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13.6 Inherited Retinal Disorders
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Deep learning algorithms have been developed
for automated quantication of the segmented
RPE and photoreceptor layers on SD-OCT volume modelling to monitor the therapeutic efcacy of various treatment strategies [50].
RPE Cell Implantation inDry AMD
Another approach was successfully tested in preclinical studies, and limited human studies have
shown that implanted RPE cells retain their
functionality. The RPE cells can be derived from
various sources, including human embryonic
stem cells, iPSC from adipose broblasts or bone
marrow CD34+ cells. These can be injected in
intravitreal, subretinal or suprachoroidal space as
a cellular suspension or transplanted on a bioengineered monolayer under the retina to rescue the
degenerating photoreceptors. Meta-analysis for
early trials for dry AMD patients has shown these
to be a safe and effective strategy with modest
improvement in visual acuity [51]. Many human
phase 1/2 studies are underway to study the role
of RPE transplant in restoring vision in patients
with advanced macular degeneration [52].
In one such study, human embryonic cellsderived RPE cells on an ultrathin parylene substrate were implanted under the retina as an
outdoor procedure in patients with advanced dry
AMD. The follow-up was available for 1 year.
The implant successfully improved visual acuity
in 27% of eyes. Loss of vision >5 letters was seen
in 47% of untreated eyes versus 33% of treated
eyes. Four of the 16 eyes had severe ocular
adverse events, including RPE detachment,
haemorrhage, and oedema [53]. However, longterm outcomes have yet to be discovered. One of
the signicant concerns of cellular transplants
remains the risk of tumorigeneses.
13.6 Inherited Retinal Disorders
13.6.1 Introduction
Inherited retinal disorders (IRD) affect millions
of people worldwide. Most of them suffer from
retinitis pigmentosa (RP), a disease characterized by progressive degeneration of predomi-
nantly the rod or cone photoreceptors (Fig.13.6).
Most patients have night blindness in the early
stages, but eventually, many go blind. RP has
been recognized ever since the invention of the
ophthalmoscope in 1851. Although it is not an
inammatory disease, the term retinitis pigmentosa, suggested more than 165 years ago, has
stayed [54]. The familial nature of the disease
has been known for more than 100years, and
the focus was on Mendelian inheritance patterns. The most common RP is an autosomal
recessive disorder with early onset and is the
most severe. The autosomal dominant pattern is
comparatively less common and milder.
X-linked RP is rarely seen but has the most
severe phenotype. In the early 1980s, the database of RP (all ages) in Philadelphia (US) and
childhood RP in Toronto (Canada) was created.
The turning point was the discovery of a point
mutation in the rhodopsin gene in patients with
an autosomal dominant form of RP [55] that
focused attention on clinical genotype-phenotype correlation.
It became apparent that IRDs predominantly
involving the macula, or the peripheral retina, is a
group of heterogeneous genetic disorders with
varying ages of onset, severity, and progression.
These may affect vision early in life, or the vision
may be preserved until late. There is often discordance between genotypes and phenotypes; many
genetic mutations may give rise to a similar phenotype, or several mutant genes may cause a single phenotype. Even in the same family,
phenotypical discordance may be seen. The
pathogenic variants in the same gene may cause
different phenotypes. For instance, pathogenic
variants in the PRPH2 gene may cause many pattern dystrophies and peripheral retinitis pigmentosa [56]. With the increasing sophistication of
gene sequencing technology, the phenotypegenotype correlation has become more crucial.
There are variations in genes that are of no consequence (non-pathogenic); there are pathogenic
and likely pathogenic variants. Thus, an extensive database of the various phenotypes and genotypes of IRDs is necessary.
In the past, most patients with IRD were dismissed with a remark that ‘nothing can be done’.
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13 Macular Degeneration, Geographic Atrophy, andInherited Retinal Disorders
e f
Fig. 13.6 A 30-year-old male had an insidious progressive diminution of vision in both eyes since childhood.
Visual acuity was reduced to HM in the right and CF in
the left eye. He had temporal disc pallor, attenuation of
Recent advances in genetics, molecular biology,
and gene therapy have rekindled interest in IRDs.
Ultra-wideeld (UWF) fundus imaging,
FAF studies, SD-OCT, perimetry, and electrophysiology provide tools to document clinical
phenotypes accurately. Close collaboration is
required for systemic evaluation by paediatricians and physicians to detect systemic involvement. Geneticists and bioinformatics experts
analyze and interpret the humongous data which
is generated. Rapid advances have taken place in
molecular gene testing, such as ‘Sanger sequenc-
retinal vessels and bony spicule pigmentation in both eyes
(a, b), with corresponding changes on fundus autouorescence (c, d). OCT shows loss of the photoreceptors in
both eyes (e, f)
ing’ to conrm the gene variation with almost
100% accuracy, ‘next-generation sequencing’
(NGS), and ‘whole exome sequencing’ (WES) to
now more comprehensive ‘whole genome
sequencing’ (WGS).
Even with all the advances, the genetic defect
remains unknown in many patients with
IRD. Until 2006, only 100 mutant genes were
known for inherited ocular disorders. In 2006, the
National Institutes of Health (NIH) created an
‘eyeGENE’ network to create a database of clinical manifestations and a repository of molecular
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genetic data from patients with inherited ocular
disorders and their families from the USA and
Canada [57].
In a multigene panel testing of 85 unrelated
paediatric-age patients with syndromic or nonsyndromic IRD, the molecular test was positive
in nearly 80% of the patients, which included
67% with the autosomal recessive, 25% with
X-linked and 7.5% of autosomal dominant
IRD. Often it was successful in differentiating
stationary from progressive disease. Since molecular genetic testing is likely to be more positive in
early-onset disease (paediatric age group), it was
recommended that if IRD is clinically suspected
based on the phenotype or electroretinography,
multipanel gene testing should be done early in
the course of the disease [58].
Performing a WGS will likely improve the
diagnostic yield of single-nucleotide variants in
IRD over and above the targeted panel NGS
technique [59]. In a cohort of 1000 families with
IRD, clinically focused molecular testing found
that 76% harbour a pathogenic variant. Of the
104 genes detected in this cohort, 75% were
small enough to be packed in an attenuated adenovirus (AAV) vector with implications for
future gene therapy. Nearly 23% of the families
had mutations in the ABCA4 gene. Eighty genes
caused phenotype in less than ve families each
[60].
At present, >250 defective genes are known to
cause retinal degeneration. Large NGS panels
can determine the genetic basis in up to 76% of
IRD cases [56]. Among more than 6000 patients
from 5385 families with 30 different inherited
eye disorders, the most common IRD was retinitis pigmentosa (Fig. 13.6), Stargardt’s disease
(Fig. 13.7), cone-rod dystrophy, Best disease
(Fig. 13.8), pattern macular dystrophies
(Fig. 13.9), and choroideremia (Fig. 13.10).
Among >5000 patients tested for defective genes,
pathogenic or likely pathogenic genes were seen
in 62%, and 30% had gene variants of uncertain
signicance. Notably, ten pathogenic genes
account for 68% of all the pathogenic or likely
pathogenic variants in the database. Based on the
current gene therapy trials, nearly one-fth of the
patients would be eligible for clinical trials [57].
13.6.2 Ancillary Lab Testing
inInherited Retinal Disorders
The three most useful ancillary tests for evaluating IRD in the ofce of the ophthalmologist
include electroretinography, fundus imaging, and
optical coherence tomography (OCT).
13.6.2.1 Electroretinography [61]
Electroretinography (ERG) is the most critical
investigation in patients with IRD.Briey, fulleld ERG (ffERG) involves the recording of
electrical signals from the retina on exposure of
almost the entire retina to a uniform light stimulus in the dark-adapted (20 min to eliminate
cone function) and light-adapted (10 min to
eliminate rod function) states of the retina. The
pupil is maximally dilated. After anaesthetizing
the cornea, the recording electrode is placed on
the conjunctiva. Alternatively, the electrode
embedded in a corneal contact lens can be used.
A negative electrode is placed on the skin on the
lower orbit margin. In the dark-adapted eye,
three recordings of DA 0.01, DA 7.5, and DA 10
are done by increasing the ash intensity from
0.025, 7.5, and 25cd/m2, respectively. The dura-
tion of each ash should not exceed 5ms, and
intervals between ashes ≥2, ≥10, and ≥20s,
respectively, with increasing intensity. The
response is recorded as implicit time (ms) from
the ash’s onset to the response’s generation.
The amplitude is measured in μV. Essentially,
the ERG response consists of a negative ‘a’
wave and a positive ‘b’ wave. In the darkadapted eye, ERG records responses mainly
from rod photoreceptors. A weak light intensity
(DA 0.01) elicits no ‘a’ wave, and the rst positive response is a ‘b’ wave generated by the ON
bipolar cells. Increasing the light intensity generates a negative ‘a’ wave response from rods
and cones, but predominantly from the rods. It is
followed by a positive ‘b’ wave from ON/OFF
bipolar cells. The amplitude of ‘a’ is measured
from the baseline (0 μV) to the trough of the
maximum response. The implicit time for the
‘b’ wave is from the ash’s onset to the wave’s
peak. The ‘b’ wave amplitude is measured from
the trough of the negative ‘a’ wave to the peak
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13 Macular Degeneration, Geographic Atrophy, andInherited Retinal Disorders
Fig. 13.7 (A) Right and left fundus photos demonstrat-
ing pisciform ecks typical of Stargardt’s disease (a, b).
Some ecks have lost the vitelliform material. FAF shows
the hyper autouorescent ecks and a few areas of hypo
autouorescent non-central atrophy (c, d). Dark choroid
of the background fundus seen on uorescein angiogram
(e, f). OCT shows a thick RPE layer with patchy ellipsoid
line loss and some thinning of the overlying outer nuclear
layer (g, h). (B) ABCA4 dystrophy with atrophy. Both
of the positive ‘b’ wave. Similar recordings are
done for the light-adapted eye using the light
intensity of 3cd/m2 and 31Hz icker frequency,
eliminating the rod response. In the icker ERG
in light- adapted eyes, the amplitude is measured
from the trough to the peak of each wave. The
light- adapted ERG’s implicit time and amplitude are also measured as described above for
the dark- adapted eye. In the light-adapted eye,
eyes’ macula shows islands of atrophy with a few ecks
around them (a, d). The FAF image shows hypo autouorescence corresponding to the atrophy and a few hyper
autouorescent ecks (b, e). OCT shows atrophy of the
RPE, the overlying photoreceptors, some inner nuclear
loss, and the choriocapillaris thinning (c, f). (Images courtesy of Dr Anita Agarwal, West Coast Retina Medical
Group, San Francisco, CA)
the negative ‘a’ wave is mainly from cones and
the ‘b’ wave from the On/Off bipolar cells.
In retinitis pigmentosa, the scotopic ERG
responses are abnormal and may be undetectable.
The light-adapted responses are also generally
abnormal. In the advanced stage of RP, there are
no ERG responses in dark or light-adapted eyes.
Leber’s congenital amaurosis has no ERG
responses early in infancy.
ef
gh
B
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Fig. 13.7 (continued)
In cone-rod RP, the light-adapted responses
are more affected than the dark-adapted eyes. In
cone dystrophy, on the other hand, only the lightadapted responses are affected with nearly normal dark-adapted responses. https://eyewiki.aao.
org/Electroretinogram, accessed on Dec 17,
2022.
13.6.2.2 Fundus Imaging andFundus
Autouorescence
Fundus imaging is essential in documenting the
clinical picture of IRDs, and the course of the
disease in follow-up. The traditional fundus cameras capture only 30–55° colour fundus pictures
of the post pole and required the preparation of
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Fig. 13.8 (A) Best vitelliform macular dystrophy seen as
subretinal yellow deposits in the right eye (a) and eggyolk appearance in the macula in the left eye (b). The
vitelliform material appears brightly hyperautouorescent
(c, d). The OCT shows subretinal uid (blue arrow) in the
right eye (e) and deposition of vitelliform material (red
arrows) in subretinal space in the left eye (f). (B) Right
eye with subretinal brosis from a prior choroidal neovascular membrane and scrambled egg stage of Best disease
manual or automated montages to capture the
retinal periphery from multiple images. Wideeld cameras capture images of the retina up to
100, marked by the posterior edge of the vortex
vein ampulla. Ultra-wideeld fundus (UWF)
imaging with Optomap (Optos Inc., Marlborough,
MA 01752, USA) uses a low-power laser (Blue,
488nm; green, 532nm; and red, 633) to capture
the macula and the retinal periphery up to 200° in
(a, b). Left eye with scrambled egg stage of the Best disease (c). Fundus autouorescence of the left eye with a
ring of hyper autouorescence corresponding to the residual vitelliform material (d). OCT of the right eye with
subretinal brosis (e) and OCT of the left eye with persistent vitelliform space seen in Best disease (f).
(Images13.8B courtesy of Dr Anita Agarwal, West Coast
Retina Medical Group, San Francisco, CA)
one frame. In one capture, it covers 80% of the
retina and makes an automated 220° montage. In
addition, it can capture red-free images, choroidal images, FFA, ICG, and fundus autouorescence (FAF), and recently an integrated 23mm
swept-source OCT line scan can also be done.
The confocal scanning laser ophthalmoscope
(Spectralis, Heidelberg Engineering Inc.
Franklin, MA 02038, USA) uses infrared, green
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Fig. 13.9 A 75-year-old woman with metamorphopsia
presented with a vitelliform lesion (blue arrow) in the macula of left eye suggestive of adult-onset foveomacular
vitelliform degeneration (a). Fundus uorescein angiogra-
phy showed hyperuorescence (red arrow) of the lesion
(b). Three years later, there was an increase in the size
(blue arrow) of the lesion (c) which was intensely hyper
autouorescent (red arrow) on fundus autouorescence (d)
Fig. 13.10 A patient with choroideremia (a, b), showing
diffuse chorioretinal atrophy sparing an island of foveal
and parafoveal centre on OCT (c, d). (Images courtesy of
Dr Anita Agarwal, West Coast Retina Medical Group, San
Francisco, CA)
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13 Macular Degeneration, Geographic Atrophy, andInherited Retinal Disorders
and blue wavelengths to capture images of the
different retinal layers and generates a highquality and contrast multicolour image. It captures a wide-eld view (105°) which can be
automatically montaged to generate ultrawideeld images. It is convenient for small children and uncooperative patients. The UWF FFA
and ICG angiography can also be done. For IRDs,
FAFimaging is crucial for clinically differentiating the functioning from dead areas of photoreceptors and RPE (Fig.e 13.6). A2E is an
autouorescent component of lipofuscin, an end
product of the phagocytosed outer segments of
photoreceptors which accumulate in the RPE
throughout a person’s life. RPE cells under stress
produce more A2E than usual, and these areas
appear hyperautouorescent on SW FAF imaging. The areas that have dead RPE cells appear
dark. In patients with IRD, the FAF pattern can
provide a map of the A2E deposits in the RPE
and provide a more accurate phenotype assessment than the colour fundus picture. It is advantageous in delineating subclinical lesions in
Stargardt’s disease and the progression of the
Best disease. In patients with Rod-cone dystrophy, a ring of hyperautouorescence (RobsonHolder ring) marks the boundary of the dead
peripheral RPE and the central area where the
RPE is still viable [62]. Outside the ring, the
ELM lies next to the RPE layer as the photoreceptors are lost.
Notably, in the light-adapted normal retina,
the pigments in the photoreceptors absorb blue
light and obscure the autouorescence signals
from the RPE layer; thus, the posterior pole
appears dark. The photopigments are bleached in
the dark-adapted normal retina, and excitation
with SW-FAF image reveals the autouorescence
from the RPE. In patients with RP, wide-eld
hypoautouorescence areas correspond to the
visual eld scotoma [63]. The FAF images are
used to monitor the progression of lesions.
13.6.2.3 Optical Coherence
Tomography
Optical coherence tomography (OCT) is a noninvasive imaging tool to obtain cross-sectional
microstructural details of the different layers
of the retina and choroid. Currently, two technologies are being used to obtain OCT images.
The spectral domain technology uses a broadband near-infrared super luminescent diode as
a light source and a spectrometer to detect the
Fourier transformation of the reected light
from the tissue interfaces. The axial resolution
with SD-OCT is 1–3μ. Fast acquisition time
has enabled obtaining information from each
point of the retinal structures to construct a
3-D retina model. Apart from the crosssectional image of the various microstructures,
layer-by-retinal-layer information can be
obtained as en face imaging. The swept-source
OCT uses a narrow band of a tunable laser
source. The higher acquisition speed with
SS-OCT to 100,000 scans/s compared to
50,000 scans/s with the SD-OCT has allowed a
12×12mm wider scan line compared to a 6 ×
6mm line scan with SD-OCT.Using a higher
wavelength of 1050 nm than the SD-OCT
(840 nm), SS-OCT gives higher resolution
images (1μ) of the deeper retinal structures and
choroid and can delineate even the choroidoscleral interface [64, 65].
In patients with RP, the OCT delineates the
absence of an EZthat correlates with visual acuity centrally. More importantly, the absence of
ELM on OCT indicates a more severe phenotype.
Besides, it detects CME as a complication, especially in syndromic RP. Most patients with RP
show abnormalities of the vitreoretinal interface
[66]. Further, in RP, the interdigitation zone (IZ),
the rst to be affected, is the shortest line, the
next to go is the EZ and the longest is the ELM,
indicating that in RP, the rst structural change is
seen at the level of IZ, followed by the EZ, and
nally the ELM. Histopathological changes in
RP also show that the outer segments of the retina
are affected rst. The SD-OCT also shows ndings consistent with this observation [67]. The
next change in the order of a progressive disease
is thinning of the outer nuclear layer (ONL). The
thinning of ONL is accompanied by normal or
even thicker inner retinal layers, possibly due to
glia-neuronal remodelling. Moreover, hyperreective foci in the ONL correspond to the RPE
changes [67].
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13.6.2.4 Genetics ofNon-syndromic
Retinitis Pigmentosa
In non-syndromic RP, the most common pathologic variants are USH2A, BBS8, and RP1
genes. The other affected genes are ARL6,
BBS1, BBS9, C2orf71, C8orf7, CLRN1,
FAM161A, MAK, OFD1, RP2, RPGR,
TOPORS, TULP1. Pathogenic variants have
been found in the RPGR gene localized to the
connecting cilium, which can lead to both the
cone RP and rod-cone RP. Variants have also
been found in genes RPGRIP1, C8orf37,
RAB28, and TTLL5 localized to the cilium base
in patients with cone-rod RP. Pathologic variants in Leber’s congenital amaurosis involve
CEP290 [68].
Patients with macular dystrophy (MD) need to
be differentiated from RP.In MD, gene variants
have been found in RPGR and RP1L1. MD
patients have colour vision defects and loss of
central vision ([68].).
The IRDs may be isolated or associated with
systemic disorders involving multiple organs, the
former termed non-syndromic IRDs and the latter syndromic IRDs. Nearly 23% of working-age
persons in Australia with low vision had IRD.Of
these, non-syndromic RPaccounted for 54%, and
Stargardt’s Disease for 12% [69].
13.6.3 Non-syndromic Retinitis
Pigmentosa: Clinical Signs
Retinitis pigmentosa (RP) is one of the commonest IRDs, with a prevalence of nearly 1:3000–
1:4000 population in the USA and Europe. It is
estimated that nearly 2 million people worldwide
may be suffering from RP. The disease usually
manifests in the second decade when the patients
complain of night blindness. The onset is insidious, and the initial symptoms of difculty navigating in the dark may be ignored. In the early
stages of RP, the retina may appear normal without any pigmentary changes. Without a family
history, the diagnosis of RP is often ignored. It
most commonly affects rod photoreceptors followed by cones and is termed Rod-Cone degen-
eration. Day vision is normal in patients with
rod-cone degeneration (Fig.13.11).
In some cases, it may primarily affect the
cones rst when it is termed cone-rod degeneration. These patients are detected earlier as they
have daylight photophobia and reading vision
challenges. It is a progressive disease, although
the rate of progression may vary from one patient
to the other. In the later stages, fundus examination reveals pigmentary changes in the midretinal periphery, which may involve all four
quadrants or be limited to even one quadrant.
The pigmentary changes are typically
described as bone-spicule. In the late stages,
there is attenuation of retinal arterioles, retinal
atrophy, and optic disc pallor [70]. The perimetry
in the early stages reveals a ring scotoma; eventually, as the disease progresses, patients may be
left with tunnel vision. The development of a
complicated cataract or cystoid macular oedema
may affect central vision. Over several decades,
RP eventually leads to blindness.
Autosomal dominant forms are the mildest
and start late in life. Autosomal recessive ones
start early so does the X-linked RP. The most
common gene involved in AD RP is RHO,
responsible for 25% of the cases; USH2A, for
20% of the AR cases; and RPGR, responsible for
most of the X-linked RP cases [71].
Autosomal recessive RP (arRP) with RP1
mutations and X-linked RP (xLRP) with RPGR
or RP2 mutations have signicant myopia compared to the arRP with other genetic mutations
[72].
13.6.4 Leber Congenital Amaurosis
Leber congenital amaurosis (LCA) is one of the
severest non-syndromic RP with an early onset
and is characterized by very poor vision, nystagmus, and an oculodigital sign. The affected children rub their eyes with their ngers to generate a
sensation of light (phosphene). The wave formation on ffERG is either absent or grossly subnormal. Over 25 genes have been identied,
accounting for 70–80% of all LCA cases. The
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13 Macular Degeneration, Geographic Atrophy, andInherited Retinal Disorders
Fig. 13.11 Fundus photographs (a, b) and uorescein
angiography (c, d) of cone-rod dystrophy, with OCT (e, f)
showing foveal atrophy and diffuse loss of photorecep-
severest form of LCA leads to visual disability
that does not allow daily activities before 3 years.
If the child has limited vision but is not disabled
for up to 10years, it is termed severe early childhood onset retinal dystrophy (SECORD). If the
affected child does not become blind by ten, it
has been termed early childhood onset retinal
dystrophy (ECORD) [60]. Given the heterogeneity in phenotypes and genotypes, the LCA is best
described as a phenotype-genotype (Kumaran
etal.2017).
The most frequent genes associated with LCA
include GUCY2D, followed by CRB1, AIPL1,
and NMNAT1. Frequent genes associated with
SECORD include RPE65, RDH12, and LRAT
[73]. GUCY2D and AIPL1 are involved in photo-
tors. (Images courtesy of Dr Anita Agarwal, West Coast
Retina Medical Group, San Francisco, CA)
transduction, the former in the cones and the latter in the rods. The genes RPE65, RDH12, and
LRAT are involved in the retinoid cycle in the
RPE cells.
GUCY2D is the most frequent LCA genotype
and encodes for a retina-specic membrane protein, guanylate cyclase, which is expressed in the
outer segments of cone/rod photoreceptors. A
deciency of the protein leads to phototoxicity.
Heterozygous mutations of this gene are associated with autosomal dominant cone dystrophy
and autosomal dominant cone-rod degeneration
[74]. The patients present with relatively preserved rod function but lose central and colour
vision. In a comparative study of the OCT in
GUCY2D, RPE65, CEP290 or AIPL1-related
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