens.56,57
Duane's Solution
Figure 74.5. A. Example of total or mature cataract. B–C. Examples of ant's egg cataract,
courtesy of R. Riise and Lars Hansen.
View Figure
Molecular Biology of Cataracts
Lens Crystallins
Crystallins can be defined as proteins that are found in high concentration in the lens. They make up more than 90% of water-soluble lens protein and fulfill a critical structural role for
transparency and refraction.19 Classically, the ubiquitous crystallins, found in all species, can be separated into three soluble and one insoluble fraction.58 The soluble fractions
comprise the α-, β-, and γ-crystallins, found in all vertebrate lenses (Table 74.1). 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 later discussion).
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,59,60,61 with αA-crystallin containing
173 and αB-crystallin 175 residues, both having a predominantly β-sheet structure.62 Native α-crystallins exist in the lens as globular complexes ranging from 300 to 12,00 kDa.
Currently, the most favored structural.63 model proposes that the α-crystallin aggregate behaves as a protein micelle.64,65 It can be shown that αA and αB occupy equivalent and
dynamic positions in the aggregate, with subunit exchange occurring easily.65,66,67,68 Cryo-electron microscopy has shown that recombinant αB-crystallin has a hollow central core
surrounded by a protein shell with variable monomer packing.69 Although αA-, αB-, and even αAins-crystallins appear to occupy equivalent positions in the α-crystallin
aggregate,65,66 they are expressed in different tissues, have radically different effects in knockout mice,70,71 and differ in their phosphorylation,72,73 structural properties,74 and
chaperone functions.74, 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,75,76 even though there is some evidence that αB-crystallin binds ATP specifically.77 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,78 which
participates in structural transitions resulting in the appropriate placement of hydrophobic surfaces within a multimeric molten globular state,79 perhaps with hydrophobic and
hydrophilic regions bound by discrete parts of the α-crystallin protein.80 The chaperone function of the α-crystallins should serve to protect against cataractogenesis by reducing the
aggregation of partially denatured proteins that accumulate within the lens during aging. αB-Crystallin and, to a lesser extent, αA-crystallin are expressed in tissues outside the lens.81
In this fashion, 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. Autosomal-dominant congenital zonular, nuclear, fan-shaped, and polar cataracts have been associated
with mutations of αA-crystallin on chromosome 21q22.3 (Table 74.2). A presenile lamellar cataract progressing to total cataract has been associated with a G98R mutation, and an
autosomal-recessive total cataract with microcornea and punctate lenticular opacities in carriers has been associated with an R54C mutation. Interestingly, all cataractogenic
mutations identified in CRYAA to date involve arginine residues or are truncations, suggesting that these residues might be particularly critical for α-crystallin stability or chaperone
activity. Mutations in αB-crystallin can cause autosomal-dominant cataracts (Table 74.2), at least one of which acts through a dominant-negative mechanism on αB-crystallin's
chaperone function.82 However, when arginine 120 is changed to glycine (R120G), it forms large aggregates with desmin in smooth muscle cells, causing a severe myopathy
associated with mild discrete cataracts.83 This is reminiscent of the behavior of αB-crystallin in αA-crystallin knockout mice,70 whereas αB-crystallin knockout mice develop a latehttp://www.duanessolution.com/pt/re/duanes/bookcontent.01222986-2009_E...vHbRXGvWHFyqcbpG82wZMJHNC2L!1739349167!181195629!8091!-1!1260568801817 (5 of 46)12/11/2009 5:03:48 PM
Duane's Solution
onset fatal myopathy without cataracts.71
Table 74.2. Mapped Mendelian cataract loci and mutations.
Locus
Chrom Inh
Morphology
Mutations
MIM
References
ASMD and
FOXE3
1p32
AD cataracts
1p34.3PSC
32.2
L315AfsX116, 601094 228
membranous
229
AR and PSC
variable
(progressive
central and
zonular nuclear
CCV (Volkmann)
CTPP (Posterior
Polar)
1p36
cataract with
sutural
AD component)
116600 48,230
1p34-p36 AD posterior polar
connexin 50
(cx50, GJA8,
CAE1,CZP1,Duffylinked)
1q21-q25 AD
1q25nuclear
1q31
AD
Cataract,
Crystalline,
Corraliform
2p24
AD
CCNP
115665 49
2p12
zonular
pulverulent
nuclear with
nystagmus
P88S, E48K,
I247M, R23T,
V64G, P88Q,
V44E, R198Q,
T203NfsX46,
P198L, D47N 116200 107,163,164,231,232,233,234,235,236,237,238,239
corraliform
congenital
embronic
nuclear
AD progressive
γC-crystallin
(CRYGC, includes
Coppock-like and
variable nuclear) 2q33-q35 AD
nuclear lamellar
(Coppock-like), T5P,
aculeiform,
C42AfsX62,
variable nuclear R168W
240
115800 241
607304 242
601286 243,244,245
Duane's Solution
R14C, R37S,
R58H, R36S,
γD-crystallin,
(includes CACA)
aculeiform,
P23T, W156X,
crystalline
E107A, P23S,
2q33-35 AD cataract
Y134X
123690 106,107,108,243,245,246,247,248,249,250,251,252,253
3p22CATC2
24.2
610019 254
AR
congenital
nuclear and
sutural
cataracts in dln,
juvenile lamellar
BFSP2 (CP49,
cataracts in
E233del,
phakinen)
3q21-q22 AD missense.
Progressive
R287W
603212 197,255,256,257,258
CRYGS
3q26.3
G18V
123730 .259
GCNT2
EYA1 (ASD)
CAAR
PITX3
CRYAB (αBcrystallin)
AD cortical
associated with
6p23-p24 AR I blood group
congenital
cataracts and
anterior
segment
anomalies, 1
8q13.3 AD with BOR
adult onset
9q13-q22 AR pulverulent
ASMD and
10q25
cataracts
posterior polar
cataracts with
del, or
11q22.3myopathy and
33.1
AD cataracts
110800 260,261,262,263
R514G,
E330K, G393S 601653 264
?
212500 199,265
insertion, S13N602669 16,266
450delA,
R120G
123590 82,83,267,268
Duane's Solution
variable
embryonal
nuclear,
progressive
bilateral
12q12AQP0 (MIP, ADC) 14.1
puctate, with
E134G,
asymetric polar T138R, del
AD opacification
G213
GJA3 (CX46, Gap
N63S,
Junction Protein
insC380 giving
46 kD, CZP3,
CAE3)
13q11q13
zonular
frameshift,
AD pulverulent
P187L
congenital with
CHX10
14q24
AR iris colobomas
central
CCSSO
15q21q22
saccykare with
AD sutural opacities
HSF4 (CAM,
Marner)
16q22
601286 269,270,271,272,273
601885 57,165,235,274,275,276,277,278,279,280,281,282,283
microphthalmia,
MAF
CTAA2 (Anterior
Polar)
16q23
17p13
R200Q, R200P 142993 284
605728 200
L114P,
variable
R120C, A20D,
(progressive
I87V, c.1327
central and
+4A>G,
zonular nuclear, R175P,
anterior polar or G195EfsX14,
AD stellate)
R74H
116800 265,285,286,287
cataract, iris
coloboma,
R288P,
AD microcornea
K297R, R299S 177074 288,289,290
AD anterior polar
variable, often
nuclear lamellar
CRYBA3 (βA317q11with sutural
I33A119del,
crystallin, CCZS) q12
AD component
G91del
cerulean
CCA1 (Cerulean (nuclear and
blue dot)
17q24
AD cortical)
nuclear
CATCN1
19q13.4 AR congenital
601202 47,291
600881 248,292,293,294,295
115660 201
609376 296
Duane's Solution
cortical irregular
or spherical
cortical
19q13.4 AD vacuolated
LIM2
Ferritin
19q
AR presenile
297
F104V
154045 298
T246AfsX7
600886 299
603307 300
(Hyperferritinemia
and cataracts)
19q13.4 AD
BFSP1
20p11.23 AR developmental
progressive,
disc-shaped
CPP3
20p12q12
posterior
subcapsular
AD opacity
posterior polar
605387 301,302
CRYAA (αAcrystallin)
and
subcapsular
progressive
20q11.22 AD childhood
congenital
zonular nuclear
with cortical and
posterior
AD, subcapsular as
21q22.3 AR adults
R116C, W9X,
R49C, R21L,
R116C, G98R,
R12C, R21W,
R116H, R54C 123580 107,304,304,305,306,307,308,309
CRYBB2 (βB2crystallin, CCA2,
Cerulean - blue
dot)
cerulean,
Copock-like
22q11.2 AD (CCL)
Q155X,
W151C,
D128V
CRYBB1 (βB1crystallin)
pulverulent and
dense nuclear,
some with polar
AD, component and
22q11.2 AR cortical riders
G220X,
X235R,
S228P,
N58TfsX106
CRYBB3 (βB3crystallin)
22q11.2 AR nuclear
G165R
600929
Bottom
of Form 127,317,318,319
123630
Bottom
of Form 126
CRYBA4 (βA4crystallin)
congenital
22q11.2 AD lamellar
F94S
123631 125
CHMP4B
D129V, E161K 610897 303
601547 310,311,312,313,314,315,316
Duane's Solution
A796fs,
A1153fs,
R373X,
#240fs,
R134fsX61,
C1246AfsX15,
Q8996fsX10,
Q39X,
K868EfsX5,
R373X,
R879X,
C1208X,
NHS (Nance
Q370X,
Horan syndrome) Xp22.13 XL congenital, total T1303RfsX4
300457 259,320,321,322,323,324
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%,84 and conserved tertiary
structure of their central globular domains.85,86 They differ with respect to their developmental expression and association of the β-crystallins 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 ofγB-, γD-, γE-, and γF- crystallin have been determined and are very similar.87,88,89,90 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.87 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.89 γ-Crystallins can be subdivided into two groups, γABC- and γDEFcrystallins.91,92 Proteins in the latter group have higher critical temperatures for phase separation and are largely responsible for the occurrence of the “cold cataract,”.93 a reversible
opacity, which occurs on cooling of the lens.90 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,94 to CRBG-GEOCY of the sponge Geodia cydonium,95 and to A1M1, a tumor suppressor gene.96 These microbial proteins can be induced
by physiological stresses such as osmotic stress,94 providing a functional parallel to the α-crystallins and some taxon-specific crystallins (see later discussion).
γS-crystallin (formerly called βS-) represents a link between the β- and γ-crystallins.97,98,99,100 Many physical and chemical properties of the γS protein resemble those of βcrystallins.101,102 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,103 and is expressed in birds and reptiles.104,105 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,98,99 making it similar to the other γ-crystallins and distinctly different from the β-crystallins,
which are encoded by genes with six exons.19 However, while most γ-crystallin genes are clustered on chromosome 2, the γS-crystallin gene is found alone on chromosome 3.86
Frameshift and missense mutations in γC-crystallin have been associated with autosomal-dominant nuclear and nuclear lamellar cataracts. The Coppock-like cataract, is an
autosomal-dominant pulverulent nuclear or nuclear lamellar cataract (Table 74.2). Similarly, missense and frameshift mutations in γD-crystallin can cause autosomal-dominant
cataracts, in one case associated with high myopia.106 and in another with microcornea.107 Although the molecular mechanism of most of these has not been experimentally
delineated, their predicted effects on the protein structure suggest that they might destabilize the γ-crystallin, resulting in denaturation, precipitation, and light scattering. In contrast,
two interesting congenital cataracts, one resulting from an R36S mutation and consisting of crystallized γD-crystallin within lens fiber cells and the second resulting from an R58H
http://www.duanessolution.com/pt/re/duanes/bookcontent.01222986-2009_...HbRXGvWHFyqcbpG82wZMJHNC2L!1739349167!181195629!8091!-1!1260568801817 (10 of 46)12/11/2009 5:03:48 PM
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mutation, also has dramatically lower solubility.108,109 In addition, an R14C mutation in γD-crystallin causes cataracts by increasing susceptibility to thiol-mediated aggregation
without changing the protein fold.110 These last three 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.86 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.19 The β-crystallin polypeptides range in size from approximately 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 35% identical with sequences of γ-crystallins.19,111,112 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.111,112,113 Basic β-crystallins have both N- and C-terminal arms, whereas acidic β-crystallins have
only N-terminal arms. The β-crystallins may undergo posttranslational modification, including proteolytic cleavage of βB1,114 phosphorylation of βB2 and βB3,115,116 and
glycosylation of βB1.117
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,118 and mouse.119,120 and cat.119 retina. γ- and βA4-Crystallins were detected in nonlens tissues in
Xenopus development,121,122 bovine cornea, and mouse retina.123 Nonlens expression of the βγ—crystallins suggests that they might have nonrefractive functions similar to the αcrystallins. Although this is unclear, βB2-crystallin does appear to have autokinase activity.124
Mutations in β-crystallins have also been implicated in human cataracts (Table 74.2). Perhaps the most common are mutations in βB2-crystallin, which have been associated with
cerulean, Coppock (nuclear lamellar), and polymorphic cataracts. Mutations in βA3-crystallin are also fairly common, and tend to cause variable nuclear zonular and sutural opacities.
A mutation in βA4-crystallin has been associated with congenital lamellar cataracts as well as microphthalmia in one case.125 Mutations in βB1- and βB3-crystallins result in nuclear
cataracts varying from pulverulent to dense, in one family associated with cortical riders. It is of note that the cataract associated with a βB3-crystallin G165R mutation is autosomalrecessive, as is the cataract in one of the four families with mutations in βB1-crystallins, a frameshift mutation, perhaps suggesting a nonstructural role for the basic βcrystallins.126,127
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.19 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.128,129,130,131 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.130
Proteins that serve as taxon-specific crystallins in other organisms are expressed in humans, but it remains unclear if 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,49 although that gene is not expressed at high levels in the human lens. Recent reviews of enzymecrystallins are available.131
Membrane Proteins
Approximately 2% of lens proteins with a wide range of molecular masses ranging from 10 to >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.132 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.133 The calpactins are extrinsic membrane proteins attached to the membrane through
calcium and are probably involved in membrane-cytoskeleton interactions.37,38 Other membrane proteins are enzymes such as glyceraldehyde 3-phosphate dehydrogenase and
other glycolytic enzymes on the endoplasmic reticulum.134 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.135 A number of 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 aquaporin 0 (AQP0, also known as intrinsic membrane protein 26, MP26, or MIP). It is a lens-specific single polypeptide with a
molecular mass of 28,200 kDa (263 residues), which comprises about 50% of the lens membrane protein.37,38,136 AQP0 is a member of the aquaporin (AQP) family, which
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transports small molecules such as water and glycerol and has a pH optimum of 6.0.137,138 The AQP0 monomer is composed of six membrane-spanning, tilted alpha-helices that
form a barrel that encloses a water-selective channel with two constrictions.139 The C- and N-termini are both on the cytoplasmic side, consistent with a possible role for AQP0 as a
junctional protein,140 and the C terminus interacts with the cytoskeletal proteins BFSP1 and BFSP2.141 AQP0 can associate into thin junctions where it appears not to function as a
water channel, but rather to be involved in cell adhesion with surrounding gap junctions conducting water, ions, and metabolites.142 These complexes fall into disarray in age related
cataracts.12 The genes for both AQP2 and AQP0 are on chromosome 12q13.143
Electron microscopic immunocytochemistry suggests that AQP0 occurrs in junctional complexes of lens fiber cell plasma membranes but not in the anterior lens epithelia or nonlens
cell membranes.144,145 It is found in thin (11 nm 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. AQP0 also forms channels permeable to ions and other small molecules in liposomes and artificial membrane
systems.146,147,148,149 AQP0 may bind calmodulin.150 It is a substrate of endogenous protein kinase,151,152 raising the possibility that metabolic control of its structure has
functional significance. In addition, MP26 is palmitoylated, as is its degradation product MP22.153
Cataracts in four families have been mapped to chromosome 12q12-14.1 and associated with the aquaporin 0 gene (Table 74.2). The morphology of these cataracts varies from total
congenital cataracts to fine congenital lamellar and sutural cataracts, both progressive and nonprogressive. Interestingly, three of the four families have mutations in transmembrane
helix 4 of AQPO. Mutations in lens intrinsic membrane protein 2 (LIM2, MP19), a phosphorylated membrane protein that binds calmodulin, also cause presenile cataracts.
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 gap
junctions found in other tissues, containing connexins in homomeric or heteromeric combinations.154 Lens junctions contain the intrinsic membrane protein connexin 50 (Cx50), also
called gap membrane channel protein alpha8 (Gja8) or MP70, A member of the connexin family.144,154,155,156 Connexin 50 is expressed in the anterior epithelia along with
connexin 43. In outer cortical fibers the Cx 43 is degraded and Cx50 undergoes age-related degradation to MP38, which continues in functional gap junctions.157 However, in central
nuclear fiber cells, coupling appears to rely primarily on Cx46.158 Cx50 is also phosphorylated by a specific membrane-associated kinase.159,160 Conductance of connexin
hemichannels is regulated by extracellular calcium, and in Cx50, this regulation appears to be dependent on sodium and potassium.161
Aberrations in Cx50 and Cx46 have been implicated in autosomal-dominant human cataract. The autosomal-dominant lamellar (central pulverulent) cataract (CAE) originally described
by Nettleship and Ogilvie in 1906.162 was linked to the Duffy locus on chromosome 1q21-q25 by Renwick and Lawler.163 It is associated with a C to T transition in codon 88 of
connexin 50 (GJA8),164 resulting in substitution of a serine for a highly conserved proline residue, P88S.164 Other autosomal-dominant congenital cataracts resulting from CX50
mutations range from zonular pulverulent to congenital total in morphology, including PSC and stellate. Cx50 mutant cataracts have also been associated with microcornea with or
without myopia, and nystagmus in a total congenital cataract. Most cataracts associated with Cx46 mutations have been zonular or nuclear pulverulent, although they include the
distinctive ant egg cataract and a “pearl box” cataract described in an Indian family.57,165 Disruption of connexins 46 and 50 are 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.166,167
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 erythrocytes.168 helps to remodel and control the shapes of differentiating fiber cells of the lens cortex through
interactions with other cells and the extracellular matrix. Microtubules containing α- and β-tubulins are arrayed lengthwise in the peripheral cytoplasm in cortical fiber cells but are rare
in nuclear fiber cells and epithelial cells.169 Microtubules may maintain the elongated shape of fiber cells and may be involved in nuclear migration in dividing lens epithelial cells.170
Actin filaments, which are closely associated with lens-cell membranes,171 are critical for remodeling of lens epithelia into fiber cells,172,173 perhaps in association with αcrystallin,174 and may effect accommodation.32,175,176 Lens microfilaments, also called thin filaments, contain nonmuscle β- and γ-actins.38 These actin filaments may interact with
intercellular junctions.177,178 Tropomodulin and α-actinin also interact with actin in microfilaments, especially in elongating cortical fibers.179,180
Vimentin usually occurs in mesenchymally derived cells but also forms the intermediate filament in lens epithelia.181 These 10 nm filaments, which can be highly phosphorylated,182
can occur as extrinsic membrane proteins but are more commonly found in the cytoplasm.36 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 CP49.183 Vimentin expression increases approximately threefold
during embryonic chicken lens development and then decreases after hatching.184,185 Glial fibrillary acidic protein (GFAP), an intermediate filament protein usually seen in cells of
neurectodermal origin, is also expressed in lens anterior epithelial cells and disappears on differentiation to fiber cells.186,187 Although the developmental patterns of vimentin and
GFAP suggest that their disappearance is related to fiber cell differentiation, their specific roles remain unknown.188,189
The beaded filament consisting of a 7- to 9-nm backbone filament with 12- to 15-nm globular protein particles spaced along it.37 appears to be unique to the lens.39 The central
filament contains beaded filament structural protein 1 (BFSP1, also called CP-115 and filensin), and and the globular beads contain BFSP1 as well as beaded filament structural
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protein 2 (BFSP2, also called CP-49, and phakinin).188,190,191 Both of these proteins are highly divergent members of the intermediate filament family.192 As mentioned earlier,
beaded filaments appear in the differentiating fiber cells as vimentin-containing intermediate filaments disappear.183 This is discussed in detail in several excellent reviews of lens
membrane and cytoskeletal proteins and their biochemistry.36,193,194
α-Crystallins appear to function in 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.190,195 However, when they assemble in the presence of α-crystallin, a structure similar to a lenslike beaded chain is formed.195 In addition, α-crystallins
inhibit the in vitro assembly of both GFAP and vimentin in an ATP dependent manner,196 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.
Mutations in both BFSP1 and BFSP2 have been associated with congenital and childhood cataracts (Table 74.2). Cataracts associated with BFSP2 mutations have usually involved
the sutures with or without a nuclear or cortical component, and in four of five families have been progressive in nature. One family has been reported with associated myopia.197
Although, BFSP2 mutations have been described in five families of several different ethnicities, all but one of the mutations has been the same three base pair deletion, resulting in a
deletion of glutamic acid at position 233 (E233del). A frameshift mutation in BFSP1 has been implicated in a single Indian family with autosomal-recessive childhood cortical cataracts.
Other Genes Implicated in Hereditary Cataracts
Mutations in a number of additional genes of various types have been shown to cause cause congenital cataracts (Table 74.2). Mutations in alternatively spliced GCNT2 cause the
adult I blood group, and cataracts in a subset of patients with the mutations in exons common to all forms. In addition, mutations in growth factors active in ocular and lens
development have been shown to cause congenital cataracts, including EYA1, PITX3, CHX10, HSF4 (the Marner cataract), and MAF. Mutations in CHMP4B, a component of the
endosomal sorting complex involved in degradation of surface proteins and formation of endocytic multivesicular bodies, have been shown to result in posterior polar and posterior
subcapsular cataracts in two families. Finally, mutations in NHS cause the X-linked Nance Horan syndrome and are characterized by dense nuclear cataracts and dental abnormalities
in affected males and relatively mild sutural cataracts in carrier females.
Hereditary Cataracts of Unclear Etiology
Cataracts at a number of mapped loci have not yet been associated with sequence changes in candidate genes (Table 74.2). The Volkmann cataract, which has variable progressive
central and zonular nuclear and sutural morphology, has been mapped to chromosome 1p36,49 and a second family has cataracts cosegregating with the Evans phenotype in the
same chromosomal region.198 A morphologically distinct posterior polar cataract also maps to the same region.48 Whether these represent one or several loci is not yet clear. A locus
for autosomal-recessive congenital progressive pulverulent nuclear and PSC cataracts maps to chromosome 2q13-q22.199 Autosomal-dominant central pouchlike cataracts with
sutural opacities map to chromosome 15q21-q22.200 A locus for an autosomal-dominant congenital anterior polar cataract lies on chromosome 17p13,47 and a locus for autosomaldominant nuclear and cortical cerulean congenital cataracts maps to chromosome 17q24.201 Finally, a locus for spastic paraparesis with bilateral zonular cataracts maps to
chromosome 10q23.3-q24.2.202
Metabolic Cataracts
Cataracts associated with systemic metabolic diseases tend to be bilateral and symmetrical (Table 3). Although many are not congenital, most can occur during childhood and are
briefly included here for completeness. The hyperferritinemia-cataract syndrome includes isolated autosomal-dominant catarcts caused by systemic overexpression of the ferritin Lchain.203 Metabolic cataracts can also result from galactosemia and can be the only finding other than galactosuria in galactokinase deficiency, although there are severe systemic
effects with transferase deficiency galactosemia. (These are discussed further in Chapter 72b Pathogenesis of Cataracts and in Chapter 73 Clinical Types of Cataracts.) Severe
systemic findings including mental retardation are also found with cataracts due to phenylketonuria.
Table 3. Inherited Syndromes Associated with Cataracts
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Syndrome
Reference
Primarily ocular syndromes
Autosomal dominant
Aniridia
325
Anterior Segment Mesenchymal Dysgenesis
16
Autosomal dominant optic atrophy and cataract, ADOAC (also AR 3-methylglutaconic
326
aciduria type III)
Cornea guttata
327
Granular corneal dystrophy
328
Familial exudative vitreoretinopathy
329
Foveal hypoplasia
330
Hyaloideoretinal degeneration of Wagner
331
Hyperferritinemia with congenital cataracts
332
Iris pigment layer cleavage
333
Mesenchymal dysgenesis of the anterior segment
334
Microcornea
335
Microphthalmia
336
Persistent hyperplastic pupillary membrane
337
Retinitis pigmentosa
Snowflake vitreoretinal degeneration
338,339
340
Vitreoretinochoroidopathy
341
Autosomal recessive
Amyloid corneal dystrophy
342
Cone-rod degeneration
338
Choroideremia
338
Favre hyaloideoretinal degeneration
343
Leber congenital amaurosis type I
344
Microphthalmia and nystagmus
345
X-linked
338,339
Microcornea and slight microphthalmia
336
Norrie disease
346
Nystagmus
347
348
Other Genetic Syndromes Associated with Cataracts
Autosomal dominant
Aberrant oral frenula and growth retardation
349
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Cerebellar ataxia, deafness, and dementia
350
Chondrodysplasia punctata
351
Clouston syndrome
347
Cochleosaccular degeneration
352
Congenital lactose intolerance
353
Desmin-related myopathy
83
Dwarfism with stiff joints and ocular abnormalities
354
Esophageal and vulval leiomyomatosis with nephropathy*
355
Fechtner syndrome
347
Flynn-Aird syndrome*
356
Hallermann-Streiff syndrome (new mutation)
357
Hereditary mucoepithelial dysplasia
358
Histiocytic dermatoarthritis
359
Incontinentia pigmenti (autosomal dominant new mutation)
360
Long chain 3-hydroxyacyl CoA dehydrogenase deficiency
361
Metatropic dwarfism type II (Kniest disease)
362
Kyrle disease (follicular keratosis)
363
Mitochondrial myopathy (two types)
Marshall syndrome
364,365
366
Multiple epiphyseal dysplasia with myopia and conductive
367
deafness*
Myotonic dystrophy
368
Nail-patella syndrome
369
Neurofibromatosis type II
370
Oculodentodigital syndrome
347
Optic atrophy and neurologic disorder
371
Osteopathica striata and deafness
365
Paronychia congenita syndrome
347
Progeria syndrome (autosomal dominant new mutation)
372
Schprintzen velocardiofacial syndrome
373
Sorbitol dehydrogenase
374
Split-hand and congenital nystagmus
375
Stickler syndrome
376
Trichomegaly
377
Autosomal recessive
Absence leg deficiency*
378
Agenesis of the corpus callosum, combined
379
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immunodeficiency, and hypopigmentation*
Axonal encephalopathy with necrotizing
380
myopathy and cardiomyopathy*
Bardet-Biedl syndrome
381
Cataract, microcephaly, failure to thrive and
347
kyphoscoliosis (CAMFAK) syndrome
Cardiomyopathy
382
Cerebral cholesterinosis (cerebrotendinous xanthomatosis)
383
Cerebrooculofacioskeletal (COFS)
384
syndrome
Chondrodysplasia punctata
351
Cockayne syndrome
385
Congenital ichthyosis
386
Crome syndrome*
387
Dysequilibrium syndrome
388
Galactosemia (kinase and transferase)
389
Glutathione reductase deficiency
390
Gyrate atrophy
55
Hallermann-Streiff syndrome
391
Hard-E syndrome
392
Homocysteinuria
393, 2009, 1089
Hypertrophic neuropathy*
394
Hypogonadism*
395
Osteogenesis imperfecta with microcephaly*
396
Mannosidosis
397
Majewski syndrome
398
Marinesco-Sjogren Marinesco-Sjögren syndrome
399
Martsolf syndrome
400
Mevalonic aciduria
401
Myopathy and hypogonadism*
402
Nathalie syndrome*
403
Neu-Laxova syndrome
404
Neuraminidase deficiency
405
Neutral lipid storage disease
406
Pellagra-like syndrome*
407
Phenylketonuria
408
Polycystic kidney and congenital blindness
409
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Preus oculocerebral hypopigmentation syndrome
410
Refsum syndrome
411
Roberts-SC phocomelia syndrome
412
Rothmund Thomson syndrome
413
Schwartz-Jampel syndrome
412
Short stature, mental retardation, and ocular
414
abnormalities*
Smith-Lemli-Opitz syndrome
415
Tachycardia, hypertension, microphthalmos, and
416
hyperglycinuria*
Toriello microcephalic primordial dwarfism*
417
Usher syndrome
418
Werner syndrome
419
Wilson disease
420
Zellweger syndrome
411
X-linked
Albright hereditary osteodystrophy
421
Alport syndrome
422
Fabry disease
423
Glucose 6-phosphate dehydrogenase deficiency
424
Incontinentia pigmenti
360
Lenz dysplasia
425
Lowe syndrome
217
Nance-Horan syndrome
426
Pigmentary retinopathy and mental retardation
427
Renal tubular acidosis II
428
X-linked dominant chondrodysplasia punctata
429
Chromosome anomalies
Trisomy 10q
412
Trisomy 13
412
Trisomy 18
412
18p-
412
18q-
412
Trisomy 20p
412
Trisomy 21
412
XO syndrome
412
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*This syndrome has been described in a single kindred.
NOTE: Although references are given in which the cataracts found in the above syndromes are described, useful clinical
summaries of most of these syndromes are found in Smith412 or McKusick.347 In some cases, no single best source was
obvious and the summary in Smith or McKusick is given as the primary reference.
Chromosome Abnormalities and Complex Syndromes Associated with Cataracts
Chromosomal abnormalities can disrupt the structure or expression of nearby genes with resultant cataracts. Isolated congenital total cataracts have been described in a father and
son with a translocation t(3;4)(p26.2.;p15).204 Isolated congenital anterior polar cataracts occurred in four family members with a balanced translocation, t(2:14)(p25;q24),205 and
another family had a balanced t(2:16)(p22.3;p13.3) co-inherited with congenital cataracts and microphthalmia in four members.206 Cataracts have also been associated with
unbalanced chromosomal rearrangements,207,208,209 and with trisomy of chromosomes 13, 18, 21, and 20p, as well as 18p-, 18q-, and XO syndrome as listed in Table 74.3. The
etiology of these cataracts is less clear, as the patients, of course, have additional abnormalities. Statistically, cataracts have been associated with cytological abnormalities involving
2q23, 4p14, 11p13, and 18q11-12.27
Table 74.1. Chromosomal Location of Human
UBIQUITOUS CRYSTALLIN GENES
Crystallin
Chromosome
αA—crystallin
21q22.3
αB-crystallin
11q22.3-q23.1
βA1/A3-crystallin
17q11.1-q12
βA2-crystallin
2q34-q36
β-crystallin cluster
βA4-crystallin *
22q11.2-q12.1
βB1-crystallin *
22q11.2-q12.1
βB2-crystallin *
22q11.2-q12.1
βB3-crystallin *
22q11.2-q12.1
ψβB2-crystallin
22q11.2-q12.1
γ—crystallin cluster
γA-crystallin ^
2q33-q35
γB-crystallin ^
2q33-q35
γC-crystallin ^
2q33-q35
γD-crystallin ^
2q33-q35
ψγE-crystallin ^
2q33-q35
ψγF-crystallin ^
2q33-q35
ψγG-crystallin ^
2q33-q35
γs-crystallin
*,^ closely linked
3pter
Cataracts also occur in association with a variety of multiple malformation syndromes listed in Table 74.3. In some cases, this association appears truly to be the result of pleiotropic
effects of a single gene, whereas in others, the cataracts appear to be secondary to pathology occurring primarily in the retina or ciliary body. These cataracts can also be
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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 74.3. 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 (e.g., choroid, ciliary body, iris). Colobomas are not uncommonly associated with cataracts and can be seen in Stickler and Marfan
syndromes.210,211 Microspherophakia describes a small spherical lens, which, due to 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), which in turn causes an acute onset of elevated intraocular pressure. Cataract is
a frequent complication. Microspherophakia is a component of the Weill-Marchesani syndrome, a rare syndrome also associated with short stature, brachycephaly, prognathism, and
peg-shaped teeth.212
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 is frequently 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.213
Abnormal lens position can occur with weakened, stretched, or broken zonules, resulting in a partial dislocation or subluxation. These frequently present clinically with iridodonesis
(tremulous iris movement), astigmatism, and occasionally monocular diplopia. They can be complicated by pupillary block (see earlier discussion), chorioretinal damage, or an ocular
inflammatory (uveitic) response. Genetic diseases associated with subluxation of the lens include Marfan syndrome,214 in which the lens is usually dislocated up and outward, and
homocystinuria,215 in which the lens is usually dislocated downward. Lens dislocation can also occur in the Weill-Marchesani syndrome,216 Lowe syndrome,217 and other rare
conditions, such as sulfite oxidase deficiency.124 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 15q21.1.216,218
Evaluation
After establishing the significance of and classifying the cataract by type, the evaluation of a cataract consists of a careful assessment of its effect on the visual acuity and function.
The first assessment in small children (0 to 3 years of age) is usually carried out by observation-fixing, following, and by covering alternative eyes and observing the response.
Covering the eye with good vision will cause more fretting, objecting, and crying. More accurate assessment is provided by specialized testing including visually evoked cortical
responses, preferential looking, or the forced choice method.)219,220 With older children, subjective tests, including identification of the illiterate E or Allen cards (picture-differentiating
tests), are utilized. Finally, once the alphabet is learned, conventional acuity testing by a logEDTRS or Snellen chart may be used.
Cataracts may be visualized in a variety of ways. When viewed with a handlight, a cataract may present 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 slit-lamp 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: (1) prenatal causes including virus or other infectious disease. Rubella directly involves the lens whereas other
infectious agents result in ocular inflammation (uveitis): toxoplasmosis, mumps, measles, influenza, chickenpox, herpes simplex, herpes zoster, cytomegalovirus, and echovirus type
3. These can be screened for by TORCH titers. (2) 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. (3) Perinatal-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. (4) 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). (5) 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.
Treatment
When unilateral and bilateral cataracts are thought to reduce visual acuity significantly, management should include early diagnosis with prompt evaluation to identify etiology when
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possible. Galactosemia is an example in which rapid diagnosis and treatment will permit recovery of the lens to a normal state of clarity. Determination of the extent of compromise in
visual acuity is important, and surgery may be required.
Studies begun in kittens.221 and extended to nonhuman primates.222,223 show that unequal input into cortical neurons due to 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, whereas bilateral dense
cataracts can be scheduled in a more routine fashion. Usual practice suggests that limited dense cataracts can be operated successfully in the first weeks of life, whereas bilateral
cataracts can be operated successfully until 3 months of age. With prompt surgery, the visual prognosis is better for bilateral as compared with unilateral cases and in less dense
cataracts as compared with total opacities. Chronic dilation of the pupil in small centrally located congenital cataracts, allowing the infant to see around the cataract, may be useful in
some cases when cataract surgery may not be immediately feasible. When congenital cataracts are associated with other ocular abnormalities and/or systemic disease, a poorer
visual outcome often results.223,224,225 Finally, it should be emphasized that communication between clinicians, therapists, and teachers combined with counseling of patients are
very important in the treatment of young cataract patients and their families.226
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