Hereditary Retinal Diseases: Diagnosis

Hereditary Retinal Diseases: Differential Diagnosis

• If retinal signs are symmetric in both eyes, consider hereditary disease, especially in young patients, as it is true for all hereditary eye diseases.
• Disease classification schemas include progressive versus stationary and central (macular) dystrophies versus generalized.
• Important patient history includes specific symptoms like central scotomas or night blindness.
• Rod injury initially presents as night blindness (nyctalopia).
• Cone injury results in the ability to see at night but not in bright light, indicating macula injury.
• Examining other family members and a complete past medical history are also helpful.
• Electrophysiological tests like ERG are important, providing sometimes the only evidence of the condition.
• Visual electrophysiologic tests are ancillary tests.
• Electrophysiologic tests are the objective tests that measure function.

Full-Field ERG (Electroretinogram)

• The full-field ERG records the summary of transient, mass electrical responses from the entire retina.
• Adaptation in the dark for 30 minutes prior is required for the most accurate results.
• Full-field ERG doesn't provide topographical information about localized defects.
• Multifocal ERG (mfERG) is more appropriate for detecting macular dysfunction.
• ERGs are usually normal unless 20% or more of the retina is affected.

Multifocal ERG

• Multifocal ERG is a calculated field map of electrical responses.
• This measures local retinal function and provides topographical retinal function.

EOG (Electro-Oculogram)

• This measures the potential between the cornea and Bruch's membrane.
• It also measures resting membrane potential.
• The origin of the EOG signal is the RPE - retinal pigment epithelium.
• Electro-Oculogram considered an adjunct to the ERG.
• Confirming Best's vitelliform macular dystrophy is the most common use of the EOG.

VEP (Visually Evoked Potential)

• Is the only electrophysiologic test that assesses visual cortex activity and includes the retina, optic nerve, and brain.
• An impaired VEP is anatomically non-specific unless combined with other tests like ERG and EOG.

Autofluorescence (AF)

• Lipofuscin (LP) accumulation occurs in the RPE.
• Light blue-green wavelength (488-514 nm) highlights the presence of xanthophyll in the macula
• Xanthophyll always appears dark in FAF because it's able to absorb light.
• Metabolic activity will cause a lesion to expand and is considered active
• This is visible by the hyperfluorescence border.

Inherited Retinal Dystrophies

• Retinitis Pigmentosa (Progressive rod, Rod/Cone Dystrophy) belongs to a group of pigmentary retinopathies.
• It is a generic name for retinal dystrophies with loss of photoreceptors and retinal pigment deposits.
• Initial loss of peripheral vision occurs, with macular function generally preserved until adulthood
• The primary pathologic mechanism centers around long outer segments of the rods containing membrane discs where phototransduction takes place.
• Discs at the apex are phagocytosed daily by the RPE and replenished daily by the synthesis of new ones at the base of the rod's outer segments with the support of intense mRNA and protein synthesis.
• Starts as rod issues with subsequent degeneration of cones, known as Rod-cone dystrophy.
• The prevalence of rod-cone dystrophy is 1:5000 and is the most common hereditary retinal dystrophy
• Classification is done by distribution of retinal involvement to describe subtypes, namely central, pericentral, sector and peripheral
• Half of RP cases are sporadic (simplex) and the other half have a family history

RP Genes

• Over 80 genes have been identified to cause syndromic and non-syndromic RP.
• Most common genes involved are RHO in autosomal dominant cases, USH2A, and RPGR in X-linked recessive cases

Mitochondrial Inheritance

• Mitochondria: inherited from the mother, can cause defects in mitochondrial DNA leading to disorders which are then inherited

Syndromic versus Non-syndromic Classification

• Most patients with RP presents as non-syndromic.

Photoreceptor Classification

• Rod or Rod/Cone can be affected
• Cone-rod dystrophy (inverse RP) has peripheral vision is good but the macula is affected

Usher Syndrome

• Also known as Usher–Hallgren syndrome, retinitis pigmentosa-dysacusis syndrome, or dystrophia-dysacusis syndrome, this is the most common syndromic form in which retinitis pigmentosa is associated with neurosensory deafness
• ~14% of all RP cases are Usher syndrome
• Usher Syndrome is known as an autosomal recessive ciliopathy, with sensorineural hearing loss, retinitis pigmentosa, and, in some cases, vestibular dysfunction.

Usher Syndrome Types

• Type 1 Usher syndrome: caused by mutations in the CDH23, MYO7A, PCDH15, USH1C, and USH1G genes. Results in profound congenital hearing loss or deafness, severe balance issues, vestibular ataxia, and difficulty walking before 18 months of age.
• Type 2 Usher syndrome: Due to mutations in the USH2A, GPR98, and DFNB31 genes and involves moderate to severe hearing loss at birth, with typically normal balance.
• Type 3 Usher syndrome: is caused by mutations in the CLRN1 gene and the exact action and effects are not fully understood.

Bassen-Kornzweig Syndrome (Abetalipoproteinemia)

• Caused by pathogenic variants in the MTTP gene which is crucial for the assembly of lipoproteins
• Mutations in MTTP lead to abetalipoproteinemia, disrupting fat and vitamin absorption
• Pattern is autosomal recessive
• Features systemic symptoms such as diarrhea, vomiting, and steatorrhea.
• Causes delayed growth, and impaired bone development, typically in the first year/early childhood
• Later onset may additionally cause progressive ataxia, peripheral neuropathy, slurred speech
• Can cause cardiomopathy and liver complications

Refsum Disease

• Classic Refsum Disease presents as an adult form
• Characterized by the accumulation of phytanic acid in the body.
• This condition is caused by mutations in the PAHX or PHYH gene that produces phytanoyl-CoA hydroxylase or the gene that encodes peroxin-7 (PEX7).
• Autosomal recessive inheritance pattern
• Systemic symptoms involve anosmia, deafness, and various skin abnormalities
• Retinitis pigmentosa is the ophthalmological sign

Infantile Refsum Disease

• Infantile Refsum Disease is caused by mutations in the PEX1, PEX2, PEX26, PHҮН, or PEX7 genes
• This is the least severe form of Zellweger spectrum disorder
• Inheritance pattern is autosomal recessive
• Shows systemic signs which can include ataxia, polyneuropathy, and mild facial dysmorphism
• Causes cardiomyopathy and also systemic symptoms including anosmia, sensorineural hearing loss and mild facial dysmorphism
• Retinitis pigmentosa typically begins in infancy, along with ophthalmic effects.

Laurence-Moon Syndrome

• Also known as Laurence–Moon–Biedl syndrome
• Involves six cardinal signs: obesity, atypical retinitis pigmentosa, mental deficiency, genital dystrophy, polydactylism and familial occurrence.
• Anomalies include genu valgum, coxa vara, scoliosis and deafness as well.

Neuronal Ceroid Lipofuscinosis (Batten Disease)

• Also known as amaurotic idiocy, Batten disease involves a protein encoded by the CLN3 gene, found in lysosomes and synapses
• Predominantly autosomal recessive inheritance, but there are autosomal dominant forms
• The four forms are differentiated by age of onset.
• The infantile form presents with infantile symptoms around 6 to 8 months of age.
• Late infantile form starts between 2 and 4 years.

Alström Disease

• Also known as Alström syndrome, retinitis pigmentosa-deafness-obesity-diabetes mellitus or Hallgren-Alström syndrome, retino-otodiabetic syndrome and Alström-Hallgren syndrome
• Distinctions vs Bardet-Biedl: Alström syndrome is distinguished by the absence of polydactyly, hypogenitalism, and intellectual disabilities
• Diagnostic criteria include hearing loss, obesity, diabetes mellitus (DM), acanthosis nigricans, and retinitis pigmentosa (RP)
• Caused by mutations in the ALMS1 gene and inheritance is autosomal recessive
• Includes cardiovascular conditions such as cardiomyopathy and cardiomegaly and also obesity and type 2 diabetes mellitus.

Kearns-Sayre Syndrome

• Also referred to as Kearns-Sayre mitochondrial ciliopathy or oculocranio-somatic syndrome
• Caused by sporadic deletions in mitochondrial DNA
• The mtDNA can result from point mutations within the mtDNA
• Systemic symptoms include sensorineural deafness, cerebellar ataxia, dysarthria, dysarthria, bilateral facial weakness as well as endocrine/cardiac issues
• Ophthalmic sings progressive external ophthalmoplegia, ptosis, night blindness, and pigmentary retinopathy with salt-and-pepper retinopathy with diffuse stippled areas of retinal pigment epithelium

Clinical features of RP Overview

• Presentation: Bilateral
• Onset during first to 2-3 decade
• Visual field Loss: Progressively from mid-peripheral scotomas to ring scotoma.
• Central vision is lost at the end.
• Visual Acuity in RP
  • Typical rod-cone RP is associated w/ good central vision.
  • Generally remains until later stages of the disease.
  • If they have adRP good, they are more likely to maintain acuity to 60 y/o+
  • If XLRP bad; legally blind (20\200 or worse) by younge rage

Fundus findings of RP

• Require bilaterality
• Bone Spicules only appear on bilateral
• Attenuated vessels
• Waxy pallor of the optic nerve

Retinitis Pigmentosa Types

• Retinitis pigmentosa sine pigmento: RP symptoms can be present with no pigmentary changes.
• Retinitis punctata albescens: has multiple, punctate white spots in the midperiphery.
• Sector retinitis pigmentosa: pigmentary changes are limited to a small retinal area.
• Retinitis pigmentosa inversus: Macula and posterior pole are affected

Retinitis Pigmintosa Signs

• Vessels so thin because atrophy.
• Ganglion atrophy - waxy ONH
• Other: CME, PSC and myopia are more common with XL type

Retinitis Pigmintosa Testing

• Initial reduction of response R/T rods
• Abnormal ERG can be seen even without fundus findings
• In early stages: there is early decline on dark-adapted ERG.

Retinitis Pigmintosa Other Tests and Approach

• OCT: can asses for CME, ERM
• FA
• VF: field abnormalities
• Approach: Genetic Testing

Retinitis Pigmintosa Therapy Options

• A 351-gene panel through Blueprint Genetics targeting genes associated with IRDs is available and useful.
• Vitamin A Palmitate- supplement
• Important to get genetic testing- because vitamin A can sometimes be contraindicated.
• Ocular- Voretigene neparvovec (Luxturna): Useful for biallelic RPE65 mutations

Retinitis Pigmintosa Ddx

• Syphilis: can cause salt and pepper fundus
• Rubella: Also causes salt and pepper fundus
• Pigmentary paravenous retino-choroidal atrophy: RPE degeneration that tracks along vessels

Types of Punctata Albescenes & Fundus Albipunctatus

Retinitis Punctata Albescens: rare with AR primarily, mutation in RL BP1 Uniform punctate Albescenes (Fundus Albipuntatus)- rare with AR, patient is born with defect - can be seen at birth Visual pigment regeneration process (applies to both)-- visual pigment regen issue with rods

Treatment of Retinitis Pigmintosa Punctata and Fundus Albipunctatus

• Both will have OCT hyperrflective due to rods being in RPE layer.
• Both will test with High dosages of carotenoids being used.

Congenital Stationary Night Blindness

• Oguchi's and Fundus Albipuntatus are included in CSNB
• AD, X-linked and AR forms exist
• Light activated enzymatic processes involved
• Most maintain 20/40 of vision later in life

Case Study

• 16 y/o with blurriness + Nyctalopia
• 20/400 vision, reduced CV
• Dx: retinoschisis

ESCS & Goldmann-Favre

• NR2E3 issue- autosomal recessive
• Retinal adhesion is a factor

Goldmann-Favre

• Patients are hyperopic
• Foveal Scchisis
• ERG: Very low Rod and COne responses

X-linked retinoschesis (XLRS)

• Gene testing should be pursued and Macular Schisis should be tested with CAI.

XLRS Diagnosis

• Muler cells are affected because defects in them prevent cells from adhereing correctly.
• Domelike elevation can be seen
• ERG presents as normal A-wave and negative B Wave.

Cone Dys

• Inherited issues with cones or processing following cones.
• Major clinical problems: VA lost, Color vision Abnormal, Photophobia, often stationery but can progress

###Types of ERGM testing of cone dys

1. Red monochromatisim- most severe! complete absence of COne 2. progressive cone sys- vision will declien over time.

Stargardt

• Lipofuscin in RPE
• AR trait is caused by ABCA4 gene
• silent dark coronoid sign
• Test is abnormal with ERG loss following scotopic pattern

Best VIT

• Autosomal dominant
• Mutation in BEST1 mutation
• Most have yolk-like lesions
• Abnl chloride conduits disrupt transfer in RPE
• In OCT, yolk sac is seen