Retinal Dystrophies part 1 and 2 Flashcards
(90 cards)
1
Q
What is the important thing to understand about retinal dystrophies ?
A
they are inherited
2
Q
What are the retinal dystrophies caused by ?
A
mutations at loci on chromosome
3
Q
What does it mean when retinal dystrophies can have variable penetrance/expressivity ?
A
this means the same mutation can be variably expressed in different people- e.g different signs and symptoms of disease even though they have the same mutation
4
Q
What is an example of various different retinal dystrophies that are caused by different mutations ?
A
retinitis pigmentosa - group of conditions caused by a whole range of different genetic mutations- one person with his may have a very different genetic profile to another person with this.
5
Q
What are degenerations in retinal dystrophies ?
A
they are age related macular degeneration , arcus seniles ( circle you see around the cornea in elderly) and cataract
6
Q
What can retinal dystrophies affect ?
A
- the full macula or just the macular region
- different layers of retina- RPE or cones or just rods or choroid
7
Q
What do retinal dystrophies usually affect ?
A
Structural Proteins
Ion Channels
Visual Cycle
Phototransduction
8
Q
What are the diseases caused by retinal dystrophies affecting the full retina ?
A
- Retinitis Pigmentosa (RP) (can be inherited in 3 different ways)
- Leber’s Congenital Amaurosis (LCA)
- Congenital Stationary Night Blindness (CSNB )
9
Q
How can you get -Retinitis Pigmentosa (RP)?
A
it can be inherited in 3 ways
Autosomal Dominant RP
Autosomal Recessive RP
X-linked RP
10
Q
What are the diseases caused by retinal dystrophies affecting the macula ?
A
- Bests Vitelliform
- Juvenile X-linked retinoschisis
- Autosomal dominant drusen
- Stargardt Fundus Flavaimaculatus
- Sorsby Disease
11
Q
What is retinitis pigmentosa ?
A
Heterogeneous group of retinal disorders- not just one conditions
-Rod-cone dystrophy
Progressive dysfunction of rods, then subsequently the dysfunction of the cone photoreceptors and RPE
- (3 sub types) Dominant, recessive, X-linked and sporadic forms(means coming on as a spontaneous mutation ) caused by
Mutation of rhodopsin gene
12
Q
what is the prevalence of retinitis pigmentosa?
A
Prevalence 1:3000 to 1:5000 (Weleber et al., 2006)
-m:f is equal
13
Q
Are there any known risk factors of retinitis pigmentosa ?
A
- No known risk factors,
- Collection of many different genetic disorders
14
Q
What are the signs of retinitis pigmentosa ?
A
- pigmentary changes - call it bone spicule pigmentation- which is clumping of pigment in mid periphery of the fundus
- see patches of hyper and hypo pigmentation of rpe - Thinning/attenuation of blood vessels- arteries thinner
- Pale waxy optic disk
-Bilateral involvement can be associated with : -PSC cataracts -CMO -Myopia and astigmatism
15
Q
What are the symptoms of retinitis pigmentosa ?
A
- first symptom- night blindness called Nactylopia - due to progressive loss of rod photoreceptors
- in RPE there is progressive shortening of the outer segment of rod photoreceptors due to abnormal phagocytosis - gradual loss of rhodopsin and photoreceptors which leads to dark adapted sensitivity . - Progressive loss of peripheral vision- noticed later on - leading to tunnel visions
16
Q
What is sectoral retinitis pigmentosa ?
A
affecting one sector of the retinal
17
Q
How can we compare and distinguish this sectoral retinitis ?
A
from another condition called fundus albipuntactis-
18
Q
What does fundus albipunctatis show ?
A
instead of getting darkened area of hyperpigmentation we get pale flecks across the mid peripheral retina
-characterised by poor night vision and falls under the condition congenital stationary night blindness
19
Q
What is the diagnosis of retinitis pigmentosa ?
A
- discuss with he px their family history of visual abnormality and dysfunction -genetics
- functional tests -
1. Full-field ERG (grossly abnormal in this condition )- Reduced a and b wave amplitude (rod and cone)- flat
- Dark adaptation
Grossly elevated rod and cone thresholds
Prolonged dark adaptation - visual fields-
via Kinetic Goldmann
-see Isolated scotomas 20º from fixation
-which progress onto Mid-periphery ring scotoma
-ring scotoma expands out into periphral vision and consrticts into central vision- to gradually squeeze out the remaining visual function - px left completely blind in many cases
-Tunnel vision
20
Q
What are the different modes of inheritance of retinitis pigmentosa ?
A
- Autosomal Dominant RP
- Autosomal Recessive
- X linked RP
21
Q
What is Autosomal Dominant RP caused by ?
A
- a Single gene mutation
- responsible for 15-25% of cases
- ~30 causative genes have been identified. Rhodopsin gene (RHO) most common.
- M=F - as it is autosomal
- 50% risk of passing onto offspring
22
Q
What is Autosomal recessive RP caused by ?
A
- responsible 5-20% of cases
- Faulty gene must be inherited from both parents
- Can be mutation in genes including RHO (rhodopsin) gene, gene encoding alpha or beta subunit of cGMP phosphodiesterase, or the alpha subunit of the cGMP gated channel.
23
Q
What is X linked RP caused by ?
A
- ~5-15% of RP in UK
- Most cases (70%) due to a mutation in RGPR gene on the X-chromosome
- Severe form of RP
- Childhood onset night blindness 1st decade of life
- Poor central vision
- associated with Myopia
24
Q
What is X linked RP expressivity ?
A
- different expressivity in males and females because women have 2 X chromsomes
- and a normal copy on the one X chromosome can partially compensate for a pathological variant on the other X chromosome. - can carry the gene without showing the strong expression of the gene itself .
- Female carriers have variable expression.
25
What happens if you have a carrier mother and unaffected father in X linked RP?
50% of sons will be affected
50% will be unaffected
and 50% will be carriers ( will have one defective gene and one normal gene)
26
What else can retinitis pigmentosa be associated with ?
systemic conditions or syndromes
27
What are some conditions that are associated with having RP?
- if you have hearing loss with RP - Ushers syndrome- responsible for 18% of RP
- Kearns-Sayre syndrome (external ophthalmoplegia, lid ptosis, heart block)
- Bardet-Biedl syndrome (polydactyl (more fingers or toes), truncal obesity, short stature)
28
What is another cause of night blindness that is inherited ?
Leber’s Congenital Amaurosis (LCA)
29
What is Leber’s Congenital Amaurosis (LCA)?
- Autosomal recessive inheritance
- At least 20 different forms of LCA, each caused by a defect in a different gene important for normal visual function
- Variable rate of progression, prognosis poor.
- involves abnormal development of photoreceptor cells
- Prevalence ~3 in 100,000
- Presents in early childhood ~ 2 to 3/12
- Most common form of inherited sight loss in children
- Can be associated with cataract/keratonoconus
- Can have systemic associations e.g. on kidneys
30
What are some signs/clinical features of Leber’s Congenital Amaurosis (LCA)?
- Parents may notice lack of visual responsiveness, nystagmus, tropia, oculodigital reflex (children press on eyes)
- Nyctalopia from birth
- Photophobia
- Decreased VF from 1 yr
- VA ~ 6/36
- May be associated with high hyperopia or myopia
- Confirmed with genetic test
31
What are some results of tests of LCA?
- An abnormal ERG- useful way to investigate visual function in small babies
- find dramatically reduced scotopic and photopic response
- Retina may be normal
- Subtle RPE granularity
- BV attenuation
32
What is another condition that presents with night blindness ?
-Congenital Stationary Night Blindness (CSNB)- group of conditions caused by a whole range of different mutations
33
What does CSNB involve?
- it involves high myopia at a young age, nystagmus, reduced VA and strabismus are common (especially in X-linked inheritance).
- Dysfunction depends on mutation.
- Diagnosis is by ophthalmological appearance, family history, genetic testing, electroretinogram.
34
What is the difference in diagnosis in CSNB and RP ?
- THIS IS a non-progressive condition
| - vision may be poor of CSB but it doesnt progress
35
What can stationary night blindness be ? look at slide 24
-CSNB- X linked and AR and AD - Usually normal fundus
Cone dark adaptation is normal, rod phase of recovery is absent.
- AR-2 conditions Oguchi diseases and fundus albipunctatius- as they present with an abnormal fundus and some RHO mutations
36
What is the most useful way of evaluating CSNB?
ERG
37
What is the csnb RESULTS like? slide 25
Both complete and incomplete CSNB have a negative mixed rod and cone ERG (scotopic white) i.e. the a-wave is intact because the defect is post receptoral, the b-wave is absent.
The photopic ERG is reduced
EOG is normal
38
What is the difference between complete and incomplete csnb ?
- in the complete form there is a complete absence of rod function- can see that from flat scoptopic
- incomplete csnb there is some residual rod function left- see in middle ERG in left hand side - there is a little bit of a B wave there.
39
What are the abnormal fundus conditions shown in CSNB ?
- Fundus Albipunctatus
| - Oguchis disease -
40
What does -Fundus Albipunctatus show ?
- dull white spots on retina
41
What is the oguchis disease ?
-Rare autosomal recessive
Fundus looks grey/yellow metallic (but appears normal after prolonged dark adaptation).
Regeneration of pigment normal
Post-receptoral abnormality
Cone adaptation normal, rod adaptation grossly delayed (2-24 hours). Eventually normal thresholds.
42
What is the Fundus Albipunctatus disease ?
- Autosomal recessive
- Affects rod and cone photopigment kinetics- affects how quickly they dark adapt
- Grossly extended adaptation times.
- Eventually normal thresholds.
- ERGs and EOGs eventually normal, but only after prolonged period of adaptation prior to testing.
43
What type of inheritance does retinitis pigmentosa follow?
A) Autosomal recessive
B) Autosomal dominant
C) X-linked recessive
44
What is the difference between a dystrophy and a degeneration?
- A dystrophy is inherited, usually as a result of a single gene mutation.
- Degenerations are age-related. There may be certain genetic mutations which predispose towards development (e.g. CFH mutations in AMD) but onset is usually multifactorial (not purely inherited).
45
What kind of fundus appearance might you see in someone with LCA?
RPE granularity
| or normal fundus
46
Low vision, squint and myopia are most associated with which form of CSNB?
x- linked recessive
47
What is tapetal reflex seen in ?
in carrier females of RP
48
What is tapetal reflex seen in ?
in carrier females of RP
49
What are the range of dystrophies affecting the macula region ? slide 4 part 2
```
Dominant drusen
Sorsby
RDS
Best
Macular dystrophy
Stargardts
MIDD
AD cone-rod dystrophy
AR cone-rod dystrophy
X-linked retinoschisis
```
50
What is Best Vitelliform Macular Dystrophy?
- Autosomal dominant
- Best1 VMD2 gene
- Encodes protein bestrophin
- Chromosome 11q13
- Diagnosis on clinical appearance
- Egg yolk
- Bilateral
- Abnormal EOG
- Normal ERG
51
What is bestrophin associated with ?
- abnormal chloride conductance
which disrupts fluid transport across RPE and leads to accumulation of debris between Bruch's membrane and the RPE/photoreceptor complex
-this debris leads to the accumulation of lipofusion in the central macula- gives a egg yolk appearance
-Mutations affect RPE metabolism and therefore function of the outer retina
(EOG): Universally abnormal, with an Arden ratio (light:dark) of 1.5 or less.
52
What does an EOG recording look like with a normal person ?
get an increase in amplitude of EOG when we go from dark adapted to light adapted condition
53
What does an EOG recording look like with someone with Best's disease?
this light rise , increase in amplitude when we got rod dark to light is significantly reduced due tot he abnormality which are developing in the RPE
54
What are the stages of Bests disease ?
- Earliest stage- pre vitelliform (EOG already abnormal )
- Vitelliform- Multifocal Best’s gives rise to lots of the lesions- VA is still good
- Pseudohypopeon (lipofuscin breaks through RPE to subretinal space)- this forms Pseudohypopeon- which is like a semi circular region of lipofusion with a flat top
- Vitelliruptive (moderate VA reduction)- lipofucin breaking down and dispersing- scrambled egg stage
- Atrophic stage- VA dramatically reduced - some progress to CNV ( choroidal neovascularisation)
55
What is Juvenile X-linked retinoschisis?
- rare
-
= caused by mutations in the Retinoschisin gene (XLRS1)- this is a protein which is in involved in intracellular adhesion and cellular organisation in the retina
-Mainly affects males
Incidence: 1 in 15,000-30,000- as X linked recessive as females would need to inherit an infected X chromosome from both parents to inherit the disease whilst males only have one X chromosome
-Depressed b-wave on ERG
56
What does the juvenile X-linked retinoschisis condition result in?
-splitting in the inner retinal layers in the macular area while ~50% also have splitting in peripheral retina- peripheral schisis
57
What does the macula look like in the Juvenile X linked retinoschisis?
-the lesion of the macula looks like the spokes of a wheel (macular lesion ) and schisis leads to atrophy
58
When do px present in Juvenile X-linked retinoschisis?
around about school age and complain of poor vision
-parents may notice in early stages of life- as they may be present with nystagmus, strabismus, hyperopia, foveal ectopia, vitreous haemorrhage, retinal detachment.
59
What can the Juvenile X-linked retinoschisis disease range from ?
- there is a wide varaibiility in disease severity which can range form normal vision all the way to legal blindness - vision often deteriorates in early life then stabilises for a while until it gets worse again later on in 50s or 60s.
60
What does the oct show of a px with uvenile X-linked retinoschisis disease ?
split in the middle of retina and black pockets show how retina is torn apart- shows isrutption of cellular adhesion due to the mutation
61
What does the ERG show of a px with uvenile X-linked retinoschisis disease ?
- B wave disappeared and just have an A wave
- this makes sense because A wave comes from photoreceptors and when you look at OCT the outer retinal layers are intact and everything beyond the is abnormal
- the bipolar are not receiving a proper signal from photoreceptors so they are not producing. the B wave
62
What is a fundus with autosomal dominant drusen ?
it is also known as Doyne Honeycomb Retinal Dystrophy and ‘Mallatia Levantinese’
- caused by a mutation in the gene EFEMP1
63
What is the autosomal dominant drusen?
a conditions where white spots of waste material-druse form into a radial pattern around the macula and optic disc- can be described as a honeycomb pattern.
64
What are the symptoms that can be noticed in autosomal dominant drusen?
- prognosis variable
- VA can be excellent but van worsen from age
- Onset 20-30s- asymptomatic
- May develop CNV,
- otherwise gradual visual loss
- May notice metamorphopsia
65
What are autosomal dominant drusen, oyne Honeycomb Retinal Dystrophy and ‘Mallatia Levantinese’?
mutations of the same gene
66
What is Stargardt’s Fundus Flavimaculatus?
-Autosomal recessive- need to receive an affected gene from each parent- if both parents have it 25% of offspring will have the condition
-Genetic defect in visual phototransduction cycle
-Mutations in ABCA4-leading to Defective ATP binding cassette transporter protein in photoreceptors
means that cannot remove N-retinylidene-PE from photoreceptors as this protein is defected.
-that substance combines with other substance and accumulates as lipofuscin in RPE.- causing white flecks around rpe and can see around macula
67
What can you see in the fundus image of Stargardt’s Fundus Flavimaculatus?
white flecks around RPE
68
What is the problem in this toxic lipfuscin ?
-Lipofuscin build up in RPE
1 in 10,000
-results in progressive vision loss in the macula area- gets worse over time and worse in central vision and low light levels
69
What does Stargardt’s Fundus Flavimaculatus cause?
- Loss of central vision
- Metamorphopsia
- Blind spots
- Impaired CV
- Dark adaptation problems
70
What can build up of lipofuscin affect in the Stargardt’s Fundus Flavimaculatus?
-build up of lipofuscin in beneath the retina means its much harder for visual pigment to regenerate - get delays in dark adaptation
71
What can be used to diagnose Stargardt’s Fundus Flavimaculatus?
ERG- to diagnose and the subtypes
-more than 640 mutations in the ABCa4 gene- which have been put down to cause this disease- different mutations can give slightly different visual outcomes- and diagnosing the exact one can get a better idea of px prognosis.
72
What is Sorsby Macular Dystrophy disease ?
-Autosomal dominant - 50 % of child of an affected parent getting it.
-Gene mutation TIMP3 which encodes a protein involved in extracellular matrix remodelling esp in bruchs membrane
-responsible for angiogenesis
-can look similar to AMD in the early stages- can see mid peripheral drusen
-Early on VA normal and fundus normal or midperipheral drusen
-px may have slight night reduction
-CNV from 5th decade- present in early 40s with a sudden va loss - due to untreatable CNV membrane later on developing to
-Geographic atrophy
where you see dense Black pigmentation
Deposits
73
What do you see in bests disease ?
yellow of macula- egg yolk form lesion
74
What do you see in Stargadts ?
white flecks
75
What do you see in X linked juvenile retinoschisis ?
spoke like pattern around macula
76
How is the early visual dysfunction detected?
Abnormal EOG- classic early sign of bests disease
77
What condition results in splitting of retinal layers ?
X-linked juvenile retinoschisis
78
Which electrophysiologial waveform is reduced in the OCT scan in the slide show?
ERG b wave
- as the a wave is attributable to photoreceptor activity and the photoreceptor layer is still fairly intact
- the C wave and EOG come from the RPE - which is fairly intact here
- the b wave is reduced here as comes from bipolar cells
79
What is waves are generated by the RPE ?
EOG and C wave in conjunction with a acitivty off the photoreceptors
80
What is the ERG a wave generated by ?
photoreceptor activity
81
What is the ERG b wave generated by ?
bipolar cell
82
What are the oscillitary potentials generated by ?
amacrine cells
83
What do the pattern ERG , photopic negative response (PhNR), scotopic threshold response (STR) generated by ?
ganglion cell activity
84
What can we pinpoint from looking at the pattern of loss of these different waveforms?
pinpoint areas of dysfunction in the retina
85
What can you see in these unusual rare inherited dystrophies ?
the precise pattern of the ERG abnormality is very helpful for diagnosing exactly what the condition is.
86
What is flickering ERG (shown in panel A ) slide 27 ?
- always generated by cone pathway as rods cant detect flicker as they dont have the temporal resolution to detect flicker.
87
What is the 2nd waveform seen in B ?
is photocpic response to a flash
- here you can see the n negative trough being the A wave and the peak of the B wave
- the rising edge of the B wave can see a little wiggle- which is a oscillatory potential
88
What is the scoptic responses you can see in C and D ?
- both in response to a bright flash presented to the dark adapted to eye
- they are a mixture of rod and cone activity - can see the a wave and the black arrow is pointing to the b wave- it is much bigger and broader than in the cone response
89
What does E show ?
rod only repsonse
- recorded to a dim flash presented to the dark adapted eye
- cant see a wave mainly just b wave
90
ERG
ERG at the bottom presenting a very dim flash presented to dark adapted eye as we can increase brightness of flash you start to see B wave as flash gets brighter and brighter and bigger
- when we get to brighter flashes is when A wave appears- it becomes more prominent as the flash gets brighter
- Photopic hill- b wave starts to get smaller as you get to the high flash intensity.
