2. Lens

28

Cataract

Morphology of cataract

Locus

Gene

Chromosomal

Number of

location

families

Volkmann

CCV

-

1pter–p36.13

1

Zonular pulverulent

CZP1

GJA8

1q21–q25

2

Posterior polar

CTPP2

CRYAB

11q22–q22.3

1

Aculeiform

CACA

CRYGD

2q33–q35

2

Coppock-like

CCL

CRYGC

2q33–q35

1

Juvenile, progressive punctate

-

CRYGD

2q33–q35

1

Variable zonular pulverulent

-

CRYGC

2q33–q35

1

Juvenile/congenital

-

BFSP2

3q21–q25

2–3

Polymorphic/lamellar

-

MIP

12q14

2

Zonular pulverulent

CZP3

GJA3

13q11

3

Sutural “pouch-like”

-

-

15q21

1

Marner/zonular

CAM

-

16q22.1

1

Anterior polar

CTAA2

-

17p13

1

Zonular with sutural opacity

CCZS

CRYBA1

17q11.1–q12

2

Cerulean

CCA1

-

17q24

1

Posterior polar

CPP3

-

20p12–q12

1

Zonular nuclear

-

CRYAA

21q22.3

1

Coppock-like

-

CRYBB2

22q11.2

1

Cerulean

CCA2

CRYBB2

22q11.2

1

Cortex

Capsule

Anterior

Posterior

pole

pole

Lens

29

Morphology of cataract

Locus

Gene

Chromosomal

Number of

location

families

Recessive

-

-

3q

6

Pulverulent

CAAR

-

9q13-q22

1

Recesssive progessive

CRYAA

CRYAA

21q22.2

1

Recessive presenile

LIM2

LIM2

11q22-q22.3

1

30

Cataract

Pulverulent cataract.

Anterior polar cataract.

Aculeiform cataract.

Sutural cataract.

Lens

31

MIM

115700; 123690 (CRYGD)

Clinical features

Aculeiform cataract is characterized by needle-like crystals projecting

in different directions, through or close to the axial region of the lens.

The opacity does not respect sutures or the direction of lens fibers

and appears to originate from the fetal and postnatal nuclei,

suggesting a congenital origin with postnatal progression. Congenital

crystal-forming cataracts have also been described in which

multiple, fine, longitudinal crystals are found throughout the lens.

Age of onset

Cataract may be present at birth or noted during infancy.

Inheritance

Presumed autosomal dominant

Chromosomal location

2q33–q35

Gene

gD Crystallin (CRYGD)

Mutational spectrum

Two missense mutations in the gD crystallin, the most abundant

of the g crystallins, have been shown to have differing phenotypes

associated with crystal formation.

The heterogeneous nature of ADCC is underlined by the observation

that a congenital non-crystalline, punctate, progressive juvenile

cataract is also caused by a missense mutation in CRYGD. Unlike

many ADCC, these were not apparent at birth but were observed in

the first year or two of life. The opacification was progressive and

necessitated removal in childhood/early adolescence.

Effect of mutation

Presumed dominant negative mutations

32

Aculeiform cataract

Lens

33

MIM

601202

Clinical features

Anterior polar cataracts, small opacities on the anterior surface of

the lens, do not usually interfere with vision as they are significantly

removed from the nodal point of the eye. Anterior polar cataracts

have also been described in association with forms of anterior

segment dysgenesis as well as Fuchs’ endothelial corneal dystrophy.

Age of onset

Anterior polar cataract may be present at birth or noted during

infancy.

Inheritance

While autosomal dominant forms are recognized, anterior polar

cataracts have been described in consanguineous families,

suggesting that the condition may also be autosomal recessive.

Chromosomal location

17q13 (type II, linkage only)

Gene

Unknown

Effect of mutation

Unknown

34

Anterior polar cataract

MIM

115660

Clinical features

Cerulean cataracts comprise predominantly peripheral blue/white

opacities which are seen in concentric layers. The opacities are

observed in the superficial layers of the fetal nucleus as well as

the adult nucleus of the lens. Visual acuity is often only mildly

reduced in childhood. Opacification is progressive and may lead

to later lens extraction.

Age of onset

Cataract may be present during infancy. Symptoms may not begin

until adult life.

Inheritance

Autosomal dominant

Chromosomal location

17q24 (Type I, CCA1, linkage only); 22q11.2 (Type II, CCA2)

Gene

CCA1 – unknown

CCA2 – βB2 crystalin (CRYBB2)

Mutational spectrum

A single mutation resulting in the production of a polypeptide lacking

the terminal 55 amino acid residues. This mutation has been shown

to cause Coppock-like cataract in a second family.

Effect of mutation

Semi-dominant, resulting in protein truncation. It is not known

whether this allows the formation of a functionally active mutant

protein. A 12 bp, in-frame deletion in bB2 crystallin (CRYBB2) in

the Philly mouse underlies an inherited mouse model of cataract.

In this case, the mutation causes disruption of the tertiary structure

of the protein.

36

Congenital cerulean cataract

Diagnosis

As with other forms of inherited human cataract, information is sparse

regarding variability of mutations in the CRYBB2 gene. That the

identical mutation causes cataract of different morphology and severity

in different families suggests the heterogeneity exists amongst

mutations at this locus. In one branch of the family with CCA2, an

affected family member was the daughter of affected first cousins.

She had bilateral microphthalmos and microcornea at birth. Severe

cataracts required extraction by the age of 5 years and she lost all

visual perception by adolescence. This suggests that the disorder is

more severe in the homozygous state (i.e. partial or semi-dominant).

Lens

37

MIM

600881; 123610 (CRYBA1)

Clinical features

Lamellar cataract with opacification of the Y-shaped sutures that

represent the juxtaposed ends of the secondary lens fibers. There

is considerable intrafamilial variability.

Age of onset

Congenital

Inheritance

Autosomal dominant

Chromosomal location

17q11–q12

Gene

βA1 crystallin (CRYBA1)

Mutational spectrum

A deletion of exons 3 and 4 as well as a splice-site mutation have

been demonstrated in CRYBA1.

Effect of mutation

Not defined. The deletion would result in a significantly shortened

protein consisting only of the C-terminal domain. In this case, it is

not known whether the protein is formed, or whether the mutation

results in haploinsufficiency. A mutation in the mouse homolog also

causes cataract.

38

Congenital zonular cataract with sutural opacities

Including: variable zonular pulverulent cataract.

MIM

604307; 604219 (variable zonular pulverulent cataract)

Clinical features

Dust-like lens opacities are mainly located within the fetal nucleus

(central pulverulent) and do not affect the total nucleus. The

absence of significant cortical lamellar opacities renders the

cataract smaller than zonular pulverulent cataract (q.v.) and

therefore causes a milder phenotype.

A family described with variable dominant zonular pulverulent

cataract demonstrates the intrafamilial variability within ADCC.

Two-thirds had unilateral cataract of variable morphology including

zonular and nuclear pulverulent cataract or dense nuclear cataracts

that required early surgical removal.

Age of onset

Cataract is usually present at birth or develops during infancy.

Inheritance

Autosomal dominant. It has been suggested that there may be

autosomal recessive forms (see below).

Chromosomal location

2q33–q35: γ3 crystallin (CRYGC)

and genes

22q11.2: βB2 crystallin (CRYBB2)

(see page 36 for congenital cerulean cataract, Type II).

Mutational spectrum

The first family with Coppock-like cataract to be characterized at

the molecular level resulted from a mutation in CRYGC. However,

Coppock-like cataract is heterogeneous and a mutation in the βB2

crystallin gene has also been shown to cause Coppock-like cataract.

Two mutations have been described in CRYGC that further show the

variability within and between families for ADCC. In Coppock-like

cataract a conserved missense substitution (thr5-to-pro) has been

Lens

39

described which would result in altered folding of the protein.

In variable dominant zonular pulverulent cataract a 5 bp exon 2

duplication insertion was found within the gene.

Effect of mutation

The gamma crystallins are a family of seven genes which encode

major structural proteins of the lens. The g-crystallin proteins are

folded into two domains containing a ‘Greek-key’ motif. Pathological

effects of missense and nonsense mutations are therefore likely to be

different and may explain the variability of phenotype.

Diagnosis

Clinical examination. Although most families follow a dominant

pattern of inheritance, the description of Arab siblings with bilateral

Coppock cataracts born to unaffected parents who were first cousins

suggests that this phenotype may also be autosomal recessive.

40

Coppock-like cataract

MIM

154050; 604219 (MIP)

Clinical features

Autosomal dominant cataracts may show intrafamilial variability

in severity and morphology. This is illustrated by two families

with variable phenotypes shown to have a similar genetic basis.

In the first family, affected individuals had congenital, progressive,

punctate lens opacities limited to midand peripheral lamellae;

some individuals had asymmetric anterior and posterior polar

opacification. In the second family, affected members had

congenital, fine, non-progressive lamellar and sutural opacities.

Age of onset

Cataract present at birth or noted during infancy

Inheritance

Autosomal dominant

Chromosomal location

12q13

Gene

Major intrinsic protein of the ocular lens fiber membrane (MIP);

aquaporin O (AQPO).

Mutational spectrum

Missense mutations within conserved residues of transmembrane

domain 4 of MIP.

Effect of mutation

Presumed dominant negative mutations. MIP is primarily expressed

in the lens and has been shown to be defective in the mouse Fraser

cataract. It is a member of the aquaporin family of membrane-bound

water channels and it is predicted that the mutations alter water flux

across the lens cell membranes.

Lens

41

MIM

116600 (CTPP1); 123590 (CTPP2 – CRYAB); 605387 (CTPP3)

Clinical features

Posterior polar cataract may have a marked effect on visual acuity

due to its location close to the optical center of the eye.

Age of onset

Among the families with isolated posterior polar cataract, the opacity

is often present either at birth or soon afterwards. Often the site of

the opacity remains very localized.

Inheritance

Autosomal dominant

Chromosomal location

1pter–p36.1 (CTPP1, single family)

11q22.3–q23.1 (CTPP2 [CRYAB] single family)

20p12–q12 (CTPP3)

Gene

CTPP2 – αB crystallin (CRYAB)

Mutational spectrum

A single frameshift mutation (450delA) that produces an aberrant

protein from amino acid 149.

Effect of mutation

While the exact effect of this mutation is unknown it is suggested

that protein aggregation as well as the chaperone activity of the

protein is affected. The αB crystallin is a member of the small

heat-shock protein family of molecular chaperones that protect

other proteins under conditions of stress.

42

Posterior polar cataract

CZP1 is said to be the first inherited disease to be linked to a human

autosome. (Linkage to Duffy was described in 1963). The location

of the Duffy locus on 1q was established in 1968.

MIM

116200 (CZP1); 601885 (CZP3)

Clinical features

Zonular pulverulent lens opacities are located in what is thought

to be the embryonic and fetal nucleus. There are innumerable

scattered, powdery opacities in the nucleus with similar opacities in

a lamellar distribution. There may also be more superficial cortical

opacification.

Age of onset

Cataract is present at birth or develops during infancy. Surgery is

usually required in early childhood.

Inheritance

Autosomal dominant

Chromosomal location

MIM

Locus

Chromosome

Gene

Other gene titles

and genes

121015

CZP1

1q21.1

GJA8

CX50

600897

CZP3

13q11

GJA3

CX46

Mutational spectrum

Two missense mutations have been described within the connexin

(CX) 50 gene. Three missense mutations have been described within

the CX46 gene.

Effect of mutation

Dominant negative

CX50 forms multimeric gap junction channels that are thought to

maintain the homeostatic environment of, in particular, mature lens

fibers. Mutant isoforms have been shown to abolish gap junction

conductance. The mouse knockout develops a sharply demarcated

particulate nuclear cataract and microphthalmia.

Lens

43

44

Zonular pulverulent cataract

MIM

600886; 134790 (ferritin light chain)

Clinical features

Congenital nuclear cataract is associated with an elevated serum ferritin

that is not related to iron overload. Hematological investigation reveals

normal serum iron and transferrin saturation in the presence of a high

serum ferritin. Red cell count is normal and venesection results in

anemia. In suspected hemochromatosis cases, liver biopsy has shown

faint iron staining and accumulation of light (L)-rich ferritins.

Age of onset

Affected members may have early-onset bilateral cataract in which

there are dust-like spots (pulverulent cataract) throughout the lens

with variable effects. Some patients remain asymptomatic into

adulthood, while others require surgery in the first years of life.

Inheritance

Autosomal dominant

Chromosomal location

19q13.3–q13.4

Gene

Ferritin Light Chain (FTL)

Mutational spectrum

Mutations within the 5´, non-coding iron responsive element (IRE)

have been described amongst 11 families.

Effect of mutation

Ferritin is the main iron-storing molecule, which comprises 24 subunits

of two types: heavy (H) and light (L). Ferritin synthesis is regulated at

the transcriptional level by the binding of a cytoplasmic protein, iron

responsive protein (IRP), to the IRE of the FTL mRNA. When iron supply

to the cell is reduced, the IRP binds to the IRE and represses ferritin

synthesis. Mutations in the IRE lead to excess ferritin production which

accumulates within tissues leading to hyperferritinemia and cataract.

Diagnosis

Diagnosis of this rare condition may be suspected among patients

with hyperferritinemia with no evidence of hemochromatosis.

Lens

45

MIM

309000

Clinical features

Lowe oculocerebrorenal syndrome is an X-linked disorder involving

the eyes, kidney and nervous system that is caused by loss of

function in the OCRL1 gene.

Dense cataract in boy with OCRL.

Posterior capsular plaque in female OCRL carrier.

46

Lowe oculocerebrorenal syndrome

Extraocular

Hypotonia is present at or soon after birth, and motor development

is delayed. Hypermobile joints are also common with about 50%

of affected boys developing scoliosis. Short stature is common.

Intellectual impairment varies widely; around 50% of individuals

are severely delayed and 25% are in the mild to moderate range

of mental retardation. Seizures occur in about 50% of patients.

Day-to-day functioning is often impaired by characteristic behavior

patterns. Boys have a characteristic facial appearance with frontal

bossing, a hypotonic appearance and sunken eyes.

Renal tubular dysfunction usually becomes apparent by 1 year of age

and progresses to renal failure (a major cause of premature death) from

about 10 years. As a result, vitamin D resistant rickets is common.

Age of onset

Congenital

Inheritance

X-linked recessive

Chromosomal location

Xq26.1

Gene

OCRL1

Mutational spectrum

A large number of mutations have been described. Nonsense/

premature terminations form around 50% of mutations. Around 70%

of missense mutations are found within conserved residues of exon 15.

Effect of mutation

It is likely that most mutations lead to loss of function. The OCRL1

gene encodes a polypeptide that is similar to human inositol

polyphosphate 5-phosphatase, a ubiquitously expressed enzyme

which is localized in the Golgi apparatus. The enzyme converts

phosphatidylinositol 4,5-bisphosphate to phosphatidylinositol

4-phosphate. Abnormalities of inositol metabolism/transport have

been implicated in the pathogenesis of cataracts in galactosemia

and diabetes mellitus.

Lens

47

Diagnosis

Although the condition may be suspected on clinical grounds and

supported by abnormal urine amino acids, definitive diagnosis can

now be confirmed by testing for the presence of phosphatidylinositol

4,5-bisphosphate 5-phosphatase in fibroblasts. Detection of enzyme

activity in amniocytes allows for prenatal diagnosis. Mutation testing

may supplement biochemical analysis but is generally only available

on a research basis.

While most of the counselling issues regarding Lowe syndrome are

likely to be dealt with by clinical geneticists, the ophthalmologist

may be directly involved with carrier detection. In experienced

hands this is highly sensitive, although the lens opacities are not

in themselves pathognomonic of the condition.

48

Lowe oculocerebrorenal syndrome

MIM

160900

Clinical features

Ocular

Cataract is the cardinal ocular feature of DM. Due to the variable

nature of the condition as it passes from generation to generation

(genetic anticipation, see below), cataract in older patients may be

the presenting feature in a family. The characteristic feature is the

‘Christmas tree’ cataract in which there are multiple refractile colored

opacities throughout the lens. These may be progressive and become

associated with cortical or posterior subcapsular lens opacification.

While retinal findings have been described in DM, including macular

pigmentary disturbance and mild ERG changes, these are seldom

visually significant. As the disease progresses muscle weakness can

lead to ophthalmoplegia.

Extraocular

In the classical form, patients develop muscle weakness (particularly

distal) and wasting. The typical impassive (myotonic) faces are due to

facial muscle weakness, and are associated with frontal balding and

ptosis. Myotonia (inability to relax muscles voluntarily, particularly in

the cold) may interfere with daily activities such as using tools and

household equipment. Smooth muscle involvement may produce

dysphagia and gastrointestinal symptoms. DM seldom progresses

to the point where the patient is confined to a wheelchair. Cardiac

conduction abnormalities and cardiomyopathy are common and

are a significant cause of early mortality.

Affected females risk giving birth to children with congenital DM.

Such infants may present before birth with polyhydramnios and

reduced fetal movement. After birth the main features are severe

generalized weakness, hypotonia and respiratory compromise.

Lens

49

In these children, mortality from respiratory failure is high but

surviving infants experience gradual improvements in motor

function. Mental retardation is present in 50–60% of such patients.

Age of onset

The age of onset for classical myotonic dystrophy is typically in the

second to third decades, although there may be subtle features

evident in childhood.

Epidemiology

An approximate prevalence of 1:20,000 is estimated worldwide.

Inheritance

Autosomal dominant. The condition shows anticipation (increase in

severity of disease symptoms and/or a decrease in age of onset of the

relevant phenotype). When passed on by a female, the abnormal

DM gene expansion may enlarge further since it is unstably

transmitted through female meiosis. Since larger alleles have a more

severe phenotypic effect, DM is likely to show increased severity as it

passes through the generations. Data concerning the likelihood that

an affected mother will have an offspring with a particular size CTG

repeat or phenotype are useful in recurrence risk counselling.

Chromosomal location

19q13

Gene

Dystrophia myotonica protein kinase (DMPK)

Mutational spectrum

Within the non-coding portion of the gene there is a CTG

trinucleotide repeat region (i.e. CTGCTGCTG……CTG). In normal

individuals there are 5–37 CTG trinucleotides arranged in tandem.

Expansions of 50–150 copies are seen in those with mild DM.

Those with classical DM carry one allele with around 100–1000

copies, while those with congenital DM carry >1000.

Effect of mutation

DMPK is an intracellular protein found within heart and skeletal

muscle in structures associated with intercellular conduction and

impulse transmission. The effects of the CTG repeat are uncertain;

it may be that the CTG repeat causes abnormal DMPK mRNA

50

Myotonic dystrophy

processing. In addition, the expansion may alter expression of genes

close to DMPK. For example the SIX5 gene, which is nearby on

chromosome 19, causes cataracts in the mouse when disrupted—

it has been hypothesized that alteration of SIX5 expression may

cause the cataracts in DM.

Diagnosis

When cataract secondary to DM is suspected clinically, neurological

investigation is indicated. Molecular analysis will enable detection of

an abnormal repeat expansion. Since DM is, in its classical form, an

adult-onset and progressive condition, the advent of genetic testing

carries with it the potential hazards of presymptomatic diagnosis. In

general this should not be undertaken by those unfamiliar with the

recognized protocols for dealing with such circumstances.

Surgery carries additional hazards in DM patients; some patients

experience respiratory depression in response to benzodiazepines,

opiates and barbiturates. Myotonia may be increased by

depolarizing agents.

Lens

51

MIM

154700; 129600 (isolated ectopia lentis); 134797 (fibrillin 1)

Clinical features

MFS1 is a multisystemic connective tissue disorder characterized

in particular by skeletal, cardiac and ophthalmic manifestations. A

positive diagnosis requires the presence of sufficient major features

of the disorder in at least two categories (family history, cardiac,

ocular, skeletal, pulmonary or spinal).

52

Marfan syndrome (including isolated ectopia lentis)

Lens

53

Marfanoid habitus.

Lumbar striae.

The major complication of MFS1 is aortic root dilatation leading

to aortic dissection or development of a thoracic aortic aneurysm.

Mitral valve prolapse and regurgitation are also common.

Patients with MFS1 may have a history of spontaneous pneumothorax.

These result from apical pulmonary blebs.

Patients with MFS1 often have striae (‘stretch marks’) which can be

extremely prominent over the lumbar region and reflect both rapid

growth and skin fragility.

On MRI of the lumbosacral spine, dural ectasia is a common finding

that represents a major criterion of high specificity and sensitivity.

Family history

A family history of MFS1 or of a fibrillin gene defect are both

important positive indicators that diagnostic criteria in first-degree

relatives indicates true Marfan syndrome.

Epidemiology

Marfan syndrome has an incidence of 1:15,000–25,000 births

Age of onset

Lens luxation is of early-onset and patients may present with

reduced vision during childhood. Infrequently, children with de novo

fibrillin mutations may be born with ‘congenital Marfan syndrome’,

54

Marfan syndrome (including isolated ectopia lentis)

Inheritance

Autosomal dominant with highly variable expression.

Chromosomal location

15q21.1

Gene

Fibrillin 1 (FBN1)

Mutational spectrum

A broad range of mutations throughout the FBN1 gene have been

described. The majority are family-specific and are missense

changes. There is little genotype-phenotype correlation. Mutations

in exons 59–65 may be more likely to be associated with a mild

phenotype than those in earlier exons, but this is not a sufficiently

close relationship to be clinically useful. Mutations in neonatal

MFS1 cluster around exons 24–32.

Effect of mutation

The FBN1 gene is large (~110 kb) and comprises 65 exons, which

makes mutation testing highly labor-intensive. The gene encodes a

2871 amino acid protein that contains 47 tandem EGF domains,

suggesting a role in protein-protein and cell-cell interactions.

Fibrillin is a large ubiquitously distributed connective tissue

glycoprotein, which is the major component of extracellular

microfibrils. Elastic fibers are complex structures that comprise

elastin, 10–12 nm microfibrils, lysyl oxidase and proteoglycans.

The microfibrils consist of several proteins, one of which is fibrillin.

Microfibrils associated with amorphous elastin are found in skin,

lung, kidney, blood vessels, cartilage and tendons. In addition, they

are found without elastin in the ciliary zonules. Microfibril function

is poorly defined but it is suggested that they act as scaffolding for

elastic fibers as well as potentially anchoring them to cells.

Diagnosis

MFS1 can lead to reduced life-expectancy from progressive aortic

root dilatation, dissection or rupture, or valvular regurgitation which

impairs cardiac function. Progression of the cardiac complications

can be slowed in response to medical treatment (reducing blood

pressure, slowing heart rate) and through avoidance of excessive

physical activity. These should be monitored during high-risk

periods such as pregnancy.

Lens

55

56

Marfan syndrome (including isolated ectopia lentis)