4. Inherited retinal disease

MIM

216900 (ACHM2); 262300 (ACHM3)

Clinical features

Achromatopsia or rod monochromatism is a stationary cone disorder

characterized by an absence of normally functioning cones. Patients

present with congenital nystagmus at birth or early in life. They are

photophobic and describe vision that is better in dim light. Achromats

have normal retinal examination. There is complete color blindness

and visual acuity of around 6/60. ERG shows an absence of cone

responses, in the presence of normal rod responses. Some patients

with partial achromatopsia retain better visual acuity with residual

cone function.

Epidemiology

Achromatopsia is estimated to affect around 1:30,000 in the USA.

Age of onset

Congenital

Inheritance

Autosomal recessive

Chromosomal location

2q11 (ACHM2); 8q21–q22 (ACHM3)

Gene

ACHM2: cyclic nucleotide-gated cation channel, alpha subunit

(CNGA3)

ACHM3: cyclic nucleotide-gated cation channel, beta subunit

(CNGB3)

Mutational spectrum

CNGA3: missense mutations (including frameshift and protein

truncating mutations) have been described in highly conserved amino

acids. It is likely that the missense mutations result in improper

folding or inability to integrate the protein into the plasma membrane.

CNGA3 mutations have also been described in a small number of

patients with evidence of severe progressive cone dystrophy.

82

Achromatopsia

CNGB3: missense, frameshift and protein truncation mutations have

all been described. Homozygous null mutations cause an identical

phenotype to missense mutations.

Effect of mutation

It is likely that all mutations result in loss of function. Cyclic

nucleotide-gated channels are important in vertebrate sensory

systems. CNGA3 and CNGB3 encode the a- and b-subunits of

a single cyclic nucleotide-gated channel that is located in the

photoreceptor plasma membrane. The cone cGMP-gated cation

channel is an a/b-2 heteromeric tetramer required for development

of the light-evoked responses of cones. The proteins contain six

transmembrane domains and a hydrophilic pore structure. Loss

of function would result in an inability to respond to cGMP, and

elimination of the dark current resulting in a situation akin to

permanent light exposure.

Diagnosis

Mutation screening is available on a research basis only.

Inherited retinal disease

83

MIM

303700

Clinical features

Blue cone monochromats have only functional rods and short

wavelength (blue) cones. Patients have severely reduced central

vision and photophobia, abnormal color discrimination and

nystagmus. Retinal examination is normal. ERG examination reveals

normal scotopic and photopic responses demonstrating absence of

cone responses to white and red light. There is preservation of blue

cone function, which allows discrimination of yellow objects on a

blue field.

Age of onset

Congenital

Epidemiology

Rare, less than 1:100,000

Inheritance

X-linked recessive

Chromosomal location

Xq28

Gene

Red cone pigment, including protanopia (MIM 303900).

Green cone pigment, including deuteranopia (MIM 303800).

Mutational spectrum

The red and green pigment genes are carried on the X chromosome

at Xq28. They lie in a head-to-tail tandem array, which predisposes

to homologous recombination and rearrangement of the region. This

mechanism gives rise to over 90% of the red and green cone color

vision variations.

In the normal state, each X chromosome carries one red pigment gene

and one or more green pigment genes. Blue cone monochromatism

results from a number of conformations of the red/green pigment

arrays including:

84

Blue cone monochromatic color blindness

• point mutations inactivating X chromosome pigment genes. In the

majority of individuals in this group, homologous recombination

reduces the pigment gene array to a single gene. A second

mutational event then inactivates this gene. Both missense and

nonsense changes are described, but the mutation of cysteine to

arginine at codon 203 is the most common.

Effect of mutation

Absence of functional red and green cones. In general, this is a

static condition although some patients have a late-onset, slowly

progressive, central retinal dystrophy. This suggests that normal

genes are required for long-term maintenance of cones.

Diagnosis

CBBM, when suspected clinically, may be confirmed by ERG testing.

There is often a clear history consistent with X-linked inheritance.

In some cases, female carriers are said to have abnormal cone

responses on ERG testing.

Inherited retinal disease

85

Gene

RDS/peripherin (RDS)

Guanylate cyclase activator 1A (GUCA1A); MIM 600364

Cyclic nucleotide-gated cation channel, alpha subunit (CNGA3)

Mutational spectrum

A small number of families with missense changes in RDS (e.g.

serine-27-phenylalanine) have been described with progressive

cone dystrophy (see section on RDS).

A single missense mutation (Y99C) has been described in GUCA1A.

Effect of mutation

GUCA1A is a calcium-binding protein expressed exclusively in

photoreceptors, particularly cones. In photoreceptors, cGMP is

synthesized by RetGC, which is activated by GUCA1A at low levels

of intracellular Ca2+ (i.e. light-adapted photoreceptors) and

inhibited at high Ca2+ levels. At all physiological Ca2+

concentrations, the mutant GUCA1A results in RetGC activation,

which leads to constitutive cGMP synthesis. Elevated cGMP alters

Ca2+/Na+ flux and this is thought to result in progressive retinal

damage.

Diagnosis

Many patients with a childhood-onset cone dystrophy pattern

develop rod dysfunction (i.e. cone-rod dystrophy). The genetic basis

of the most progressive cone dystrophies remains undefined and

genetic testing is not yet available.

Inherited retinal disease

87

88

Macular dystrophies

Table 5.1

Disorder

Gene

Chromosome

Inheritance

MIM

Age-related macular

-

1q25–q31

AD

603075

degeneration

Stargardt disease

ABCA4

1p21–p22

AR

248200

Doyne honeycomb

EFEMP1

2p16–p21

AD

126600

dystrophy

STGD4

-

4p

AD

603786

Adult vitelliform

RDS

6p21.2-cen

AD

179605

dystrophy

Butterfly-shaped

RDS

6p21.2-cen

AD

179605

dystrophy

Central areolar

RDS

6p21.2-cen

AD

179605

choroidal dystrophy

Best disease

VMD2

11q13

AD

153700

Pseudoxanthoma

ABCC6

16p13.1

AD/AR

177850

elasticum

Stargardt disease (3)

ELOVL4

6q14

AD

600110

North Carolina

-

6q14–q16.3

AD

136550

macular dystrophy

Central areolar

-

17p13–p12

AD

215500

choroidal dystrophy

Sorsby fundus

TIMP3

22q12.1–q13.2

AD

136900

dystrophy

Inherited retinal disease

89

MIM

126600

Clinical features

Characteristically, drusen involving the posterior pole, macula and

optic disc (including nasal to the disc) appear in early adult life.

The drusen are frequently distributed in a radial pattern and may

progress to form a ‘honeycomb’. In younger individuals there may

be hard drusen at the macula. The syndromes described by Doyne

in England and by Vogt in Switzerland (malattia leventinese)

represent the same condition.

A 55-year-old patient with a dominant family history of early central visual loss

and acuities of 6/24 in each eye. Notice the juxta-papillary lesions characteristic

of this disorder.

Age of onset

While there are occasional reports of patients with early-onset visual

loss, the majority of patients will not develop symptoms until adult

life. Advanced disease is associated with severe visual loss and

posterior pole atrophy. Increasing age is not invariably associated

with severe visual loss.

90

Doyne familial honeycombed choroiditis

Inheritance

True autosomal dominant. One individual who is homozygous for the

characteristic mutation has been shown to have a retinal phenotype

identical to heterozygotes of similar age.

Chromosomal location

2p16–21

Gene

EGF-containing fibrillin-like extracellular matrix protein 1 (EFEMP1)

Mutational spectrum

A single missense mutation (arginine to tryptophan substitution of

residue 345) has been found in all families.

Effect of mutation

The exact role of this extracellular molecule in retinal function is

unclear. As a result it is not yet known why defects lead to DHRD.

Inherited retinal disease

91

MIM

264800

(autosomal recessive); 177850 (autosomal dominant);

603234

(ABCC6)

Clinical features

PXE is characterized by yellowish papular plaques in the skin of

the flexures (pseudoxanthomata) associated with angioid streaks

of the retina.

92

Pseudoxanthoma elasticum

Inherited retinal disease

93

Dermatological

Pseudoxanthomata are yellowish papules or plaques that are seen

on the flexural aspects including the neck, axillae, antecubital fossa

and groin. Although asymptomatic, they may have poor cosmetic

consequences. The skin in these areas may become lax with time,

and surgery, attempted for cosmetic reasons, may heal poorly.

Gastrointestinal

Gastric hemorrhage is a recognized complication. Although the

exact prevalence is uncertain, a 10% lifetime risk of hemorrhage is

quoted. An increased frequency of GI bleeds during pregnancy has

also been reported.

Cardiovascular

Mitral valve prolapse, hypertension, ischemic heart disease and

peripheral vascular disease have all been associated with PXE.

Their exact prevalence is uncertain.

Age of onset

While ocular manifestations (e.g. peau d’orange) may be present

in childhood, angioid streaks develop later. Subretinal neovascular

membranes (SRNVMs) generally develop during adulthood.

Epidemiology

Incidence has been estimated at 1:25,000–50,000.

Inheritance

Among those cases with a family history, the majority are

consistent with autosomal recessive inheritance. However,

autosomal dominant kindreds may be seen. A large number

of cases are sporadic.

Chromosomal location

16p13.1

Gene

ATP-binding cassette, subfamily C, member 6 (ABCC6); alternative

name: multidrug resistance protein 6 (MRP6).

94

Pseudoxanthoma elasticum

Mutational spectrum

Among autosomal recessive pedigrees, homozygous mutations

including deletions, frameshifts, splice-site and missense mutations

have all been described. These include a recurrent R1141X

mutation which generates a stop codon and is shown to result

in loss of ABCC6 expression.

Both frameshift and missense mutations have been described in

presumed dominant families. These also include the R1141X

mutation, which has therefore been shown to be associated with

PXE phenotypes in both the heterozygous and homozygous state.

The majority of sporadic individuals have been found to have

heterozygous mutations although some are recessive. There is,

as yet, no clear-cut genotype/phenotype correlation.

Effect of mutation

ABCC6 is a member of the ATP-binding cassette transmembrane

transporter family (like ABCA4, see Stargardt disease), and is

involved in drug-resistance, especially relating to cancer

chemotherapy. ABCC6 is expressed highly in the kidney and liver

where its function is unknown. It is suggested that altered ABCC6

function may result in the defective transport of compounds that

are essential for extracellular matrix turnover or deposition.

Diagnosis

PXE is diagnosed on clinical grounds. Mutation analysis is not yet

widely available.

In addition to PXE, angioid streaks are seen in sickle cell anemia,

thalassemia, Paget disease of bone and beta alipoproteinemia. All

patients with angioid streaks should be examined for evidence of

PXE. Patients with apparently isolated angioid streaks should be

monitored to exclude the possibility of PXE, which may become

more apparent with time.

Patients should be aware of the risks of SRNVM and are advised

to seek specialist help if there is any change or distortion of vision,

or altered performance on an Amsler grid test. While GI and

cardiovascular complications are recognized, they are not common.

Inherited retinal disease

95

(also known as: SFD)

MIM

136900; 188826 (TIMP3)

Clinical features

SFD is characterized by loss of central vision due to subretinal

neovascular membrane (SRNVM) formation in middle life. The

eyes are affected sequentially leading to severe and sudden loss of

vision in virtually all affected individuals. Examination prior to the

development of SRNVM demonstrates pigmentary disturbance,

fine drusen-like deposits and atrophic lesions at the macula.

The peripheral retina is affected and patients may also describe

nyctalopia, which may precede the maculopathy. This may be

accompanied by peripheral visual field loss, decrease in dark

adaptation, and subnormal scotopic and photopic ERGs. There

is progressive peripheral chorioretinal atrophy and a generalized

retinal dystrophy may develop with bone spicule pigmentation,

vascular attenuation and choroidal atrophy.

A 45-year-old female with family history of Sorsby fundus dystrophy, proven on

TIMP3 mutation analysis. Vision is normal. Note the distribution of drusen around

the arcades.

Age of onset

Major symptoms result from development/hemorrhage of SRNVM.

This occurs in the fourth and fifth decades.

Inheritance

Autosomal dominant. Reports of recessive inheritance have been

shown to be incorrect.

96

Sorsby pseudoinflammatory fundus dystrophy

Chromosomal location

22q12.1–q13.2

Gene

Tissue inhibitor of metalloproteinase 3 (TIMP3)

Mutational spectrum

Only six mutations in this gene have been described to date, five of

which are missense mutations introducing a novel cysteine residue

into the C-terminal domain. Of these mutations, one (a serine to

cysteine substitution of residue 181) has been found in the majority

of UK families tested to date. This suggests a stronger founder effect

in British families.

Effect of mutation

Gain of function/dominant negative effect. All mutations give rise to

a protein that has characteristics of the normally functioning protein

but which forms stable dimers. These are thought to accumulate in

the retina, giving rise to an increase in TIMP3 activity within the

retina, which ultimately causes the disease process. Increased

TIMP3 expression has been observed in other retinal dystrophies

and it is suggested that TIMP3 overexpression may be a secondary

step in the progression of other degenerative retinopathies.

Diagnosis

In suspected SFD patients, genetic analysis is quick and highly

reliable. However, while proving an aid to diagnosis, DNA testing

does not alter the management of the condition. SFD is a highly

penetrant autosomal dominant condition associated with sudden

and severe loss of vision. Counselling of at-risk individuals is highly

complex. Both clinical examination and genetic testing can identify

those who are carriers of causative mutations. For many, the

knowledge of future visual disability is an enormous burden. As

some may live to regret presymptomatic diagnosis, genetic testing

and examination of unaffected relatives should be undertaken with

caution and with the support of those familiar with presymptomatic

testing protocols for other late-onset inherited conditions.

Inherited retinal disease

97

Including: age-related macular degeneration; RP19; CORD3

MIM

248200; 601691 (ABCA4)

Macular atrophy in autosomal recessive Stargardt disease.

Clinical features

STGD is one of the most common early-onset forms of macular

degeneration. The course of the disease is rapidly progressive and

the final visual outcome is poor.

The condition causes progressive loss of central vision, but, in

general, patients have good preservation of peripheral/night vision

even in the final stages of the disorder. Visual loss continues over a

period of several years, progressing to, and stabilizing at, around

6/36–3/60. Many patients with STGD are registered blind.

Throughout the posterior pole there are round, linear or pisiform

lesions—the characteristic retinal flecks—which may extend to the

equator. Fundus flavimaculatus (in which such retinal flecks are

more widespread) and STGD form part of a spectrum of flecked-

98

Stargardt disease: autosomal recessive

retina disorders. The retinal flecks represent lipofuscin-containing

deposits which accumulate in the RPE layer. The deposition of

lipofuscin gives rise to the ‘dark choroid’ sign on fluorescein

angiography due to masking of the underlying choroidal vasculature.

Electrophysiology is relatively uninformative. ERGs are normal early in

the disease but show reduction in the later stages. EOGs may be normal

or slightly depressed. With time, the retinal flecks may reduce or

disappear. There is progressive and generalized atrophy of the RPE and

choroidal vascular atrophy leading to widespread macular/RPE atrophy

and the development of a ‘beaten-bronze’ appearance at the macula.

Age of onset

Patients are usually diagnosed before the age of 20 years. Loss of

central vision may begin from around 6 years of age. However,

sometimes symptoms do not appear until adulthood.

Epidemiology

STGD is one of the most common causes of macular degeneration

in children, with a frequency of around 1:10,000.

Inheritance

Autosomal recessive

Chromosomal location

1p21–p22.1

Gene

ATP-binding cassette, subfamily A, number 4 (ABCA4); alternative

name: ATP-binding cassette transporter, retina-specific (ABCR).

Mutational spectrum

Mutations of this gene show a broad range of phenotypic

heterogeneity.

STGD and fundus flavimaculatus

A wide variety of disease-causing mutations have been described

in STGD. Using current techniques, mutations are found in

around 60% of cases. While both protein truncating and missense

mutations may cause STGD, the majority are missense mutations

affecting amino acids that are conserved between species and are

thought to be necessary for protein function.

Inherited retinal disease

99

CORD3

ABCA4 mutations have been shown to be an important cause of

autosomal recessive CRD.

ARMD

The role of ABCA4 in the etiology of classical ARMD remains

controversial.

Effect of mutation

While the major expression of ABCA4 is confined to rods,

immunofluorescence microscopy and Western blot analysis suggest

that the protein is present in cones as well. It is uncertain whether

the pathogenic effects relate to direct cone-mediated damage or a

more widespread effect. In the rod, ABCA4 is found on the disc

membrane of the retinal outer segments.

ABCA4 knockout mice show delayed dark adaptation, increased

levels of all-trans-retinaldehyde following light exposure and

lipofuscin deposition. Biochemical data suggest that ABCA4

facilitates transmembrane transport. Abnormal ABCA4 is

hypothesized to lead to accumulation of an opsin/all-trans-

retinaldehyde complex in discs.

Diagnosis

Ophthalmic examination and electrophysiological assessment are

often sufficient for diagnosis. STGD1 is often diagnosed in a child

after parents have decided to have more offspring and carries a 25%

a priori risk to siblings. A small number of dominant phenocopies

are described, although these are rare.

100

Stargardt disease: autosomal recessive

Inherited retinal disease

101

MIM

600110 (STGD3); 603786 (STGD4)

Clinical features

STGD is one of the most common early-onset forms of macular

degeneration. As discussed in the previous section, the condition is

generally autosomal recessive. However, a number of phenocopies

are recognized that are inherited in a dominant manner. Amongst

the dominant forms at least two have been shown to link to regions

distinct from chromosome 1, ABCA4 locus that causes the typical

recessive form of STGD. The form linked to chromosome 6 (STGD3)

shows reduced central vision (onset is in the first and second

decades) progressing to a final visual acuity in the range of 3/60 or

less. Patients have a well circumscribed atrophic lesion of the

choriocapillaris and RPE at the macula with surrounding flecks. As

with ‘typical’ STGD, the ERG is well preserved early on although

there may be mild reduction in later life. Fluorescein angiography

demonstrates absence of the ‘dark choroid’ sign that is seen in

typical, recessive STGD.

102

Stargardt disease: autosomal dominant

Age of onset

First or second decades

Epidemiology

The dominant forms of STGD are rare

Inheritance

Autosomal dominant

Chromosomal location

6cen–q14 (STGD3)

4p (STGD4)

Gene

Elongation of very long-chain fatty acids-like gene 4 (ELOVL4;

MIM 605512).

Mutational spectrum

To date, a single 5 bp deletion has been described in five families;

four families had AD STGD while the fifth family had ‘autosomal

dominant macular atrophy’.

Effect of mutation

The mutation described results in a frameshift and premature

protein termination. ELOVL4 is a member of a family of genes

important in fatty acid elongation. The gene is highly expressed

in the photoreceptors and shows low expression in the brain.

Diagnosis

STGD is generally a recessive condition and the majority of

individuals have been found to carry mutations in the ABCA4 gene

on chromosome 1. Ophthalmic examination and electrophysiological

assessment are usually sufficient for diagnosis.

Among the few proven dominant families the ‘dark choroid’ sign seen

on fluorescein angiography was not found. However, the single family

with a dominant form of STGD linked to chromosome 4 does show

the ‘dark choroid’ sign. As a result this cannot be used as a reliable

indicator of inheritance pattern. Currently, genetic testing of the

Stargardt genes is on a research basis only.

Inherited retinal disease

103

MIM

153700

(L) ‘Egg yolk’ lesion early in disease progression. At this stage central visual

acuity remains good. (R) Scarring of macular region. This 40-year-old has a

visual acuity of 6/18.

Clinical features

In the initial stages, a bright yellow cyst forms under the RPE beneath

the macula. This classical lesion is the round or oval, yellow ‘egg yolk’

(vitelliform) lesion at the macula. Characteristically, fundoscopic

changes precede visual impairment and, despite the presence of the

cyst, visual acuity may remain normal or near normal (between 6/9

and 6/18) for many years. Peripheral vision is generally unaffected.

In many individuals, the cyst eventually ruptures (vitelliruptive stage)

leading to visual loss from macular/RPE atrophy. At this stage there

may be deterioration of central vision.

Amongst the inherited macular dystrophies, clinical outcome in

VMD2 is relatively optimistic. Many patients retain a binocular

visual acuity of 6/18 or better, at a late stage of the disease course.

Significant asymmetry is often noted. While older patients tend to

have worse visual acuities, many retain useful central vision in one

eye with a visual acuity of about 6/12 in the better eye. There is

marked intrafamilial variability in macular pathology (even amongst

families with different mutations within the VMD2 gene).

104

Vitelliform macular dystrophy

Diagnosis is confirmed by electrophysiology. There is a grossly

reduced EOG (reduced light-induced rise <125%) which, in the

presence of a normal ERG, is strongly suggestive of VMD2. The

abnormal EOG is suggestive of a primary pathology of the RPE;

this is supported by evidence from histopathologic analysis of post-

mortem eyes showing widespread RPE accumulation of lipofuscin.

Age of onset

Although the age of onset of VMD2 can vary, it is usually diagnosed

during childhood or adolescence. The age of onset of manifest visual

disability varies significantly from early childhood to middle-age.

Inheritance

Autosomal dominant. This is a truly dominant condition since

descriptions of homozygotes suggest that they are phenotypically

indistinguishable from heterozygotes.

Chromosomal location

11q13

Gene

VMD2

Mutational spectrum

A large number of mutations, predominantly missense, have now

been described in the VMD2 gene for bestrophin; the majority are

situated in the first half of the gene. In addition, some patients with

adult vitelliform macular dystrophy carry mutations in the VMD2

gene. A single case of ‘bull’s-eye’ maculopathy has been reported

with a VMD2 mutation. However, results of analysis in two large

series of patients suggest that VMD2 does not play a major role in

the etiology of ARMD.

Effect of mutation

The VMD2 gene encodes a 585-amino acid protein that is predicted

to contain four transmembrane domains. Apart from expression in

the Sertoli cells of the testes, the gene is exclusively expressed in

the RPE.

Diagnosis

Fundoscopic examination and electrodiagnostic evaluation (i.e.

grossly reduced EOG), particularly in association with a positive

Inherited retinal disease

105

106

Vitelliform macular dystrophy

MIM

303100

Adult male with choroideremia.

Clinical features

Symptoms of visual field constriction and night blindness are similar

to those of RP. Effects on central visual function follow much later.

The fundoscopic appearances are characteristic. In the first decade,

there is RPE loss and granularity with subsequent development of

scalloped lesions through which large choroidal vessels can be seen.

During the second and third decades the characteristic peripheral,

geographic loss of choriocapillaris and RPE spreads centrally with

the characteristic scalloped areas of loss finally encroaching upon

the posterior pole. The ERG is markedly reduced with delays in

b-wave implicit time and absence of rod responses.

Virtually all heterozygous females describe no symptoms and have

no visual defects. However, they often show striking fundoscopic

changes with irregular pigmentary disturbance. Their ERGs are

usually normal. A small number of affected females have been

reported, of whom several had X chromosomal rearrangements.

Inherited retinal disease

107

Age of onset

In the majority of boys, fundoscopic abnormalities are visible from

around 10 years onwards. Diffuse chorioretinal degeneration is first

seen between 10–20 years. Central macular function is preserved

until very late in the course but affected males retain little, if any,

useful vision beyond 60 years.

Choroideremia: fundus periphery of female carrier showing abnormal pigment

distribution. Patient had no symptoms and normal ERGs.

Inheritance

X-linked recessive

Chromosomal location

Xp21.2

Gene

Rab escort protein 1 (REP-1)

Effect of mutation

Virtually all mutations result in absence of the REP-1 protein product

or in abolition of its function.

Rab proteins are GTPases that are crucial for vesicular membrane

trafficking. Post-translational modification of these proteins by

addition of 20-carbon isoprenoid (geranylgeranyl) groups to cysteine

motifs in the C-terminal is important for their membrane association

and function. This is catalyzed by Rab geranylgeranyl transferase

(Rab-GGTase), a multi-subunit enzyme consisting of a catalytic

heterodimer and an accessory component, REP-1.

108

Choroideremia

REP-1 is a widely expressed protein but it is hypothesized that

certain retinal or ocular-specific Rab proteins depend upon REP-1

function. If so, this might explain the ocular-specific phenotype.

Diagnosis

In familial cases, intragenic polymorphic markers may be used for

accurate presymptomatic and carrier diagnosis. If required, mutation

testing for sporadic cases—or those in which the diagnosis is

uncertain—may be achieved either by conventional DNA-based

mutation testing or by protein truncation testing (q.v.).

Inherited retinal disease

109

Clinical features

CRD is often characterized by early impairment of vision. In

the outset there is reduced visual acuity and loss of color vision,

reflecting initial degeneration of cones. This is followed by night

blindness and loss of peripheral vision, due to rod degeneration.

The condition is progressive and symptoms are accompanied by

widespread retinal degeneration affecting both central and peripheral

retina. Initially, ERG changes usually show loss of cone-mediated

responses, although later there will be widespread reduction of

both cone and rod-mediated responses.

Age of onset

First decade. Some families are described (e.g. CORD7) with

adult-onset.

Inheritance

Autosomal dominant; autosomal recessive; X-linked

Chromosomal location and genes

Gene

Locus

Chromosomal location

MIM

Inheritance

-

CORD1

18q21.1–q21.3

600624

Deletion

CRX

CORD2

19q13.3

120970

AD

ABCA4

CORD3

1p13–p21

604116

AR

-

CORD5

17p12–p13

600977

AD

GUCY2D

CORD6

10p13

600179

AD

-

CORD7

6cen–q14

603649

AD

-

CORD8

1q12–q24

-

AR

-

CORD9

8p12–q11

-

AR

HRG4

Cone-rod dystrophy

17q11.2

-

AD

RPGR

COD1

Xp11.4

304020

X-linked

110

Cone-rod dystrophy

Diagnosis

CRD is often a distressing diagnosis as it is frequently severe and of

early-onset. The condition is highly heterogeneous both genetically

and phenotypically and as a result molecular analysis is not yet

available.

Inherited retinal disease

111

Including: Goldmann-Favre syndrome

MIM

268100; 604485 (NR2E3)

Clinical features

ESCS is a rare retinal degenerative disease. Fundoscopy reveals

degenerative changes around the vascular arcades including yellow

flecks, RPE atrophy or pigment deposition. Macular changes are

common and include CMO in around 50% of cases. Dark adaptation

shows little or no rod contribution.

ERG testing is characteristic. In the dark-adapted state there is no

response to dim stimuli. There is a large, often supernormal, slow

response to a single white flash in both the light-adapted and dark-

adapted states. The photopic ERG is more sensitive to blue/green

wavelengths than red/orange. While there is decreased sensitivity

of rods and middleand long-wavelength cones there is enhanced

sensitivity of short wavelength (blue) cones, or S-cones.

Age of onset

Patients have early-onset night blindness, but few problems with

peripheral or color vision.

Inheritance

Autosomal recessive

Chromosomal location

15q23

Gene

Nuclear receptor subfamily 2, group E, member 3 (NR2E3)

Mutational spectrum

In one study, mutations were found in over 90% of patients with

ESCS. The majority were loss of function mutations including one

splice-site alteration, a single in-frame 9 bp deletion and several

missense mutations. Mutations have been found in a form of arRP

seen in Portuguese crypto-Jews. This suggests either that ESCS is

112

Enhanced S-cone syndrome

similar to RP in later stages or that the phenotype may differ on

different genetic backgrounds.

Effect of mutation

Members of the nuclear receptor family are transcription factors,

characterized by discrete DNA and ligand-binding domains. They

have various functions including the regulation of pathways involved

in development. NR2E3 is a photoreceptor cell-specific nuclear

receptor that is thought to have a role in controlling the normal

development and topography of cone subtypes.

Diagnosis

ESCS is diagnosed by characteristic ERG responses. Enhanced

S-cone function is seen in Goldmann-Favre syndrome, a recessive

retinal degeneration that is also characterized by vitreous

degeneration and foveal and peripheral schisis. It has been

suggested that ESCS and Goldmann-Favre syndrome are allelic.

Inherited retinal disease

113

(also known as: LCA)

Clinical features

The LCAs are a group of autosomal recessive early-onset retinal

dystrophies that are a common cause of congenital visual impairment.

Infants may have photophobia and eye-poking (Franceschetti’s sign).

Patients have roving eye movements and are unable to fix and follow

at birth. Nystagmus develops later. Pupil reactions are sluggish,

occasionally with a paradoxical response. Refractive error is common

and many patients are highly hypermetropic. Keratoconus is a

recognized association.

Initially, fundoscopy is normal but this changes with time. Ultimately,

there is evidence of a widespread retinopathy with peripheral

pigmentation, vessel attenuation and optic disc pallor. Macular

changes are common—in many there is early pigment disturbance

with later atrophic changes. Macular colobomatous changes have

also been described and reflect the range of heterogeneity. Patients

have a non-detectable ERG by 3 months of age.

Classically, LCA is an isolated retinal dystrophy. The mutations in

the underlying genes have been found amongst individuals without

extraocular manifestations. Heterogeneity amongst early-onset

dystrophies includes the association of mental retardation in some

patients. Herein, LCA is defined solely as an ocular condition.

Age at onset

Birth, or in the first few weeks of life.

Inheritance

Autosomal recessive

As there is evidence for some correlation of genotype and phenotype

among the different types of LCA, the phenotypic range of mutations

in GUCY2D, CRX, etc. are described here.

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Leber congenital amaurosis

Chromosomal location

Disorder

Gene

Chromosome

MIM

LCA1

GUCY2D

17p13.1

204000

LCA2

RPE65

1p31

204100

LCA3

-

14q24

604232

LCA4

AIPL1

17p13.1

604393

LCA5

-

6q11–q16

604537

LCA6

RPGRIP1

14q11

605446

LCA

CRX

19q13.3

604393

LCA

CRB1

1q31–q32.1

604210

Variability of phenotypes

Disorder

Gene

Phenotypes

MIM

LCA1

GUCY2D

LCA1

600179

adCORD6

LCA2

RPE65

LCA

180069

Juvenile retinal

dystrophy

RP20 (arRP)

LCA4

AIPL1

LCA

604392

LCA

CRX

LCA

602225

adRP

adCORD2

LCA

CRB1

LCA

604210

RP12 (arRP)

RP with Coats-like

exudative vasculopathy

GUCY2D

Clinical features

Leber congenital amaurosis (LCA1)

Mutations in GUCY2D are said to result in a severe, early-onset

cone-rod degeneration. Characteristically, there is high

hypermetropia and severe photophobia. Retinal changes develop

Inherited retinal disease

115

Autosomal dominant cone-rod dystrophy (CORD6)

Affected individuals display cone dysfunction (reduced VA,

photophobia, altered color vision) in the first decade. At this stage

there is severe loss of photopic ERG with relative preservation of

the scotopic ERG. Visual acuity decreases dramatically during the

second and third decades, to be followed by night blindness in

the fourth and fifth decades, at which stage the ERG becomes

unrecordable.

Gene

Guanylate cyclase 2D (GUCY2D); alternative name: RetGC1.

Mutational spectrum

LCA1

A broad range of mutations have been found to cause LCA1. The

frequency of mutations in cases of LCA1 is uncertain—reports vary

from 6–20%. These include frameshift, nonsense, splice-site and

missense mutations.

CORD6

Missense mutations in residues 837 and 838 alter a region critical

to dimerization of GUCY2D. These result in autosomal dominant

cone-rod dystrophy.

Effect of mutation

Phototransduction results in hydrolysis of cGMP, closure of cGMP-

gated cation channels, and plasma membrane hyperpolarization.

In the dark (recovery) phase, cGMP levels are restored through the

conversion of GTP to cGMP by guanylate cyclase, which reopens

the channels and leads to an influx of Ca2+ and Na+. In LCA1, it

is presumed that there is loss of function of RetGC1. cGMP-gated

channels are permanently closed as cGMP levels are not restored to

dark levels. In effect there is constant light exposure, explaining the

early impairment of rod and cone function.

In CORD6, GUCY2D mutations in the dimerization domain result

in gain of function (i.e. dominant negative) effects. The mutations

result in altered sensitivity to Ca2+ and increased sensitivity to

activation by GUCA1A (see CORD3). The resultant alteration of

116

Leber congenital amaurosis

Ca2+ concentration and cGMP channel activity may result in retinal

degeneration. A mutation in GUCA1A in cone dystrophy also results

in alteration of the GUCA1A/Ca2+ sensitivity, suggesting that the two

diseases share a similar etiology.

RPE65

Clinical features

Patients with RPE65 mutations have a severe early-onset retinal

degeneration characterized by moderate or absent hypermetropia

(even low myopia). Symptoms are noted from birth onwards, as in

other forms of LCA, with an inability to follow light or objects, and

roving eye movements. This is followed by the development of

pendular nystagmus. Parents notice a transient improvement in

vision, particularly in well-lit conditions, while night blindness is a

major symptom. Central visual acuity is in the range of 6/36–6/60.

Visual fields are recordable and show concentric field loss while the

ERG is unrecordable.

In some families there is an early-onset severe retinal dystrophy,

which is said to be less aggressive than LCA, although whether this

is truly a different entity to LCA is debatable. Patients are noted to

have a rod-cone dystrophy causing severe visual impairment before

the age of 5 years (i.e. not at birth). Such patients retain useful visual

function up to (and in some cases beyond) the age of 10 years.

Gene

Retinal pigment epithelium-specific protein, 65 kDa (RPE65)

Mutational spectrum

RPE65 is a 65 kDa protein expressed in the RPE. The protein is

and effect of mutation

important in retinal vitamin A metabolism and is thought to be essential

for isomerization of 11-cis retinol, a key step in the RPE visual cycle.

Mutations in the LRAT gene, encoding lecithin retinol acyltransferase

(an early enzyme in the pathway involved in 11-cis retinal synthesis)

causes a similar, early-onset and severe, recessive retinal dystrophy.

Premature termination, nonsense, splicing and missense mutations

cause 6–16% of cases of LCA and are thought to abolish RPE65

function.

Inherited retinal disease

117

Screening of a panel of patients with arRP demonstrated mutations

in around 2% of cases. Some families had one allele with a missense

mutation that did not alter amino acid charge. It is thought that

these mutations retain some residual function (hypomorphic allele)

which may explain the milder phenotype.

AIPL1

Clinical features

Although the retinal features associated with mutations in AIPL1 are

not distinctive, many patients with LCA4 also have keratoconus.

Gene

Arylhydrocarbon-interacting receptor protein-like 1 (AIPL1)

Mutational spectrum

Missense, nonsense and frameshift mutations are all described,

and effect of mutation

suggesting that mutations result in severe diminution or loss of

function. One study suggests that AIPL1 mutations cause around

7% of LCA. The function of AIPL1 in the retina is not known

although it is thought to be important in protein folding or trafficking.

RPGRIP1

Clinical features

The clinical features of LCA type VI are typical of classical forms of

the condition.

Gene

RPGRIP1 (RPGR-interacting protein)

Mutational spectrum

RPGR is the gene mutated in one form of X-linked RP (RP3).

and effect of mutation

RPGRIP1 is expressed strongly in the retina and interacts with

RPGR and co-localizes with it in the photoreceptors. It is suggested

that RPGRIP1 is important in the connecting cilia of rods and cones.

The protein is predicted to have two coiled-coil domains which are

seen in proteins involved in vesicular trafficking.

118

Leber congenital amaurosis

Clinical features

A wide variety of clinical phenotypes have been described associated

with CRX mutations, including classical forms of LCA, cone-rod

dystrophy and late-onset rod-cone dystrophy. CRX mutations are

found in 2–3% of cases of LCA.

Gene

CRX is a photoreceptor-expressed transcription factor that binds to

DNA sequences upstream of several photoreceptor-specific genes

including opsins, arrestin and b-phosphodiesterase.

Mutational spectrum

Mutations in CRX have demonstrable effects in the heterozygous

state. Frameshift and missense mutations have been described.

The majority of missense changes are within the homeodomain.

Effect of mutation

Cases of LCA have been shown to be due to de novo mutations

that were not present in the parents. One exception was a family

with LCA in which both parents were heterozygous for a missense

mutation that caused a mild cone-rod dystrophy. The homozygous

state was associated with LCA.

Diagnosis

LCA was originally defined as a recessive condition of severe

and early onset. Genetic testing is not widely available. However,

demonstration that de novo mutations in CRX are associated with

LCA suggests that in some families the condition is a new dominant.

Therefore, in these families, recurrence risks are significantly lower

than 25%, and affected individuals have a 50% chance of passing

the condition on to their offspring.

Inherited retinal disease

119

MIM

180090 (RLBP1)

Clinical features

RPA is characterized by the presence of numerous, punctate

yellow/white dots throughout the fundus. They spare the macular

region and often fan out in apparently radial patterns, being most

numerous in the equatorial region. The punctate lesions may show

little change with time, although as retinal degeneration continues

there may be more classical features of RP with pigment deposition,

arteriolar attenuation and optic disc pallor. Symptoms of night

blindness, peripheral visual loss and reduced visual acuity are similar

to other rod-cone dystrophies and are variable in their age of onset.

Among six unrelated families with RLBP1 mutations, all had RPA.

One family from Sweden had a form of RPA, known as Bothnia

dystrophy, which is common in northern Sweden.

Age at onset

In patients with RLBP1 mutations, night blindness is noted in the

first decade progressing to legal blindness in their 20s. Often, even

late in the disease, there is no retinal pigment dispersion.

Inheritance

Autosomal recessive

Autosomal dominant. Mutations in rhodopsin and RDS/peripherin

have been shown to cause progressive retinal degeneration

associated with retinal flecks.

Chromosomal location

15q26 (recessive RPA)

Gene

Retinaldehyde-binding protein 1 (RLBP1); alternative name: cellular

retinaldehyde-binding protein (CRALBP).

Mutational spectrum

Missense mutation of conserved residues, splice-site mutation and

frameshift mutations have all been described.

120

Retinitis punctata albescens

Effect of mutation

The majority of isolated retinal degenerations described to date

result from defects in proteins expressed in the photoreceptors. A

number are now recognized, such as RLBP1, that are expressed in

the RPE. RLBP1 is involved in the visual cycle, the process whereby

11-cis retinaldehyde (which is converted to its all-trans isomer by

light) is regenerated via a complex biochemical pathway that

involves both photoreceptors and RPE. RLBP1 binds 11-cis retinol

and promotes its oxidation to 11-cis retinaldehyde within the RPE

before the latter is transferred back to the photoreceptor.

Mutated versions of RLBP1 have been shown to lack the ability to

bind 11-cis retinaldehyde. This may lead to an inability to regenerate

rhodopsin or, through the depletion of 11-cis retinaldehyde, may lead

to a disturbance of rod outer-segment physiology.

Diagnosis

RPA is characterized by the presence of yellowish dots throughout

the fundus. It should not be confused with fundus albipunctatus,

which is a stationary disorder (see section on congenital stationary

night blindness).

Inherited retinal disease

121

Bone spicule retinal pigmentation of retinitis pigmentosa.

Clinical features

Patients first experience night blindness, constriction of the peripheral

visual field and eventually lose central vision. They describe difficulties

in dark or poorly-lit surroundings and have trouble changing from well-

to poorly-lit conditions, reflecting abnormal dark adaptation. Some

patients may also have photophobia.

Diagnosis is based on a progressive, bilateral, photoreceptor

dysfunction associated with undetectable or reduced amplitude

ERGs in which rod-mediated responses are more severely affected

than cone-mediated (i.e. rod-cone dystrophy). However, within

these boundaries there are wide variations at the clinical level, as

defined by inheritance pattern, age at onset, speed of progression

and fundoscopic appearance.

Fundoscopy classically shows redistribution of pigment with

RPE disturbance and intraretinal accumulation in a bone-spicule

distribution. Pigment may also be seen within the vitreous cavity.

The pigment may be distributed in a perivascular fashion and is

122

Retinitis pigmentosa

Epidemiology

The prevalence of RP is around 1:3500–4000 in the USA

and Europe.

Inherited retinal disease

123

124

Retinitis pigmentosa

Clinical features

The clinical characteristics of adRP may be highly variable. As with

other inheritance patterns, there are now a large number of different

genes that are recognized to cause adRP, which represents around

20–25% of cases of RP.

Autosomal domant retinitis pigmentosa.

Genes

The majority of the genes known to cause adRP are photoreceptor-

specific. Of the remainder, NRL (neural retinal-specific leucine

zipper transcription factor gene) has been shown to display its

highest level of expression in the photoreceptor. Rhodopsin (RHO),

RDS/peripherin and ROM1 are all found in the rod outer segments.

RHO was the first gene shown to cause RP and is a significant cause

of adRP; it is estimated that 30–40% of adRP is caused by RHO

mutations. Mutations in RDS/peripherin have been shown to cause

a wide range of retinal phenotypes including one form of RP, termed

‘digenic’, in which mutations of two genes (RDS/peripherin and

ROM1) together result in a phenotypic effect.

Of the remaining genes, both CRX and NRL are retinal-specific

transcription factors that are important in regulating developmental

gene expression. RP1, a form of adRP linked to chromosome 8q11,

Inherited retinal disease

125

Loci and genes

Gene

Locus

Chromosomal

MIM

implicated in adRP

location

PRP31

RP18

1q13–q23

601414

RHO

RP4

3q21–q24

180380

RDS/peripherin

RP7

6p21.2–cen

179605

-

RP9

7p13–p15

180104

IMPDH1

RP10

7q31.3

180105

RP1

RP1

8q11–q13

180100

ROM1/RDS

Digenic RP

11q13

180721

NRL

RP27

14q11.2

162080

PRPC8

RP13

17p13.3

600059

-

RP17

17q22

600852

CRX

-

19q13.3

602225

HPRP3

RP11

19q13.4

600138

126

Autosomal dominant retinitis pigmentosa

Including: autosomal dominant macular dystrophy; pattern/butterfly-

shaped dystrophy; adult vitelliform dystrophy; central areolar

choroidal dystrophy (CACD); retinitis punctata albescens;

progressive cone dystrophy.

MIM

179605

Clinical features

The range of phenotypes caused by mutations in the peripherin/RDS

gene is remarkable, including widespread dystrophies such as RP,

macular dystrophies and isolated cone dystrophies. There is

significant inter and intrafamilial variation.

Many of the early-onset macular dystrophies have been named on

morphological grounds. Adult vitelliform dystrophy is characterized

by small, circumscribed subfoveal lesions that present from the third

decade of life onwards. Morphologically similar to Best disease, the

condition lacks the characteristic EOG changes. Adult vitelliform

dystrophy may be relatively mild, but in some cases can progress

and result in significant bilateral macular damage. ERG/EOG

examination is normal.

Inherited retinal disease

127

128

Peripherin/RDS

Gene

Retinal degeneration slow (RDS). The RDS gene was the second

gene shown to cause RP. In the mouse a naturally occurring mutant

causes the RDS phenotype.

Mutational spectrum

A broad range of mutations have been described throughout the

gene including missense, nonsense and frameshifts. The protein

contains four transmembrane domains and is situated in the rod

outer segment discs. There are two cytoplasmic loops situated in

the lumen of the discs. Many mutations are situated in the larger

of the intradiscal loops.

Effect of mutation

RDS is an integral structural protein of rod outer segment discs

associated with ROM1 (q.v.). These proteins are situated at the lip

of the discs and are thought to be important in stabilization of the

curved disc edges. It is presumed that the mutations have specific

dominant negative effects that result in photoreceptor degeneration.

Inherited retinal disease

129

Including: rhodopsin-related retinitis pigmentosa; autosomal

recessive retinitis pigmentosa; retinitis punctata albescens;

congenital stationary night blindness, rhodopsin-related; autosomal

dominant retinitis pigmentosa type 4; RP4.

MIM

180380

Clinical features

A wide variety of pedigrees with rhodopsin mutations have now been

analyzed. These demonstrate a high degree of inter and intrafamilial

variability. Some individuals have severe RP4 in the first and second

decades, in others it is delayed (fourth-fifth decades or later).

ERG examination reflects this variability, with some patients having

extinguished or severely reduced ERGs early in life. Others may have

entirely normal examination until adulthood. In general, ERGs show

early deterioration of rod-mediated responses; cone-mediated

responses decline later in life.

Fundoscopy may also vary widely. The majority of patients have

classical RP. Sector RP has been described, in which the inferior

retina is more severely affected than the superior retina, with

superior field loss. Retinitis punctata albescens is a dominantly

inherited retinal dystrophy in which the characteristic feature is

the presence of white/yellow dots scattered throughout the fundus.

CNSB has also been associated with certain rhodopsin mutations.

Chromosomal location

3q21–q24

Gene

RHO

Mutational spectrum

A wide range of mutations have been described throughout the gene.

The majority are missense mutations with no strong evidence of

genotype-phenotype correlation. There is a general tendency

130

Rhodopsin

towards a gradient of severity with the more severe mutations being

located at the 3´ end of the gene and the milder ones at the 5´ end.

Certain mutations have been associated with the specific

phenotypes described above, although the findings are by no means

clear-cut. An arginine to tryptophan substitution at position 135 has

been described in association with retinitis punctata albescens and

classical RP in the same family. Sector RP has been described with

missense mutations at the 5´ end of the gene while CSNB has also

been described in association with a small number of missense

changes (see CSNB).

A small number of families have been found with arRP as a result of

null rhodopsin mutations. These cause absent rhodopsin expression.

Effect of mutation

In recessive mutations it is likely that retinal dystrophy is caused

by the absence of rhodopsin. As heterozygous carriers of such

mutations do not manifest symptoms, haploinsufficiency is not

disease-causing and in the majority of cases missense mutations

are likely to act in a dominant-negative manner. The exact cause of

photoreceptor decay is not certain; accumulation of the abnormal

protein has been demonstrated in the endoplasmic reticulum,

cytoplasm and cell membrane and is thought to contribute to

photoreceptor apoptosis.

Inherited retinal disease

131

A large number of different genes are recognized to cause autosomal

recessive retinal dystrophies. In addition to those causing Leber

congenital amaurosis and syndromic forms of arRP (e.g. Usher

syndrome and Bardet-Biedl syndrome), around 20 loci are already

known to cause isolated arRP.

arRP represents 15–30% of cases of RP.

Clinical features

The clinical characteristics amongst patients with arRP—age at

onset, speed of progression, visual acuity—vary widely and cannot

be generalized. With the burgeoning information regarding the genes

involved, many groups have developed large screening panels of

DNA from patients with arRP. Such groups of patients are analyzed

for each novel gene and mutations are defined. Detailed clinical

descriptions are often not allied to such a process. However, there are

some recessive retinal dystrophies with characteristic clinical features

such as PPRPE or retinitis punctata albescens (multiple punctate

white/yellow dots). These are dealt with in separate sections below.

Genes

A large number of genes are known to cause arRP, suggesting that a

range of mutations can result in a similar ‘final common pathway’ of

photoreceptor and RPE dysfunction, apoptosis and retinal atrophy.

The majority of these arRP genes are expressed in the photoreceptor

and a number of photoreceptor-specific processes have been

implicated—the most important of which is the phototransduction

cascade. Several proteins involved in phototransduction (such as

RHO, PDE6A, PDE6B and CNGA1) and its recovery phase (such as

arrestin or SAG) are now recognized to cause isolated arRP. A number

of RPE-specific proteins have also been identified, such as RPE65

(see Leber congenital amaurosis), LRAT and RLBP1 (see retinitis

punctata albescens).

132

Autosomal recessive retinitis pigmentosa

The function of many of the genes that have been identified is

currently unknown. An example is TULP1 which causes rare forms

of arRP. A member of a family of highly conserved proteins, TULP1

is expressed in photoreceptors and is thought to play a role in their

development and maintenance. However, as with many other genes

that cause isolated retinal dystrophies, TULP1 is not exclusively

expressed in the retina and is found in extraocular tissues.

As would be expected, the majority of mutations in the genes

underlying arRP result in loss of function. In almost all cases one

normal allele (i.e. the heterozygous state) is compatible with

normal function.

Diagnosis

Diagnosis of arRP remains a complex issue, in particular amongst

cases of simplex or isolated RP, and requires careful clinical

examination and evaluation. Amongst the childhood-onset forms,

symptoms often become apparent at a stage when parents may

already have had further children. The clinician is then faced with

asymptomatic younger siblings who have a 25% risk of developing

symptoms. Deciding when to examine family members and then

preparing parents for bad news is a difficult issue that may require

considerable clinic time.

The high proportion of single individuals with no family history of

the disease (simplex RP) remains one of the greatest diagnostic

challenges among patients with non-syndromic RP. While the

majority represent recessive forms, it is nevertheless possible that

some will be due to new or reduced penetrance dominant mutations,

or even X-linked forms of RP. The advent of molecular testing will

undoubtedly have a significant role to play in the future for

facilitating the diagnosis of such forms of RP and will help to define

inheritance patterns and prognosis for those in whom family history

offers no clue. However, the sheer complexity of RP is only now

beginning to unfold and technology is as yet unable to offer adequate

genetic screening tests to answer these questions.

Inherited retinal disease

133

Gene

Locus

Chromosomal location

MIM

RPE65

RP20

1p31

180069

ABCA4

RP19

1p21–p22

601718

CRB1

RP12

1q31–q32.1

268030

USH2A

USH2A

1q41

279901

-

RP28

2p11–p15

-

MERTK

MERTK

2q14.1

604705

-

RP26

2q31–q33

-

SAG

SAG

2q37.1

181031

RHO

RP4

3q21–q24

180380

PROML1

PROML1

4p12–p16.2

604365

PDE6B

PDE6B

4p16.3

180072

CNGA1

CNGA1

4p12–cen

123825

LRAT

LRAT

4q31.2

604863

-

RP29

4q32–q34

-

PDE6A

PDE6A

5q31.2–q34

180071

TULP1

RP14

6p21.3

600139

-

RP25

6cen–q15

602772

RGR

RGR

10q23

600342

RBP4

RBP4

10q24

180250

RLBP1

RLBP1

15q26

180090

-

RP22

16p12.1–p12.3

602594

134

Autosomal recessive retinitis pigmentosa

Including: Leber congenital amaurosis, RP with Coats’-like exudative

vasculopathy.

MIM

268030; 600105 (RP12); 604210 (CRB1)

Clinical features

This is an uncommon and aggressive form of early-onset arRP with a

characteristic retinal phenotype. Within areas of generalized retinal

atrophy there is relative preservation of the para-arteriolar retinal

pigment epithelium. Visual acuity is lost early in the disease process.

Patients are often hypermetropic and may have disc drusen.

Age of onset

First decade of life

Inheritance

Autosomal recessive

Chromosomal location

1q31–q32.1

Gene

Crumbs, Drosophila homolog of, 1 (CRB1)

Mutational spectrum

PPRPE: amongst patients with PPRPE, both homozygous missense

and protein truncating mutations have been described.

LCA: a significant proportion of patients with Leber congenital

amaurosis carry mutations in the CRB1 gene. While there is

variability of phenotype associated with mutations in this gene,

there is no obvious correlation with site or type of mutation.

However, patients with null alleles and nonsense, frameshift and

splice-site mutations (i.e. those that would not be predicted to

form a protein) most frequently develop LCA rather than PPRPE.

Inherited retinal disease

135

RP with Coats’-like exudative vasculopathy: a small number of

patients with RP develop an exudative vasculopathy reminiscent of

Coats’ disease, often unilaterally. A number of patients with CRB1

mutations have been found to have a Coats’-like reaction, although

this was not always present in affected family members.

Effect of mutation

In Drosophila melanogaster, the crumbs protein is important in

maintaining epithelial polarity. The homology to CRB suggests a role

for CRB1 in cell-cell interaction and in maintenance of cell polarity

in the retina. The distinctive RPE changes suggest that CRB1

mutations act via a novel pathogenic mechanism.

136

Retinitis pigmentosa with preserved para-arteriolar retinal pigment epithelium

MIM

180721 (ROM1)

Clinical features

Classical retinitis pigmentosa

Inheritance

Digenic

Chromosomal location

11q13

Gene

Rod outer segment protein 1 (ROM1)

Mutational spectrum

Mutations in ROM1 alone have not been proven to be pathogenic.

However, when present in association with a specific

RDS/peripherin missense mutation (leucine to proline substitution

of residue 185), ROM1 mutations result in RP. Since this requires

specific genetic changes at two loci this is termed ‘digenic

inheritance’.

Digenic inheritance is difficult to identify, but may explain how

mutations at different loci interact to cause disease or to modify the

phenotypic effects of a mutation. Such interactions may underlie the

variability seen in some genetic conditions.

Effect of mutation

ROM1 is found in the rod outer segment discs, where it is important

for stabilizing the disc edges. The protein interacts closely with

RDS/peripherin, which explains the pathogenicity of the

combination of the two genetic changes.

Inherited retinal disease

137

Clinical features

XLRP is a severe form of RP that affects males in their first decade

of life and progresses to blindness by the third or fourth decades.

Males are generally myopic and present with a rod-cone dystrophy,

although families with variable presentation have also been

described and individuals within proven RP3 kindreds have been

shown to have cone-rod dystrophy. XLRP is an important cause of

RP accounting for 10–23% of all cases.

In addition to these forms of XLRP, X-linked forms of CSNB, cone-rod

and cone dystrophies have been described. Linkage has been

defined for several of the X-linked loci, but for many the underlying

genes have not been identified. It remains possible, therefore, that

mutations at novel loci might be responsible for more than one of

these phenotypes.

Clinical manifestations in carrier females

As with other X-linked conditions, female carriers may manifest

symptoms of XLRP, albeit to a milder degree than their male

relatives. The age of onset among female carriers is highly variable.

This mild phenotype has been ascribed to the variability of

X-inactivation. However, in certain pedigrees symptomatic females

are common. This suggests that for some forms of XLRP, inheritance

may be X-linked dominant.

Determination of carrier status is often possible by fundoscopy and

ERG examination, although this is less reliable in younger females.

Clinically, the two most common forms of XLRP (RP3 and RP2) may

be differentiated by the presence in carrier females of a ‘tapetal-like’

reflex on direct ophthalmoscopy. This glistening metallic white/gold

reflex is most noticeable in the paramacular region and is suggestive

of an RPGR mutation. It is not present in all carriers or within all

pedigrees linked to the RPGR gene.

138

X-linked retinitis pigmentosa

Age of onset

XLRP begins in the first decade.

Inheritance

X-linked recessive. Some families are recognized in which

phenotypic manifestations are common in carrier females,

suggesting X-linked dominant inheritance.

Chromosomal location

As with other inherited forms of RP, XLRP shows both clinical and

and genes

genetic heterogeneity.

Gene

Locus

Chromosomal location

MIM

Frequency

-

RP23

Xp22

-

Single family

-

RP6

Xp21.3–p21.2

312612

Single family

RPGR

RP3

Xp21.1

312610

75%

RP2

RP2

Xp11.3

312600

10%

-

RP24

Xq26–q27

300155

Single family

Mutational spectrum

RP3

Inherited retinal disease

139

RP2

RP2 is a ubiquitously expressed protein of unknown function.

The protein is localized to the cell membrane in fibroblasts and

the cytoplasm of COS-7 cells. The localization in retinal cells is

undetermined. The N-terminus is homologous to cofactor C, a

chaperone protein which acts as a protein involved in the folding

of a- and b-tubulins. Mutations fall into two classes: missense

mutations clustered in the cofactor C homologous domain – these

mutations do not alter subcellular localization of the protein and

are hypothesized to reduce function of the important N-terminal

domain; premature protein truncation – these constitute the majority

of the remaining mutations.

Diagnosis

Identification of X-linked inheritance is important when defining

recurrence risks in families with RP. Clinical definition of carrier

status in females of child-bearing age within families affected by

XLRP can be unsatisfactory. Recent developments in identification of

the RP2 and RPGR genes allow accurate definition of carrier status

and early diagnosis in young males in the majority of XLRP families.

140

X-linked retinitis pigmentosa

Distinct genetic forms of stationary night blindness

Disorder

Gene

Chromosomal location

Inheritance

MIM

CSNB1

NYX

Xp11.4

XL

310500

CSNB2

CACNA1F

Xp11.23

XL

300071

CSNB3

GNAT1

3p21

AD

163500

CSNB3

RHO

3q21–q24

AD

180380

CSNB3

PDE6B

4p16.3

AD

180072

Clinical features

CSNB is characterized by night blindness in the presence of normal

retinal examination. Nystagmus is common and patients are often

diagnosed as having ‘congenital nystagmus’. Patients have variable

reduction in visual acuity. In autosomal dominant forms, this may

be in the normal range (6/6–6/12) while in recessive and X-linked

forms there may be a more significant reduction (6/24 or greater).

Patients with the complete form of X-linked CSNB (CSNB1) are

often moderately or highly myopic. Visual field testing in photopic

conditions is normal, as is color vision.

Electrophysiology is required to diagnose CSNB. A number of

different ERG patterns have been described and while these do not

respect an inheritance pattern exactly, a number of generalizations

can be made:

• normal A wave, absent/small amplitude B wave on scotopic

ERG. This ‘negative wave ERG’ pattern is seen in the X-linked

and autosomal recessive forms of CSNB. When dark adaptation

is tested, some patients have no rod contribution (complete

CSNB, CSNB1); others have reduced rod contribution

(incomplete CSNB, CSNB2).

Inherited retinal disease

141

Age of onset

Birth

Genes

Gene

Gene name

MIM

CACNA1F

Calcium channel alpha-1

300110

subunit

NYX

Nyctalopin

300278

GNAT1

Alpha subunit of rod

139330

transducin

RHO

Rhodopsin

180380

PDE6B

Beta subunit, rod cGMP

180072

phosphodiesterase

142

Congenital stationary night blindness

Inherited retinal disease

143

Diagnosis

When suspected clinically, diagnosis of CSNB is generally supported

by electrodiagnosis. At the current time, the degree of heterogeneity

precludes molecular analysis, which is not widely available.

Fundus albipunctatus

MIM

136880; 601617 (RDH5)

Clinical features

In fundus albipunctatus, congenital night blindness is present

with well-preserved, or normal, visual acuity. Fundus examination

reveals white dots scattered throughout the retina. There is no

RPE degeneration and no progression with time. ERG testing is

characteristic of CSNB with reduction on the B wave of the scotopic

ERG. However, this returns to normal with prolonged dark

adaptation (up to 3 h).

Fundus albipunctatus. 20-year-old Asian female with non-progressive

night blindness.

Age of onset

Birth

Inheritance pattern

Autosomal recessive

Chromosomal location

12q13–q14

144

Fundus albipunctatus

Gene

Retinol dehydrogenase 5 (RDH5)

Mutational spectrum

Both missense and frameshift mutations have been described

in RDH5.

Effects of mutations

Several molecules that are important in the visual cycle regenerating

retinol dehydrogenase 5 have been implicated in retinal

degeneration. RDH5 is expressed in the RPE and catalyzes the

conversion of 11-cis retinol to 11-cis retinal. RDH5 mutations have

been shown severely to reduce its activity. It is thought that reduced

enzyme levels lead to reduced production of 11-cis retinal, which

in turn leads to abnormally slow regeneration of cone and rod

photopigments. Ultimately, photopigments do regenerate, which

may explain the normalization of the ERG after prolonged dark

adaptation, and may result from residual enzyme activity.

Diagnosis

When suspected clinically, diagnosis of fundus albipunctatus,

as opposed to retinitis punctata albescens, is supported by

electrodiagnosis. Mutation testing is only available on a research

basis at the current time.

Oguchi disease

MIM

258100; 181031 (SAG); 180381 (RHOK)

Clinical features

Oguchi disease is a form of congenital stationary night blindness

(CSNB) rarely seen outside Japan. In the light-adapted state, the

retina has a greenish hue that returns to normal after dark adaptation.

ERG testing reveals a CSNB negative waveform pattern. Unlike

fundus albipunctatus, this does not improve with dark adaptation.

Age of onset

Birth

Inheritance pattern

Autosomal recessive

Inherited retinal disease

145

Chromosomal location

2q37.1 (SAG)

13q34 (RHOK)

Gene

S-antigen (SAG); alternative name: arrestin.

Rhodopsin kinase (RHOK)

Mutational spectrum

Rhodopsin kinase and arrestin act together to deactivate rhodopsin

and effect of mutations

after stimulation by light. RHOK phosphorylates rhodopsin at

specific residues. This modified form of rhodopsin is then complexed

by arrestin. Null mutations in both result in the same clinical

phenotype. Loss of function mutations (deletion, missense and

frameshift) are described in RHOK, and protein truncation mutations

in arrestin. Mutations would, therefore, result in reduced

deactivation of rhodopsin.

Diagnosis

Oguchi disease is rare ouside Japan.

146

Oguchi disease

MIM

203800

Clinical features

ALMS1 is an under-diagnosed multisystemic condition associated

with obesity, diabetes, retinal degeneration and acanthosis

nigricans. Unlike Bardet-Biedl syndrome, polydactyly is not present

and intelligence is often normal.

Ocular

Children with ALMS1 develop an early-onset severe cone-rod

dystrophy. Nystagmus is often present and children are photophobic.

The ERG is usually extinguished when tested but, if present, shows

better preservation of rod responses. Patients may progress to having

no light perception by the end of the second decade. Fundoscopy

reveals vessel attenuation early in the course of the disease with

disc pallor. Bull’s eye maculopathy or bone corpuscular pigmentation

is rare.

Extraocular

The majority of children are found to have dilated cardiomyopathy,

which is a common cause of death in infancy. Children are

overweight and often develop hearing loss before 10 years of age.

Children may have acanthosis nigricans. Diabetes and progressive

renal dysfunction may develop in adult life.

Age of onset

Birth

Inheritance

Autosomal recessive

Chromosomal location

2p13

Gene

ALMS1

Inherited retinal disease

147

Mutational spectrum

Frameshift and nonsense mutations have been described.

Effect of mutation

The ALSM1 protein is an uncharacterized protein encoded by a

ubiquitously expressed gene of 23 exons. The protein is large

(4169 amino acids) and contains a tandem repeat encoding

47 amino acids.

Diagnosis