Genetics in Posterior Segment Disease

Transcription

1 1 Genetics in Posterior Segment Disease Sherry J. Bass, OD, FAAO I. Age-Related Macular Degeneration A. The Dawn of Pharmaco-Genetics in AMD a. Rationale for Pharmacogenetics i. AMD is the most common etiology of vision loss in the US. The AREDS 1 and 2 studies confirm that anti-oxidants and zinc can reduce the risk of progressing from Category 3 AMD to more serious vision loss by about 25%. ii. Based upon a landmark study published in Aug 2013 in the journal Ophthalmology and July, 2016 in BJO, the presence or absence of high risk alleles in CFH and ARMS2 genes determines the most effective nutraceutical for each patient. b. Introduction i. What is AMD and how common is AMD? ii. Age related? Race related? c. Genetic and environmental considerations d. Diagnostic Modalities i. Standard Fundus Exam ii. SD OCT iii. Fluorescein angiography (FA) iv. Fundus Autofluorescence (FAF) v. Multispectral Imaging vi. Microperimetry vii. Pattern ERGs (pergs) and VEPs viii. Preferential hyperacuity perimetry (PHP) and Home PHP e. Genetics of AMD i. 12 known genes define nearly all of AMD genetic risk ii. Genetics can now predict the 2,5, and 10 year risk of marked vision loss iii. Genetic risk can be stratified into one of five categories 1. Determines type and frequency of follow-up 2. Low risk patients (e.g.category 1) a. Have only about 3% chance of vision loss

2 2 i. Can be followed annually 3. High risk patients (e.g.category 5) a. Have greater than 70% chance of significant vision loss i. Should be followed more aggressivelyevery 3-4 months 4. Best estimate: Genetic and epigenetic considerations a. Smoking history plays a role b. Systemic diseases play a role i. Obesity ii. High cholesterol 5. Significance of peripheral drusen f. Nutritional considerations i. Carotenoids 1. Lutein 2. Zeaxanthin 3. Meso-zeaxanthin ii. Omega 3 s g. AREDS 1 Results and Implications h. AREDS 2 Results and Implications i. Continue to use 80 mg of zinc but beta carotene should be replaced by lutein and zeaxanthin ii. Omega 3 s not of help in the overall group but did show an effect in the lowest quartile i. What are the appropriate nutraceuticals for each patient? i. Landmark Study #1: Awh, et al. Ophthalmology September 2013-based on 12 year follow-up of 995 subjects from AREDS 1 with intermediate AMD in one eye 1. Patients with high risk complement factor H (CFH) allesles should not be taking zinc a. Zinc may have a deleterious effect on such patients and may increase risk of progressing to advanced AMD 2. Patients with high risk age-related macular degeneration (ARMS2) alleles should not be on beta carotene 3. Lutein, zeaxanthin and meso-zeaxanthin were not included in the original AREDS study hence no 12 year follow-up

3 3 ii. Landmark Study #2: Seddon et al.:bjo, July 2016: Effectiveness of antioxidant and zinc supplementation differs by genotype iii. Implications 1. Genetics determines what neutrceutical is best for each intermediate AMD patient and 2, 5 and 10 year risk of progression. 2. One formulation is not good for all iv. Macular Risk test (PGX test) for patients with Intermediate AMD (Arctic Dx) 1. Cheek swab test to collect DNA 2. Easy to administer; results are faxed in 3 weeks 3. Patient is billed $50 whether or not insurance pays 4. Results include 2,5,and 10 year risk of progression and recommended neutrceutical B. Treatment of Wet AMD a. Numerous studies support that intravitreal anti-vegf injections are effective in preventing progression and can even improve vision if used in a timely fashion b. Without timely treatment, disciform scars develop which do not respond to anti-vegf agents c. Injections are monthly to bi-monthly i. Expensive ii. Requires patient compliance and lots of visits d. Treatments are being investigated that will lengthen the time between treatments e. Greographic atrophy does not respond to anti-vegf treatment i. Other modalities are being investigated C. The Evolving Standard of Care in AMD a. ODs are recently getting sued for poor detection of wet and dry AMD b. Consider risk factors to provide better care as we have been doing in glaucoma for years II. Retinitis Pigmentosa a. Prevalence i. 1 in 3500 people worldwide; 100,000 in the US b. Clinical characteristics i. Attenuated arterioles ii. Pigment degeneration iii. Pale waxy disc iv. PSC cataract v. CME

4 4 c. Symptoms (typical) i. Night blindness ii. Field loss iii. Regionalized forms or pericentral RP pts may be asymptomatic d. Types i. Diffuse RP ii. Sector RP iii. RP Sine Pigmento-no pigment abnormalities iv. RP Albescens-RP with white spots v. Syndromic RP 1. Laurence-Moon 2. Bardet-Biedl 3. Usher s Syndrome a. Types I, II, III e. Diagnostic testing i. SD-OCT 1. absence of the photoreceptor integrity line (PIL) outside the macula with eventual absence of the PIL as disease progresses and acuity drops a. The PIL line: not a true line, but a refractive interface between the inner and outer segments of the photoreceptors. b. Is a biomarker of photoreceptor integrity ii. RNFL assessment: RNFL is above normal thickness except in later stages of the disease iii. ERG 1. Rod and cone responses are reduced are absent in most forms of RP iv. Fundus Autofluorescence 1. Imaging technology which takes advantage of the autofluorescence of the normal retina; uses special filters in a camera to demonstrate RPE and photoreceptor integrity a. Hyperautofluorescence: accumulation of lipofuscin which demonstrates areas of stressed RPE/photoreceptors b. Hypoautofluorecence: areas of RPE/photoreceptor degeneration c. In RP, macula demonstrates a hyperautofluorescent ring ; patches of hypoautofluorecence outside the macula that correspond to areas of RPE degeneration/perivascular pigmentary migration v. Visual Fields 1. Typically constricted, starting from the mid-periphery (ring scotoma) and spreading peripherally and centrally 2. Photoreceptor death results in dense regionalized scotomas in pericentral and sectoral forms of RP

5 5 III. f. Hereditary patterns of RP i. AD, AR, Sex-linked g. Differential from cone-rod dystrophies i. CR dystrophies typically present with reduced acuity and color vision abnormalities and initially the cone responses are affected, not the rod response h. Genetics i. Dominant RP Genes 1. RHO (Rhodopsin)-30% a %: Pro23His mutations b. 5%: Pr0347Leu mutations 2. Peripherin/human Retinal degeneration Slow (RDS-10% ii. Recessive 1. As many as 60 genes iii. X-linked RP 1. RPGR gene (75%) 2. RP2 (25%) i. Treatment i. Low Vision ii. Medicinal treatment 1. Vitamin A 2. DHA/Omega 3 s 3. Lutein iii. Clinical Trials investigating therapies to protect, reactivate and restore the photoreceptors. Leber Congenital Amaurosis a. Prevalence i. Estimated 3000 cases in the US b. Clinical characteristics i. Normal fundus early on but can look like anything ii. Eventual mottling and degeneration c. Symptoms i. Reduced VA from birth ii. Nystagmus iii. Night blindness d. Diagnostic tests i. SD-OCT-absence of PIL throughout the retina ii. ERG- No response iii. A flat ERG + congenital nystagmus is diagnostic. e. Hereditary patterns i. AR ii. AD (extremely rare) f. Genetics i. Eighteen genes account for 70% of cases g. Value of molecular genetic testing in the diagnosis of LCA h. Treatment

6 6 i. Human clinical trials 1. Gene therapy for patients with RPE65 and LRAT mutations IV. Choroideremia a. X-linked progressive retinal degenerative disease that affects choroid and retina b. Symptoms similar to RP c. Gene therapy trials underway for replacement of REP-1 (Rab-escort protein) V. ABCA-4 Dystrophies: ABCA4=Transporter gene a. Stargardt Disease/ Fundus Flavimaculatus i. Prevalence 1. 1 in 10,000 children; 30,000 overall estimated cases in the US ii. Clinical characteristics (may include one or more) 1. Three types with differing prognoses a. Type I: mildest; non-progressive b. Type 3: progresses to RP-like disease 2. Early macular granularity 3. Beaten-bronze macula 4. Bull s Eye macula 5. Fish-tail shaped lipofuscin flecks iii. Symptoms 1. Loss of acuity in teenage years 2. Various rates of progression iv. Diagnostic testing 1. ERG a. Normal in Types 1 and 2 b. Progressively deteriorates in Type 3 2. FA a. Usually a dark or silent choroid: lack of choroidal flush b. Central window defects; hyper and hypofluorescence in areas of fundus flecks 3. VF: Scotomas (superior paracentral) on visual fields 4. Microperimetry: Central scotomas 5. Fundus autofluorescence imaging: Hyperautofluorescence in areas of lipofuscin accumulation; central hypoautofluorescence in areas of RPE/photoreceptor degeneration v. Hereditary patterns 1. AR 2. AD: Stargardt-Like Dystrophy (ELOVL mutations) vi. Differential Diagnosis from other White Dot Diseases 1. Congenital Stationary Night Blindness 2. Dominant Drusen 3. Retinitis punctata albescens

7 7 vii. Genetics 1. Known ABCA-4 mutations on short arm of chromosome 1 account for 50% of cases a. Results in formation of toxic A2E i. Contributes to lipofuscin formation b. Other ABCA-4 Dystrophies i. Cone and Cone-rod dystrophy 1. Clinical characteristics a. Bull s eye macular lesion b. Macular granularity 2. Symptoms a. Color vision loss b. Acuity loss c. Variable progression 3. Diagnostic tests a. SD-OCT: abnormal or absent central PIL or absent PIL in a bull s eye formation b. ERG: abnormal or absent cone reponse; normal rod response c. FA: Central window defects d. VF: Superior paracentral scotomas e. Microperimetry: Central scotomas f. Fundus autofluorescence imaging: 4. Hereditary patterns a. AR, AD ii. AMD (1-2%) VI. Other Genetic Macular Disorders a. X-Linked Juvenile Retinoschisis i. Clinical Characteristics 1. Foveal schisis of inner retinal layers 2. Reduced VA at birth 3. Inferotemporal schisis (50%) ii. Hereditary pattern 1. Sex-linked 2. Males affected iii. Diagnostic testing 1. SD-OCT: demonstrates macular schisis and thickened fovea

8 8 2. ERG: Electronegative (normal a wave, but abnormal or no b wave), because the photoreceptors are intact a wave iv. Treatment 1. Dorzolamide 2% TID for 3-5 months may reduce foveal thickness and can improve VA v. Genetics 1. RS1 gene mutations-affect the retinoschisin protein that provides the retinal glue to keep the inner retinal layers together b. Best s Vitelliform Dystrophy i. Clinical characteristics 1. Lipofuscin disorder of the RPE 2. Egg-yolk macular lesion early on with good VA 3. Scrambled-egg lesion with reduced VA a. CNV development ii. Diagnostic testing 1. SD-OCT: hyperreflective lipofuscin in outer retina elevates the macula 2. EOG: Abnormal Arden ratio: greatest light peak response over the lowest dark trough response (ratio=less than 1.6) iii. Hereditary pattern-ad iv. Differential from other lipofuscin vitelliform maculopathies 1. Adult-onset vitelliform dystrophy v. Genetics 1. Bestrophin gene mutations c. Importance of Genetic Testing in Diagnosing Hereditary Retinal Disease d. Finding a Clinical Trial to Investigate On-Going Research i.