Day 14 (1): Ocular Genetics Flashcards
Why the need for ocular genetics?
- 4th MC organ involved in genetic disorders
- 50% of pediatric blindness is genetic
- Genetic etiology of eye diseases elucidated
- Can be examined non-invasively
Review of genetics terms
- DNA
- molecule that carries genetic information for the development and functioning of an organism - Gene
- basic physical and functional unit of heredity
- composed of DNA sequences - Chromosome
- collection or storage unit of genes
- 23 pairs of chromosomes: 22 pairs of autosomes and 1 pair of sex chromosomes - Genome
- collection of the entire genetic information made of all 23 chromosomes and the genes that form them - Polymorphism
- nucleotide sequence changes or variations that DOES NOT cause disease - Mutation
- nucleotide sequence changes or variations that disrupt genes and cause abnormalities or diseases - Vertical Transmission
- disease noted in a parent and a child - Horizontal Transmission
- disease noted between siblings
Differentiate Autosomal Dominant vs Autosomal Recessive vs X-linked Recessive transmission.
AUTOSOMAL DOMINANT
- vertical transmission: manifests between parents and children
- one parent manifests the disease
- 50% chance of having an affected child
- affected males ~ affected females
- can be passed on from males to their sons
- disease manifests immediately if inherited
- mutation not inherited = unaffected
AUTOSOMAL RECESSIVE
- horizontal transmission: manifests between siblings
- parents are carriers
- 25% chance of having an affected child
- affected males ~ affected females
- can be passed on from males to their sons
- disease may NOT manifest if mutation is inherited; only becomes a carrier
- needs both copies of the defective gene from both parents for disease to manifest
- consanguinity may allow the disease to manifest (if both are carriers)
X-LINKED RECESSIVE
- disease-causing gene is on the X chromosome
1. MALES are usually affected:
- phenotype always expressed in males because they are immediately homozygous for the mutation, having only one X chromosome
- NO male-to-male transmission: Y chromosome is passed by fathers to sons
2. FEMALES are unaffected carriers unless:
- they carry the mutation in BOTH X chromosomes leading to expression of disease
- with skewed X-inactivation causing milder or later onset of symptoms
- normal allele in the other X chromosome suppresses expression of the diseased gene
3. Female carriers and an unaffected male have a 25% chance of each possible outcome.
4. Affected males produce carrier daughters (X) and unaffected sons (Y)
What is aniridia?
Aniridia
- total or partial hypoplasia of the iris tissue
- congenital (genetic, bilateral) or acquired (traumatic, unilateral)
- isolated or part of a syndrome
CLASSIC Aniridia
- panocular disorder with NO systemic manifestations
- mutation: PAX6 (in c11p13; master control gene for eye development)
- inheritance: 2/3 are autosomal dominant
- parents may be tested to ascertain if mutation was passed on or sporadic
Components:
1. Partial or near total absence of iris
2. Horizontal pendular nystagmus: most common associated sign; due to foveal hypoplasia
3. Cataract: anterior polar, posterior polar or subcapsular cataracts
4. Aniridia-associated Keratopathy: limbal stem cell deficiency and peripheral pannus that progresses centrally until completely opacified
5. Glaucoma: tilted iris stump with enlarging strands that attach to the angle wall causing gradual closure of the TM and the angle
6. Foveal hypoplasia: absence of macular reflex and foveal pit; presence of abnormal retinal vessels crossing the fovea
7. Optic disk hypoplasia
8. Ciliary body hypoplasia and anterior rotation
Diagnostics:
1. Single Gene Testing/Next Gen. Sequencing
- targeted test: analyzes only a single gene
- sequences nucleotides in the PAX6 gene
- counseling MUST be provided before and after
2. Electroretinogram
- decrease in amplitude of all the waveforms suggesting abnormality in all retinal layers
WAGR Syndrome
- contiguous deletions of PAX6 & WT1 (c11p13)
- Wilms’ Tumor Suppressor Gene 1 (WT1): encodes for a protein, mutation of which causes development of Wilm’s Tumor
- extent of phenotype dependent on the length of the deletion
- early presentation
Components:
1. Wilms’ Tumor
2. Aniridia
3. Genitourinary anomalies: cryptorchidism, ambiguous genitalia, streak ovaries
4. Mental retardation/Intellectual disability: most common neurological manifestation
Diagnostics:
- any infant presenting with sporadic aniridia and developmental delay requires a molecular diagnosis to rule out WT1 deletion to manage potential development of Wilms’ tumor
1. Karyotyping: if (-) –>
2. FISH Analysis: if (-) –>
3. Single Nucleotide Polymorphism (SNP) Array
- done for genetic diseases involving MULTIPLE organ systems involving more than one gene
- broader test: analyzes several segments of chromosome
- result:
+ single prominent phenotype: Aniridia/WAGR
+ copy number variations: deletions/duplications
MANAGEMENT
1. Protection from glare: glasses, hats
2. Monitor for refractive errors and amblyopia
3. Monitor for glaucoma
4. Renal ultrasound every 3 months until 8 yo then yearly thereafter: to monitor for GU defects and Wilms’ Tumor
What is Leber Congenital Amaurosis?
- family of autosomal recessive retinal dystrophies that results in SEVERE vision loss at an EARLY age
- MOST severe retinal dystrophy causing blindness by the age of 1 year
Pathophysiology
- degenerative process involving the outer retina and the photoreceptors
- mutation of genes encoding for proteins that catalyze the enzymatic reactions in the visual cycle that generate 11-cis retinal leading to the eye’s inability to undergo phototransduction
Mutations
1. CEP290 - most frequently involved
2. RPE65 - only one with approved treatment
3. CRB1
4. GUCY2D
Presentation
1. Severe infantile visual impairment
- present with decreased visual response
- associated with nyctalopia (night blindness)
2. Sluggish or absent pupillary light reflex
3. Nystagmus
- pendular or roving
- present since birth and in all gaze directions
4. High hyperopia (> 5 D)
- result from impaired emmetropization due to early-onset vision loss
5. Franceschetti oculodigital sign
- repeated poking, pressing or rubbing of the eyes with a knuckle or finger in an effort to stimulate the retina
6. Keratoconus
7. Enophthalmos: due to orbital fat atrophy
Ophthalmoscopy
- initially appears normal
1. Chorioretinal degeneration and thinning
2. Bony-spicule pigmentation
3. Marbled fundus appearance
4. Macular thickening
5. Vascular attenuation
Diagnostics
1. LCA Gene Panel
2. Perimetry: constricted visual field
3. OCT: thinned RPE, PRL and ONL
4. ERG: decreased or absent signals
Management
1. Voretigene Neparvovec-rzyl
- treatment of bi-allelic RPE65-associated LCA
- normal RPE65 allele carried by a viral vector is injected in the subretinal space
- must have enough remaining cells in the retina
- however, there is a progressive decline of clinical benefits following peak at 6 - 12 months
- NOT indicated for other mutations
2. CRISPR-based Genome Editing (experimental)
3. Correction of refractive error
4. Use of low-vision aids
5. Avoid smoking and eat fatty fish 3x/week
What is X-Linked Juvenile Retinoschisis?
Mutation: RS1 gene
- codes for Retinoschisin
- involved in retinal intercellular adhesion, retinal architecture development and organization
- X-linked recessive inheritance
Presentation
1. Poor vision
- usually presents at school age
- range from 20/20 to blindness depending on the amount and location of schisis
- deteriorates slightly but then remains relatively stable until the fifth or sixth decade
- peripheral vision normal in unaffected areas
- normal color vision
2. Macular/foveal schisis
- spoke wheel pattern radiating from the fovea
- domelike elevation of a thin layer of retina predominantly in the NFL
- symmetric bilateral involvement
- peripheral involvement in > 1/2 of patients
3. Vascular attenuation and sheathing
4. Vitreous hemorrhage
5. Rhegmatogenous Retinal Detachment
Diagnostics
1. Red-Free Illumination: highlights schisis
2. Fundus Autofluorescence:
- increased in the areas of schisis
3. OCT:
- reveal areas of schisis not visible on IO
- schisis in superficial NSR with thinning of NSR
- predominantly in NFL but can occur anywhere
- cystic-like spaces in the fovea and perifovea
4. Fluorescein Angiography
- differentiates foveoschisis (NO petaloid leakage) vs CME (WITH petaloid leakage)
5. Electroretinogram
- scotopic: reduced dark-adapted B-wave amplitude with preserved A-wave amplitude
- photopic: normal
- not diagnostic; maybe normal in some
6. Single Gene Testing/Next Gen. Sequencing
- sequencing of RS1 gene
Management:
1. Avoid head trauma and high-contact/impact sports: due to risk of RRD
2. Amblyopia monitoring
3. Low vision aids
4. CAI (Dorzo/Acetazolamide): improvement of cystoid spaces
5. AAV8-RS1 Gene Therapy
6. Genetic counseling
Important points to remember when you encounter ocular genetics patients.
- Review of systems and systemic PE are important to rule out involvement of other organ systems as multiple genes maybe involved.
- Family history and examination of the parents & siblings provide clues to disease inheritance
- ALWAYS do PRE- and POST-test counseling.
- explain risks and benefits of testing
- improve understanding of disease & prognosis
- advise of risk of recurrence in offsprings
- treatment options - Genetic testing only offered to patients with:
- findings suggestive of MENDELIAN disorder
- causative genes already IDENTIFIED
- most SPECIFIC tests should be ordered
- direct-to-consumer testing is AVOIDED - Genetic testing AVOIDED if:
- genetically-complex disorders involving multiple genes
- no specific treatment or surveillance strategies are shown to be of benefit
- asymptomatic but suspecting an untreatable disease
