41 terms

AHG2-L29: Genetics of Eye Disease by Wiggs

STUDY
PLAY

Terms in this set (...)

Image of Eye and Location of Diseases
...
Retinitis Pigmentosa: pathogensis
Rods and Cones, (photoreceptors)
degenerate in retinitis pigmentosa.

Detected as loss of retinal activity.
Retinitis Pigmentosa:Genetics.
• Over 200 genes

• Autosomal dominant (Rhodopsin)

• Autosomal recessive (Leber congenital amaurosis)

• X-linked (RP2 and RPGR )

• Digenic (peripherin/RDS and ROM1)

• Mitochondrial (Kearns-Sayres)

• Syndromic
--- Bardet-Biedl (obesity, hypogenitalism)
--- Usher's syndrome (deafness)
Treatable forms of Retinitis Pigmentosa
• Gyrate Atrophy (OAT deficiency)

• Refsum's disease (restrict phytanic acid)
Causes of RP
...
Retinoblastoma: Epidemiology
Annual incidence of RB : 5.8 per million

0-4 year olds : 10.9 per million

5 years + : 0.6 per million
Retinoblastoma: Mechanism
...
Retinoblastoma: Genetics
• RB gene recessive at molecular level

• Familial Retinoblastoma inherited as an AD trait with reduced penetrance
Retinoblastoma: Disease manifestation
• Sporadic/unilateral:
-- The probability of two spontaneous mutation events in the same cell in a normal individual is very low, so most sporadic cases are unilateral.
-- 'Second hit' can be new mutation or mitotic crossover (LOH)

• Familial/bilateral/multifocal:
-- Spontaneous mutations will occur in at least one cell in each retina of both eyes in the heterozygote.
-- 90-99% of heterozygotes develop tumors and most are bilateral.
Retinoblastoma: Genetic counseling
...
Retinoblastoma: Risk Management
• Children at risk need EUA every 3 months until age 5.

• Genetic testing can be useful in hereditary cases.

• Most families have private mutations.

• Initial genetic testing requires sequencing of entire gene
Glaucoma: Pathogenesis
...
Glaucoma: Causes by Age of onset
...
Glaucoma: Genetics of Congenital form
AR

CYP1B1
LTBP2
Glaucoma: Genetics of Developmental Form
AD

PITX2
FOXC1
PAX6
LMX1B
Glaucoma: Genetics of Primary Open Angle Form
EARLY ONSET: 3-20yo
--- AD: MYOC

NORMAL TENSION: >20yo
--- Complex:
OPTN
TBK1
WDR36
CDKN2BAS
8q22

ADULT ONSET: > 20yo
--- Complex:
CAV1/CAV2
CDKN2BAS

EXFOLIATION: > 50yo
--- Complex:
LOXL1
Northern latitude
Cataract: Pathogenesis and Genetics
Inherited forms appear at birth or early childhood

Mutations in lens proteins:
• Crystallins
• Aquaporins
• Connexins

Adult Forms: Common and Complex
Macular Degeneration: Basics and Findings
Leading cause of blindness world-wide.

Loss of vision is primarily due to fluid leakage and scarring caused by neovascular membranes.
Macular Degeneration: Main Genes
CFH - Complement Factor H
- Serum glycoprotein that regulates the
function of the alternative complement pathway in plasma and on cellular
surfaces.
- The protein has been found in drusen and may play a role in their
formation.

ARMS2 - HTRA1
- Protein function is not known. Initial studies suggested the gene could contribute to neovascular membrane formation.
Albinism: Different Forms
• Oculocutaneous
• Ocular
• Hermansky Pudlak
• Chediak Higashi
Albinism: Oculocutaneous form
Tyrosinase defect
AR
Albinism: Ocular Form
Nettleship Falls
X-linked
OA1 defect
(ocular melanosomes)
Albinism: Hermansky Pudlak
Abnormal platelets
AR
8 types HPS1-8
(organelle abnormalities)
Albinism: Chediak Higashi
Recurrent bacterial infections
AR
LYST defect
(Lysosome abnormalities)
Albinism: Retinal Pathways
...
Aniridia: Genetics
- PAX6 (paired box, transcriptional regulator)
- Autosomal dominant
- Malformation of iris and other anterior segment structures

- 11p13 deletion syndrome associated with Wilm's tumor
- Genitourinary abnormalities
Fabry's Disease: Genetics and Eye Findings
- Alpha galactosidase (defects cause accumulation sphinolipids)

- X-linked recessive

- Female carriers, hemizygous males: cornea verticillata
Neural lipid storage disorders: Forms and Eye findings
• GM2 gangliosidosis
Tay-Sachs (hexosaminidase A gene)
Sandhoffs (hexosaminidase B gene)

• Galactosialidosis
- Aplha neuraminidase deficiency

"Cherry Red Spot"
(Lipid accumulation in ganglion cells)
Marfan Syndrome: Genetics and Eye Findings
- Fibrillin-1
- Component of extracellular microfibrils
- AD

- Fibrous connective tissue
- Skeletal, ocular, and cardiovascular

- Blue sclera
- Megalocorneas,
- Spherophakia
- Lens dislocation
- Severe myopia
- Retinal detachments
Neurofibromatosis: Genetics and Eye findings
- Phakomatosis
- Neurofibromin (tumor suppressor gene)
- AD

- Lisch Nodules (melanocytic hamartoma)
Noonan Syndrome: Genetics and Findings including Eye findings
- PTPN11: PROTEIN-TYROSINE PHOSPHATASE, NONRECEPTOR-TYPE, 11
- AD

- Dysmorphic facial features
- Short stature
- Heart disease
- Hypertelorism (74%)
- Epicanthic folds (39%)
- Ptosis (48%)
- Strabismus (48%)
- Prominent corneal nerves (46%)
Sturge Weber: Genetics and Eye Findings
- Phakomatosis
- ?Inheritance pattern
- ?Gene defect

- Episcleral venous arterial malformations
- Glaucoma early onset
- Choroidal hemangiomas
Tuberous Sclerosis: Genetics and Eye Findings
- Phakomatosis
- TSC1 and TSC2 (tumor suppressor)

- Benign tumors: central nervous system, kidney, heart, lung, and skin

- Ocular: Astrocytic hamartoma
- Flat, translucent lesion (70%)
- Multinodular "mulberry" lesion (55%)
Wilson's Disease: Genetics and Eye Findings
- ATP7B (membrane copper transport protein)
- AR

- Intracellular hepatic copper with subsequent hepatic and neurologic
abnormalities.

- Kayser-Fleischer ring
Coloboma: Assoications
- 60% sporadic nonsyndromic

- Can be AD

- Retinal detachments (10%)
- Lens dislocation (10%)
Coloboma Formation
Incomplete closure of choroidal fissure
Cornelia de Lange: Genetics and Eye Findings
- NIPBL 5p13

- Brow hypertrichosis
- Synophrys (unibrow)
- Long arcuate eyelashes
- Nystagmus
- High Myopia
Smith Magenis: Genetics and Eye Findings
- 17p11
- Iris anomalies (70%)
- Microcornea (50%)
- Myopia (42%)
- Strabismus (32%)
Trisomy 18 Edwards: Eye Findings
Ankyloblepharon
Connection between the upper
and lower lids
Trisomy 21 Downs Syndrome: Eye Findings
Keratoconus: common (7 times population risk)

Brushfield spots: Possible Hamartoma.
Areas of iris atrophy
Williams syndrome: Genetics and Eye Findings
7q11
Stellate iris pattern (80%)
Strabismus (54%)