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0V2022 Introduction to eye diseases > Retinal Dystrophies part 1 and 2 > Flashcards

Retinal Dystrophies part 1 and 2 Flashcards

1
Q

What is the important thing to understand about retinal dystrophies ?

A

they are inherited

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2
Q

What are the retinal dystrophies caused by ?

A

mutations at loci on chromosome

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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

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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.

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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

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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

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7
Q

What do retinal dystrophies usually affect ?

A

Structural Proteins
Ion Channels
Visual Cycle
Phototransduction

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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 )
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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

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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
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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
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12
Q

what is the prevalence of retinitis pigmentosa?

A

Prevalence 1:3000 to 1:5000 (Weleber et al., 2006)

-m:f is equal

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13
Q

Are there any known risk factors of retinitis pigmentosa ?

A
  • No known risk factors,

- Collection of many different genetic disorders

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14
Q

What are the signs of retinitis pigmentosa ?

A
  1. 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
  2. Thinning/attenuation of blood vessels- arteries thinner
  3. Pale waxy optic disk
-Bilateral involvement
can be associated with : 
-PSC cataracts
-CMO
-Myopia and astigmatism
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15
Q

What are the symptoms of retinitis pigmentosa ?

A
  1. 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 .
  2. Progressive loss of peripheral vision- noticed later on - leading to tunnel visions
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16
Q

What is sectoral retinitis pigmentosa ?

A

affecting one sector of the retinal

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17
Q

How can we compare and distinguish this sectoral retinitis ?

A

from another condition called fundus albipuntactis-

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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

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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
  1. Dark adaptation
    Grossly elevated rod and cone thresholds
    Prolonged dark adaptation
  2. 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
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20
Q

What are the different modes of inheritance of retinitis pigmentosa ?

A
  • Autosomal Dominant RP
  • Autosomal Recessive
  • X linked RP
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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
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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.
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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
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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.
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25
Q

What happens if you have a carrier mother and unaffected father in X linked RP?

A

50% of sons will be affected
50% will be unaffected
and 50% will be carriers ( will have one defective gene and one normal gene)

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26
Q

What else can retinitis pigmentosa be associated with ?

A

systemic conditions or syndromes

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27
Q

What are some conditions that are associated with having RP?

A
  • 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)
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28
Q

What is another cause of night blindness that is inherited ?

A

Leber’s Congenital Amaurosis (LCA)

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29
Q

What is Leber’s Congenital Amaurosis (LCA)?

A
  • 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
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30
Q

What are some signs/clinical features of Leber’s Congenital Amaurosis (LCA)?

A
  • 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
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31
Q

What are some results of tests of LCA?

A
  • 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
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32
Q

What is another condition that presents with night blindness ?

A

-Congenital Stationary Night Blindness (CSNB)- group of conditions caused by a whole range of different mutations

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33
Q

What does CSNB involve?

A
  • 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.
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34
Q

What is the difference in diagnosis in CSNB and RP ?

A
  • THIS IS a non-progressive condition

- vision may be poor of CSB but it doesnt progress

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35
Q

What can stationary night blindness be ? look at slide 24

A

-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
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36
Q

What is the most useful way of evaluating CSNB?

A

ERG

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37
Q

What is the csnb RESULTS like? slide 25

A

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
Q

What is the difference between complete and incomplete csnb ?

A
  • 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
Q

What are the abnormal fundus conditions shown in CSNB ?

A
  • Fundus Albipunctatus

- Oguchis disease -

40
Q

What does -Fundus Albipunctatus show ?

A
  • dull white spots on retina
41
Q

What is the oguchis disease ?

A

-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
Q

What is the Fundus Albipunctatus disease ?

A
  • 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
Q

What type of inheritance does retinitis pigmentosa follow?

A

A) Autosomal recessive
B) Autosomal dominant
C) X-linked recessive

44
Q

What is the difference between a dystrophy and a degeneration?

A
  • 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
Q

What kind of fundus appearance might you see in someone with LCA?

A

RPE granularity

or normal fundus

46
Q

Low vision, squint and myopia are most associated with which form of CSNB?

A

x- linked recessive

47
Q

What is tapetal reflex seen in ?

A

in carrier females of RP

48
Q

What is tapetal reflex seen in ?

A

in carrier females of RP

49
Q

What are the range of dystrophies affecting the macula region ? slide 4 part 2

A 
Dominant drusen
Sorsby 
RDS  
Best
Macular dystrophy
Stargardts
MIDD
AD cone-rod dystrophy
AR cone-rod dystrophy 
X-linked retinoschisis
50
Q

What is Best Vitelliform Macular Dystrophy?

A
  • Autosomal dominant
  • Best1 VMD2 gene
  • Encodes protein bestrophin
  • Chromosome 11q13
  • Diagnosis on clinical appearance
    • Egg yolk
  • Bilateral
  • Abnormal EOG
  • Normal ERG
51
Q

What is bestrophin associated with ?

A
  • 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
Q

What does an EOG recording look like with a normal person ?

A

get an increase in amplitude of EOG when we go from dark adapted to light adapted condition

53
Q

What does an EOG recording look like with someone with Best’s disease?

A

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
Q

What are the stages of Bests disease ?

A
  • 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
Q

What is Juvenile X-linked retinoschisis?

A
  • ## 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
Q

What does the juvenile X-linked retinoschisis condition result in?

A

-splitting in the inner retinal layers in the macular area while ~50% also have splitting in peripheral retina- peripheral schisis

57
Q

What does the macula look like in the Juvenile X linked retinoschisis?

A

-the lesion of the macula looks like the spokes of a wheel (macular lesion ) and schisis leads to atrophy

58
Q

When do px present in Juvenile X-linked retinoschisis?

A

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
Q

What can the Juvenile X-linked retinoschisis disease range from ?

A
  • 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
Q

What does the oct show of a px with uvenile X-linked retinoschisis disease ?

A

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
Q

What does the ERG show of a px with uvenile X-linked retinoschisis disease ?

A
  • 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
Q

What is a fundus with autosomal dominant drusen ?

A

it is also known as Doyne Honeycomb Retinal Dystrophy and ‘Mallatia Levantinese’
- caused by a mutation in the gene EFEMP1

63
Q

What is the autosomal dominant drusen?

A

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
Q

What are the symptoms that can be noticed in autosomal dominant drusen?

A
  • 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
Q

What are autosomal dominant drusen, oyne Honeycomb Retinal Dystrophy and ‘Mallatia Levantinese’?

A

mutations of the same gene

66
Q

What is Stargardt’s Fundus Flavimaculatus?

A

-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
Q

What can you see in the fundus image of Stargardt’s Fundus Flavimaculatus?

A

white flecks around RPE

68
Q

What is the problem in this toxic lipfuscin ?

A

-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
Q

What does Stargardt’s Fundus Flavimaculatus cause?

A
  • Loss of central vision
  • Metamorphopsia
  • Blind spots
  • Impaired CV
  • Dark adaptation problems
70
Q

What can build up of lipofuscin affect in the Stargardt’s Fundus Flavimaculatus?

A

-build up of lipofuscin in beneath the retina means its much harder for visual pigment to regenerate - get delays in dark adaptation

71
Q

What can be used to diagnose Stargardt’s Fundus Flavimaculatus?

A

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
Q

What is Sorsby Macular Dystrophy disease ?

A

-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
Q

What do you see in bests disease ?

A

yellow of macula- egg yolk form lesion

74
Q

What do you see in Stargadts ?

A

white flecks

75
Q

What do you see in X linked juvenile retinoschisis ?

A

spoke like pattern around macula

76
Q

How is the early visual dysfunction detected?

A

Abnormal EOG- classic early sign of bests disease

77
Q

What condition results in splitting of retinal layers ?

A

X-linked juvenile retinoschisis

78
Q

Which electrophysiologial waveform is reduced in the OCT scan in the slide show?

A

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
Q

What is waves are generated by the RPE ?

A

EOG and C wave in conjunction with a acitivty off the photoreceptors

80
Q

What is the ERG a wave generated by ?

A

photoreceptor activity

81
Q

What is the ERG b wave generated by ?

A

bipolar cell

82
Q

What are the oscillitary potentials generated by ?

A

amacrine cells

83
Q

What do the pattern ERG , photopic negative response (PhNR), scotopic threshold response (STR) generated by ?

A

ganglion cell activity

84
Q

What can we pinpoint from looking at the pattern of loss of these different waveforms?

A

pinpoint areas of dysfunction in the retina

85
Q

What can you see in these unusual rare inherited dystrophies ?

A

the precise pattern of the ERG abnormality is very helpful for diagnosing exactly what the condition is.

86
Q

What is flickering ERG (shown in panel A ) slide 27 ?

A
  • always generated by cone pathway as rods cant detect flicker as they dont have the temporal resolution to detect flicker.
87
Q

What is the 2nd waveform seen in B ?

A

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
Q

What is the scoptic responses you can see in C and D ?

A
  • 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
Q

What does E show ?

A

rod only repsonse

  • recorded to a dim flash presented to the dark adapted eye
  • cant see a wave mainly just b wave
90
Q

ERG

A

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.

0V2022 Introduction to eye diseases (22 decks)

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