Hereditary retinal dystrophies

1. Presenter
Dr. Farhad Uddin Ahmed
MS Phase B student
NIO&H

2. Chairman
Professor Dipak Kumar Nag
Dpt. of Vitreo-retina
NIO&H
Moderator
Asst. prof. Dr Koushik Chowdhury
Dpt. of Vitreo-retina
NIO&H

3. Introduction
Retinal dystrophies can be subdivided into four
groups-
1. Generalized photoreceptor dystrophies
2. Macular dystrophies
3. Generalized choroidal dystrophies
4. Hereditary vitreo-retinopathies

4. Generalized Photoreceptor dystrophies:
 Retinitis pigmentosa
 Atypical RP
 Cone dystrophy
 Bietti crystalline choreoretinal dystrophy
 Alport syndrome
 Congenital stationary night blindness

5. Macular dystrophies:
 Stargardt Dystrophy
 Best vitelliform macular dystrophy
 Pattern dystrophy of the retinal pigmented epithelium
 North Carolina macular dystrophy
 Sorsby pseudoinflammatory dystrophy

6. Generalized choroidal dystrophies:
 Choroideremia
 Gyrate atrophy
 Progressive Bifocal Chorioretinal Atrophy

7. Hereditary Vitreoretinopathies-
 Juvenile X linked Retinoschisis
 Stickler syndrome
 Wagner Syndrome
 Familial exudative vitreo-retinopathy
 Snowflake vitreoretinal degeneration
 Autosomal dominant vitreoretinochoroidopathy

8. Generalized Photoreceptor
dystrophies

9. Retinitis Pigmentosa
 Most common hereditary
Pigmentary retinal dystrophy
 Affecting
Rod
Cone
 Incidence: - 1: 5000
 Age- Appears in childhood
 Race- Equal in all races.
 Sex- Males > Females 3:2
 Usually Bilateral

10. Cont.
Inheritance:
1. Sporadic- 60%
2. Inherited- 40%
a) Autosomal Dominant- 43%;
b) Autosomal Recessive- 20%
c) X-linked – uncommon 10%;
d) Uncertain family history 6-8%

11. Retinitis Pigmentosa
Symptoms of RP-
1. Night blindness
2. Dark Adaptation difficulties
3. Visual field loss
4. Others-
• Photopsia,
• Diminished contrast sensitivity.
5. Visual acuity remains normal till late stage disease.

12. Theories of Retinitis
Pigmentosa:
1. Vascular theory-
a) Sclerosis of choroid and
choriocapillaris.
b) Sclerosis of retinal vessels.
2. Pigmentary changes-
Changes in neuroepithelium and
pigmentary epithelium.
3. Abiotrophic- Early
degeneration and loss of
function of cells.
4. Premature seniling and death
of cells of specified tissue.
Progression of RP

13. Fundus Finding of RP-
1) Bony spicules like
pigmentation
2) Waxy pallor Optic nerve
head:
3) Vascular changes: arteriolar
narrowing.
4) Macular change: Loss of
foveal reflex.
5) Vitreous change: Fine dust
like particles

14. Investigations:
1. ERG- Early Reduced scotopic rod
and combined responses.
2. EOG- Subnormal
3. Visual fields
4. OCT
5. Fundus Autofluorescence- Lack of
signals on FAF
6. Genetic analysis

15. Treatment of RP-
1) No definitive treatment is yet available.
2) Regular follow up
3) Smoking to be avoided
4) High dose Vit A supplementation
5) Cataract surgery for PSC
6) Low vision aids-
• Optical aids
• Non optical device

16. 7. Valproate/Phenytoin- Is used as a retino-
protective drug.
8. Potential retinotoxic medications should be
avoided.
9. CMO in RP responds to oral Acetazolamide
10. Retinal prosthesis/Implants-
• Bionic eye
• Argus 2 implant

17. Atypical RP
Atypical RP with systemic disorder [Syndromic
association]-
1) Usher Syndrome-
Autosomal Recessive.
About 5% of cases- profound deafness
and blindness in children .
Fundus findings-
• Salt and pepper retinal pigmentation
• optic atrophy

18. 2) Kearns-Sayre syndrome-
 Mitochondrial inheritance.
 Chronic progressive external
ophthalmoplegia with ptosis
 Fundus findings- salt-pepper
appearance most striking at the
macula
3) Bassen-Kornzweig syndrome-
 Autosomal recessive.
 Failure to thrive
 Blood film shows thorny red cells
 Fundus finding- Scattered white dots
 Vit supplementation and low fat diet
are implemented.

19. 4) Refsum disease-
 Autosomal recessive.
 Phytanic acid accumulates throughout
the body causing ichthyosis
 Retinal changes may be similar to RP or
salt-pepper appearance
 Associated with cataract and optic
atrophy.
5) Bardet-Biedel syndrome-
 Genetically heterogenous. Associated
polydactyl and mental handicap.
 Fundus picture- Bull’s eye maculopathy
due to cone-rod dystrophy

20. Retinitis Punctata Albescens
 AR or AD inheritance
 Scattered whitish-yellow spots, most
numerous at the equator, usually sparing
the macula
 Eventually progresses to geographic
atrophy
 Visual field becomes more constricted.
 Symptoms- Night blindness, Progressive
visual field loss.
 Prognosis is poor. ERG reduced.
 Treatment- No definitive treatment. Low
vision aids are useful.

21. Cone Dystrophy
 Inheritance- Sporadic (most common),
AD, XLR.
 Presentation- In early adulthood, with
impairment of central vision
 Symptoms- Gradual bilateral impairment
of central and color vision.
 Signs-
 Macula may virtually be normal or show non-
specific central pigmentary changes or
atrophy.
 Bull’s eye maculopathy is classically found
 Eventual progression to geographic atrophy.

22. Cont.
 Investigations-
1) FAF-Shows annular pattern concentric with
the fovea.
2) ERG- Photopic responses are sub normal
3) EOG- Normal or subnormal.
4) Color vision- Severe deuteron- tritan defect.
5) FA- Shows a round hyperfluorescent window
defect with hypo fluorescent center.
 Prognosis- Poor, with visual acuity of 6/60
or worse.
 Treatment- No specific treatment.

23. Leber Congenital Amaurosis
 Severe rod-cone dystrophy
 Autosomal recessive
 Presentation-
 Blindness at birth or early infancy
 Roving eye movements or
 Nystagmus
 Signs-
1. Absent or diminished pupillary light
reflex.
2. The fundi may be normal in early life
3. Initially mild peripheral pigmentary
retinopathy, salt- pepper changes
and less frequently yellow flecks.
4. Severe macular pigmentation or
coloboma like atrophy.

24. Cont.
5. Oculodigital syndrome .
6. Others -strabismus, hypermetropia and cataract.
7. First sign noticed by parents is nystagmus.
 ERG is usually non-recordable.
 Prognosis- Poor.
 Treatment- No definite treatment..
 Systemic association- Mental handicap, Deafness,
Epilepsy, CNS anomaly, Renal anomaly, Skeletal
malformation and Endocrine dysfunction.

25. Alport Syndrome
 X-linked Recessive.
 Mutation in major gene of type 4 collagen,
major basement membrane component.
 It is characterized by chronic renal failure and
sensorineural deafness.
 Fundus: Scattered yellowish punctate flecks in
perimacular area
 ERG is normal
 Visual prognosis is excellent.
 Anterior lenticonus and posterior
polymorphous corneal dystrophy may be
present.

26. Familial Benign Fleck Retina
 Rare Autosomal Recessive disorder.
 Asymptomatic
 Incidental finding
 Fundus- Yellow-white polymorphous
lesion spare the fovea and extend
to the far-periphery.
 The flecks are made of lipofuscin,
show auto-fluorescence
 ERG is normal.
 Prognosis excellent.

27. Congenital Stationary Night Blindness
 Group of disorders characterized by infantile-onset
nyctalopia but non progressive retinal dysfunction.
 With Normal fundus appearance-
1. Type 1 (complete)- complete absence of rod pathway
function and essentially normal cone function clinically
and on ERG.
2. Type 2(incomplete)- Impairment of both rods and cones
function.
3. Inheritance- AD form is usually associated with normal
visual acuity, AR, XLR patients have poor vision with
nystagmus, often significant myopia.

28. Cont.
With an Abnormal Fundus Appearance-
1) Oguchi disease-
 Autosomal Recessive inheritance.
 The fundus has an unusual golden-
yellow color in the light adapted
state which becomes normal after
prolonged DA. (Mizuo or Mizuo-
Nakamura phenomenon).
 Rod function is absent after 30
minutes of DA but recovers to a
near normal level after a long
period of DA.

29. Cont.
2) Fundus Albipunctatus-
 Inheritance- AR or AD.
 There are multiple tiny white dots
that are very regularly spaced,
involve the posterior pole, spare the
fovea, and extend into the mid-
periphery.
 Prognosis-Excellent.
 FA- Shows mottled
hyperfluroscence.
 ERG- Reduced.

30. Macular dystrophies
 “Macular dystrophy” has been used to refer to a
group of heritable disorders that cause
ophthalmoscopically visible abnormalities in the
portion of the retina bounded by the temporal
vascular arcades.
 Inherited in a Mendelian fashion

31. STARGART DISEASE
 Most common Macular dystrophy.
 Accumulation of Lipofuscin within the RPE.
 Types:
1. STGD1- Autosomal Recessive. Most common
type. Mutation in gene ABCA4.
2. STGD3- Autosomal Dominant.
3. STGD4- Autosomal Dominant.
 Presentation in Childhood/Adolescence.
 Prognosis for maculopathy is poor.
 Visual acuity is usually 6/12 to 6/60.
 Patients with flecks in early stages have
relatively good prognosis.

32. Continue...
 SYMPTOMS:
• Slowly progressive
• Gradual impairment of central vision(6/12 to
6/60).
• Reduced color vision & dark adaptation.
 SIGN:
• Non specific motling
• Perifoveal flecks .
• Oval area of atrophy of RPE in the macula,
typically described as “snail slime” or
“beaten bronze” appearance.
• Subsequently Geographic atrophy
• More flecks appear beyond the macula but
do not extend into the periphery.
• The disk and blood vessels remain normal

33. Investigation
 FA-
 Dark choroid .
 Macula- mixed hyper & hypofluorescence.
 Fresh flecks- early hypofluorescence & late
hyperfluorescence
 Old flecks- RPE window defect
 FAF-
 Hyperautofluorescent flecks &
 Peripapillary And macular
hypoautofluorescence
 VF-
 Cetral scotoma

34. Cont.
 OCT: Foveal thickness & foveal atrophy
 ERG: Photopic is normal to sub
normal , scotopic may be normal.
 EOG: Commonly subnormal,
especially in advanced cases.
 ICGA shows fresh hypofluroscent
spots.

35. Management
 No specific treatment, condition remains incurable .
 Isotretinoin or Vit A is not recommended.
 Low vision aids can be useful.
 General measurement : protection from excessive high
energy light exposure by UV blocking sunglass.
 Gene therapy.

36. BEST DISEASE/Juvenile onset vitelliform dystrophy
 Autosomal dominant
condition.
 It is one of the most common
Mendelian macular
dystrophies
 Prognosis is usually good until
middle age, after which VA
declines in one or both eyes.

37. Genetics
 The causative gene is encoding for
bestrophin.
 The protein has been localized to the
plasma membrane of RPE and work as
transmembrane ion channel. Abnormal
chloride conductance might be the
initiator of the disease process.
Histological Features -
 Increased RPE lipofuscin.
 Loss of photoreceptors
 Sub-RPE drusenoid material accumulation
in cells and material in the subretinal
space.

38. Clinical features
 Previtelliform stage. This is evident as a
small, round yellowish dot at the site of
foveola. Subnormal EOG.
 Vitelliform stage can lead to appearance
of cyst with fluid level or sometimes clear
space in center with the material situated
all round. Sub- retinal neovascularization
(CNVM) is complication.

39. Cont.
 Pseudohypopyon may occur when part of
the lesion regresses often at puberty.
 Vitelliruptive: the lesion breaks up and visual
acuity drops
 Atrophic stage can be represented by area
of RPE atrophy or sometimes disciform scar if
complicated by CNVM

40. Investigation:
1. FAF- hyperautoflurorescent, in
atrophic stages
hypoautofluorescent
2. OCT macula- materials beneath,
above & within RPE
3. FFA- central hypofluorescence at
vitelliform stage and
hyperfluorescence later due to
atrophic RPE .
4. EOG- Typically EOG is affected early
in the stage of the disease.
5. ERG- completely normal

41. Cont.
Management:
 Treatment for BEST1 disease consists primarily
recognizing choroidal neovascularization and treatment
with anti-VEGF therapy.
 Even in the absence of CNV, subretinal hemorrhage
can occur in Best disease following relatively modest
head or eye trauma.
 Protective eyewear is recommended for all sports

42. PATTERN DYSTROPHY
 Originally described with black pigmentation in the
macular area.
 Subsequent reports included yellow, gold and gray
subretinal deposits as well.
 GENETICS-
 Mutations in a single gene, PRPH2.
 The condition is autosomal dominant in
transmission.
 Peripherin and RDS gene mutations have been
identified in these families.

43. Cont.
Butterfly-shaped:
Foveal yellow and melanin pigmentation,
commonly in a spoke-like or butterfly wing-
like conformation. Drusen- or Stargardt-like
flecks may be associated with any pattern
dystrophy.
FA
Shows central and radiating
hypofluorescence with surrounding
hyperfluorescence

44. Cont.
Multifocal pattern dystrophy:
 Simulating fundus flavimaculatus:
 Multiple, widely scattered, irregular
yellow lesions;
 They may be similar to those seen
in fundus flavimaculatus .
FA
Shows hyperfluorescence of the
flecks; the choroid is not dark

45. Cont.
Macroreticular (spider-shaped):
 Initially pigment granules are seen at
the fovea
 Reticular pigmentation develops that
spreads to the periphery
 Fluorescein angiography reveals the
patterns more clearly.
 ERG is normal while EOG can be
variable.

46. NORTH CAROLINA MACULAR DYSTROPHY
 North Carolina macular dystrophy was
originally described in a family in North
Carolina.
 Now identified all over the world and in various
ethnic groups.
 Non progressive condition
 Transmit as autosomal dominant trait.
 Characterized by drusen in the posterior pole
leading to disciform scar .
 Sometimes staphylomatous chorioretinal scars
in the posterior pole.

47. Sorsby pseudoinflammatory Dystrophy
 This condition was first described in five British families.
 Autosomal dominant condition.
 Mutations in the tissue inhibitor of metalloproteinase-3 (TIMP- 3)
have been identified as a possible cause of the disease.
 SYMPTOMS:
 The disease presents as reduced central vision along with night
blindness.
 SIGNS:
 Choroidal neovascular membrane (CNVM) formation .
 subretinal haemorrhage followed by disciform scar formation
 sometimes extending to the periphery as well.

48. Cont.
Confluent flecks
nasal to the disc
Exudative
maculopathy
Subretinal
Scarring in end-
stage disease

49. DOMINANT FAMILIAL DRUSEN
 Familial Dominant Drusens (Doyne
honeycomb choroiditis) represents a
early onset variant of ARMD.
 Autosomal Dominant. Mutation in
EFEMP1 gene
 Asymptomatic yellow-white, elongated,
radially oriented drusen develop in the
second decade.
 With age the drusens increasingly
become dense and acquire a
honeycomb pattern

50. Cont.
 Described as ‘stars in the sky’ or ‘milky way’ they seen
in clusters in the posterior pole.
 Visual symptoms may occur in 4th to 5th decade due
to RPE degeneration, geographic atrophy or
occasionally CNV.
 ERG is normal
 EOG is subnormal.

51. Generalized Choroidal Dystrophies

52. Choroideremia
 Progressive diffuse degeneration of the choroid, RPE and
Photoreceptors.
 Inheritance is XLR
 Female carriers
 Presentation is in the 2nd–3rd decades with nyctalopia, later by loss
of peripheral vision.
 Signs –
1) Mid-peripheral RPE abnormalities.
2) Atrophy of the RPE and choroid spreads peripherally and
centrally.
3) End-stage disease shows a few large choroidal vessels coursing
over the bare white sclera, vascular attenuation and optic
atrophy.

53.  ERG- Scotopic is non-recordable;
photopic is severely subnormal.
 FA shows filling of the retinal and
large choroidal vessels but not of
the choriocapillaris. The intact
fovea is hypofluorescent and is
surrounded by hyperfluorescence
due to an extensive window
defect

54. Gyrate atrophy
 Autosomal Recessive
 Presentation is in the 1st–2nd decades with myopia and nyctalopia.
 Signs-
1. Mid-peripheral depigmented spots associated with diffuse
pigmentary mottling may be seen in asymptomatic cases.
2. Sharply-demarcated circular or oval areas of chorioretinal
atrophy
3. Extreme attenuation of retinal blood vessels.
4. Vitreous degeneration and early-onset cataracts are common.
 FA shows sharp demarcation between the choroidal atrophy and
normal filling of the choriocapillaris.
 ERG is subnormal

55. Cont.
 Treatment
 There are two clinically different subtypes of
gyrate atrophy based on response to
pyridoxine (vitamin B6), which may
normalize plasma and urinary ornithine
levels.
 Patients who are responsive to vitamin B6
generally have a less severe and more
slowly progressive clinical course than those
who are not.
 Reduction in ornithine levels with an
arginine- restricted diet is also beneficial.

56.  Prognosis is generally poor with blindness
occurring in the 4th–6th decades from
geographic atrophy, although vision may
fail earlier due to cataract, CMO or
epiretinal membrane formation.

57. Vitreo-Retinopathies

58. X-LINKED JUVENILE RETINOSCHISIS
 X- linked recessive
 Bilateral maculopathy with poor prognosis.
 The disease is caused by mutations in the retinoschisis
associated gene.
 The protein retinoschisin is expressed only in the
retina, in the inner and outer retinal layers.
 Misfolding of the protein, failure to insert into the
endoplasmic reticulum membrane and abnormalities
involving the disulfide linked subunit assembly have
been found to be abnormalities causing retinoschisis.

59. Clinical features
 Difficulty in reading.
 VA deteriorates during 1st two decades.
 But remain stable until 5th or 6th decades .
 Squint or nystagmus occurs in infancy
 Associated with peripheral retinoschisis & vitreous
haemorrhage
 Macular RPE atrophy occurs leading to gross loss of central
vision
 Silvery peripheral dendritic figures, vascular sheathing &
flecks are common
 It differs from retinal detachment in being bilateral usually,
with taut dome like elevation without undulations, thin
inner layer.

60. Investigation
 FAF shows spoke like patterns & central
hypoautofluorescence with surrounding
hyperautofluorescence
 OCT cystic space in inner nuclear & outer plexiform
layer.
 FA: window defect

61. Treatment
 Topical or oral carbonic anhydrase inhibitors(dorzolamide 3 times daily)
 Vitrectomy is recommended for vitreous hemorrhage and retinal
detachments.
 Retinal detachment cannot be ruled out .
 When it does not clear in a short period, pars plana vitrectomy can
clear the hemorrhage.
 RD due to breaks in the outer layer in the periphery by scleral buckling.
 Gene therapy

62. Take Home Message
 With continious improving technology and increasing experties of clnician
we have gain the ease of diagnosing Retinal dystrophy
BUT
Considering effective treatment we are still lagging behind
 Recognising the condition timely and proper rehabilitation should be the
approach of management.