Ophthalmogenetics Prof. Maciej Krawczyński, MD, PhD
the first modern description of a hereditary disorder (protanopia, Dalton, 1798); the first linkage of a disease locus to a chromosome (daltonism linked to X chromosome, Wilson, 1911); the first linkage of a disease locus to other trait (daltonism and haemophilia, Bell & Haldane, 1937); the first book on human genetics (Waardenburg, 1938); the first linkage of a disease locus to an autosome (catar. centr. pulver. to Duffy blood group on chrom. 1, 1963); the first mtDNA mutation in humans (11778G>A in LOHN, Wallace, 1988) the first description of a digenic disorder in humans (RDS and ROM1 genes in retinitis pigmentosa, Dryja, 1995).
Ophthalmogenetics in numbers OMIM (On-line Mendelian Inheritance in Man) database lists 1417 hereditary disorders, related to eye pathology: 1202 – known phenotype and known gene; 123 – known phenotype and mendelian inheritance; 92 – known phenotype with suspected mendelian inheritance.
Ophthalmogenetics in numbers RetNet database lists 256 cloned or mapped genes that cause hereditary retinal disorders.
Oculogenesis Process of embryonal eye ball development: genetically controlled; susceptible to damaging environmental factor (teratogens); embryo (fetus) age dependent.
Genetic regulation of oculogenesis primary switch – PAX6 gene; leading role of cascade: PAX6-EYA1/SIX3-DACH1; complex network of dependences, synergies and inhibitions; evolutionary and tissue conservative process; mutations of these genes are the cause of many developmental defects.
PAX6 gene locus: 11p13; transcriptional factor; the main oculogenesis regulator – it is electively expressed in the developing eye: initially in major part of head ectoderm; later - only in optic vesicle and lens placode (lens vesicle). mutations of PAX6 gene cause; aniridia (with macular hypoplasia, cataract, corneal opacities); Peters anomaly, congenital cataract with late corneal dystrophy; hereditary keratitis, isolated macular hypoplasia; isolated pupil dislocation; multiple eye defects without aniridia; homozygotic mutations – cause congenital anophthalmia ! 11p13 microdeletion – WAGR syndrome.
Aniridia always bilateral, 1:50.000 births; PAX6 gene mutations; AD inheritance; clinical classification (6 types): I: total, with low VA, macular hypoplasia and nystagmus; II: partial with normal VA; III: with ataxia and MR (Gillespie s.) – AR, very rare; IV: with Wilms tumour, genitourinary system defects and MR (WAGR s., Miller s.) – 11p13 microdeletion or AD; V: with other eye defects; VI: with other systemic defects. in 75% of patients - glaucoma – needs early surgical intervention; regular ultrasound examination of kidneys; karyotype analysis is necessary (to exclude microdeletion).
Other oculogenesis genes EYA1 – its mutations cause BOR s. (branchio-oto-renal syndrome); SIX3 – its mutations cause holoprosencephaly with severe eye defects (cyclopia, microphthalmia, hypotelorismus); SIX6 (OPTX2) – its mutations cause microphthalmia with congenital cataract; PAX2 – its mutations cause optic nerve head defects and colobomas with kidneys defects (papillo-renal syndrome); PAX3 – its mutations cause Waardenburg syndrome; CHX10 – its mutations cause complex microphthalmia; PITX2 – its mutations cause Axenfeld-Rieger syndrome.
Axenfeld-Rieger syndrome AD inheritance, PITX2 gene; posterior embryotoxon ! prominent, anteriorly displaced Schwalbe line; peripheral iris streaks connected to embryotoxon; developmental iris defects (pseudopolycoria, corectopia, hypotrophia); glaucoma risk: 50-60%; hypo-, oligo-, anodontia; malar hypoplasia, hypertelorismus; umbilical hernia; „empty saddle” syndrome.
Waardenburg syndrome AD inheritance; PAX3 and MITF genes heterochromatic irides; uveal hypopigmentation; telecanthus and dislocation of lacrimal points; white forelock; local skin decoloration; neurosensory deafness.
Tumour suppressor genes in ophthalmology retinoblastoma - RB1 - 13q14; von Hippel-Lindau disease - VHL - 3p26; neurofibromatosis type 1 - NF1 - 17q11; neurofibromatosis type 2 - NF2 - 22q12; tuberous sclerosis - TSC1 - 9q34, TSC2 – 16p13; malignant melanoma - CDKN2/p16 - 9p21; polypous colon cancer - APC - 5q21
Retinoblastoma malignant embryonic neoplasm of retina, in children before 5 yrs; white or grey pupil (leucocoria); persistent unilateral strabismus; eye or orbit inflammatory reaction; secondary glaucoma. 60% - non-hereditary cases; 40% - hereditary cases; germinal RB1 gene mutations; 90-95% penetrance; in 3-6% children with retinoblastoma – 13q14 microdeletion: facial dysmorphy, low-set ears, MR;
Neurofibromatosis AD inheritance, NF1 gene; Lisch nodules on the iris; multiple skin neurofibromas; „cafe-au-lait” skin spots; optic nerve gliomas (15%); other CNS tumours (1-2%), pheochromocytomas (1-3%); arterial hypertension (2%), epilepsy (3%);
Tuberous sclerosis AD inheritance, TSC1, TSC2 genes; facial fibroangiomas (adenoma sebaceum, 50%); retinal astrocytoma (50%); skin decoloration spots; shagreen skin (20-40%); enamel defects (70%); intracranial calcifications; epilepsy (90%), MR (50%), kidneys tumours (60%), heart myomas (30%).
Von Hippel-Lindau disease AD inheritance, VHL gene; retinal haemangiomas (60%); embryonic haemangiomas of cerebellum, spinal cord and brain stem (70%); renal cancers (28%); pheochromocytomas (7%); renal, pancreatic, hepatic and epidydymic cysts.
Sturge-Webera syndrome usually sporadic; facial haemangioma; ipsilateral soft meninges haemangioma uveal eye haemangioma and secondary glaucoma; sometimes: epilepsy, paresis, MR.
Hereditary optic nerve neuropathies Leber hereditary optic nerve neuropathy (LHON) - Mt; Kjer hereditary optic nerve neuropathy (ADOA) - AD; simple, recessive optic nerve neuropathy - AR; hereditary XR optic nerve neuropathy – OPA2 gene (Xp11); complex Behr optic nerve neuropathy - AR.
LHON mitochondrial inheritance; 85% - males (40-80% penetrance), usually in 15-30 yrs.; 15% - females (10-20% penetrance); 1/7 – sporadic cases, 6/7 – affected maternal family members; Wallace (1988) - identification of the first point mutation (11778 mtDNA) – present in 50-75% of patients in Europe.
Unusual phenomena in LHON genetics mutations heterogeneity: primary: mainly 11778, 3460, 14484; secondary (synergy); suppressor - eg. 4136. heteroplasmy – normal and mutant mtDNA in one person: different recurrence risks; changes from one generation to the next. mtDNA interaction with nuclear genome: suspected specific XR allele of loss of vision predisposition – not confirmed.
Kjer optic nerve neuropathy (ADOA) AD inheritance; 3 genes: OPA1 (3q28-29), OPA3 (19q13) and OPA4 (18q12); differential diagnosis with LHON: earlier onset (usually<10 yrs); blue color vision defect; better visual prognosis; acute phase present in LHON (peripapillar teleangiectatic microangiopathy).
Recessive optic nerve neuropathy AR inheritance; rare, age of onset - usually < 5yrs; very pale optic head with retinal vessels narrowing (like in retinal dystrophies); Behr syndrome – complex optic nerve neuropathy (with: cerebellar ataxia, spasticity, muscular hypertonia, MR).
Hereditary hypopigmentations melanine production defects: oculo-cutaneous albinism (OCA) - AR, ocular albinism (OA) - XR; OCA-associated syndromes. melanocytes migration defects: albinoidism - AD, piebaldism - AD, Waardenburg syndrome - AD.
Oculo-cutaneous albinism (OCA) OCA1 – linked to tyrosinase: 1A - „classical”, 1B - „yellow”, 1MP, 1TS – milder forms; OCA2 – linked to P gene: (P protein in melanosome membrane is responsible for tyrosine transport); OCA3 – linked to TRP1 gene: (protein that takes part in melanine production).
Chediak-Higashi syndrome AR inheritance; partial OCA; High predisposition to infections in children; hepatomegaly and lymphadenopathy; lymphomas in youth.
Hermansky-Pudlak syndrome AR inheritance; classical or partial OCA; blood plates dysfunction; subcutaneous haemorrhages; pulmonary fibrosis; enterocolitis.
Ocular albinism Nettleship-Falls type - XR; the most frequent type of OA, in female-carriers: partial iris translucency and granular eye fundus depigmentation; Aland Islands type - XR; autosomal recessive type – very rare.
Retinal dystrophies macular dystrophies (central); peripheral retinal dystrophies; hereditary vitreoretinopathies; choroidal dystrophies; stationary photoreceptor dystrophies:
Macular dystrophies Stargardt disease – AR, Leber congenital amaurosis (LCA) – AR, Best vitelliform macular dystrophy – AD, cone-rod dystrophy („bull’s eye”) – AD, XR, juvenile retinoschisis – XR, pattern macular dystrophies – AD, Sorsby pseudo-inflammatory dystrophy – AD, North Carolina macular dystrophy – AD, familal macular drusen – AD, cystic macular dystrophy – AD.
Stargardt disease s.c. juvenile macular degeneration, 1:10.000; first description – Stargardt, 1909; diagnosis: in 35% <10yrs, in 70% <20yrs, in 95% <40yrs; course: progressive central vision loss, in early onset – VA: 0.1 in the beginning of the second life decade; prognosis: in 5 years VA decreases to 0.1 – than very slowly.
Stargardt disease Diagnosis: decreased VA (often suspected simulation), visual field (central scotoma); ophtalmoscopy – initially normal, than yellow granularities in macula, and typical maculopathy (sometimes „fundus flavimaculatus”); fluorescein angiography (FA) !!! – „masked choroidea” in 80% of patients; family history – usually negative; ABCR gene molecular analysis.
Stargardt disease Genetics: AR inheritance, ABCR gene (locus: 1p21-p22); population carrier frequency – 1:50; retina-specific, ATP-binding transport protein, expressed in outer segments of photoreceptors; >600 different mutations;
Leber congenital amaurosis (LCA) the first description – Leber, 1869; AR inheritance – approx. 20 genes; 1:30.000, 10-20% of congenital blindness in developed countries; in children: usually VA<2/50, in 10-20% - 5/50-5/16; adults are usually blind.
Leber congenital amaurosis (LCA) Diagnosis: nystagmus, photophobia, „eye-fingers” symptom; no pupil light reaction; hyperopia, very low VA; totally absent ERG responses !!! 0-3yrs – normal eye fundus, than – „leopard skin” appearance; molecular analysis of causative genes !
LCA genetics mutations identified in 80% of patients; 20 mapped genes, 18 cloned genes; LCA1 – GUCY2D (6-21%); LCA2 – RPE65 (3-16%); LCA3 – RDH12 (~4%); LCA4 – AIPL1 (4-8%); LCA5 – locus 6q11-q13 – lebercilin; LCA6 – RPGRIP1 (~5%); LCA7 – CRX (~3%); LCA8 – CRB1 (5-15%); LCA9 – locus 1p36 – gene ??? LCA10 – CEP290 (10-22%); LCA11 – IMPDH1; LCA12 – RD3; LCA13 – locus 14q24 – gene ??? LRAT i TULP1.
Leber congenital amaurosis (LCA) Treatment: natural animal model – French Briard dogs – often suffer from RPE65-dependent LCA; successful gene therapy with AAV virus (vector); permanent functional, electrophysiologic and biochemical success; V. i X. 2007 – first clinical tests on 9 persons – Univ. College of London, Univ. of Pennsylvania, Univ. of Florida 28.04.2008 – first results described (N.Engl.J.Med.)
Cone-rod dystrophies many entities with similar symptoms but different dynamics; usually AD inheritance, rare XR, min. 25 genes; Diagnostic: photophobia, nystagmus (not always); decreased VA, color vision defects; ophthalmoscopy and FA – „bull’s eye” maculopathy; visual field (central scotoma); ERG – photopic response reduction !;
Alström syndrome AR inheritance; cone-rod dystrophy; obesity, hypogonadism; diabetes, asthma; hypothyroidism; cardiomyopathy, hypertension; sensorineural hearing loss; normal IQ.
Juvenile retinochisis first symptoms: <10yrs; XR inheritance - RS1 gene – retinoschisin; >100 known mutations; protein that is responsible for intracellular adhesion; Diagnosis: ophtalmoscopy – always typical „bicycle-wheel” maculopathy, than – vitreo-retinal tractions; FA – usually normal; ERG – elective B wafe reduction !!! family history, gene molecular analysis.
Best vitelliform macular dystrophy first description – Best, 1905; AD inheritnace, BEST1 (VMD2) gene – bestrophin; elective expression in cell membrane of RPE and forms a chlorine channel; typical, atypical (VMD1 gene), adults forms; beginning: decreased VA and metamorphopsia, vitelliform changes in macula present directly after birth or with later onset, typical evolution; prognosis: useful VA – until 7. decade.
Best vitelliform macular dystrophy Diagnosis: VA, Amsler test; ophthalmoscopy; ERG – normal; EOG – typical !!! – no increase in light (Arden factor <1,5);
Peripheral retinal dystrophies retinitis pigmentosa - AD, AR, XR, AD, Mt; juvenile retinoschisis - XR; Leber congenital amaurosis - AR; fundus flavimaculatus - AR; fundus albipunctatus - AR.
Retinitis pigmentosa many entities with similar symptoms; prevalence: 1:4000; inheritance: AD, AR, XR, XD, Mt, digenic; approx. 60 different genes: phototransduction proteins; rod outer segments proteins; retinol metabolism proteins; other proteins – eg. RPGR (GTPase regulator). molecular analysis of causative genes.
Retinitis pigmentosa - diagnosis ophthalmoscopy – typical triade of symptoms; visual field – concentric narrowing ! night blindness – first sign ! ERG – scotopic resonse reduction, than no response; molecular analysis of causative genes !
Usher syndrome AR inheritnace, min. 12 genes; several types; retinitis pigmentosa; congenital sensorineural hearing loss (deafness); sometimes labirynthine dysfunction and psychotic symptoms.
Bardet-Biedl syndrome inheritance: oligogenic triallelic or AR; atypical retinitis pigmentosa with maculopathy; obesity and hypogonadism; polydactyly, renal defects; sensorineural hearing loss; sometimes MR.
Kearns-Sayre syndrome mitochondrial inheritance; large mtDNA deletions; chronic progressive external ophthalmoplegia; retinitis pigmentosa (atypical); short stature, ataxia, heart block, deafness, diabetes, hypothyroidism, hypogonadism, myopathy.
Cohen syndrome AR inheritance (Finland, Israel, Libanon); progressive myopia; retinitis pigmentosa (atypical); muscular hypotony in infancy; MR; obesity, elongated fingers; prominent incisors; dysmorphic features.
Hereditary vitreoretinopathies Norrie disease - XR; juvenile retinoschisis - XR; Goldmann-Favre syndrome - AR; Wagner s., Stickler s., Marshall s. - AD; familial exsudative vitreoretinopathy (FEVR): ADFEVR (Criswick-Schepens s.) - AD; XLFEVR - XR; familial neovascular inflammatory vitreoretinopathy (ADNIVR) - AD; familial vitreoretinochoroidopathy (ADVIRC) - AD.
Choroidal dystrophies choroideremia - XR; atrophia gyrata - AR; central areolar choroidal dystrophy - AR, AD; generalized choroidal dystrophy - AD.
Stationary photoreceptors dystrophies congenital stationary night blindness (CSNB): known 8 genes - AD, AR, XR; congenital olor blindness (daltonism): protanopia, deuteranopia - XR; tritanopia - AD; blue-cone monochromacy - XR; rod monochromacy (achromatopsia) - AR.
Multifactorial eye disorders Age-related macular degeneration (AMD) Primary open angle glaucoma (POAG)
AMD predisposition genes ARMD1 – 1q24-q25 – FBLN6 (HMCN1) (2003) ARMD2 – 1p21-p13 – ABCR (1997) ARMD3 – 14q32 – FBLN5 (2004) ARMD4 – 1q32 – CFH (2005) ARMD5 – 10q11 – ERCC6 (2006) ARMD6 – 19p13 – RAXL1 (2005) ARMD7 – 10q25-q26 – HTRA1 (2006) ARMD8 – 10q25-q26 – ARMS2 (2005) ARMD9 – 9p13 – C3 (2007) ARMD10 – 9q32-q33 – TLR4 (2005) ARMD11 – 20p11 – CST3 (2006) 1q31-q32 – CFHR1 and CFHR3 (2006) 6p21 – CFB and C2 (2006) 3pter-p21 – CX3CR1 (2007) 6q25 – ESR1 (2007) mtDNA – MTTL1 (2006)
POAG predisposition genes GLC1A – 1q24-q25 – TIGR (MYOC) gene 1997r. GLC1B – 2cen-q13 1996r. GLC1C – 3q14-q24 1997r. GLC1D – 8q23 1998r. GLC1E – 10p14-p15 – OPTN gene 2002r. GLC1F – 7q35-q36 1999r. GLC1G – 5q22 – WDR36 gene 2005r. GLC1H – 2p15-p16 2007r. GLC1I – 15q11-q13 2000/2005r. GLC1J – 9q22 2004r. GLC1K – 20p12 2004r. GLC1L – 3p 2005r. GLC1M – 5q22-q32 2004/2007r. GLC1N – 15q22-q24 2006r.
Alarming eye symptoms in infants corneal diameter (normal: 10-12mm); corneal transparency (leucoma ?); pupil color (leukocoria ?); shape and size of the pupil (aniridia, coloboma); permanent unilateral strabismus; congenital nystagmus (in first 3 months); photophobia (usually with lacrimation); no visual contact (3-month-old children).