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13.6 Inherited Retinal Disorders
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LCA, all three patients with GUCY2D mutations
showed preserved retinal layers and the ellipsoid
zone, although the vision was poor. The other
three genotypes had disorganized lamellar structures of the retina. Patients with CEP290 mutations had preserved the outer nuclear layer in the
fovea with macular thickening. The macular
thickness was markedly reduced in patients with
RPE65 and AIPL1 mutations [75].
13.6.5 RPE 65-Associated LCA
RPE 65-associated LCA accounts for ~5% of all
RP patients and is seen in 1:80,000 normal population. RPE 65 gene participates in the RPE’s
visual cycle and encodes for a protein retinoid
isomerohydrolase. This protein binds retinal
esters to isomerase and generates11-cis-retinal.
Mutations in RPE65 lead to a deciency of
11-cis-retinal. RPE65 has been targeted for gene
supplementation and is in clinical use for several
years. These children have preserved cone function but have night blindness. Mild pendular nystagmus is noted. They have variable visual acuity
defects, varying from 20/200 to 20/100. Colour
vision is affected to a variable extent. In very
early cases, the fundus may appear normal, but
later, the pigmentary changes, retinal atrophy,
and waxy pallor of the optic disc become apparent (Fig.13.12). Parafoveal areas of retinal atrophy may be seen. On perimetry, the peripheral
visual eld is lost. Even with a large object size,
it is restricted to the central 20–40°. On OCT, the
ONL may be preserved in the macular area in the
ECORD phenotype, with signicant thinning in
the paramacular area. In other patients, the outer
nuclear layer may become thinner with an
approximation of the EZ with the RPE.There is a
lack of hyperautouorescence on short-wave
FAF, signifying a lack of lipofuscin in the RPE in
these patients [76].
Compared to the RPE 65-associated LCA, the
LRAT-associated RP is generally milder and may
show preservation of the parafoveal outer retinal
layers. LRAT encodes for the lecithin-retinol
acyltransferase, a key enzyme in vitamin A
metabolism and production of the retinyl esters.
The fundus appearance is variable. Nearly half of
them may show white dots. They reach blindness
levels late in life. The ffERG is undetectable in
all. The OCT shows thinning of retinal layers
with preservation of parafoveal outer retinal layers [77].
Fig. 13.12 A patient with Leber’s congenital amaurosis
having bilateral (a, b) optic disc pallor and attenuated retinal blood vessels. Fundus shows widespread pigment disruption and clumping scattered all over the retinal
periphery. Macula in both eyes shows extensive atrophic
changes. (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
13.6.6 CEP290-Associated Retinal
Dystrophy
CEP290 encodes for a centrosomal protein found
in the connecting cilia of photoreceptors and
regulates the transport of proteins between the
inner and outer segments of photoreceptors.
Abnormal gene expression of CEP290 in other
organs can result in syndromic RP, such as
Bardet-Biedl Syndrome, Meckel-Gruber
Syndrome, and Senior-Loken syndromes (discussed in the syndromic RP). Biallelic loss of
CEP290 can result in a severe form of early-onset
RP termed LCA10. It may be responsible for up
to 30% of all LCA cases. The clinical picture is
heterogeneous [78].
13.6.7 Primary Ciliopathies andRP
Visual transduction occurs in the outer segment,
with hundreds of discs carrying a vast amount of
visual pigment. The RPE cells phagocytose
nearly 10% of the outer segment discs daily. The
mRNA transcription synthesizes proteins in the
inner segments transported through the connecting cilium to the outer segments. There are several proteins in photoreceptors such as rhodopsin,
subunits α and β of rod phosphodiesterase, subunits α and β of cGMP, cytoskeleton proteins,
trafcking RPGR, RP1, RP2, and many others
involved in the differentiation of photoreceptors,
extracellular matrices, lipid, and other metabolic
pathways. All these must function in a muchregulated fashion to transduce visual signals [70].
In contrast to non-vertebrates, non-motile
cilia are present in all vertebrate cells. Long
considered redundant, only in the last two
decades the role of these sensors in maintaining
homeostasis and health has emerged [79]. These
cilia act as sensors to provide information from
the extracellular to the intracellular or within the
intracellular compartment. The cilia cannot produce proteins but transport them along the axoneme (Intraagellar transport). They also act as
signal transducers. The highly metabolic photoreceptor inner segments have cell bodies packed
with mitochondria. There is a high turnover of
protein transcription in the inner segments. The
photoreceptors’ outer segments in the retina are
specialized cilia forming a photoreceptor sensory cilium complex. Genetic mutations or pathological variants in the cilia genes are called
primary ciliopathies and lead to syndromic and
non-syndromic disorders involving multiple
organs, including the eye, brain, heart, kidneys,
liver, and other structures. It is estimated that
genes involved in the structure or function of
primary cilia account for nearly one-third of
IRD [80].
13.6.8 Systemic Diseases Associated
Patients at the time of IRD diagnosis may already
have systemic organ involvement. A team
approach involving an ophthalmologist, geneticist, and primary care physician is required for
early diagnosis, genetic testing, counselling, and
early and appropriate management [81]. The
major syndromic RP are discussed below. See
Boxes 13.1, 13.2, 13.3, and 13.4.
withInherited Retinal
Degeneration
13.6 Inherited Retinal Disorders
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Box 13.1 Syndromic Inherited Retinal
Degenerations and the Genes in Primary
Ciliopathies
Syndrome Inheritance Gene/locus
Bardet-Biedl
syndrome
(BBS)
AR CCDC28B;
SDCCAG8; IFT172;
WDPCP; BBS5;
LZTFL1; ARL6;
BBS7; BBS12;
PTHB1; TMEM67;
CFAP418; IFT74;
TRIM32; BBIP1;
BBS1; BBS10;
CEP290; TTC8;
BBS4; BBS2; MKS1;
MKKS; IFT27
Alström
AR ALMS1
syndrome
(ALMS)
SeniorLoken
syndrome
(SLS)
AR NPHP1; NPHP4;
SDCCAG8;
TRAF3IPI; IQCB1;
SLSN3; WDR19;
CEP290;
RPRGRIP1L/NPHP8;
SDCCAG8/NPHP10;
BBS14; BBS16
Joubert
syndrome
(JBS)
AR INPP5E; CEP104;
NPHP1; TMEM237;
ARMC9; PDE6D;
ARL13B; CC2D2A;
CPLANE1; CEP120;
AHI1; CEP41;
CSPP1; TMEM67;
IFI74; FAM149B1;
TCTN3; SUFU;
ARL3; TMEM138;
TMEM216;
TMEM218; CEP290;
TECT1; TECT2;
PIBF1; TOGARAMI;
KIAA0586; KIF7;
KATNIP; ZNF423;
RPGRIP1L;
TMEM231;
KIAA0753;
TMEM231;
TMEM107; B9D1;
MKS1; B9D2; OFD1
Jeune
syndrome or
asphyxiating
thoracic
AR TTC21B; NPHP12;
WDR19; NPHP13;
IFT80; DYNC2H1;
IFT140; TTC21B
dystrophy
(JATD)
Syndrome Inheritance Gene/locus
Meckel-
Gruber
syndrome
(MKS)
AR CC2D2A; CEP290/
BBS14/NPHP6;
CSPP1; MKS1/
BBS13; NPHP3;
RPGRIP1L/NPHP8;
TMEM216/MKS2;
PHP11; TMEM 67/
MKS3 as modier;
WDPCP/BBS15
Reference: Werdich etal. [81]
Box 13.2 Bardet-Biedl Syndrome: Salient
Clinical Features
Organ Abnormality Frequency
Eye Rod-cone dystrophy >90%
Gonads Hypogenitalism;
~90%
delayed puberty
Obesity Overweight/obesity >75%
Limbs Polydactyly
Brachydactyly
CNS Ataxia; abnormal
~70%
~46%
30–40%
gait
Kidney Calyceal clubbing,
24–46%
parenchymal cysts,
etc.
Dental High arched palate >80%
Speech High pitched ~50%
Behaviour Immaturity ~30%
Development Delayed 50%
Learning Mild to moderate
~60%
difculty
Adapted from Beales etal. [82]
Box 13.3 Alström Syndrome-Salient
Systemic Involvement
Organ Abnormality Frequency
Eye
a
Cone-rod
Early 100%
dystrophy;
nystagmus;
photophobia
a
Hearing
Deafness by 7
88%
years
Heart
a
Infantile
cardiomyopathy,
42%
18%
adolescent/adult
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13 Macular Degeneration, Geographic Atrophy, andInherited Retinal Disorders
Organ Abnormality Frequency
Diabetes
a
Second to third
decade; insulin
~82%
92%
a
resistance;
hyperinsulinemia
Gonads Hypogonadism
Reduced fertility
Gynecomastia
Obesity
Limbs
a
CNS
b
b
Infantile obesity ~90%
Short stature ~32%
Clonic tics
Muscle weakness
Kidney/liver Chronic
a
77%
b
100%
a
20%
29%
a
49
–63%
nephropathy;
rapid decline in
eGFR; ESRD
Hepatitis
Dental
a
Speech
Motor delays 46%
Behaviour Delays
Development Delays 46%
Learning Language and
11–16%
cognitive
a
Adapted from Marshall etal. [83]
b
Adapted from Russell-Eggitt etal. [84]
c
Adapted from Baig etal. [88]
Box 13.4 Dierential Diagnosis of Dual
Sensory Impairment Syndromes
Associated
systemic
features
Vestibular
dysfunction in
rst decade in
USH1. No or
variable
vestibular
dysfunction in
USH2.
Congenital
vestibular
dysfunction in
Ocular phenotype
Usher syndrome
(USH1B-H and
K; USH2A,C,D:
USH 3A; USH 4)
RP in the rst
decade in USH1
and second
decade in USH2;
post- pubertal in
USH3 and at
40years in USH 4
Hearing
impairment
Congenital
deafness in
USH1
Deafness in
second decade
in USH2
Late-onset
deafness in
USH3
USH 3 and no
vestibular
dysfunction in
USH4.
Associated
systemic
features
Renal
dysfunction,
obesity,
hypogonadism,
polydactyly,
brachydactyly,
and cognitive
Ocular phenotype
Bardet Biedl
syndrome
Age at diagnosis
of RP ~10years
and blindness by
~15years.
Hearing
impairment
Hearing loss in
21%; mostly
conductive due
to otitis media;
rarely
sensory-neural
deafness
impairment.
Alström
c
syndrome
Cone-rod
dystrophy early
onset; nystagmus
Progressive
sensory-neural
deafness in
90% beginning
in the rst
Obesity;
hypogonadism;
brachydactyly;
type2 DM;
cardiomyopathy
decade;
conductive
loss due to
otitis media
Stickler
syndrome
High myopia;
vitreoretinal
degeneration;
membranous or
beaded vitreous;
RD
Sensorineural
or conductive
hearing loss
Underdeveloped
jaw; backward
displacement of
the tongue that
frequently
blocks the
airway
(Pierre-Robin
face); cardiac
and skeletal
abnormalities
Waaredenburg
syndrome
Heterochromia;
choroidal
hypopigmentation
Sensorineural
deafness
increased from
69% in WS
type 1 to 87%
in WS type 2
White forelock;
partial albinism;
at root of nose;
telecanthus;
synophrys
eyebrows;
musculoskeletal
abnormalities
MIDD syndrome
Pattern dystrophy;
punctate hyper
Deafness in
75% develops
at a young age
Type 2 diabetes
and
hypouorescent
dots; continuous
or discontinuous
areas of
pericentral
chorioretinal
atrophy
Alport syndrome
Flecked retina;
lenticonus; foveal
hypoplasia; giant
macular holes
Variable
hearing loss
Haematuria;
progressive
brosis of
kidneys with
renal failure
Reference: Guimaraes etal. [90]
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13.6.8.1 Bardet-Biedl Syndrome
Bardet-Biedl syndrome (BBS) is a highly heterogeneous, autosomal recessive syndrome which
may have variations in clinical manifestations in
the same family. BBS1 is the most frequently
affected gene on the long arm of chromosome 11
(11q13.2), modied by genes CCDC28B
(1p35.2) and ARL6 (3.q11.2). There are more
than 20 known phenotypes of BBS. (https://
omim.org/phenotypicSeries/PS209900). At
times, clinical diagnosis of BBS may be difcult.
They present with night blindness and a fundus
picture of RP.The major clinical features include
retinitis pigmentosa, polydactyly (hands/feet),
obesity, hypogonadism, renal anomalies, and
learning disability. Minor/rare features include
high arched palate, dental crowding, hepatic
brosis, speech delay, and mental disorders. Four
major or three major and two minor clinical features make the diagnosis of BBS. The salient
clinical features and systemic associations
include rod-cone dystrophy, hypogonadism, and
delayed puberty in more than 90% of the affected
patients. Others include obesity, polydactyly, and
mild to moderate learning disability [82].
13.6.8.2 Alström Syndrome
Alström syndrome (ALS) is a rare autosomal
recessive disorder caused by biallelic mutations
or compound heterogeneous mutation in a
single- gene ALMS1 located on the short arm of
chromosome 2 (2p13.1). Unlike BBS, RP in
Alström syndrome has an early onset and is
characterized by the predominant involvement
of cones. They present with photophobia and
nystagmus in early childhood because of early
involvement of the macula. The diagnosis of
Alström syndrome is difcult due to the slow
unfolding of the complete phenotypes [83].
Unlike BBS, these children do not have polydactyly but may have gynecomastia and infertility.
They have type 2 diabetes, increasing insulin
resistance, obesity, and deafness. Most of these
children have early- onset cardiomyopathy and
die of heart failure [84]. Nearly 50% of nonobese Alström patients have a deciency of
growth hormone, leading to short stature [85].
As the ALMS1 gene regulates insulin transport,
these patients have extreme insulin resistance
[86]. There is a gradual progression from obesity
to diabetes because of the progressive decline in
insulin from pancreatic β-cells [87]. Salient features of ALS syndrome include cone-rod dystrophy, nystagmus, deafness by 7 years of life,
cardiomyopathy, and type 2 diabetes mellitus in
their 20s due to insulin resistance and hyperinsulinemia [83]. Chronic nephropathy may vary
from 49% to 66% [83, 88]. The other common
feature is infantile obesity. Nearly one-third may
have short stature [84].
13.6.8.3 Dierentiating BBS
Differentiating the two syndromes, Bardet-Biedl
from the rarer Alström Syndrome, is important
because children need early care for systemic
complications. Both have retinal dystrophy, are
obese, and suffer from hypogonadism. Alström
Syndrome has an onset earlier than BBS, and
they present with nystagmus due to cone-rod dystrophy, unlike BBS, which causes rod-cone dystrophy. Developmental delays are more frequent
in BBS than in Alström Syndrome. BBS has both
polydactyly and brachydactyly, whereas Alström
Syndrome has only brachydactyly. The Alström
Syndrome is characterized by type 2 diabetes
mellitus in most patients and has cardiomyopathy
more frequently than BBS.Hearing loss is more
common in Alström Syndrome than in BBS [89].
13.6.8.4 Usher Syndrome
It is an autosomal recessive disorder characterized by RP and sensorineural deafness and occasional disturbance in vestibular functions. This is
also called dual sensory impairment syndrome. It
is caused by mutations in USH protein network
located in the periciliary region of the photoreceptors. Several syndromes have dual sensory
impairments with variable frequency. Apart from
Usher syndrome, most patients with Alström
syndrome also have progressive sensorineural
deafness starting in the rst decade, and nearly
three-fourth of those with maternally inherited
diabetes and deafness (MIDD) and type 2
Waardenburg syndromes have impaired hearing.
Hearing loss is less frequent in Bardet-Biedl,
fromAlström Syndrome
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13 Macular Degeneration, Geographic Atrophy, andInherited Retinal Disorders
Fig. 13.13 An individual with macular dystrophy due to
MIDD having macular and peripapillary depigmented
lesions in both eyes (a, b). Fundus autouorescence
shows mixed areas of increased (subretinal deposits) and
Alport’s, and Stickler’s syndromes. Apart from
hearing loss, each has highly characteristic signs
decreased (atrophy) autouorescence (c, d). (Images
courtesy of Dr Anita Agarwal, West Coast Retina Medical
Group, San Francisco, CA)
ment of cystoid macular oedema and more so in
Usher’s syndrome [91] (Fig.13.15).
(Fig.13.13) [90].
At least four USH ocular phenotypes have
been identied. USH2 is the commonest phenotype and accounts for most of the non-syndromic
RP (Fig.13.14). While deafness starts in the rst
decade, the RP starts in the second decade. USH1
is the severest and has congenital neurosensory
deafness. As a consequence, these children do
not learn to speak. The RP in USH1 starts in the
rst decade. They also have vestibular dysfunction. USH3 and USH4 are rare. The USH3 is
associated with the late onset of progressive RP
but has congenital vestibular dysfunction. The
RP in USH4 starts in the fourth decade. Vestibular
dysfunctions lead to problems with posture, balance, hand-eye coordination, and even reading or
eye tracking [90]. Nearly 32% of patients with
early-onset IRD are complicated by the develop-
13.6.8.5 Senior-Loken Syndrome
(SLS)
Senior-Loken syndrome (SLS) is a rare ciliopathy wherein LCA type RP is associated with
inammation and scarring of the kidneys (nephronophthisis). It is also called hereditary renal–
retinal dysplasia. It was initially described as
‘familial juvenile nephronophthisis’ [92], characterized by progressive renal function deterioration with minimal or no haematuria and
albuminuria. The autopsy reveals marked thinning of the cortex and peri glomerular brosis,
and interstitial brosis. The association of tapetoretinal degeneration was described in six of the
13 children in a family with nephronophthisis by
Senior etal. [93]. In the same year, two siblings
died of renal dysplasia at 8 and 9years, one of
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Fig. 13.14 Retinitis pigmentosa in a patient with Usher’s
syndrome as seen on fundus photograph (a, b), fundus
autouorescence (c, d) and OCT (e, f). (Images courtesy
whom showed retinal dysplasia and, on autopsy,
showed loss of the outer nuclear layer of the retina and rod photoreceptors [94]. The SeniorLoken patients present with night blindness,
bone-spicule pigmentation of the peripheral retina, arterial attenuation, and optic disc pallor. The
median age of the patients is 13years when they
present with polydipsia, polyuria, and thirst.
The gene NPH1 encodes for the nephrocys-
tin1 protein located on 2q13.
SLS is the commonest cause of inherited endstage renal disease in childhood and adolescence.
On ultrasonography of the kidneys, it is difcult
to differentiate the renal cortex from the medulla
and may show the presence of cysts. Eight of the
of Dr Anita Agarwal, West Coast Retina Medical Group,
San Francisco, CA)
13 known nephrocystins genes are located in the
cilium of photoreceptors and cilia and the centrosomes of the renal epithelium cells. Mutations in
the nephrocystins affect protein transport in the
cilia. In the eye, it accumulates rhodopsin and
transducin in the inner segment, which is not
transported to the outer segments. Outer segments of the photoreceptors are not formed, leading to photoreceptor retinal degeneration [95].
Although SLS accounts for only 1% of retinal
dystrophies, these children are not routinely
screened for renal involvement. In one of the
reported families, whole exome sequencing in a
sibling affected with RP led to the discovery of
two deletions in the IQCB1 gene, one of the
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13 Macular Degeneration, Geographic Atrophy, andInherited Retinal Disorders
e
f
Fig. 13.15 A case of retinitis pigmentosa showing pigmentary changes in both eyes (a, b). Note hyperautouorescent ring around the fovea in both eyes (c, d). OCT
nephrocystins associated with SLS. His younger
sibling presented with nocturnal enuresis, fatigue,
and slow growth. The timely discovery of the
genetic mutation led to the early detection of
nephronophthisis. An early renal transplant saved
the dialysis dependency of the child [59].
shows cystoid macular edema in both eyes (e, f). (Images
courtesy of Dr Anita Agarwal, West Coast Retina Medical
Group, San Francisco, CA)
13.6.8.6 Joubert Syndrome (JBTS)
Joubert etal. [96] rst described four children in
a family with remote consanguinity, characterized by abnormal breathing (episodic hyperpnoea
with spells of apnoea), mental retardation, ataxia,
and nystagmus associated with the absence of
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vermis on autopsy in one sibling and on imaging
of the brain in others. Children with this rare
autosomal recessive syndrome present with
ataxia, abnormal breathing (episodic hyperpnoea), hypotonia, and nystagmus due to maldevelopment or absence of cerebellar vermis and
malformations of the brain stem. There are
remarkable developmental delays in both motor
skills and cognition. The axial MRI gives a characteristic ‘molar tooth’ sign because of the lack
of normal decussating cerebellar peduncles and a
missing vermis. The most signicant ocular features include the inability to move eyes voluntarily (ocular motor apraxia, periodic alternating
nystagmus) in 80%, followed by strabismus in
74%, ptosis in 43%, chorioretinal coloboma in
33%, RP in 38%, and optic atrophy in 22% [97].
A homozygous mutation in the INPP5E gene
on chromosome 9q34 causes Joubert
Syndrome (JBTS). JBTS is a highly heterogeneous syndrome with at least 40 subtypes of JBTS
known due to pathological variants in different
genes/loci [81]. Of the many subtypes, including
JS-Ret, the predominant eye involvement is retinitis pigmentosa or JS-Ren with nephronophthisis or
JS-OR with both oculorenal involvements. There
are other subtypes as well. More than 40 genes
have been described in JBTS, concerned with the
cilia’s structural proteins (https://omim.org/
entry/213300?search=Joubert%20
Syndrome&highlight=joubert%20syndrome%20
syndromic, accessed Dec 16, 2022, https://rarediseases.org/rare- diseases/joubert- syndrome/,
accessed Dec 15, 2022). In a family with developmental delay, hypotonia, oculomotor abnormality,
and cerebellar dysplasia, whole exome sequencing
led to the detection of new pathogenic disease
variants in four genes, conrming the diagnosis of
JBTSin four siblings. This helped in genetic counselling and guidance for future pregnancy [98].
manifestations. However, RP is only rarely a part
of these syndromes. The JATD is diagnosed before
or shortly after birth and is characterized by skeletal abnormalities that primarily affect the rib cage
forming a bell-shaped chest, short limbs, abnormal
pelvis, and brachydactyly. Retinal pigmentary dystrophy is seen only occasionally. They have serious
breathing difculties. The gene variants causing
the JATD include IFT80, DYNC2H1, WDR19,
IFT140, and TTC21B. https://rarediseases.info.
nih.gov/diseases/3049/jeune- syndrome.
The MGS is the severest ciliopathy and often
results in stillbirth, or the babies die soon after
birth. It has highly heterogeneous manifestations
and displays allelism with other ciliopathies like
BBS and JBTS. It is characterized by posterior
encephalocele, polydactyly (hands and feet), and
other craniofacial abnormalities. Other salient
manifestations include renal cystic dysplasia that
causes massive enlargement of the kidneys and
hepatic abnormalities/brosis. In the eye, it
causes choroidal coloboma. Variants in the genes
C5orf42, CSPP1, and CEP55 are responsible for
most MGS cases [99].
13.7 Inherited Macular
Dystrophies
Several well-characterized and poorly characterized
macular dystrophies present with loss of central
vision in the young or even later in life. These may
have autosomal dominant, autosomal recessive or
X-linked inheritance. The variants in the affected
genes have been identied for many of them.
Phenotypic expression of the disease may vary
among the family members. In general, macular
dystrophies with autosomal dominant transmission
have milder symptoms. Salient features of macular
dystrophies are given in Boxes 13.5 and 13.6.
13.6.8.7 Jeune Syndrome or
theAsphyxiating Thoracic
Dystrophy (JATD)
andMeckel- Gruber
Syndrome (MGS)
Jeune syndrome, asphyxiating thoracic dystrophy
(JATD), and Meckel-Gruber syndrome (MGS) are
rare primary ciliopathies with severe systemic
13.7.1 Stargardt’s Disease
andFundus Flavimaculatus
(ABCA4 Disorders)
Of all the macular dystrophies, Stargardt’s disease (STGD) is one of the most common macular
dystrophies seen in young people, with an esti-
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13 Macular Degeneration, Geographic Atrophy, andInherited Retinal Disorders
Box 13.5 Salient Features of Inherited Macular Dystrophies-1
Ocular phenotype Salient clinical signs Inheritance Gene/locus
Stargardt’s disease/fundus
avimaculatus if no central
atrophy
Best vitelliform macular
dystrophy (Best disease)
Commonest macular dystrophy; progressive
decline in VA; yellow ecks; bronze-beaten
foveal atrophy; HAF ecks
Childhood-onset; egg-yellow vitelliform
lesion, progresses to pseudohypopyon,
vitelliruptive, atrophic stages; VA decline in
AR; rare ADABCA4
1p21–22
AD Bestrophin1
(BEST1)
11q12.3
stages 3–5; HAF vitelline material
EOG: light/dark ratio<1.5
AD-vitreoretinal- choroidopathy VA not affected
AD BEST1
360° peripheral pigmentary changes;
demarcation line at the equator; vitreous cells;
no night blindness
Normal ERG; ±ERG
Adult vitelliform macular
dystrophy
Asymptomatic >50%
Mild VA symptoms in the third to fth decade
AR RDS/PRPH2
6p21
Heterogeneous phenotypes; variable shapes of
yellow-white lesions with pigmentation; HAF;
ERG/EOG normal
Autosomal recessive
bestrophinopathy
Onset rst decade or later; serous macular
detachment; HAF dot lesions
AR BEST 1
11q12
EOG: light rise absent or grossly reduced
ERG: pattern-ERG mild to severely reduced
amplitude; ffERG: delayed and low amplitude
Occult macular dystrophy
(Miyake disease) East Asia
a
The median age of onset 25years (range
2–73)
AD RP1L1
8p23
Median VA: Log MAR 0.65 (range: 0.08–
1.22); Snellen 20/24–20/330 (median 20/90)
Fundus: normal; FFA: normal; VF: central
scotoma; OCT: blurred EZ and absent IZ
ffERG: normal; mfERG: central decrease in
amplitude
Late-onset macular dystrophy
Late-onset dominant RP; or
AD-LCA
b
Age of onset 20–60years; photophobia; loss
of central vision, rapid in old age
Bull’s eye maculopathy; central
AD CRX
hypoautouorescence and ring of HAF
OCT: loss of outer retinal layers in the fovea;
subretinal hyperreective material. ffERG and
mfERG low amplitude; pERG, non-recordable
Source: Johnson etal. [110]
VA visual acuity, HAF hyperautouorescent, AR autosomal recessive, AD autosomal dominant, ABCA4
ATP-binding cassette subfamily A member 4, EOG electrooculography, ERG electroretinography, RDS retinal
degeneration slow, PRPH2 peripherin 2, HAF hyperautouorescence, ffERG full-eld ERG, OCT optical
coherence tomography, EZ ellipsoid zone, IZ interdigitating zone, mfERG multifocal ERG, RP1L1 retinitis
pigmentosa- 1-like-1, CRX cone-rod homeobox, LCA leber congenital amaurosis, pERG pattern ERG
a
Fujinami etal. [136]
b
Yahya etal. [137], Sohocki etal. [138]
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