Hereditary Retinal dystrophies Flashcards
Nwhat is OMIM?
the online mendelian Inheritance in Man (website)
how many genetic disorders affect the retina and choroid?
nearly 750 according to OMIM
name 2 websites to look for genetic information on retinal diseases?
OMIM and RetNet
most retinal hereditary disease are unilateral or bilateral?
most are bilateral if unilateral please suspects -infections or inflammatory
name a reversible cause of retinal degeneration?
vitamin A
what are the mendelian patterns of inheritance?
AD AR X-linked recessive x-linked dominant mitochondrial
if a patient has a retinal degeneration but no family history …
the patient may have a ne novo mutation or the family members may have a mild form of disease making them asymptoatic
within a same gene there could be different mutations
and each of these can give a different phenotypes for example mutation in the RDS/peripherin can cause: - RP - cone-rod dystrophy - pattern dystrophy mutations in rhodopsin gene cause: -CSNB -RP mutations in CRX (cone-rod homeobox containing gene) can cause: -LCA -cone-rod dystrophy mutaions in Stargardt gene cause: -stargardt disease -severe progressive cone-rod dystrophy -RP
what percentage of patients with the Usher sd mutation have usher without hearing loss?
5%
tell me about Autosomal dominant inheritance
the disease presents in each generation there is 50% chance of passing the disease to offspring no sex predilection
tell me about autosomal recessive inheritance
the affected individual passes the disease to 25% of offspring not every generation affected no sex predilection
what is the inheritance in Stargardts disease?
most common is AR ( stARgardts) with most common gene ABCA4 BUT… it can also be AD with the gene ELOV4
what is the inheritance in RP?
all forms… AR, AD, x-linked to remember it is also like stargardts in a way because th emost common inheritance is AR (70%) then AD (15%) ad x-linked (15%) the most common genes for RP are: if: AR (ABCA4 and Ush2A AD (30% by rhodopsin) x-linked (80% RPGR - most severe so remember RP grrrrrr angry) and RP2 10%
most common genes in RP
the most common genes for RP are: if: AR (ABCA4 and Ush2A AD (30% by rhodopsin) x-linked (80% RPGR - most severe so remember RP grrrrrr angry) and RP2 10%
RPE functions
Absorption -of scattered light -of energy and heat Phagocytosis - of photoreceptor outer segment discs TRansport - of photreceptor waste products to choroid - of nutrients fro choroid to photoreceptors Blood retina barrier Retinal adhesion
so doctor….. why do I need the genetic testing?
well… if we know the precise diagnosis… - we can give you a more definitive prognosis - we can rule out syndromes or systemic diseases (important in LCA) - it will give you peace of mind - give you better genetic counseling - identify if we need to test your family - keep you posted on clinical trials MY JOB IS TO ORDER the most specific gene testing so you don’t waste money ALSO I will give you a copy of the report.
PPRCA Pigmented paravenous retinochoroidal atrophy
rare disease unknown etiology PIGMENT accumulation along the retinal vessels WITH sectors of NORMAL retina in between. usually, vision is normal First described on 1937 no genes found more common in males involves the RPE and choroid
what is the name of the contact lens electrode used for ERG?
Burian-Allen
How many genetic disorders affect the eye?
750
How many retina degenerations with an identified gene are listed in RetNet?
Over 200
If disease is unilateral what should you think?
Infection inflammation cancer
Depending on where the mutation lies on the gene…
The phenotype will be different
Different mutations in the RDS/peripherin can cause…
Cone-rod dystrophy RP Pattern dystrophy
Different mutations in the rhodopsin gene can cause
RP CSNB
Different mutations in the CRX (cone-rod homeobox containing gene) can cause…
LCA Cone-rod dystrophy
Different mutations in the USH2A an cause…
Usher Usher type 3 (no hearing loss) 5%
Different mutations in the ABCA4 gene can cause
Stargardts RP Mike cone-rod Severe cone-rod
How to classify the Hereditary dystrophies?
1) macular dystrophies 2) diffuse photoreceptor dystrophyies 3) choroidal dystrophies 4) VR or inner retinal
Which are the diffuse photoreceptor dystrophies?
1) RP 2) RP variants - sectorial RP - central RP - pericentral RP - unilateral RP - retinitis punctata albescence 3) LCA 4) cone dystrophies 5) cone-rod dystrophies
Which are the choroidal dystrophies?
1) choroideremia 2) gyrate 3) regional - central areolar choroidal dystrophy - NC macular dystrophy m
Which are the VR/inner retina dystrophies?
XLRS Goldman-Favre syndrome
what are purines?
ATP, ADP
what is the muller cell function?
They regular the extracellular fluid balance.give homestotic and metabolic support to retinal neurons.
mullers cellc can be activated by?
any pathogenict mechanism
when are Purines release in the retina?
in the dark
muller cells have lots of which purine receptor?
P2X7
what happend to muller cells in hepatic or renal failure?
there is muller cell edemabecause the blood beomes diluted (hypoosmotic) and thus the fuid goes from extracellular space in to muller cells.
what happens to muller cel in diabetic retinopathy?
the ischemia and hypoxia downregulat and inactivate Kir 2.1 and Kir 4.1 (potassium channels).these Kir channels mediate K influx in to muller cellsAll these results in osmotic imbalance and edema of muller cells
how can steroids help in macular edema?
they can help in the non-leaking edema by stimulating clearance by muller cells.Triamcinolone inhibit Triamcinolone activates the final steps in the swellinginhibitorypurinergic signaling cascade
tell me the role of the purinergic system in macular edema?
the purinergic system inhibits swelllingtriamcinolone activates the purinergic system,
what is juvenile retinoschisis?
* x-linked * inherited VR disorder * of retinal splitting at the macula * 50% have the periphery affected affecting VF * affects 1:5K males in the Us and 1 in 25K worldwide
history of XLRS?
* first described by Haas in 1898 * names sex-linked Juvenile retinoschisis by Deutman in 1971
XLRS is a disease of…
BOYS BOYS BOYS
which is the pathognomonic findings in XLRS?
a spoke-wheel patternstarts at the fovea and radiates 1-1.5 DD
XLRS natural history
* starts early infancy * kids cant see at distance * get glasses for hyperopic astigmatism * later cant be corrected to 20/20 * fundus shows spoke wheel pattern * OCT confirms diagnosis * history in males in the family * peripheral retina affected in 2/3 peripheral retina appears as vitreous veils * it is an stationary condition as vision stays in the 20/60-20/100 but later macular atrophy develops and they become legally blind
what kind of scotoma does the peripheral schisis cause?
* ABSOLUTE scotoma * because the transmission of signal is interrupted by splitting
does XLRS present varied phenotypes?
the variabiloity is lowso the PENETRANCE is highas high as 95%meaning that 95% will have the macular splitting
what is the Mizuo-Nakamura phenomenon?
* the fundus appearance is different in the light adapted condition as compared to the dark adapted condition * in XLRs patients can have a macular sheen or beaten-bronze appearance in light adapted that dissapears in dark adapted
in XLRS * what is the affected gene? * what is the affected protein * what is the function of the protein?
* RS1 * RS retinoschisin * adhesion/stabilization
what happens in females with XLRS?
* its a disease for BOYS * females are carriers * they do not have retinopathy (except few case reports) * they can have mild ERG changes * even in those cases if the prtein RS is low, a little amount is enought to function. This is because they contain a combo o normal a mutant products * this means that for therapy, probably we only need to make the retin aproduce a little bit of the protein and not reach a normal level
which are the two forms of XLRS by age?
* <25 yo = cystic form * >25 yo atrophic form
what do you see in XLRS in: visual acuity HVF color test ERG
* decreased but stationary * normal except if peripheral schisis causing absolute scotoma * normal except in atrophic disease where you can see triptanopia. “electronegative form” with * normal a wave * reduced b-wave. This b-wave does not reach the baseline level. Yes, you can also see an electronegative wave in CSNB
differential diagnosis of electronegative wavemeaning:b wave that does not reach the baseline
CSNB * XLRS This si because the b wave is for bipolar and muller cells so its conduction and the conduction is afected in these two diseases.But CSNB causes nyctalopia and XLRS does not cause nyctalopia
XLRS differential diagnosis
acquired retinoschisis (both sex, bilateral, asymptomatic, older than 50, NFL splitting) Goldman-Favre (also VR, both sex, macular schisis, NO VEILS, severe ERG depression, and is AUTOSOMAL RECESSIVE) Wagner disease (autosomal DOMINANT, vitreous syneresis, macular pigment clumps and cataracts) Norrie Disease (also also x-linked bilateral in babies but bilateral retinal detachments and mental retardation and deafness) nicotinic acid maculopathy (bilateral CME that resolves after medication discontinuation)
where is the peripheral schisis more common in XLRS?
infero-temporal
who discovered the RS1 gene and when?
* Sauer in 1997 * the are more than 150 mutations identified * mutations in RS1 gene are present in 95% of XLRS patients *
what is heterogeneity?
Heterogeneity is a word that signifies diversity. A classroom consisting of people from lots of different backgrounds would be considered having the quality of heterogeneity.
name 4 syndromic IRDs?
- Bardet-Biedl
- Kearns-Sayre
- Usher
- Ahlstrom
name 5 vitreoretinopathies
- Sticklers
- Norriers
- XLRS
- Wagner
- FEVR
- ADNIV