Other Retinal Degenerations

Slide 1 · Other Retinal Degenerations

Photoreceptor degeneration · Retinitis pigmentosa

Inherited pathology, functional loss and diagnostic localization

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Localize retinal degeneration to photoreceptors and the retinal pigment epithelium (RPE).

Explain the genetic and cellular basis of retinitis pigmentosa (RP).

Correlate rod–cone loss with functional impairment and morphology.

Interpret key clinical investigations and distinguish major phenocopies.

Slide 3 · Scope: Degeneration is not a single lesion

The Robbins subsection “Other Retinal Degenerations” specifically discusses retinitis pigmentosa.

The term encompasses disorders of photoreceptors and/or RPE rather than one uniform molecular defect.

This lecture develops the RP example, with brief comparisons that establish diagnostic boundaries.

Slide 4 · Identify the primarily affected retinal compartment

Vitreous

Nerve fiber / ganglion

Inner plexiform + nuclear

Outer plexiform + nuclear

Photoreceptors: Rods + cones

Retinal pigment epithelium

Bruch membrane / choroid

Outer retinal photoreceptor injury is the central pathologic event.

Retinal vessel narrowing and pigment redistribution develop as degeneration advances.

Schematic

Slide 5 · Retinal microanatomy explains the symptoms

Vitreous

Nerve fiber / ganglion

Inner plexiform + nuclear

Outer plexiform + nuclear

Photoreceptors: Rods + cones

Retinal pigment epithelium

Bruch membrane / choroid

Outer retinal photoreceptor injury is the central pathologic event.

Retinal vessel narrowing and pigment redistribution develop as degeneration advances.

Schematic

Slide 6 · The RPE–photoreceptor relationship

Photoreceptor / RPE defect

Photoreceptor dysfunction

Cell loss

Visual impairment

Schematic

The RPE forms the outermost retinal epithelial layer adjacent to photoreceptor outer segments.

The integrity of the photoreceptor–RPE unit is essential for photoreceptor survival.

Genetic defects affecting either element can culminate in the RP phenotype.

Slide 7 · Rods and cones perform distinct visual tasks

RODS

CONES

Dark adaptation

Peripheral function

Central acuity

Later involvement in typical RP

Slide 8 · Localizing peripheral versus central vision loss

Intact field (conceptual)

Ring scotoma

Constricted field

Conceptual visual-field schematic

Typical RP often begins with rod dysfunction and peripheral field impairment.

Slide 9 · Retinitis pigmentosa: A clinicopathologic definition

An inherited group of progressive photoreceptor degenerations.

Pathogenic variants disturb rods, cones, RPE function or associated photoreceptor processes.

Its expression ranges from mild visual impairment to profound loss of vision.

Slide 10 · “Retinitis” is a historical misnomer

Feature

Retinitis pigmentosa

Inflammatory retinitis

Primary process

Hereditary neurodegeneration

Inflammatory injury

Cellular target

Photoreceptors / RPE

Retina affected by inflammation

Interpretive clue

Progressive rod–cone deficit

Assess infection / immune context

Slide 11 · Phenotypic diversity follows genetic diversity

Many genes / variants

Shared photoreceptor vulnerability

Different clinical trajectories

Schematic

Different genes can generate a similar rod–cone degenerative phenotype.

Different variants within one gene may result in different clinical phenotypes.

Age at onset, rate of decline, and residual central vision are therefore heterogeneous.

Slide 12 · Autosomal dominant RP

Affected parent → affected child may appear in successive generations

Male

Female

Filled = affected; Illustrative pedigree only

Schematic

Slide 13 · Autosomal recessive RP

Clinically unaffected parents can have an affected child

Male

Female

Filled = affected; Illustrative pedigree only

Schematic

Slide 14 · X-linked RP

No male-to-male transmission for an X-linked variant

Male

Female

Filled = affected; Illustrative pedigree only

Schematic

Slide 15 · Pedigrees: Interpretation requires caution

A simplex case is the only known affected individual in a family—not necessarily a recessive case.

Reduced expression, family size, and incomplete ascertainment may obscure inheritance.

The clinical phenotype and molecular result must be interpreted together.

Slide 16 · Selected genes named in the Robbins discussion

Gene

Relevant connection

RHO

Rhodopsin / rod pathway

USH2A

Photoreceptor-associated function; Usher association

RPGR

X-linked RP; Verified official symbol

EYS

Inherited photoreceptor degeneration

Slide 17 · RHO: A gene–photoreceptor link

RHO variant

Rod pathway impairment

Rod dysfunction

Progressive visual deficit

Schematic

RHO encodes rhodopsin, a core rod phototransduction protein.

RHO-associated disease illustrates how disruption of a rod-specific function can initiate the RP phenotype.

Different RHO variants can produce more than one retinal phenotype.

Slide 18 · USH2A: Isolated and syndromic disease

Nonsyndromic

Usher spectrum

Retinal phenotype

No established extraocular syndrome

Retinal degeneration

Sensorineural hearing involvement

Slide 19 · RPGR: Reconcile the extracted gene name

The source conversion displays “RGPR” in the four-gene list.

The approved gene symbol is RPGR (retinitis pigmentosa GTPase regulator).

For clinical nomenclature and genetic testing, use verified HGNC/NCBI gene symbols.

Slide 20 · EYS illustrates heterogeneous recessive disease

Inherited retinal phenotype

Molecular heterogeneity

Broad genetic assessment

Schematic

EYS is explicitly listed among genes linked to RP.

The involvement of several genes explains why a single negative-gene test cannot exclude RP.

Comprehensive testing strategies are preferable to arbitrary single-gene exclusion.

Slide 21 · Disease-associated pathways are diverse

Molecular functions

Tissue consequences

Phototransduction

Visual cycle

Cell structure

Reduced function

Photoreceptor attrition

Visual disability

Slide 22 · The central injury is photoreceptor loss

Inherited defect

Cellular dysfunction

Apoptosis

Retinal atrophy

Schematic

Apoptotic death of rods and cones as symptoms develop.

Photoreceptor loss is progressive rather than an isolated episode of vascular occlusion.

Loss of the sensory cell population explains reduced retinal responsiveness.

Slide 23 · Cone loss involves more than rod loss

Rods affected

Cone vulnerability develops

Central function declines

Schematic

RIP kinase activation as one contributor to cone death.

This does not imply that one pathway explains all genes or stages.

Preserved cones can temporarily sustain central vision despite early rod dysfunction.

Slide 24 · Sequence of degeneration maps onto visual deficits

Rods

Peripheral vision

Cones

Central vision

Schematic

Initial rod dysfunction → poor dark adaptation.

Progressive photoreceptor attrition → reduction in peripheral visual field.

Later cone involvement → impairment of central visual acuity.

Slide 25 · Photoreceptor degeneration remodels the retina

Vitreous

Nerve fiber / ganglion

Inner plexiform + nuclear

Outer plexiform + nuclear

Photoreceptors: Rods + cones

Retinal pigment epithelium

Bruch membrane / choroid

Outer retinal photoreceptor injury is the central pathologic event.

Retinal vessel narrowing and pigment redistribution develop as degeneration advances.

Schematic

Slide 26 · Pigment migration explains “pigmentosa”

Perivascular pigment clumps

Vessel attenuation

Optic disc pallor

Schematic retinal fundus: Not a clinical image

Schematic

Slide 27 · Retinal vessel attenuation in established RP

Retinal blood vessels appear constricted/attenuated in advanced retinal degeneration.

Vascular attenuation accompanies retinal atrophy.

It should not be mistaken for the primary initiating vascular event.

Slide 28 · Optic disc “waxy pallor”

An atrophic optic nerve head with waxy pallor.

This finding commonly coexists with vessel narrowing and retinal pigmentation.

Disc pallor is nonspecific in isolation; Interpretation depends on the broader pattern.

Slide 29 · Classical fundus triad

Perivascular pigment clumps

Vessel attenuation

Optic disc pallor

Schematic retinal fundus: Not a clinical image

Schematic

Slide 30 · Early RP may have a normal-appearing fundus

Feature

Early stage

Established stage

Fundus

May be unremarkable

Pigment, vessel and disc changes

Rod function

Often impaired

Markedly reduced

Clinical value

ERG and history

Pattern recognition

Slide 31 · Fundus changes and visual disability are related, not identical

Symptoms

Fundus findings

ERG / field tests

Molecular context

Schematic

Clinical symptoms reflect photoreceptor function, not only fundus appearance.

Peripheral field loss may already impair navigation with relatively preserved central acuity.

Combine structural, functional, and molecular assessment.

Slide 32 · Nyctalopia: The classic initial clue

Intact field (conceptual)

Ring scotoma

Constricted field

Conceptual visual-field schematic

Patients report delayed adaptation after entering dimly lit settings.

Slide 33 · Peripheral visual field loss may go unrecognized

Intact field (conceptual)

Ring scotoma

Constricted field

Conceptual visual-field schematic

Mid-peripheral field defects can precede the patient’s awareness of a field problem.

Slide 34 · A ring scotoma can progress to field constriction

Intact field (conceptual)

Ring scotoma

Constricted field

Conceptual visual-field schematic

An early mid-peripheral ring scotoma may expand with progression.

Slide 35 · Central acuity can initially be preserved

Central visual acuity

Peripheral visual field

May remain preserved

Does not measure field width

Can be markedly constricted

Critical for mobility

Slide 36 · Progression varies across patients

Genotype

Age at onset

Rate of degeneration

Functional outcome

Schematic

Inheritance pattern and causal gene influence observed course.

Autosomal dominant cases with later onset than other patterns.

Do not predict an individual trajectory from inheritance mode alone.

Slide 37 · Clinical evaluation begins with phenotype

Document nyctalopia, peripheral field complaints, and central visual symptoms.

Record onset, symmetry, progression, and family history.

Ask about hearing, neurologic features, renal disease, and systemic manifestations.

Slide 38 · Fundus examination tests a pattern hypothesis

Perivascular pigment clumps

Vessel attenuation

Optic disc pallor

Schematic retinal fundus: Not a clinical image

Schematic

Slide 39 · Electroretinography interrogates photoreceptor function

Dark adapted

Light adapted

Rod-mediated response

Often affected early

Cone-mediated response

May persist longer

Slide 40 · Typical RP is rod-predominant on early ERG

Reduced rod ERG

Additional cone ERG loss

Severe generalized dysfunction

Schematic

Rod responses can be markedly diminished before a distinctive fundus pattern appears.

Cone responses may be less impaired early in rod–cone degeneration.

In late stages, both response types may be severely reduced or nondetectable.

Slide 41 · Visual field testing maps functional impact

Intact field (conceptual)

Ring scotoma

Constricted field

Conceptual visual-field schematic

Perimetry demonstrates peripheral defects or mid-peripheral scotomata.

Slide 42 · Optical coherence tomography localizes layer loss

Vitreous

Nerve fiber / ganglion

Inner plexiform + nuclear

Outer plexiform + nuclear

Photoreceptors: Rods + cones

Retinal pigment epithelium

Bruch membrane / choroid

Outer retinal photoreceptor injury is the central pathologic event.

Retinal vessel narrowing and pigment redistribution develop as degeneration advances.

Schematic

Slide 43 · Fundus autofluorescence adds an RPE-related map

Fundus autofluorescence is among the clinical imaging modalities used in RP assessment.

Pattern abnormalities provide information about RPE-related retinal changes.

Interpret autofluorescence together with OCT and functional testing.

Slide 44 · Genetic testing must match the heterogeneity

Clinical phenotype

Pedigree / counseling

Appropriate panel

Variant interpretation

Schematic

An RP multigene panel is generally more informative than sequencing only one presumed gene.

Exome or genome sequencing may be considered when targeted testing is nondiagnostic.

Variants of uncertain significance do not independently establish disease causation.

Slide 45 · Do not overlook the syndromic phenotype

Isolated phenotype

Syndromic phenotype

Retinal degeneration

No recognized systemic syndrome

Retinal degeneration

Extraocular manifestations

Slide 46 · Usher syndrome links retinal and auditory dysfunction

Robbins explicitly names Usher syndrome as an RP association.

Sensorineural hearing impairment is an important associated clue.

Vestibular abnormalities vary across Usher syndrome types.

Slide 47 · Bardet–Biedl syndrome: Recognize systemic context

Bardet–Biedl syndrome as a syndromic RP example.

Retinal degeneration can accompany a multisystem ciliopathy phenotype.

A careful systemic and family history should prompt specialist evaluation rather than an eye-only interpretation.

Slide 48 · Refsum disease has an actionable metabolic link

Retinal symptoms

Systemic neurologic clues

Metabolic diagnosis

Targeted management

Schematic

Refsum disease is specifically listed among syndromic RP associations.

GeneReviews identifies phytanic acid metabolism as the relevant systemic defect.

Unlike most RP genotypes, this phenotype has an established dietary intervention.

Slide 49 · Red flags that warrant expanded differential diagnosis

Marked asymmetry, atypical onset, prominent inflammation, or prominent central symptoms.

Hearing loss, neuropathy, ataxia, and other systemic findings.

History of drug exposure, autoimmune disease, infection, or trauma.

Slide 50 · RP versus age-related macular degeneration

Feature

Retinitis pigmentosa

Age-related macular degeneration

Typical deficit

Night / peripheral vision

Central macular vision

Principal locus

Photoreceptors / RPE

Macular RPE–Bruch unit

Signature clues

Rod loss, pigmentary triad

Drusen / CNV

Slide 51 · RP versus cone–rod dystrophy

Feature

Rod–cone degeneration

Cone–rod degeneration

Initial dominant deficit

Rods / dark adaptation

Cones / central function

Field pattern

Peripheral constriction

Central abnormalities

ERG

Rod deficit leads

Cone deficit leads

Slide 52 · RP versus retinal vascular disease

Feature

Retinitis pigmentosa

Retinal vaso-occlusive pathology

Onset

Usually gradual / progressive

May be acute

Mechanism

Photoreceptor degeneration

Vascular nonperfusion

Primary structures

Rods / cones / RPE

Retinal circulation

Slide 53 · RP versus inflammatory or toxic mimics

Infectious retinitis, autoimmune retinopathy, drug toxicity, and prior injury can mimic retinal degeneration.

Inflammation or exposure history should prompt consideration of alternative mechanisms.

Neither bone-spicule pigmentation nor night blindness alone specifies a genotype.

Slide 54 · Compare childhood severe-onset retinal dystrophy

Feature

Typical RP

Leber congenital amaurosis

Presentation

Progressive rod–cone loss

Severe early visual dysfunction

Clinical course

Variable onset

Infancy / early childhood

ERG

Rod then cone deficit

Often severely reduced early

Slide 55 · Clinical case: The patient with normal central acuity

An adolescent describes poor dark adaptation and difficulty locating objects to either side.

Central acuity is relatively preserved; Fundus findings are subtle.

Question: Which investigation best tests generalized rod-mediated dysfunction?

Slide 56 · Clinical case: Interpreting the fundus triad

An adult has constricted peripheral fields, narrowed retinal vessels, perivascular pigment and disc pallor.

The findings support a chronic pigmentary retinal degeneration.

Question: Why is vascular narrowing not sufficient to classify the process as vaso-occlusive?

Slide 57 · Clinical case: Syndrome or isolated retinal disease?

A patient with night blindness and progressive retinal degeneration also reports hearing difficulties.

The retinal phenotype should not be classified as nonsyndromic without further assessment.

Question: Which syndromic association is especially important?

Slide 58 · Three integrated diagnostic decisions

Functional localization

Structural localization

Syndrome / molecular diagnosis

Schematic

First: Is the functional pattern rod-predominant, cone-predominant, or another process?

Second: Do structural features support progressive photoreceptor degeneration?

Third: Is the condition syndromic, and what genetic evaluation is justified?

Slide 59 · Take-home clinicopathologic correlations

Inherited photoreceptor/RPE dysfunction produces progressive loss of rods and cones.

Early rod loss explains nyctalopia and peripheral field constriction; Cone loss threatens central acuity.

Pigment clumping, vessel attenuation and optic-disc pallor are characteristic late clues.

Testing integrates function, structure, systemic features, and molecular evidence.

Slide 60 · Selected references

Robbins, Cotran & Kumar: Pathologic Basis of Disease. 11th ed. 2026. Chapter 29: The Eye.

Fahim AT, Daiger SP, Weleber RG. Nonsyndromic Retinitis Pigmentosa Overview. GeneReviews. Updated 2023.

NCBI Gene. RPGR: retinitis pigmentosa GTPase regulator. Gene ID 6103.