The Genetic Mysteries of the Corneal Dystrophies The Genetic ...

The GeneticMysteries of theCorneal DystrophiesSherry J. Bass, OD, FAAOSUNY State College of OptometryNew York, N.Y.Biomicroscopic Examination Techniques• Diffuse Illumination• How many and what type of opacities• Parallelpiped/Optic Section• What layer(s) of the cornea are involved• Indirect illumination/Retroillumination• Are more opacities visible1

Features of Corneal Dystrophies andDegenerationsCorneal Degenerations (Examples)Feature Dystrophy DegenerationAge of Onset Early LateFamilial Yes NoSymmetry Symmetric AsymmetricInvolved Eye Bilateral UnilateralLocation Central PeripheralVascularity No YesInflammation No YesAssoc. disorders Rarely More frequent• Arcus senilis• Vogt’s limbal girdle• Marginal furrowdegeneration• Terrien’s degeneration• Pterygium• Salzmann’s nodulardegeneration• White ring of Coats• Band keratopathy• Corneal ectasias• Keratoconus• Non-hereditary• Pellucid MarginalDegenerationKeratoconus: Degeneration or Dystrophy?• Ectasia or thinning of the cornea-usually inferior/temporally• Hereditary in some cases• Autosomal dominant• Defective genes on chromosome 21 (SOD1 and VSX genes)• Etiology not known in non-hereditary cases-suspected causes:• eye rubbing• CL wear• Hormonal• Exacerbated by pregnancyClassification of the Corneal Dystrophies• Traditionally, classified by the affected corneal layer• Molecular genetics are changing this classification• Chromosome 1 Chromosome 4• Chromosome 5 Chromosome 9• Chromosome 12 Chromosome 16• Chromosome 17 Chromosome 20• Chromosome 21 X-chromosomeIC3D-2008 Classification of CornealDystrophies• Category 1: well-defined; gene mapped;mutations known• Category 2: well-defined; mapped to specificchromosomal loci but gene not yet identified• Category 3: well-defined; not mapped to anychromosomal locus• Category 4: suspected corneal dystrophyEpithelial Dystrophies• Epithelial Basement Membrane Dystrophy(EBMD) –Map/Dot/Fingerprint or Cogan’s• Meesman’s Dystrophy• Anterior Membrane Dystrophy• Band-shaped/Whorled Microcystic Dystrophy(Lisch dystrophy)• Recurrent Corneal Erosion Dystrophy2

Epithelial Basement Membrane Dystrophy(Map-Dot-Fingerprint Dystrophy)• Most common anterior dystrophy• Not always a true dystrophy (may be aquired asopposed to inherited)• Corneal opacities:• Maps• dots (microcysts)• Fingerprint (swirls)• bleb (putty) opacities• Painful recurrent epithelial erosions after 3rd decadeDifferentiate from other etiologies ofcorneal whorling…• Fabry disease• X-linked recessive; 1:40,000 males ; 2:40,000 females• Enzyme deficiency=accumulation of glycosphingolipids• Systemic problems• Renal, cardiac, strokes, pain• Diagnosed with genetic testing (Genzyme)• Amiodarone therapy• Treatment for atrial fibrillation (rapid heart beat)FABRY DISEASEAMIODARONE THERAPY3

RECURRENT CORNEAL EROSION (RCE)Meesman’s Dystrophy1. Opacities consist of epithelial uniform grey-whitemicrocysts seen early in life2. Increase in number over time3. Relatively rare dystrophy4. Microcysts contain intracellular keratin5. RCEs are rare-may occur early in adult life whenmicrocysts rupture6. Linkage studies identify mutations in two corneaspecificgenes:K3 (chrom. 12)K12 (chrom. 17)4

Autosomal Dominant Recurrent CornealErosion Dystrophy• Autosomal dominant; genetic locus unknown• Attacks of RCEs usually by age 5• Subside by 30-40 years• Attacks last for a few days to months• Can be triggered by URI, dry air, lack of sleep, trauma, smoke• Subepithelial fibrotic opacities (keloids)• Thickened subepithelium with chondroitin and dermatan sulfate• Hudson-Stahli line• Treatment: Problematic- ointments and PTK=marginallysuccessful; rest in dark rooms during attacksBowman’s Layer Dystrophies:Reis-Buckler’s DystrophyThiel-Behnke Dystrophy• Rod or ring-shaped opacities confined to Bowman’smembrane=honey-comb or fish-net appearance• Made up of collagen fibrils;• Thickened epithelium• Irregular astigmatism, less corneal sensation, RCEs• Vision good until later decades• PTK beneficial• Mutation maps to the Transforming Growth Factor Beta- inducedTGFBI) gene on chromosome 5 (5q31)• TGFB1 plays a role in corneal development and healing; it also interactswith collagen and other structural elements; it is expressed in the corneaand in other parts of the body.• TGFB1 mutations cause some of the stromal dystrophies as well6

Stromal Corneal DystrophiesGranular Dystrophy• Granular Dystrophy I• Lattice Dystrophy• Type I (typical)• Type II (lattice-like)• Type III, IIIA, IIIB• Type IV, V, VI, VII• Granular Dystrophy II-Avellino Dystrophy(granular + lattice)• Macular Dystrophy• Central CrystallineDystrophy of Schnyder• Fleck Dystrophy• Central Cloudy Dystrophy• Pre-Descemet’sdystrophy• Common stromal dystrophy• Opacities consist of white, round, crumb-like spotsand/or rings• Stroma in between opacities is clear early on• Good visual acuity until 7th or 8th decade when spotscoalesce and stroma between the spots is affected• Mutuation localized to the TGFBI gene on chromosome5(5q31)7

Granular Dystrophy• Opacities consist of an eosiniphilic hyaline typedeposition in the anterior stroma• Do well with PTK when VA deteriorates8

Lattice Dystrophy Type I• Opacities consist of thin, translucent lines composed ofamyloid; deposits in mid-stroma• Good vision until later in life-may need PK or DALK• Changes are central but extend to the periphery overtime• Is bilateral, but can be asymmetric and unilateral• Epithelial erosions can occur• Mutation localized to the TGFBI gene (5q31)9

Lattice Dystrophy Type II• Associated with systemic amyloidosis• Deposition of amyloid in many tissues of the body• skin• arteries• sclera• peripheral nerves• Corneal changes occur later in life• Mutation localized to the gelsolin (GSN) gene onchromosome 9 (9q34)Lattice Dystrophy Type III and IIIALater Onset Lattice Dystrophies• Type III• Thick lattice lines extendingto the periphery• Occurs later in life• Inheritance pattern isautosomal recessive• No recurrent epithelialerosions• Mutation is on the TGFBIgene on chromosome 5-same site (5q31)• Type IIIA• Autosomal dominant• Recurrent epithelial erosions• Same phenotypicpresentation as Type III butdifferent mode of inheritanceand corneal erosionsProminent amyloid deposition posterior to Bowmans layerLattice Dystrophy Type IV• Another late-onset lattice dystrophy• Deep stromal opacities made of amyloid• Mutation localized to the TGFBI gene on chromosome 5(5q31)• The list of late-onset lattice dystrophies goes on and onand on…• Types V, VI and VII have been described, based on• the pattern of lattice lines• mutation sites and defective genes• pedigree11

Combined Granular and Lattice Dystrophy(Avellino Dystrophy)• Granular and lattice type changes in the same eye• Hyaline and amyloid deposits in stroma• Granular changes early onset; lattice changes occurlater• Good vision in early stages• Both granular and lattice mutations are on the samegene (TGFBI), so is not surprising to find bothphenotypic presentations in one individualMacular Dystrophy• Autosomal recessive• Early onset• Vision more severelyaffected than in otherstromal dystrophies• Characterized by stromalhaze, and milky whiteopacities(glucosaminoglycans)• Progresses to cornealperiphery by ages 20-30• By age 40, PK may berequired• Mutation localized to thecarbohydratesulfotransferase (CHST6)gene on chromosome 16(16q22)12

Central “Crystalline” Dystrophy ofSchnyder• Characterized by centralstromal cholesterol andphospholipid deposits,sometimes with an arcus• Only 50% have “crystals”• Visual acuity onlyreduced if opacities aredense and central• Another rare dystrophyassociated with asystemic disorder• Rule out hyperlipidemia• Mutation (N102S) onshort arm of chromosome1 (1p34-36) the UBIAD1gene• Plays a role in cholesterolmetabolism13

Fleck Dystrophy• Subtle grey opacities consist of small, wreath-likeopacities in the stroma• Represent engorged keratocytes• Usually asymptomatic• Cases with photophobia , ocular surface irritation andblepharospasm have been recently reported• Opacities extend to the periphery• Visual acuity good throughout life since stroma betweenflecks remains clear• Maps to chromosome 2 (2q35)14

Pre-Descemets Dystrophy• Fine, deep white posterior stromal opacities• Lie anterior to Descemets membrane• Autosomal dominant• No effect on visual acuityCentral Cloudy Dystrophy of Francois• Central opacity in stroma looks like cracked-iceor crocodile skin; glycosaminoglycan deposition• Visual acuity is usually normal• Appearance similar to crocodile shagreen, anage-related corneal change resulting in posteriorstromal deposition• Difficult to differentiate from crocodile shagreenin the late course of disease, especially ifbilateral15

Endothelial Dystrophies• Fuch’s Dystrophy• Posterior Polymorphous Dystrophy• Congenital Hereditary Endothelial Dystrophy(CHED)Fuch’s Endothelial Dystrophy• Characterized by threestages• guttata- localizedexcresences or thickeningsin Descemet’s membrane• stromal and epithelialedema• corneal fibrosis or scarring• Results in corneal edema,usually greatest uponawakening• Women affected morefrequently than men• Affects older individuals,greater than 40 years• Early onset Fuch’sdystrophy mapped tochromosome 116

Treatment of Fuch’s Dystrophy• Monitor• If edema is present, treat with hyperosmoticagents, e.g. Muro 128• Hair dryer may be helpful in the AM• Watch the ocular hypertensive• If IOPs elevated, treat to lower IOP to reduce edema• In later stages, PK or DSAEK may be required• What about Fuch’s dystrophy and cataract?17

Posterior Polymorphous Dystrophy• Isolated and coalesced posterior vesicles• Wide areas of thickening of Descemet’smembrane• bandlike figures and lines• Diffuse stromal and epithelial edema• Peripheral anterior synechiae18

Posterior Polymorphous Dystrophy• Treatment similar to Fuch’s dystrophy• Mutation is in the COL8A gene in the 20q11locus (long arm of chromosome 20) in somecases• Other cases have mutations in chromosome 1Congenital Hereditary EndothelialDystrophy (CHED 1)• Autosomal dominant• Manifests as diffuse corneal edema a few years afterbirth• May be associated with hearing loss• Photophobia, tearing• Is progressive• Mutation for CHED1 has also been mapped to 20p11-20q11 on chromosome 20-overlaps the location of themutation causing PPD!Congenital Hereditary CornealDystrophy (CHED 2)• Autosomal recessive• Central corneal edema from birth• Nystagmus• Non-progressive but more severe edema thanCHED119

Summary of the Molecular Genetics of theCorneal Dystrophies• Meesmann’s• KRT 3, KRT 12 genes onchromosomes 12, 17• Lisch (Whorled)• Unidentified gene on Xchromosome• Reis-Buckler’s Granular Type III)• TGFBI gene on chromosome 5• Granular Dystrophy• TGFBI chromosome 5• Lattice I,III,IV, V, VI, etc.• TGFBI,chromosome 5• Lattice II• GSN,chromosome 9• Macular Dystrophy• CHST6 gene,chromosome 16• Crystalline Dystrophy• Gene ? chromosome 1• Fuch’s Dystrophy• PPD and CHED• COL8A gene on chromosome20• Chromosome 1Courtesy: Redatlas.orgConsider Classification by AffectedChromosomeImplications of Molecular Geneticsfor the Future• Chromosome 1 Dystrophies• Central crystalline dystrophy• Early onset Fuch’s dystrophy• Posterior polymorophous dyst• Chromosome 2 Dystrophies• Fleck dystrophy• Chromosome 5 Dystrophies• Lattice dystrophy (Types 1 andIIIA)• Granular dystrophy• Avellino dystrophy (GCDII)• Reis-Buckler’s dystrophy (GCDIII)• Chromosome 9 Dystrophies• Lattice dystrophy Type II• Chromosome 12 Dystrophies• Meesman dystrophy (and 17)• Chromosome 16 Dystrophies• Macular corneal dystrophy• Chromosome 20 Dystrophies• Congenital Hereditary EndothelialDystrophy Types I and II• Posterior Polymorphous Dyst• Chromosome 21 Dystrophies• A/D Keratoconus• X-chromosome Dystrophies• Lisch corneal dystrophy• Knowledge of mutations enables researchers toidentify the pathways that synthesize abnormalproteins which are deposited in the cornea• This knowledge can lead to the development ofnew drugs designed to interfere with thesepathways to decrease abnormal proteinsynthesis• Less deposition = less affect on vision = less Tx20