Retinal Dystrophy.pptx vvvvvvvvvvvvvvvvv

Introduction
• Retinal dystrophies (RD) are a group of degenerative disorders of the retina with clinical and
genetic heterogeneity
• RD occurs due to abnormalities in photoreceptors as well as defects in phototransduction
• Depending on the type of photoreceptors affected, retinal dystrophies may be
• Rod-dominated diseases
• Cone-dominated diseases
• Generalized form
• Cases may be
• Syndromic
• Non-syndromic
• Sporadic
• Familial
• AD
• AR
• XL
Talib M, Boon CJF. Retinal Dystrophies and the Road to Treatment: Clinical Requirements and Considerations. Asia Pac J
Ophthalmol (Phila). 2020 May-Jun;9(3):159-179

• over 270 genes are known to be associated but molecular diagnosis still remains
elusive in about a third of cases
• Mutations within the same gene have been associated with different
phenotypes, even within different individuals of the same family
• These genes code for proteins involved in photoreceptors and other retinal
cellular units and phototransduction
• The vast clinical heterogeneity presents another important challenge in the
evaluation of potential efficacy in future treatment trials, and in establishing
treatment
Ziccardi L, Cordeddu V, Gaddini L, Matteucci A, Parravano M, Malchiodi-Albedi F, Varano M. Gene Therapy in Retinal
Dystrophies. Int J Mol Sci. 2019 Nov 14;20(22):5722

Anatomy
Inner coat of the eye
• Thin transparent layer is in contact with choroid lining posterior 2/3 of eyeball.
 Firm attachment at margins of optic disc and ora serrata.
• Divided into 2 main layers
- outer RPE
- inner neurosensory retina
 Divided into 2 parts
-central-macula(fovea) -for day vision
-Peripheral-for night and peripheral vision
Wolff's Anatomy of the eye and orbit 8th edition

Layers
1. Retinal pigment epithelium
2. Layer of photoreceptors (Rods & Cones)
3. Outer limiting membrane
4. Outer nuclear layer
5. Outer plexiform layer
6. Inner nuclear layer
7. Inner plexiform layer
8. Ganglion cell layer
9. Nerve fibre layer
10. Inner limiting membrane

Retinal pigment epithelium
• Outermost layer
• Firmly attached to basement membrane
• Active RPE pump– pumps fluid out from sub retinal space into
choroid.
• Pigments in RPE – Melanin & Lipofuscin
• Melanin are denser in RPE cells of macula

Functions of RPE -
• absorbs light
• phagocytoses rod and cone outer
segments
• forms the outer blood–retinal
barrier
• maintains the subretinal space
• heals and forms scar tissue
• regenerates and recycles visual
pigment
The Retinal Pigment Epithelium in Visual Function OLAF STRAUSS Physiol Rev 85: 845–881, 2005

Layer of photoreceptors
Parts:
1) Outer segment- surrounded by the interphoto-receptor matrix & the
microvilli of RPE
2) Cilium- a tubular structure that connects the outer to an inner segment;
3) Inner segment- which consists an ellipsoid and a myoid portion;
4) Outer rod (or cone) fiber- which connects the inner segment to the cell
body;
5) Cell body- which contains the nucleus; and
6) Inner rod (or cone) fiber- which terminates in a specialized synoptic
ending.
The space within each sac is occupied by the visual pigments.
• Rods: contain rhodopsin, a light-sensitive pigment
• Cones: contain three different photopigments responsible for color vision.

Bipolar cells
Types:
• Midget bipolar cells -> connect single cone with
a single midget ganglion cell
• All cones synapse with at least one midget
bipolar cell and often with other bipolar cells.
• Midget bipolar cells generally synapse with a
single cone & a single midget ganglion cell.
• Flat or diffuse bipolar cells -> connect many
cones with many ganglion cells
• Rod bipolar cells - connect many rods to 1-4
ganglion cells.
• Interplexiform.

Muller cells
Function: They are large astrocytes
that mechanically support the retina
Parts:
• Cell body contain nuclei located in
the middle portion of the inner
nuclear layer.
• Outer processes attach to the outer
fibers of the photoreceptors forming
External limiting membrane.
• Inner processes Footplates
(Expanded terminations) covered by
Basement membrane Internal limiting
membrane.

ERG
ISCEV Standard for full-field clinical electroretinography (2022 update). Anthony G. Robson, Laura J. Frishman, John Grigg, Ruth Hamilton, Brett G. Jeffrey,
Mineo Kondo, Shiying Li, Daphne L. McCulloch.
Mass electrical response from the retina, usually evoked
by a brief flash of light.

EOG
• Measures the standing potential of eye
• Difference in electrical potential between the
anterior & posterior part of the eye
• Transepithelial potential of retinal pigment
epithelium
• With the cornea constantly positive, movement of
the eye produces a shift of this electrical potential
• Utilizes the RPE’s response to changing
illumination to assess the function of the outer
retina and RPE
Constable, P.A., Bach, M., Frishman, L.J. et al. ISCEV Standard for clinical electro-oculography (2017 update). Doc Ophthalmol 134, 1–9 (2017)

EOG
• The EOG is recorded during 15 min of dark
adaptation followed by 15 min of light adaptation
• This is expressed as the EOG light peak-to-dark
trough ratio (LP:DT ratio)
• EOG abnormalities are proportional to the severity of
rod-mediated ERG abnormalities
• The EOG has diagnostic importance in
• Best vitelliform macular dystrophy (Best disease)
• Autosomal recessive bestrophinopathy (ARB)
Arden ratio:
• Normal - >1.8
• Subnormal – 1.8-1.65
• Significantly subnormal -
<1.65
Constable, P.A., Bach, M., Frishman, L.J. et al. ISCEV Standard for clinical electro-oculography (2017 update). Doc Ophthalmol 134, 1–9 (2017)

INHERITED
RETINAL
DYSTROPHY
PROGRESSIVE
NON-
SYNDROMIC
MACULAR
DYSTROPHY
ROD CONE
DYSTROHY
CONE ROD
DYSTROPHY
SYNDROMIC
STATIONARY

Rod dystrophies
• Rod dominated dystrophies include rod and rod-cone dystrophies
• Retinitis pigmentosa (RP)
• Congenital stationary night blindness (CSNB)

Retinitis pigmentosa
• RP encompasses a group of progressive IRDs characterized by the primary
degeneration of rods, followed by the cones
• 1744 R.F. Ovelgün described a form of familial night blindness closely resembling
RP
• M. Schon and F.A. von Ammon reported patients with poor vision and pigmented
retinal lesions (Schon, 1828; Von Ammon, 1838)
• A.C. van Trigt provided the first description of RP viewed through an
ophthalmoscope in 1853
• “retinitis pigmentosa” was first coined by the famous Dutch ophthalmologist F.C.
Donders in 1857
• “tapetoretinal degeneration” (by Leber in 1916), “primary pigmentary retinal
degeneration,” “pigmentary retinopathy,” and “rod–cone dystrophy.”
Verbakel, S.K., van Huet, R.A.C., Boon, C.J.F., den Hollander, A.I., Collin, R.W.J., Klaver, C.C.W., Hoyng, C.B., Roepman, R., Klevering, B.J., Non-
syndromic retinitis pigmentosa, Progress in Retinal and Eye Research (2018)

Retinitis pigmentosa
• Most common retinal dystrophy
• The age of presentation and the prognosis depends on the type of inheritance
• autosomal dominant (AD) – most common (20-25%), RHO gene
• autosomal recessive (AR) (15-20%), RPE65 gene
• x- linked recessive (XLR) pattern – least common (10-15%) but most severe,
RPGR gene
Ferrari, Stefano et al. “Retinitis pigmentosa: genes and disease mechanisms.” Current genomics vol. 12,4 (2011): 238-49.
doi:10.2174/138920211795860107

Epidemiology
• Bunker et al in USA In prevalence rate 1:4756 (n=185)
• Haim et al in Denmark nationwide study Prevalence Of 1:3943
• Xu et al (n=4439) prevalence of 1:1000, m=4
• Study by Nangia et al (n=4711) prevalence of 1:750 in the adult
population in Rural Central India
• M>F
• 31-70yrs
Bunker CH, Berson EL, Bromley WC, Hayes RP, Roderick TH. Prevalence of retinitis pigmentosa in Maine. Am J Ophthalmol. 1984 Mar;97(3):357-65
Haim M. Epidemiology of retinitis pigmentosa in Denmark. Acta Ophthalmol Scand Suppl. 2002;(233):1-34
Xu L, Hu L, Ma K, Li J, Jonas JB. Prevalence of retinitis pigmentosa in urban and rural adult Chinese: The Beijing Eye Study. Eur J Ophthalmol. 2006 Nov-
Dec;16(6):865-6
Nangia V, Jonas JB, Khare A, Sinha A. Prevalence of retinitis pigmentosa in India: the Central India Eye and Medical Study. Acta Ophthalmol. 2012
Dec;90(8):e649-50

• Study by Sen et al (n=7461) in south india
• F>M
• 40-50 yrs
• Rural > Urban
• Study by G Babu et al (n=665) in a tertiary care hospital in south india
• M >F
• Peak age = 21-30yrs
• Nonsyndromic > syndromic
Sen P, Bhargava A, George R, Ve Ramesh S, Hemamalini A, Prema R, Kumaramanickavel G, Vijaya L. Prevalence of retinitis pigmentosa in South Indian
population aged above 40 years. Ophthalmic Epidemiol. 2008 Jul-Aug;15(4):279-81
G. Ravi Babu, B. Manjula, P. Nehakamalini. Clinical study of prevalence of retinitis pigmentosa in tertiary care hospital. International Journal of Contemporary
Medical Research 2017;4(9):1945-1947

• Nyctalopia
• Insidious progressive loss of peripheral field of vision
• In most cases, the inferior retina is affected first
• Central vision can be affected earlier due to
• cystoid macular edema
• epiretinal membrane
• development of retinal pigment epithelial defects in macula or fovea

Signs :
• Subtle mid-peripheral RPE atrophy associated
with mild arteriolar narrowing, and mid-
peripheral intraretinal perivascular ‘bone-
spicule’ pigmentary changes.
• Gradual increase in density of the pigmentary
changes with anterior and posterior spread

• Tessellated fundus appearance, due to
RPE atrophy and unmasking of large
choroidal vessels
• Severe arteriolar narrowing and gliotic
‘waxy pallor’ of the optic discs
• The macula may show atrophy,
epiretinal membrane formation and
CMO.

• Fundus appearance of RP classical triad :
• Retinal vessel attenuation
• Waxy pallor of the optic disc
• Bone spicule intraretinal pigmentation

Retinitis Pigmentosa (RP):
rod-cone pattern of dysfunction.
undetectable in severe disease,
ISCEV Standard for full-field clinical electroretinography (2022 update). Anthony G. Robson, Laura J. Frishman, John Grigg, Ruth Hamilton, Brett G. Jeffrey,
Mineo Kondo, Shiying Li, Daphne L. McCulloch.

Perimetry:
• Visual field loss has bilateral symmetry
• peripheral field loss occur before the central field
loss
• Begins with isolated scotomas in the
midperipheral areas
• Gradually coalesce to form a partial or complete
ring scotoma

OCT:
• Decreased thickness of the ONL and loss of
the external limiting membrane (ELM) and
IS/OS junctions
• Useful for detecting cystoid macular edema
or epiretinal membrane

Fundus autofluorescence imaging:
• An abnormal foveal ring or curvilinear arc of
increased autofluorescence
• The autofluorescent ring corresponds to an
area of outer segment dysgenesis and
lipofuscin production, with progressive retinal
thinning

Associated ocular manifestations in RP
• Cataract (PSC)
• Open angle Glaucoma
• CME

Atypical RP
• RP sine pigmento
• Sectoral retinitis pigmentosa
• Pericentral RP
• Unilateral or extremely asymmetric RP

RP sine pigmento
• Patients with very early RP without fundus
pigmentary abnormalities are termed as RP
sine pigmento
• Fine dust-like pigment cells are noted in the
vitreous cavity; these are released from the
degeneration of RPE

Sectoral RP
• Sectoral RP is characterized by pigmentary
changes limited to one or two quadrants
with limited visual field changes, good
electroretinogram (ERG) responses, and
minimal progression with time
• True sector RP can be autosomal dominant
or recessive
• Sporadic cases are, however, common and
may possibly result from non-genetic causes
of retinal degeneration

Pericentral RP
• The pericentral variant shows field loss between 5 and 15 degrees
from fixation
• areas of field deficit enlarge and coalesce over time and encroach the
central field of vision early, causing greater disability

Unilateral RP
• Unilateral RP is typically an acquired condition and is commonly
referred to as diffuse unilateral neuroretinitis
• Unilateral retinitis pigmentosa cases may also result from
postinfectious causes or blunt trauma to one eye
• extremely asymmetric RP is an entity with a genetic association.

d/d of RP
• Cancer related retinopathy
• Retinopathy following syphilis
• Chloroquine retinopathy

Cancer related retinopathy
• Severe panretinal degeneration as a remote
effect of cancer, usually either
• small-cell (oat-cell) carcinoma of the lung
• small-cell undifferentiated cervical carcinoma
• The first autoantigen in the human retina
identified with a CAR is recoverin.
• Antibodies to retinal enolase have also been
reported in CAR
• ERG – electronegative b-wave
Hoogewoud, F., Butori, P., Blanche, P. et al. Cancer-associated retinopathy preceding the diagnosis of cancer. BMC Ophthalmol 18, 285 (2018).

Retinopathy following syphilis
• Syphilitic involvement of the retina is considered
a form of neurosyphilis
• Congenital or acquired syphilis can present as a
pigmentary retinopathy
• Pigment deposits are clumps or large patches of
black pigment associated with chorioretinal scars
Breno R. Lima, Efrem D. Mandelcorn, Nupura Bakshi, Robert B. Nussenblatt & H. Nida Sen (2014) Syphilitic Outer Retinopathy, Ocular Immunology
and Inflammation, 22:1, 4-8

Chloroquine retinopathy
• a ring of hyperfluorescence (caused
by the accumulation of lipofuscin)
• later stages, a ring of
hypofluoresence (caused by the loss
of photoreceptor and retinal
pigment epithelial layers)

• Systemic association
• Syndromes-
• Bardet–Biedl syndrome
• Refsum disease
• Usher syndrome
• Abetalipoproteinemia

Systemic associations of RP
• Bardet–Biedl syndrome
• Hypogonadism
• Polydactyly
• truncal obesity
• renal anomalies
• mental retardation.
• Fundus: macular atrophy and peripheral bone spicule
pigmentation.
• Less frequently findings are typical RP, RP sine
pigmento and retinitis punctata albescens.
Weihbrecht K, Goar WA, Pak T, et al. Keeping an Eye on Bardet-Biedl Syndrome: A Comprehensive Review of the Role of Bardet-Biedl Syndrome Genes in
the Eye. Med Res Arch. 2017

Refsum disease:
• Infantile :
• Dysmorphic facies
• mental retardation
• Hepatomegaly
• deafness.
• Adult :
• cerebellar ataxia
• Polyneuropathy
• Anosmia
• Deafness
• Cardiomyopathy
• Ichthyosis
Waterham HR, Wanders RJA, Leroy BP. Adult Refsum Disease. 2006 Mar 20 [Updated 2021 Sep 30]. In: Adam MP, Ardinger HH, Pagon RA, et al.,
editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022

Usher syndrome:
• It is the most common cause of deaf–blindness
worldwide with a prevalence of between 4 to 17 in
100 000
• Systemic features include premature ageing
beginning in infancy, dwarfism, skeletal anomalies,
deafness, photosensitivity, mental handicap.
• Fundus shows RP, salt and pepper pigmentation
and optic atrophy
Toms M, Pagarkar W, Moosajee M. Usher syndrome: clinical features, molecular genetics and advancing therapeutics. Therapeutic Advances in
Ophthalmology. January 2020

Treatment modalities
• Genetic counselling & testing
• Low vision aids
• Flashlights
• Night-vision goggles
• Cataract surgery
• Complications :
• Posterior capsular opacification
• Post op inflammation

• For CME:
• Carbonic anhydrase inhibitiors
• Oral = 125-500mg/day
• Topical = Dorzolamide 2% TDS
• A meta-analysis conducted by Huang et al. showed a mean reduction in central
retinal thickness of 46%*
• Recurrence can occur after cessation of carbonic anhydrase inhibitor treatment
• Refractory CME can be treated with intravitreal steroids**
• The use of intravitreal anti-VEGF in RP patients remains unclear
*Huang, Q., Chen, R., Lin, X., Xiang, Z., 2017b. Efficacy of carbonic anhydrase inhibitors in management of cystoid macular edema in retinitis pigmentosa: A
meta-analysis. PLoS One 12, e0186180
**Huckfeldt, R.M., Comander, J., 2017. Management of Cystoid Macular Edema in Retinitis Pigmentosa. Semin. Ophthalmol. 32, 43-51.

Gene-specific and mutation-specific approaches:*
• Antisense oligonucleotides (AONs) –
• can modify pre-mRNA splicing by specifically binding to a target region in the
pre-mRNA, thereby suppressing aberrant splicing using the CRISPR/Cas9
system
Several dietary changes and dietary supplements:**
• Vitamin A
• Docosahexaenoic acid
*Collin, R.W., Garanto, A., 2017. Applications of antisense oligonucleotides for the treatment of inherited retinal diseases. Curr. Opin. Ophthalmol. 28, 260-
266.
**Rayapudi, S., Schwartz, S.G., Wang, X., Chavis, P., 2013. Vitamin A and fish oils for retinitis pigmentosa. Cochrane Database Syst Rev, Cd008428.

Recent advances
• Retinal prosthesis:
• For end-stage RP patients with little or no light
perception
• Epiretinal prosthesis systems are placed on
the surface of the neurosensory retina,
adjacent to the nerve fiber and ganglion cell
layers
• Argus II epiretinal prosthesis
Bloch, Edward et al. “Advances in retinal prosthesis systems.” Therapeutic advances in ophthalmology vol. 11 2515841418817501. 17 Jan. 2019,
doi:10.1177/2515841418817501

Alpha AMS subretinal implant:
• Subretinal implant is that by positioning the device at
the level of the degenerated PRs
• Both of these implants function by stimulating the
inner retinal layers and therefore require an intact
inner retinal architecture
• An epiretinal implant is connected to a miniature
camera mounted on eyeglasses; the implant then
stimulates the residual retinal ganglion cells
directly.
• In contrast, a subretinal implant consists of a
light-sensitive micro-photodiode array that
stimulates the bipolar cell layer
Bloch, Edward et al. “Advances in retinal prosthesis systems.” Therapeutic advances in ophthalmology vol. 11 2515841418817501. 17 Jan. 2019,
doi:10.1177/2515841418817501

Congenital Stationary Night Blindness
• non-progressive form of night blindness
• autosomal dominant, autosomal recessive, or X-linked
• CSNB is further categorized as- CSNB with normal fundus and abnormal fundus
• Some cases of CSNB with normal fundi present with reduced vision and no
history of night blindness
• CSNB with abnormal fundi includes two entities:
• Oguchi disease
• fundus albipunctatus.
Zeitz C, Robson AG, Audo I. Congenital stationary night blindness: an analysis and update of genotype-phenotype correlations and pathogenic mechanisms.
Prog Retin Eye Res. 2015 Mar

Oguchi disease
• Mizuo Nakamura phenomenon is classically observed.
• Golden sheen over the retina is noted with an unusually
dark macula on exposure to light.
• However, the retina appears normal after prolonged dark
adaptation
• Color vision and visual acuity are normal
• Histopathology: presence of an abnormal layer between
outer segments of photoreceptors and RPE

Fundus albipunctatus
• A type of CSNB with yellow-white dots over the
fundus
• In most cases, these dots are found incidentally
on routine eye checkup
• Color vision and visual acuity are usually normal

Cone disorders
• Early-onset with non progression and late-onset forms that are usually progressive
• The progressive forms include
• Cone dominated dystrophies
• Cone dystrophies.
• The stationary forms include
• Achromatopsia
• Blue cone monochromatism
Gill JS, et al. Br J Ophthalmol 2019;0:1–10. doi:10.1136/bjophthalmol-2018-313278

Cone dystrophy (CD): A cone dystrophy is a retinal
degeneration where there is generalised retinal cone system
dysfunction but normal or near normal rod ERGs

Cone rod dystrophy (CRD)
• It is usually misdiagnosed as RP with more involvement of cones than rods.
• Patients present with the early loss of vision and color vision abnormalities with
subsequent peripheral field constriction.
• Fundus examination reveals macular pigmentation and atrophy in the early stages,
followed by peripheral bone spicule pigmentation in advanced cases.
• The diagnosis is essentially based on ERG changes, which show cone affliction
more than rods.
Gill JS, et al. Br J Ophthalmol 2019;0:1–10. doi:10.1136/bjophthalmol-2018-313278

Cone-rod dystrophy (CRD): Generalised photoreceptor
degenerations where the cone ERG is more abnormal than
the rod ERG are known as cone-rod dystrophies.

Achromatopsia
• Prevalence is about 1:30 000 births.
• Loss of cone cell function
• It is an autosomal recessive
• Patients presenting with poor visual acuity since birth,
photosensitivity, and poor color discrimination
• It has two subtypes- Complete and incomplete achromatopsia
Remmer, Meredith H.; Rastogi, Neelesh; Ranka, Milan P.; Ceisler, Emily J. Achromatopsia, Current Opinion in Ophthalmology: July 2015 - Volume 26 -
Issue 5 - p 333-340

• Cases with complete achromatopsia, also known as rod monochromats,
usually have visual acuity less than 20/200.
• Incomplete or atypical forms retain a visual acuity between 20/80- 20/200
• Color vision is completely absent in complete achromatopsia cases.
• Fundus examination is usually normal in these cases
• Visual field testing - central scotoma, peripheral fields are usually normal or
mildly constricted.
• These are non-progressive changes
Remmer, Meredith H.; Rastogi, Neelesh; Ranka, Milan P.; Ceisler, Emily J. Achromatopsia, Current Opinion in Ophthalmology: July 2015 - Volume 26 -
Issue 5 - p 333-340

Cone Monochromatism
• It is an X linked recessive congenital disorder
• Two of the three cone systems are absent or significantly affected.
• The most common variety is blue cone monochromatism, in which
both red and green cone systems are completely absent.
• Visual acuity in affected individuals ranges from 20/63 to 20/200
• Clinical signs and symptoms resemble achromatopsia cases
Luo X, Cideciyan AV, Iannaccone A, Roman AJ, Ditta LC, Jennings BJ, et al. (2015) Blue Cone Monochromacy: Visual Function and Efficacy Outcome
Measures for Clinical Trials. PLoS ONE 10(4): e0125700.

Leber congenital amaurosis (LCA)
• The most common inheritance pattern is autosomal recessive.
• Prevalence between 1 in 33000 to 1 in 81000
• Presents with severe visual impairment or blindness from infancy and
extinguished ERG
• Most patients show either a normal fundus appearance or subtle RPE changes
and retinal vascular attenuation.
• The oculo-digital sign is a common association.
• Keratoconus is seen in 29% of cases
Kumaran, Neruban et al. “Leber congenital amaurosis/early-onset severe retinal dystrophy: clinical features, molecular genetics and therapeutic
interventions.” The British journal of ophthalmology vol. 101,9 (2017): 1147-1154. doi:10.1136/bjophthalmol-2016-309975

• Complicated cases have systemic features –
• Deafness
• renal anomalies
• hepatic dysfunction
• skeletal abnormalities
• Mental retardation is reported in around 20% of cases.
• Patients with RPE65 or CRB1 gene mutations have progressive vision loss with
age, with the prognosis being slightly better in those with onset after infancy.
Kumaran, Neruban et al. “Leber congenital amaurosis/early-onset severe retinal dystrophy: clinical features, molecular genetics and therapeutic
interventions.” The British journal of ophthalmology vol. 101,9 (2017): 1147-1154. doi:10.1136/bjophthalmol-2016-309975

Treatment :
• Gene therapy (clinicaltrials.gov Identifier: NCT00481546)
• Safe and substantially efficacious in the extrafoveal retina.
• No evidence of age-dependent effects was found
Jacobson SG, Cideciyan AV, Ratnakaram R, et al. Gene Therapy for Leber Congenital Amaurosis Caused by RPE65 Mutations: Safety and Efficacy
in 15 Children and Adults Followed Up to 3 Years. Arch Ophthalmol. 2012;130(1):9–24.

Stargardt disease
• Most common inherited macular dystrophy.
• Incidence 1:8000-1:10000.
• Autosomal recessive- sequence mutation in ABCA4 gene -encodes protein
involved in visual cycle
• Autosomal dominant - Rare, ELOV4 gene mutation
• Encodes photoreceptor specific membrane bound protein-long chain fatty acid
biosynthesis.
• Highly heterogenous .
• Pathology:
• ABCA4 & ELOV4 mutation-accelerated production of lipofuscin and cell death
• Accumulation of pisciform flecks at RPE concentrated at macula & progressing to central
atrophy.
Tanna P, et al. Br J Ophthalmol 2017

Clinical characteristics
• Bimodal distribution-childhood and early adulthood
• Progressive bilateral central vision loss.
• Defective colour vision & impaired dark adaptation.
• Signs:
• Non specific mottling
• Beaten Bronze appearance
• Geographic atrophy – bulls eye maculopathy.
• Numerous yellow-white round pisciform lesions-at RPE level

Diagnosis:
• Visual fields- central defects
• OCT-
• Aid in the Diagnosis
• Determining the status of photoreceptor layer at macula

Fundus autoflourescence((FAF):
• Areas of RPE atrophy
• Bulls eye changes in macula
• Flecks with Peripapillary sparing
o Tanna P, et al. Br J Ophthalmol 2017

FUNDUS Angiography:
Lipofuscin flecks and
atrophy.
Silent choroid

Electroretinography(erg):
• Normal in early cases
• Group1: Severe pattern ERG abnormality with normal Scotopic & full field
ERG
• Group2: Additional loss of photopic vision
• Group3: Loss of both scotopic & photopic vision
• Tanna P, et al. Br J Ophthalmol 2017

Treatment:
• No effective therapy approved for curing the disease.
• General measures like low vision aids & occupational counselling.
• Genetic counselling.
• More clinical trials are going on
• Gene transplantation
• Stem cell therapy
• Various pharmacological therapies.
• Gene replacement therapy* :(ClinicalTrials.gov Identifier: NCT01367444).
• Targets viable photoreceptors-slowdown / prevents progression.**
• AAV vectors used.
• Subretinal injection of lentivirus vector delivering ABCA4 gene.
• Limitaions:
• No safety concerns
• No definite evidence of efficacy
*Tanna P, et al. Br J Ophthalmol 2017
** Da Sun ,Rebecca M. Schur et al ,Molecular Therapy Vol. 28 No 1 January 2020

• Stem cell therapy trial:(ClinicalTrials.govIdentifier: NCT01469832)
• Sub retinal transplantation of embryonic stem cell derived RPE cells.
• Limitaions:
• No safety concerns
• No definite evidence of efficacy
• Pharmacotherapy:.(ClinicalTrials.gov Identifier NCT02402660).
• Specific drugs targeting the different aspects of visual cycle-slowing/stopping the progression
of disease.
• Reducing delivery of vitamin A –decrease in toxic by-product formation.
• Targeting toxic metabolites:A2E
• Chemically modified vitamin-A oral therapy
• *Tanna P, et al. Br J Ophthalmol 2017
** Da Sun ,Rebecca M. Schur et al ,Molecular Therapy Vol. 28 No 1 January 2020

Best disease:
• Slowly progressive macular dystrophy with juvenile onset.
• Second M/C macular dystrophy.
• Most common Mendelian macular dystrophy.
• Allelic variation in the Bestrophin (BEST1) gene on 11q13
• Bestrophin- acts as a transmembrane ion channel found on the
plasma membrane of RPE
• AD inheritance with variable penetrance & expressivity.
• Associated with hyperopia and angle closure glaucoma.

Pathophysiology:
Bestrophin 1 gene mutation
Dysregulation of ionic mileu and calcium sensitive chloride channels in RPE & sub retinal space.
Altered uptake of calcium by RPE &Impaired ionic flow across RPE
Altered adhesiveness between interphotoreceptor matrix & RPE
Diminution of outer segment phagocytosis
Accumulation vitelliform material throughout the retina but more at macula.
• *MacDonald IM Lee T ,Lawrence J Bestrophinopathies ,2003 gene reviews
• Najiha Rahman, Macular dystrophies: clinical and imaging features, molecular genetics and therapeutic options , BJO 2019

Clinical characteristics:
• Juvvenile Onset.
• Incidence-1 in 10000 per year.
• Asymptomatic/ Progressive central vision loss.
• Bilateral yellow yolk like macular lesions
• Sub retinal & sub RPE fibrosis, RPE atrophy with hyperpigmentation-’scrambled egg
lesion’.
• Geographical atrophy
• Choroidal neovascularisation.

Clinical Stages:
• Stage 0: normal macula. Abnormal EOG
• Stage1 : RPE disruption in the macular region. FA shows window
defects.
• Stage 2: Vitelliform lesion. FA shows –hypofluorescent lesion.

Stage 3: Pseudohypopyon phase; FA shows-hyperfluorescence
Stage 4:
A)Orange red lesion with atrophic RPE ; FA shows- Inferior hypofluorescence with
superior hyperfluorescent defects.
B)Fibrous scarring of the macula; FA shows-hyperfluorescence
C)Choroidal neovascularisation ; FA shows-hyperfluorescence with leakage

Histopathology:
• Increased RPE lipofuscin.
• Loss of photoreceptors with intact RPE
• Sub RPE Drusenoid material
• Accumulation of cells and material in sub retinal space.

Diagnosis:
• EOG: reduced Arden ratio(close to 1.1).
• ERG:
• Full field ERG normal
• Multifocal/foveal ERG-reduced central amplitudes
• Scanning laser evoked Mf ERG: significantly reduced amplitudes in the macula
• SD-OCT: splitting and elevation of outer retina &RPE

Treatment:
• Low vision aids- for significantly reduced visual acuity*.
• Individualized education plan (IEP) services.
• Occupational counselling
• Laser photocoagulation*:
• Stage 4c lesions
• Choroidal neovascularisation
• Subretinal haemorrhages
• Anti VEGFs: Bevacizumab & Ranizumab**
• Photodynamic therapy

Prognosis:
• Relatively good*
• Intrafamilial and interfamilial variability.
• Progressive resorption of sub retinal material – slow deterioration of
central vision loss.
• Best disease complicated with CNVM- marked vision loss
• AAV mediated gene replacement therapy-successful in canine models**.
*Najiha Rahman, Macular dystrophies: clinical and imaging features, molecular genetics and therapeutic options , BJO 2019
**Wood SR, McClements ME, Martinez-Fernandez A quantitative chloride channel conductance assay for efficacy testing of AAV.BEST1. Hum Gene Ther
Methods 2019;

Summary
• Retinal dystrophies are degenerative diseases of retina with marked clinical
and genetic heterogenicity.
• Progressive Poor peripheral/night vision to complete blindness.
• >270 associated genes identified.
• Syndromic and non-syndromic.
• Various inheritance patterns.
• Many are presented with progressive central vision loss
• Rod dominated diseases, cone dominated diseases & generalized retinal
degenerations.
• ERG & EOG plays important role in diagnosis.

• No definitive treatment for curing the disease.
• Many clinical trials going on for preventing & slow down the
progression of disease.
• General measures like visual rehabilitation, low vision aids,
occupational counselling & social support.
• genetic counselling & pedigree analysis is mandatory.
• Gene therapy , stem cell transplantation & various
pharmocotherapies are being tested in different phases of clinical
trials

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