Hereditary Retinal Diseases: Diagnosis

Hereditary Retinal Diseases: Differential Diagnosis

• Symmetric retinal signs in both eyes suggest hereditary disease, especially in young patients.

Disease Classification Schemas

• Diseases can be classified as progressive or stationary (present at birth).
• They can also be classified as central (macular) dystrophies or generalized.

Patient History

• Patient history should include questions specific to central scotomas or night blindness.
• Rod injury is often the first sign of night blindness, known as nyctalopia.
• Cone injury at night allows sight in dim conditions but impairs vision in bright light, inferring a macula injury.
• Examine family history for onset, bilaterality, and family history to relate systemic associations.

Electrophysiological Tests

• ERGs are important electrophysiological tests.
• ERGs are affected; it is sometimes the only evidence of a condition.

Visual Electrophysiologic Tests

• Visual electrophysiologic tests are ancillary.
• Electrophysiologic tests are objective measures of function, beyond structural tests.

Full-Field ERG (Electroretinogram)

• Records the summary of transient, mass electrical responses from the entire retina.
• Requires dark adaptation for 30 minutes.
• Does not provide topographical information on 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.
• Multifocal ERG provides data regarding local retinal function.
• Provides topographical retinal function.

Generalized Retinal Dysfunction Detection

• A test to detect generalized retinal dysfunction in patients with unexplained visual loss.
• Diagnoses retinal degenerations, macular dystrophies, CAR, and MAR.
• Signs can mimic other conditions such as pigment on the retina from hereditary degeneration contrasted with pigment from acquired inflammation like RP vs syphilitic retinopathy, both of which can feature pigmentary signs.

EOG (Electro-oculogram)

• Measures the potential that exists between the cornea and Bruch's membrane.
• Measures resting membrane potential.
• The origin of the EOG is the RPE.
• It is an adjunct to the ERG.
• It confirms Best's vitelliform macular dystrophy.

VEP (Visually Evoked Potential)

• The only electrophysiologic test that assesses visual cortex activity.
• Assesses the visual pathway including retina, optic nerve, and brain.
• An impaired VEP is anatomically non-specific unless used in combination with other tests like ERG and EOG.

Autofluorescence (AF)

• Lipofuscin accumulates in the RPE.
• Light blue-green wavelength (488-514 nm) is used.
• Macula is full of xanthophyll; it’s light absorbent so it is always dark in FAF because it can absorb the light.

FAF

• Metabolic activity causes lesion activity which will subsequently expand, creating a hyperfluorescence border.

Retinitis Pigmentosa (RP)

• Indicated by presence of lipofuschin line and hyperfluorescence, showing it will progress.

Inherited Retinal Dystrophies

• Retinitis Pigmentosa (Progressive Rod, Rod/Cone Dystrophy).
• Belongs to the group of pigmentary retinopathies, generic term for retinal dystrophies with photoreceptor and retinal pigment deposit loss.
• Peripheral vision loss, macular function generally preserved until adulthood with primary pathogenic mechanism.

RP Pathogenesis

• Long outer segments of rods contain membrane discs where phototransduction occurs.
• 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.
• Intense mRNA and protein synthesis, along with protein trafficking from rod inner segments through the connecting cilium, supports this process.
• Rods are initially affected, with subsequent degeneration of cones in rod-cone dystrophy at a prevalence of 1:5000.
• Most common hereditary retinal dystrophy.

RP Classification

• Subtypes are described based on the distribution of retinal involvement: central, pericentral, sector, and peripheral.
• Half of RP cases are sporadic/simplex (40-50%), while the other half have a family history.
• Of cases with family history, AD (15-35%) is the second most common and mildest form. AR (60%) is the most severe, and X-linked (5-18%) is the least common but worse and causes severe progression.
• Over 80 genes cause syndromic and non-syndromic RP. RHO (#180380) is the most common in autosomal dominant cases, USH2A (#608400) in autosomal recessive cases, and RPGR (#312610) in X-linked recessive cases.

Mitochondrial Inheritance

• Mitochondrial DNA is inherited from the mother, with defects leading to disorders.
• Presentation is variable due to the complexity of mitochondrial genetics.
• Kearns-Sayre and Usher-Like syndromes are believed to be inherited as mitochondrial genes.
  • Kearns-Sayre patients have RP or MG.
  • Usher-like patients exhibit RP or urine abnormalities.

RP Classification

• Can be classified as syndromic or non-syndromic, clinically speaking; most patients with RP are non-syndromic.
• Classified by photoreceptor involvement (rod, rod/cone) or cone-rod dystrophy (inverse RP) where peripheral vision is good, but the macula is affected.

Usher Syndrome

• Syndromic condition with associated RP, also known as Usher–Hallgren syndrome, retinitis pigmentosa–dysacusis syndrome, or dystrophia–dysacusis syndrome.
• The most common syndromic form which retinitis pigmentosa is associated with neurosensory deafness (14% of all RP cases are Usher syndrome).
• Autosomal recessive ciliopathy; sensorineural hearing loss, retinitis pigmentosa, and vestibular dysfunction are characteristics.
• Type 1: caused by mutations in CDH23, MYO7A, PCDH15, USH1C, and USH1G genes.
  • Profound congenital hearing loss or deafness, severe balance issues, vestibular ataxia, difficulty walking before 18 months.
  • Possible mental health issues.
  • Ophthalmological symptoms before 10 with night blindness, progressive vision loss, nystagmus, keratoconus, and optic atrophy.
• Type 2: mutations in USH2A, GPR98, and DFNB31 genes.
  • Moderate to severe hearing loss, normal balance.
  • Hearing impairment worsens, but individuals can communicate verbally and can benefit from hearing aids.
  • Possible speech issues.
  • Ophthalmological signs usually emerge in late adolescence.
• Type 3: the CLRN1 gene encodes the clarin protein, a crucial component for inner ear and retinal cell development.
  • Mechanisms are not fully understood.
  • Normal hearing is typically followed by progressive hearing loss during adolescence.
  • Ophthalmological symptoms begin in adolescence; by midlife, blind spots appear, possibly resulting in legal blindness which is central visual acuity of 20/200 or worse in the better-seeing eye with the best correction or visual field restriction.

Bassen-Kornzweig Syndrome (Abetalipoproteinemia)

• Caused by pathogenic variants in the MTTP gene, crucial for the assembly of lipoproteins.
• MTTP gene's Mutations lead to abetalipoproteinemia, which disrupts fat and vitamin absorption.
• Autosomal recessive inheritance.
• Systemic symptoms: diarrhea, vomiting, steatorrhea, delayed growth, and impaired bone development, typically in the first year or early childhood.
• Later onset may include balance difficulties, muscle weakness, progressive ataxia, peripheral neuropathy, slurred speech, cardiomyopathy, and liver complications.
• Ophthalmological signs include vision difficulties in low-light conditions, constricted visual field, pigmentary retinopathy resembling retinitis punctata albescens with angioid streaks, nystagmus, anisocoria, ptosis, ophthalmoplegia, and cataracts.

Refsum Disease

• Classic Refsum Disease characterized by phytanic acid accumulation in the body.
• Mutations in the gene responsible for phytanoyl-CoA hydroxylase (PAHX or PHYH) or the gene that encodes peroxin-7 (PEX7).
• PHYH and PAHX genes are crucial for alpha-oxidation of branched-chain fatty acids; mutations lead to elevated phytanic acid.
• Autosomal recessive inheritance.
• Systemic symptoms: anosmia, deafness, and various skin abnormalities.
• Ophthalmological sign: retinitis pigmentosa.

Infantile Refsum Disease

• Caused by mutations in PEX1, PEX2, PEX26, PHYH, or PEX7 genes.
• Is the least severe form of Zellweger spectrum disorder, and is fatal.
• Autosomal recessive.
• Systemic signs: ataxia, polyneuropathy, hypotonia, mild facial dysmorphism, and cardiomyopathy.
• Additional Systemic symptoms: anosmia, sensorineural hearing loss, growth retardation, and rare epidermal abnormalities.
• Ophthalmological signs start in infancy with retinitis pigmentosa.

Laurence-Moon Syndrome

• AKA Laurence–Moon–Biedl syndrome
• Characterized by six signs: obesity, atypical retinitis pigmentosa, mental deficiency, genital dystrophy, polydactylism and familial occurrence. Associated anomalies such as genu valgum, coxa vara, scoliosis, shortness of the hands and feet, dwarfism, deformities of the skull, deafness, strabismus, nystagmus, and congenital heart disease.

Bardet-Biedl Syndrome

Neuronal Ceroid Lipofuscinosis (Batten Disease)

• Also known as amaurotic idiocy, which involves a protein encoded by the CLN3 gene, found in lysosomes and synapses.
• Predominantly autosomal recessive inheritance, but autosomal dominant forms exist.
• Four distinct forms based on onset age.
• The infantile form (Santavouri–Haltia disease) presents with symptoms around 6 to 8 months.
• The late infantile form (Jansky–Bielschowsky disease) starts between 2 and 4 years, with ataxia and mental retardation, and death typically occurring between 8 and 12.
• The juvenile form (Batten disease, Spielmeyer–Vogt disease) appears between 5 and 8 years as progressive vision loss, seizures, and mental retardation making it the most frequent form.
• The adult form (Kufs disease) begins before 30 to 40 years, and is milder - systemic symptoms: mental retardation, seizures, ataxia, and acute spasms.
• Ophthalmological signs begin with macular involvement (cherry-red spots), progressive degeneration to the periphery, and retinal dystrophy/blindness which usually results in death between 10 and 15 years.

Alström Disease

• Also as Alström syndrome with retinitis pigmentosa–deafness–obesity–diabetes mellitus, Hallgren–Alström syndrome, retino-otodiabetic syndrome, or Alström–Hallgren syndrome.
• Resembles Bardet–Biedl syndrome (BBS); but Alström syndrome lacks polydactyly, hypogenitalism, and intellectual disabilities.
• Diagnostic criteria includes hearing loss, obesity, diabetes mellitus (DM), acanthosis nigricans, and retinitis pigmentosa (RP).
• Caused by mutations in the ALMS1 gene, on chromosome 2 (2p13) with autosomal recessive Inheritance.
• Systemic symptoms commonly include hearing loss/deafness.
• Cardiovascular conditions are often observed; also obesity and type 2 diabetes mellitus (T2DM with insulin resistance).
• Less commonly reported systemic findings include acanthosis nigricans, gout, hypothyroidism, kyphoscoliosis, and chronic nephropathy.
• Ophthalmological signs are often nystagmus, photophobia, and divergent strabismus.
• Retinal changes (cone-rod dystrophy) progresses to vision loss/blindness

Kearns-Sayre Syndrome

• Also known as Kearns-Sayre mitochondrial ciliopathy or oculocranio-somatic syndrome.
• Most often caused by sporadic deletions in mitochondrial DNA.
• Point mutations within mtDNA (including tRNA genes) or in nuclear genes (mitochondrial DNA maintenance, such as RRM2B).
• Mitochondrial or autosomal recessive Inheritance.
• Systemic symptoms are sensorineural deafness, cerebellar ataxia, dysarthria, bilateral facial weakness, skeletal muscle myopathy, intellectual disability, gastrointestinal disorders, cardiomyopathy, cardiac conduction defects, heart block, endocrine issues, delayed puberty, and hypoparathyroidism.
• Ophthalmological signs progressive external ophthalmoplegia, ptosis, night blindness, pigmentary retinopathy (salt-and-pepper retinopathy with diffuse stippled areas of retinal pigment epithelium hypopigmentation, and peripapillary epithelial atrophy).

RP Clinical Features

• Bilateral involvement.
• Presentation often during first to 2-3 decade, AR presents in early adolescence and AD presents late with 20s-30s.
• 75% of patients show symptoms by age 30 (Japanese Study shows average 35).
• Deterioration predominantly affects rod function.
• Visual field loss is progressive, with mid-peripheral to ring scotomas and central vision lost at the end.

VA in RP

• Typical rod-cone RP is associated with good central vision usually preserved in later stages.
• Patients with adRP are more likely to retain good VA beyond 60, while XLRP patients are usually legally blind (20/200 or worse) younger.
• Atypical RP, like inverse RP, can have earlier central visual impairment and other associations (CME, cataracts, ERM).

RP Fundus Findings

• Requirement for bilateral presentation to be termed RP: bone spicules.
• Additional fundus findings: arteriolar narrowing, attenuated vessels, and a waxy pallor of the optic nerve and in the initial stages, there may be an absence of any visible funduscopic changes with the only diagnostic sign being an abnormal electroretinogram (ERG).

RP Symptoms

• Earliest possible signs/symptoms include is nyctalopia and night blindness and dark adaptation difficulties.
• Other symptoms include loss of peripheral, reduced central vision at later stages, and at the end, there will be photopsias, CV, and Photophobia.
• RP Triad that consists of: bone-spicule pigmentation, attenuation vessel, disc pallor, and waxy.
• RP can be divided into: retinitis pigmentosa inversus, retinitis pigmentosa sine pigmento, retinitis punctata albescens, sector retinitis pigmentosa, and also when signs mimic each other.

Common RP Signs

• Retinitis pigmentosa Inversus with : macula and posterior pole being affected and confused with hereditary macular disorders.
• Retinitis pigmentosa sine pigmento with patients with symptoms of RP who fail to show pigmentary fundus changes, and can be seen in 20% with more pronounced cone dysfunction. Retinitis punctata albescens has multiple, punctate white spots and is scattered in the midperiphery with attenuated vessels and bone spicules while in the sector retinitis pigmentosa, pigmentary changes are limited to one retinal area that generally will not enlarge; usually inferonasal quadrant.

Clumping Associated with the Vessel Thinning

• Clumping and vessel thinning are associated with the fact the retina remodels, migration of pigment due to with atrophic retina.
• ONH waxy because of ganglion atrophy, increased vascularity and other signs are open-angle glaucoma, ONH-drusen (stagnated axoplasmic) and Vitreous pigment cells.
• Cytomaculaoedema: Break in blood-retinal barrier and fluid that is formed, is increases with age and is present also in those whom are myopic.
• Testing for RP include ERG, OCT, FA, FAF and VF's. Abnormal ERG findings may be seen the absence of fundus and will show reduction of amplitude with a prolonged implicit time as well as cone function.
• Additional ERG findings in this can show slow responses with affected cones and abnormal EOG or mfERG.

Retinitis Pigmentosa (RP) Treatment

• Can test for gene markers
• Therapies may be Vitamin A Palmitate, testing should be perform prior to avoid Vitamin A with specific genetic defects or to prevent toxicities, Ocular includes Voretigene neparvovec for biallelic RPE65 mutations which targets remaining cells and is implanted into the subretinal space corrected to refractive errors with blue-light screen filters and UV protected sunglasses co-managing with family doctors while there are surgical options to restore eye sight. Important to beware of imposters like Syphilis, or Rubella while RPE hyperplasia can have retino-choroidal atrophy.
• Retinitis Punctate Albescens an AR primarily with a mutation in RLBP1 and can have Clinical trials in RPE65 or LRAT conditions to restore visual function with some improvement and or slowing disease.

Differentiating RP

• Congenital Stationary Night Blindness (CSNB) is AD, AR, or X-linked disorder affecting infants.
• Can be differentiated from from Fundus Albipunctatus being a stationary form congenital stationary night blindness.
• W/ retina signs the condition can have can also be a 1. Oguchi’s disease from a case study where there are Macular retinoschisis, ESCS and Golder Favre syndrome with unique ERG results.

Cone Dystrophies

• Are inherited and usually caused by cone photoreceptor or post-receptors conditions, Photophobia, Reduced VA and a color vision are the major markers associated with cone dystrophy. Rod monochromatism (stationary congenital cone dystrophy, complete achromatopsia)Is the most common while additional testing should be perform to ensure these are isolated defects.
• Testing will show normal fundus and steeping or pigmentation and it is also not recommended to used strong light as with these patients tinted glasses are more helpful in preserving sight.

Progressive Macular Dystrophies

• Progressive Cone Dystophy (PCD) are progressive conditions linked to genetics and central vision decrease out of propotion of VA but can be detected with additional methods and testing.
• StarGardt’s Disease is one of the progressive conditions described where patients can show Lipofuscin abnormalities and will need genetic test to distinguish from another diseases.

Degenerative Macula Conditions

• Many are rare genetic conditions in the macula/ retina responsible for central vision. Best Vitelliform Dystrophy (BVD) is such condition that can be monitored through multiple stages but must be ruled out from other similar diseases.