Retinal Dystrophies

Etiology

Rods and cone photoreceptors are the central cellular units responsible for visual phototransduction.[5] Phototransduction is a process by which light signals are converted into action potentials within the retina, facilitating the brain's image perception. During this process, light-sensitive pigments are generated and recycled. Etiologies of retinal dystrophies include abnormalities in photoreceptors and defects in phototransduction.

Depending on the type of photoreceptors affected, retinal dystrophies can be subdivided into rod-dominated diseases, cone-dominated diseases, and generalized forms involving both rods and cones. Cases may be syndromic, nonsyndromic, sporadic, or familial. In familial cases, inheritance patterns could be autosomal dominant, autosomal recessive, or X-linked. Syndromic cases have clinical features that extend to multisystemic involvement rather than nonsyndromic varieties, which affect only the retina.[6]

The Iowa classification of IRD has 3 clinical types.[7] The photoreceptor disease type is the most common (64.7%). Retinitis pigmentosa is the major disease in this category. The second type is macular diseases, which include autosomal recessive Stargardt disease, pattern dystrophy, and Best disease.[8] The last type is "third branch disease," which includes other IRDs, including retinoschisis, optic neuropathy, and choroidopathies, such as gyrate atrophy of the choroid and retina.[7][9] Approximately 90% of patients with retinal dystrophies receive one of the following diagnoses, also called the "Big 14" according to the Iowa classification:[7] 

• Photoreceptor disease
  • Isolated
    • Acquired or progressive
      • Retinitis pigmentosa [10]
      • Cone and cone-rod dystrophy
    • Congenital/stationary
      • Leber congenital amaurosis (LCA)
      • Severe early childhood onset retinal dystrophy (SECORD)
      • Early childhood onset retinal dystrophy (ECORD)
      • Achromatopsia [7] 
  • Syndromic
    • Usher syndrome
    • Bardet-Biedl syndrome [11]
• Macular Diseases
  • Autosomal recessive Stargardt disease
  • Best disease
  • Pattern dystrophy [12][7]
• Third Branch Disorders
  • Choroideremia
  • X-linked retinoschisis (XLRS)
  • Dominant optic atrophy [7] 

Epidemiology

The exact incidence of retinal dystrophies is unknown; the most common retinal dystrophy, retinitis pigmentosa, affects around 1 in 5000 individuals worldwide.[13] Other dystrophies, such as achromatopsia, are rarer, with an incidence of 1:30000.[14] Most of these dystrophies affect children and working-age young adults, adding to the socioeconomic burden.

The most commonly mutated genes that cause retinal dystrophies include:

• ABCA4: The most common gene associated with IRDs, accounting for around 12.9% of cases
• USH2A: The second most common gene, accounting for around 6.8% of cases
• RPGR: The third most common gene, accounting for around 2.7% of cases [15][16]

Other genes causing retinal dystrophies include EYS, RHO, PRPH2, BEST1, RS1, RP1, CHM, CRB1, PRPF31, MY07A, and OPA1.[16] The so-called "North Carolina macular dystrophy" appears to be a misnomer as it has been reported worldwide, including in other parts of the United States, the United Kingdom, Europe, Australia, China, and Turkey.[17][18][19] The Island of the Colorblind is the nickname of Pingelap, a Micronesian atoll in the South Pacific.[20] Some families within that area have complete achromatopsia (ie, rod monochromacy or Pingelapese blindness).[14]

Pathophysiology

Mutations in various genes cause retinal dystrophies. These mutations can be inherited in an autosomal dominant, autosomal recessive, X-linked, or mitochondrial manner. The specific gene mutations determine the type of IRD, such as retinitis pigmentosa, Leber congenital amaurosis, or Stargardt disease.

The primary pathology in retinal dystrophies involves the dysfunction and death of photoreceptor cells (rods and cones) and the retinal pigment epithelium (RPE), including:

• Protein misfolding and aggregation: Mutations often produce misfolded proteins that aggregate within retinal cells, causing cellular stress and apoptosis.
• Defective phototransduction: Mutations in genes involved in the phototransduction cascade can impair light conversion into electrical signals, leading to photoreceptor cell death.
• Oxidative stress: Accumulating reactive oxygen species due to mitochondria dysfunction or impaired antioxidant defenses contributes to cellular damage and apoptosis.
• Inflammation: Chronic inflammation and microglia activation in the retina can exacerbate photoreceptor degeneration.
• Impaired retinal metabolism: Mutations affecting metabolic pathways in the retina can lead to energy deficits and cell death.[21]

Dysfunction of photoreceptors' outer segment is an important aspect of retinal dystrophies.[22][21] The crucial functions of these affected outer segments in various retinal dystrophies include:

• Phototransduction: The mutations affecting phototransduction may involve multiple genes, including rhodopsin (RHO), PDE6, and cyclic nucleotide-gated (CNG) channels.[23]
• Disc morphogenesis: A crucial gene for disc morphogenesis includes PRPH2.[24]
• Ciliary formation or trafficking: Major genes controlling cilia formation include USH2A (affected in Usher syndrome), RPGR, CEP290, and BBS1-22 (affected in Bardet-Biedl syndrome). The syndromes associated with ciliopathy and retinal dystrophies include Usher, Bardet-Biedl, Joubert, Senior–Løken, and Alstrom syndromes.[25][26][21]

Dysfunctions of RPE can affect the visual cycle, phagocytosis with a resultant turnover of photoreceptor outer segments, lipid homeostasis, ionic regulation, and pigment formation.[27] The most important genes affecting these include ABCA4, causing Stargardt disease, and VMD2, which encodes BEST1 or bestrophin; VMD2 mutations cause Best disease.[28][8] Affection of development, homeostasis, retina metabolism, and choroid can also cause retinal dystrophies.[21] The other changes involved in retinal dystrophies include cell adhesion, changes in the basement membrane and extracellular matrix, energy metabolism of the retina and RPE, peroxisome activity, autophagy, iron regulation, cell signaling, leucocyte activation, and activation of proinflammatory pathways.[21]

Histopathology

 The anatomical areas involved in respective types of retinal dystrophy include:

• Photoreceptor disease: cones and rods
• Macular disease: the area between photoreceptors and retinal pigment epithelium (RPE)
• Third branch disease: superficial retina or deeper choroid, depending on the disease [7] 

Retinitis pigmentosa is characterized histopathologically by progressive degeneration of the retinal photoreceptors, especially the rods, followed by cones.[29] The rods die due to various mutations and mechanisms, including apoptosis.[30] After the death of rod cells, there is a high oxygen level in the outer retina, and the remaining cones undergo progressive oxidative damage.[30] This is accompanied by reactive gliosis, loss of outer retinal layers, and migration of pigment-laden cells from the RPE and macrophages into the neural retina, especially around vessels.[31] The common findings are progressive thinning of the retinal layers, especially the outer nuclear layer, and eventual atrophy of the RPE and choriocapillaris.[32] In advanced stages, optic nerve head pallor and vascular attenuation become pronounced.[31] Please see StatPearls' companion resource "Retinitis Pigmentosa," for further information.

Cone dystrophy is histopathologically marked by selective degeneration of cone photoreceptors, initially affecting the central macula, with sparing of rod photoreceptors until later stages. This leads to thinning of the outer nuclear layer, loss of cone outer segments, and progressive atrophy of the retinal pigment epithelium (RPE), primarily in the macular region.[33] In cone-rod dystrophy, cones are affected first, followed by the involvement of the rods later, which is opposite to retinitis pigmentosa (ie, rod-cone dystrophy).[34] Macula and visual acuity are involved early in cone-rod dystrophy.[34]

Stargardt disease is histopathologically marked by lipofuscin accumulation within the RPE due to dysfunctional ABCA4 gene expression. This impairs the clearance of vitamin A and its metabolic byproducts. This leads to progressive degeneration of the RPE and secondary photoreceptor loss, particularly in the macular region. Histologic examination reveals atrophy of the outer retinal layers, including the photoreceptor outer segments. Cones are more severely damaged than rods.[35] Müller cells may show reactive hypertrophy.[36] The appearance of yellowish, pisciform flecks in ophthalmoscopy is due to abnormal lipofuscin deposits. Over time, the macular region with geographic atrophy of the RPE and choriocapillaris has profound thinning (see Image. Stargardt Disease).[8] Please see StatPearls' companion reference, "Stargardt Disease," for further information.

Best disease, or Best vitelliform macular dystrophy, is characterized histopathologically by the accumulation of lipofuscin-like material within the RPE, leading to the formation of the characteristic vitelliform lesion.[37] This material disrupts normal RPE function, resulting in the degeneration of the overlying photoreceptors over time, particularly in the macula.[38] However, these patients usually have good vision despite the prominent fundus appearance. As the disease progresses, the vitelliform material can rupture, leading to a pseudohypopyon stage, followed by atrophy of the RPE and outer retinal layers, resulting in fibrosis and choroidal neovascularization in advanced stages. Histologic findings in the late stage include RPE thinning, loss of photoreceptor outer segments, and subretinal fibrosis.[28] The histopathology of other dystrophies varies. Please see StatPearls' companion reference, "Best Disease," for further information.

History and Physical

The functions of rods include scotopic vision (night vision or low-light vision) and peripheral vision. Rod dysfunction results in night blindness (nyctalopia), delayed dark adaptation, and peripheral visual field constriction. Cone dysfunction results in poor central vision, central scotoma, color blindness, photophobia, nystagmus, and day blindness (hemeralopia).[39]

The primary clinical history that should be obtained, according to the University of Iowa Inherited Eye Disease history form, from a suspected patient with retinal dystrophies includes:

• Patient age at symptom onset
• Initial symptoms
• Initial diagnosis
• Previous diagnoses [7]
• Syndromic features: Usher syndrome is characterized by retinitis pigmentosa, hearing loss, and balance abnormality; Bardet-Biedl syndrome is associated with retinitis pigmentosa, polydactyly, short height, obesity, hypogonadism, and renal involvement.
• Use of long-term medications that can impact vision or the eye: Long-term use of drugs, including thioridazine, can cause a retinitis pigmentosa-like fundus picture. Chloroquine and hydroxychloroquine may cause bull's eye maculopathy and simulate cone dystrophy. Pentosan polysulfate can cause macular changes similar to Stargardt disease. However, the lesions usually do not spare the area around the optic disc.[40] Didanosine can cause fundus appearance similar to gyrate atrophy of the retina and retinal pigment epithelium.[41]
• Any history of cancer or autoimmune disease: Autoimmune retinopathy (AIR) may cause recent-onset nyctalopia in adults or older individuals. AIR may be paraneoplastic or nonparaneoplastic. Paraneoplastic AIR includes cancer-associated retinopathy (CAR), melanoma-associated retinopathy (MAR), bilateral diffuse uveal melanocytic proliferation (BDUMP), and paraneoplastic optic neuropathy (PON).[42]
• Any relevant family history: The family history helps create a pedigree chart that gives insight into the inheritance pattern.
• History of driving: Patients with retinitis pigmentosa may have a constricted visual field, though their central vision may be excellent. Due to the constricted visual field, the patient may not meet the minimum requirement for driving in various countries.
• Refraction of both eyes: Usually, retinal dystrophies, including retinitis pigmentosa, cone-rod dystrophy, gyrate atrophy of the retina, and RPE, are associated with myopia. Hyperopia is noted in retinal dystrophies, including Leber congenital amaurosis and Best disease.[28]
• Color vision test: Color vision is affected by cone dysfunction.

Additionally, to differentiate between rod-selective or cone-selective diseases, specific clinical features support the correct diagnosis, including:

• The clinical triad of cone dysfunction includes photo-dysphoria, dyschromatopsia, and poor central vision with or without nystagmus. Fundus findings of cone dystrophy affect the fovea and macula first, and the optic disc and retinal vessels are usually unremarkable. Also, bony spicule pigmentation at the mid-peripheral fundus is not seen in typical cone dysfunction.
• Rod dysfunction is characterized by poor dark adaptation, poor vision at night (nyctalopia), and loss of peripheral vision. On the fundus, the rod dysfunction causes attenuation of retinal arteries, optic disc pallor, and bony spicule pigmentation starting at the mid-periphery of the fundus.
• Preference for a too-dark (cone dystrophy) or a too-bright room (rod dystrophy)
• Difficulty in a movie theatre or similar dim environments (rod dysfunction)
• Ability to see the general outlines of objects under ambient lighting conditions (eg, after waking up at night and in the presence of night lights)
• Disorientation at night during a camping trip, when others can find their way easily (rod dysfunction)
• Avoidance of bright light or being uncomfortable on a sunny day (cone dystrophy)
• Worse color vision than that of peers (cone dystrophy) [7]

Photoreceptor Diseases

Rod dystrophies

Rod-dominated dystrophies include rod and rod-cone dystrophies, in which rod photoreceptors are predominantly or the first affected. These include retinitis pigmentosa and congenital stational night blindness (CSNB).

Retinitis pigmentosa

Retinitis pigmentosa is the most commonly seen retinal dystrophy. The prevalence is around 1 in 5000.[10] Retinitis pigmentosa is a progressive rod-cone disease with rods affected first and has a high level of clinical and genetic heterogeneity. The age of presentation and the prognosis depends on the type of inheritance. Like other forms of retinal dystrophies, it may be sporadic or inherited in an autosomal dominant (AD), autosomal recessive (AR), or X-linked recessive (XLR) pattern. AD is the least severe form, and XLR is the most severe. Nonsyndromic and syndromic forms are reported. The most common genes associated with retinitis pigmentosa include:

• RHO in autosomal dominant cases
• USH2A in autosomal recessive cases
• RPGR in X-linked recessive cases [43]

Nyctalopia is a constant feature, although it is not pathognomic of retinitis pigmentosa. Most cases do not report night vision problems until the ocular disease is advanced. Patients also notice an insidious progressive loss of peripheral field of vision. In most cases, the inferior retina is affected first, denoting light exposure's possible role. Hence, superior field losses are seen early. Visual field loss and night vision problems make these patients prone to accidents, especially at night. In typical retinitis pigmentosa, the rate of progression of visual field loss is usually slow. Usually, the patient does not notice these changes until it reaches the stage of tunnel vision when the patient becomes acutely aware of the changes. Central vision can be affected earlier due to secondary changes, including cystoid macular edema, epiretinal membrane, vitreomacula traction, macular hole, or the development of RPE defects in the macular or fovea.[44] In most cases, color vision remains unaffected until the later stages of the disease.

Fundus appearance of retinitis pigmentosa classically includes a triad of retinal vessel attenuation, waxy pallor of the optic disc, and bone spicule intraretinal pigmentation (see Image. Retinitis Pigmentosa). Patients with very early retinitis pigmentosa without fundus pigmentary abnormalities are termed retinitis pigmentosa sine pigmento. However, this is no longer considered a subtype of retinitis pigmentosa as it is a stage of retinitis pigmentosa in some patients.[45] Such patients who do not show typical bony spicule pigments usually show changes in fundus autofluorescence and visual field changes.[46] Fine dust-like pigment cells are noted in the vitreous cavity released from the degeneration of RPE.

Phenotypic variants based on retinal involvement are sectoral retinitis pigmentosa, pericentral retinitis pigmentosa, and unilateral or extremely asymmetric retinitis pigmentosa. Sectoral retinitis pigmentosa is characterized by pigmentary changes limited to 1 or 2 quadrants with limited visual field changes, good electroretinogram (ERG) responses, and minimal progression with time. Sector retinitis pigmentosa can be autosomal dominant or recessive. Sporadic cases are common and may result from nongenetic causes of retinal degeneration. The pericentral variant shows field loss between 5 and 15 degrees from fixation. The areas of field deficit enlarge and coalesce over time, causing early encroachment on the central field of vision and more significant disability. Unilateral retinitis pigmentosa is typically an acquired condition with diffuse unilateral subacute neuroretinitis (DUSN) as an important differential diagnosis. However, unilateral retinitis pigmentosa may have a genetic association.[47]

Congenital stationary night blindness

CSNB is a nonprogressive form of night blindness that has been present since birth. Various inheritance patterns, including autosomal dominant, autosomal recessive, and X-linked, are now recognized. The mutations usually cause defects in the phototransduction or postphototransduction transmission. CSNB is further subcategorized as CSNB with normal fundus and CSNB with abnormal fundus. Cases of CSNB with normal fundus present may be inherited in autosomal recessive, autosomal dominant, and X-linked recessive modes.

CSNB with abnormal fundi includes 2 entities: Oguchi disease and fundus albipunctatus. In Oguchi disease, the Mizuo-Nakamura phenomenon is classically observed.[48] In this variant, a golden sheen over the retina is noted, and an unusually dark fovea is observed when exposed to light. However, the retina appears normal after prolonged dark adaptation. Color vision and visual acuity are standard in these cases. Histopathological studies suggest the presence of an abnormal layer between the outer segments of photoreceptors and RPE.[49] Fundus albipunctatus is another type of CSNB with yellow-white dots over the fundus. In most cases, these dots are found incidentally on routine eye checkups. Genes involved in fundus albipunctatus include RDH5 and RLBP1.[50]

Cone disorders

Cone-dominated diseases can be further subdivided into early-onset forms with no progression and late-onset forms that are usually progressive. The progressive forms include cone-dominated dystrophies and cone dystrophies. The stationary forms include achromatopsia and blue cone monochromatism.

Achromatopsia

Achromatopsia is an autosomal recessive condition in which patients present with poor visual acuity, photosensitivity, and poor color discrimination since birth. Photosensitivity is due to poor visual acuity in bright lights instead of light intolerance. Photosensitivity is subtyped as complete and incomplete achromatopsia.[14] Cases with complete or total achromatopsia (see Table. Comparison of Rod Monochromatism and Blue-Cone Monochromatism), also known as rod monochromats, usually have visual acuity of less than 20/200.

Incomplete or atypical forms retain a visual acuity between 20/60 and 20/200. Color vision is completely absent in complete achromatopsia cases. Nystagmus may be present from 2 to 3 months of age but usually improves with time. Photophobia also improves with time. Fundus examination is generally normal in these cases; however, some cases may have a granular appearance of the macula or temporal optic disc pallor. Visual field testing may reveal central scotoma; peripheral fields are usually normal or mildly constricted. Characteristically, these are nonprogressive changes.

Cone monochromatism

Cone monochromatism is an X-linked recessive congenital disorder where 2 of the 3 cone systems are absent or significantly affected. The most common variety is blue cone monochromatism, in which both red and green cone systems are absent. Visual acuity in affected individuals ranges from 20/60 to 20/200. Clinical signs and symptoms resemble achromatopsia cases. Typically, patients can perceive blue color.[51] 

 Table. Comparison of Rod Monochromatism and Blue-Cone Monochromatism

Cone-rod dystrophy

Cone-rod dystrophy (CRD) is usually misdiagnosed as retinitis pigmentosa with more involvement of cones than rods. Patients present with early loss of vision and color vision abnormalities due to cone dysfunction with subsequent peripheral field constriction due to rod dysfunction. The fundus examination reveals macular pigmentation and atrophy in the early stages, followed by peripheral bone spicule pigmentation in advanced cases. Often, mid-periphery is affected later in the course of the disease. The diagnosis of CRD is essentially based on ERG changes, which show cone affliction more than rods.

Generalized retinal dystrophies

This category of photoreceptor diseases includes disorders like LCA. LCA is a group of disorders due to a mutation in at least 17 genes, all presenting with severe visual impairment or blindness from infancy and extinguished ERG (dysfunction of both rods and cones). Nystagmus is usually present, and the onset is before 4th birthday. Most patients show either a normal fundus appearance or subtle RPE changes and retinal vascular attenuation. Most patients have hyperopia. Eye rubbing, also known as the oculo-digital sign, is a common association. Keratoconus is seen in 29% of cases.[59][60] Enophthalmos may be noted due to the atrophy of orbital fat as a consequence of eye rubbing, as well as other genetic factors. Complicated cases have systemic features. Cases of deafness, renal anomalies, hepatic dysfunction, and skeletal abnormalities have been reported. The most common inheritance pattern is autosomal recessive. Patients with RPE65 or CRB1 gene mutations have progressive vision loss with age, with a slightly better prognosis in those with onset after infancy.[61] Clinically, the LCA spectrum has been subdivided into the following descriptive terms according to some authors:

• No educationally useful vision (eg, LCA); CEP290 is the most common gene involved.
• Educationally useful vision initially, but legally blind due to poor central vision or constricted visual field before the tenth birthday (eg, SECORD).
• Not legally blind at 10 years of age (eg, ECORD) [7]

Syndromic photoreceptor disease

Usher and Bardet-Biedl syndrome are the most common syndromes associated with photoreceptor disease. Usher syndrome, or Hallgren syndrome, is a rare genetic condition characterized by progressive vision and hearing loss. Usher syndrome has been classified into 3 major subtypes: I, II, and III, according to the genes responsible and the onset and severity of the signs and symptoms. Usher syndrome type I is the most severe subtype, characterized by marked congenital hearing loss, retinitis pigmentosa, and absent vestibular function. Usher syndrome type II is less severe. Patients with this subtype have moderate-to-severe congenital hearing loss, retinitis pigmentosa, and normal vestibular function. Usher syndrome type III involves progressive hearing loss, retinitis pigmentosa, and varying degrees of vestibular dysfunction. Onset for type III is typically within the second to fourth decades of life. These patients also tend to have better vision than the other subtypes. 

The most common genes associated with Usher syndrome include:

• MYO7A in type 1, accounting for more than 50% of cases
• USH2A in type 2, accounting for approximately 80% of cases
• CLRN1 in type 3, the most common gene associated with this type of Usher syndrome [62]

Bardet-Biedl syndrome (BBS) is a rare, autosomal recessive genetic disorder that can lead to dysfunction of multiple organ systems, including the kidneys, genitalia, brain, and eye. BBS is caused by pathogenic mutations in genes encoding proteins involved in the function of nonmotile primary cilia. The most commonly mutated gene is BBS1 (23% of cases), followed by BBS10 (15%) and BBS2 (10%)^. Fundus examination typically shows pigmentary degeneration with early macular atrophy and vascular attenuation. Pigmentary changes are seen (see Image. Pigmentary Retinopathy). A majority of patients also exhibit early obesity, polydactyly, and intellectual impairment.[11]

Macular Diseases

Stargardt disease

Stargardt disease, or fundus flafvimaculatus, is the most common childhood recessively inherited macular dystrophy. The condition has a genetic basis due to mutations in the ABCA4 gene on chromosome 1. This results in accumulating visual cycle kinetics-derived byproducts in the RPE with secondary photoreceptor dysfunction and death. Stargardt patients may be asymptomatic but most commonly present with bilateral central visual loss, photophobia, color vision abnormalities, central scotomas, and slow dark adaptation. The fundus may appear normal, considering the severity of vision loss. The fundus features include vermillion fundus, macular atrophy, beaten bronze or metallic sheen at the fovea, and pisciform subretinal flecks at the posterior pole surrounding the fovea and the optic disc typically sparing the peripapillary region (see Image. Stargardt Disease).[8] Fluorescein angiography usually shows dark choroid.[63] Mutation of the ABCA4 gene can cause multiple phenotypes.

Best disease

Best disease (best vitelliform macular dystrophy) is a rare autosomal dominant disorder due to BEST1 (or VMD2, bestrophin-1, or TU15B) gene mutation with incomplete penetrance and variable expression. Yellow vitelliform material is seen subretinally.[28] Typically, an egg yolk-like subretinal lesion is noted at the macula of both eyes with good vision (see Image. Imaging in Best Disease).[64] Electrooculogram is typically affected with the Arden ratio of less than 1.5. Mutation of the VMD2 gene can cause various phenotypes, including:

• Best vitelliform macular dystrophy
• Autosomal recessive dystrophinopathy
• Retinitis pigmentosa-50
• Retinitis pigmentosa (concentric)
• Vitreoretinochoroidopathy

Pattern dystrophies

Pattern dystrophies are a group of autosomal dominant macular diseases characterized by various patterns of pigment deposition within the macula. However, most cases of adult-onset vitelliform macular dystrophy are sporadic.[65] The primary layer of the retina affected is the RPE. RPE is responsible for removing and recycling waste within the retina. In various pattern dystrophies, this waste accumulates in the form of lipofuscin. These findings were initially attributed to mutations in the PRPH2 gene (also known as RDS), which provides instructions for making a protein called peripherin-2. Other genes include ABCA4, VMD2, and IMPG1. Considerable genetic and phenotypic heterogeneity can be present.[66] Based on the pattern of the pigment distribution, they have been classified as: 

• Adult-onset foveomacular vitelliform dystrophy or adult-onset vitelliform macular dystrophy
• Sjögren reticular pigment epithelial dystrophy
• Butterfly-shaped pigment dystrophy
• Multifocal pattern dystrophy simulating Stargardt disease
• Fundus pulverulentus, pattern dystrophy appearance may transform into another type of pattern dystrophy with time [67]

Third Branch Disorders

Choroideremia

Choroideremia is an X-linked chorioretinal dystrophy characterized by the diffuse, progressive degeneration of the RPE, photoreceptors, and choriocapillaris. A mutation in the CHM gene causes it. On fundus examination, the earliest manifestation is widespread pigment clumping at the level of the RPE, which is distinct from the characteristic perivascular bone-spicule pigment clumping seen in retinitis pigmentosa. Subsequently, patients develop well-defined regions of atrophy with visible underlying sclera and large choroidal vessels, most commonly in the postequatorial region just outside the vascular arcades. Typically, the fovea is not involved or affected very late. Some cases may clinically simulate the gyrate atrophy of the retina and retinal pigment epithelium.[68] 

X-linked juvenile retinoschisis

X-linked juvenile retinoschisis is a rare congenital disease of the retina caused by mutations in the RS1 gene, which encodes retinoschisis. On fundoscopic examination, 98-100% of patients have foveal schisis, noted as a spoke wheel pattern radiating from the fovea. Subretinal linear fibrosis, pigmentation, white retinal flecks, vascular attenuation, and vascular sheathing may also be present. Peripheral retinoschisis is seen in around half of the patients. The intraretinal split is thought to be at the nerve fiber layer, as seen in the ophthalmoscope.[69]

Autosomal dominant optic atrophy

Autosomal dominant optic atrophy is commonly associated with mutations in the OPA1 gene located on chromosome 3q28-q29. Optic disc atrophy typically shows focal, wedged-shaped temporal optic atrophy. However, diffuse atrophy may be present.[70]

Evaluation

Fundus Photo and Ultrawide Field Fundus Imaging

Color fundus photos and ultrawide field fundus imaging are important for the documentation and analysis of the progression of the disease. Specifically, ultrawide field imaging may help document the retinal dystrophies affecting the peripheral fundus, including retinitis pigmentosa and gyrate atrophy of the retina and RPE.[71][72][73]

Optical Coherence Tomography

Spectral-domain optical coherence tomography (OCT) provides valuable information for diagnosing and monitoring the disease's progression. In retinitis pigmentosa, thinning of retinal layers, especially outer retinal layers, is commonly seen. The thinning progresses towards the macula, showing the foveal layers' sparing until the advanced stages.[74] OCT also detects thinning of the outer nuclear layer, loss or disruption of the ellipsoid zone and RPE, cystoid macular edema (CME), vitreomacular traction, macular hole, choroidal neovascular membrane, subretinal deposits, macular thinning, and epiretinal membrane.[75] OCT findings in various retinal dystrophies include:

• Retinitis pigmentosa: The subfoveal ellipsoid zone is usually preserved until late in the disease course; the loss of the ellipsoid zone and thinning of the outer nuclear layer are seen outside the fovea.
• Stargardt disease: Findings include thickened external limiting membrane (ELM) in early stages [76], thinning of outer nuclear layer, disruption of subfoveal ELM, ellipsoid zone, thinning of RPE and choriocapillaris, macular thinning, optical gap in the outer retina due to loss of ellipsoid zone in some phenotypes, hyper-reflective foci in the choroid, and subretinal deposit (pisciform fleck) which may sometimes migrate intraretinally (see Image. Optical Coherence Tomography of the Macula).[77][8]
• Rod monochromatism: Findings include subfoveal loss of ellipsoid zone, an optically empty cavity at the outer retina, loss of RPE, foveal hypoplasia, and loss of outer retinal layers with foveal thinning.[78]
• Best vitelliform macular dystrophy: Findings include a thickened middle highly reflective layer (HRL) [79], vitelliform deposit (homogenous hyperreflective material) subretinally and subretinal hyporeflective spaces in patients in pseudohypopyon stage and elongated outer photoreceptors over the area with subretinal hyporeflective space.[28]

A few-shot learning (FSL) model used the following criteria to define 3 types of retinal dystrophies:

• Cone or cone-rod lesions: Photoreceptor layer disruption and thinning of the sensory retina at the fovea
• Rod-cone lesions: Photoreceptor layer disruption and thinning of the sensory retina at the fovea outside the fovea with relative preservation of the structure at the fovea
• Extensive lesions [80]

Additionally, no changes in OCT may be noted in cases of CSNB with normal fundi. Fundus albipunctatus due to RDH5 may show deposition of hyperreflective material below the ELM at the area of the white dots, and old patients may show subfoveal preserved ELM with focal loss of ellipsoid zone and debris-like material deep to the ELM.[81] In fundus albipunctatus, hyperreflective deposits are noted over RPE, corresponding to retinal flecks observed clinically.[82] Degenerative changes, including outer retinal tubulations and inner retinal pseudocysts, may be noted in retinal dystrophies, causing atrophy at or around the macula, including Stargardt disease, cone dystrophy, and maternally inherited diabetes and deafness.[83]

Optical Coherence Tomography Angiography

Optical coherence tomography angiography (OCTA) is a noninvasive imaging technique that has significantly enhanced the evaluation of retinal dystrophies by providing detailed visualization of the retinal and choroidal vasculature. In conditions such as retinitis pigmentosa and choroideremia, OCTA can reveal characteristic vascular changes, including reduced vascular density and alterations in the foveal avascular zone.[84] This modality aids in the identification of neovascularization and ischemic areas, which are critical for understanding disease progression and potential complications. Moreover, OCTA allows for monitoring treatment responses in clinical trials and therapeutic interventions, especially in choroidal neovascular membranes (CNVMs), enhancing personalized patient management. Performing OCTA alongside traditional OCT imaging facilitates a comprehensive assessment of structural and vascular changes in retinal dystrophies.[85]

Fundus Autofluorescence 

Fundus autofluorescence (FAF) is a valuable imaging modality in assessing retinal dystrophies, particularly in visualizing the health of the RPE. It provides insights into the metabolic activity of the RPE and the presence of lipofuscin, which accumulates in various retinal degenerative conditions. In retinitis pigmentosa, normal fundus autofluorescence at the fovea is usually preserved, bordered by a hyper-autofluorescent ring (Robson-Holder ring) outside which an abnormal mottled hypoautofluorescence is seen.[86] Similar rings may also be noted in other retinal dystrophies, including:

• Sector retinitis pigmentosa
• Bull's eye maculopathy
• Leber congenital amaurosis
• Cone dystrophy
• Cone-rod dystrophy
• Best disease
• X-linked retinoschisis [86][87]

The Best disease demonstrates a highly hyperautofluorescent lesion at the fovea in the vitelliform stage.[64] The vitelliform lesions in the posterior pole in autosomal recessive bestrophinopathy are also highly hyperautofluorescent.[88] Stargardt disease is characterized by hypoautofluorescence at the area of macular atrophy, and the flecks are usually hyperautofluorescent, which typically spare the area around the optic disc (compared to pentosan polysulfate maculopathy that causes autofluorescence changes around the optic disc also).[40] Choroideremia is characterized by hyper-autofluorescence in the areas with visible sclera, and the macula usually has a stellate area with normal choriocapillaris and RPE.[87] Fundus albipunctata shows a grainy image and reduced background autofluorescence, and the white dots may show hyperautofluorescence.[81] 

Fundus Fluorescein Angiogram

Stargardt disease is associated with dark choroid in at least 80% of cases. The areas of RPE atrophy at the macula due to cone dystrophy, Stargardt disease, and other retinal dystrophies cause window defects. Peripheral window defects are seen in areas of RPE atrophy in retinitis pigmentosa, gyrate atrophy, and other diseases. The vitelliform lesion in Best disease and pigments in retinitis pigmentosa may show block fluorescence. Typically, the macular edema in retinal dystrophies is nonleaking (not causing a petaloid leak in fluorescein angiogram or angiographically silent CME), hence more appropriately called maculoschisis or foveoschisis. Such CME may respond well to oral or topical carbonic anhydrase inhibitors. The retinal dystrophies associated with nonleaking macular edema include:

• Retinitis pigmentosa
• Gyrate atrophy of retina and RPE [71]
• X-linked retinoschisis
• Goldmann Favre syndrome or enhanced S-cone syndrome (NR2E3-related retinopathies)
• Choroideremia
• MIDD
• Cohen syndrome (rod-cone dystrophy) [89]

However, in some cases of retinitis pigmentosa, there may be clinical evidence of active intermediate uveitis associated with leaking CME, which responds well to periocular or oral steroids.[90][73] Fundus fluorescein angiogram also helps detect CNVMs, which can complicate many retinal dystrophies.

Visual Field Analysis

Peripheral visual field loss is common in rod-dominated disorders.[91] Mild constriction of peripheral fields is seen initially, progressing gradually to tunnel vision over the years. The visual field changes are usually symmetric in both eyes. Regular field assessments are mandatory in progressive diseases such as retinitis pigmentosa, especially if the patient drives a motor vehicle. All patients with retinitis pigmentosa must restrict night driving and eventually stop driving as the disease progresses. Regular field assessments also enable patients to understand their visual limitations, which are not realized otherwise. Though the central vision of retinitis pigmentosa cases may be excellent (20/20), they can come under the definition of legal blindness due to the visual field criteria (severely narrowed visual field).[92]

In cone-dominated disorders, peripheral field constriction is rarely seen and remains stable over the years if present. Progression of field defects rules out the diagnosis, and one must consider other differentials like cone-rod dystrophy or retinitis pigmentosa with a cone-rod pattern. Visual field defects in cone-rod dystrophies begin as central scotoma and involve the periphery in later stages.[91][34][91]

Color Vision

Retinitis pigmentosa patients maintain good color discrimination until the advanced stages when cones are affected. Color vision abnormalities are reported once the visual acuity declines below 20/40.

Color vision abnormalities are more reported in cone-dominated disorders. Complete achromats are congenitally color blind; however, they may be able to identify different pseudo-isochromatic color plates as they train themselves to identify different colors as shades of gray. Hence, higher-order color tests may be required for diagnosis. Blue cone monochromats, as the name suggests, preserve Tritan color discrimination and can be tested on higher-order color tests like Berson plates.[93]

Electrophysiology

The full-field electroretinogram (ERG) is a sensitive test for diagnosis. In the early stages of retinitis pigmentosa, diminished scotopic rod and combined responses are seen. As the disease advances, photopic responses are affected, and eventually, ERG becomes extinguished.

ERG is the mainstay in the diagnosis of the cone or cone-rod dystrophies. Decreased photopic and 30 Hz flicker ERG with delays in implicit times are seen. Multifocal ERGs will be severely diminished. Later in the course of the disease, scotopic responses are also reduced. However, reduced scotopic responses in the early stages are a pointer towards diagnosing retinitis pigmentosa. The differentiating feature of achromatopsia and blue monochromatism is that a cone signal can be obtained using a blue light flash on a yellow background in the latter.[94] Cases with Leber congenital amaurosis are known to have profoundly abnormal or extinguished ERG. ERG is also essential in differentiating retinitis pigmentosa from disorders like cone-rod dystrophy. In cases with CRD, marked reduction or absence of cone ERG responses in the presence of less reduction in rod responses are seen.

Electro-oculogram (EOG) is typically abnormal in Best disease and other retinal dystrophies caused by mutations in the bestrophin-1 gene.[95] 

Adaptive Optics

Adaptive optics (AO) allows for high-resolution photoreceptor layer and retinal microstructure visualization. This technique enhances the contrast and resolution of images, enabling the detection of early retinal changes that may not be visible with conventional imaging methods. In conditions like retinitis pigmentosa and Stargardt disease, AO can reveal abnormal photoreceptor morphology and quantify cell density, providing insights into disease progression and potential treatment outcomes.[96][97] Furthermore, AO can facilitate the evaluation of localized changes in retinal structure associated with genetic mutations, aiding in personalized management approaches. As a noninvasive method, it holds promise for longitudinal studies that track disease evolution over time.[98]

Treatment / Management

Currently, retinal dystrophies are not curable. However, supportive treatment can improve the quality of life. Major options to consider in all cases include refraction, cataract surgery when indicated, and referral for low vision aids. Patients with CME benefit from topical or systemic carbonic anhydrase inhibitors.[99] CME associated with intraocular inflammation may benefit from periocular or systemic steroids. The patients should avoid smoking and retinotoxic medications. Anti-VEGF (anti-vascular endothelial growth factor) agents are indicated in retinal dystrophies complicated by CNVM.

Patients with night vision problems benefit from night vision aids or commonly used devices like flashlights. Cases with cone dystrophies with photosensitivity benefit from tinted lenses, mainly orange or red lenses, since rod photoreceptors are less sensitive to orange and red lights.[100] Red-tinted soft contact lenses are an alternative to glasses. Low vision aids may help enhance visual acuity.

Gene Therapy

The retina is a good target for genetic manipulation due to various reasons: target cells (photoreceptors) are easily accessible for surgery and monitoring, the blood-retinal barrier provides an ocular immune privilege, and the cell population is static, which requires a small number of therapeutics to be administered. Gene therapy may work through various methods, including:

• Gene replacement
• Gene silencing
• Gene editing
• Therapeutic oligonucleotides [101]

Subretinal injections are a preferred mode of delivery for gene therapy as the agent reaches RPE and photoreceptors more precisely. Compared to intravitreal injections, the immunological response is well controlled. Several clinical trials are ongoing. In 2017, the USFDA approved subretinal injection of voretigene neparvovec for RPE65-associated Leber congenital amaurosis.[102] The gene therapy needs viral or nonviral carriers or vectors to deliver the drug to the target tissue. Viral vectors include adeno-associated virus and lentivirus.[103] Nonviral vectors include delivery systems based on nanomaterials, lipids, and magnetic nanoparticles.[101] Gene editing technologies include clustered, regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated (Cas) proteins.[103] Genetic targets for various retinal dystrophies include:(A1)

• Retinitis pigmentosa: RPGR, PDE6A, PDE6B, MERTK, RHO, RLBP1
• Achromatopsia: CNGA3, CNGB3
• Leber congenital amaurosis: CEP290, RPE65, GUCY2D
• Usher syndrome: MYO7A
• Stargardt disease: ABCA4
• Choroideremia: CHM
• Bietti crystalline dystrophy: CYP4V2
• X-linked retinoschisis: RS1 [101][103]

Stem Cell Therapy

Human pluripotent stem cells were first cultured in 1998 and were seen to have the potential to differentiate into endodermal, mesodermal, and ectodermal lineages. The retina is a good target for stem cell therapy for reasons similar to gene therapy. Moreover, the limited size of the retina requires smaller quantities of therapeutic tissue compared to other organs. Several ongoing trials mainly focus on diseases like Stargardt disease and retinitis pigmentosa.[104](A1)

Retinal Prostheses

Retinal prosthesis devices replace phototransduction within the eyes of individuals lacking photoreceptors for diseases, eg, retinitis pigmentosa. Normally, photoreceptors contain light-sensitive pigments that trigger phototransduction, which generates neuronal signals in the presence of light stimuli. The middle layers of the retina process these signals before they reach ganglion cells. These retinal ganglion cells form the optic nerve and transmit these signals to the visual cortex. In cases where the outer retinal layer/photoreceptors are lost, the retinal prosthesis transmits the signals to the inner layers.

In 2013, the FDA approved Argus II retinal prosthesis for late-stage retinitis pigmentosa. Many other retinal prostheses are under trial worldwide to explore their use in conditions like severe age-related macular degeneration, cone-rod dystrophy, and choroideremia. Argus II is composed of 60 electrodes that are implanted epiretinally. It has 3 external and 3 internal components. External components include a video camera mounted on a pair of glasses, a visual processing unit, and a coil attached to the sidearm of glasses. Internal components are an internal coil and internal processing unit, which is within a casing that is sutured to the sclera.

Retinal prosthesis is indicated in individuals with retinitis pigmentosa older than 25, with light perception or worse vision, and a previous history of useful form vision. Patients must also be highly motivated to comply with postoperative follow-up and rehabilitation. Complications reported include retinal detachment, choroidal effusion, hypotony, endophthalmitis, and implant dislocation.[105] As new therapies continue to be discovered, clinicians must recognize their clinical characteristics to determine whether patients may benefit from a specific treatment.

Genetic Consultation

Genetic counseling should be arranged once the diagnosis of retinitis pigmentosa or other retinal dystrophies is suspected. The consultation aims to confirm the diagnosis and mode of inheritance. The prognosis of the disease may also be known if the genetic mutation is known. Counseling involves taking a history and conducting a clinical examination in addition to clinical investigations and molecular genetic diagnosis. A detailed pedigree is essential for a complete workup. Once the mode of inheritance is known, tailored genetic testing must be done. Currently, at least 270 genes associated with retinal dystrophies can be tested.

Counseling must address the risk of progression and the current changes in lifestyle required. Patients must be aware of the risk of disease transmission in future generations. Pedigree charts help in assessing the mode of inheritance. For instance, in autosomal recessive families, in which both parents are carriers, each child has a 25% risk of inheritance. An individual with autosomal recessive disease has a small risk of transmitting the disease to his offspring, depending on the carrier state of the population. In such circumstances, consanguineous marriages must be avoided.

All patients must be offered a referral to support services. This is particularly important when dealing with issues like vocational rehabilitation training and schooling of a visually impaired child.

Mental Health Therapy

Psychological support and psychiatry consultation are essential parts of management as the diagnosis of retinal dystrophies may be overwhelming for patients, and such patients may have a higher risk of depression and anxiety.[106]

Nutritional Supplements

Supplementation of vitamin B6 and an arginine-restricted diet may help some patients with gyrate atrophy. Vitamin A has been used with variable success in many patients with retinitis pigmentosa. It has been noted that vitamin A supplementation should be avoided in patients with Stargardt disease as it may lead to increased production of lipofuscin, which is a metabolic byproduct of vitamin A.[107] 

The following are treatable forms of retinitis pigmentosa and their proposed management:

• The Bassen-Kornzweig disease may be treated with vitamins A, E, and K supplementation and a low-fat diet [108]
• Friedreich-like ataxia associated with retinitis pigmentosa may benefit from vitamin E therapy [108][100]
• Refsum disease patients need a phytanic acid-restricted diet [109]

Other promising options in managing retinal dystrophies include intravitreal injections of ciliary neurotrophic factor and valproic acid.[110][111] Syndromic retinal dystrophies require interprofessional collaboration for holistic patient care. With optimum management, the quality of life can be improved in most patients with retinal dystrophies.(A1)

Differential Diagnosis

Each retinal dystrophy phenotype is often confused with other genetic or acquired disorders. Misdiagnosis is common and must be avoided, as it has a great bearing on genetic and prognostic counseling. Acquired causes can be treated in many cases; therefore, timely diagnosis is necessary.

Retinitis pigmentosa must be differentiated from other conditions causing retinal pigmentation, eg, rubella retinopathy, syphilis, autoimmune paraneoplastic retinopathy, and drug toxicities. Quinine overdose can cause sudden loss of vision and manifest with optic disc pallor and vessel attenuation. It can be misdiagnosed as the sine pigmento stage of retinitis pigmentosa. ERG in quinine overdose has a negative configuration, affecting the b wave more than a wave.[112]

ABCA4 gene has extensive phenotypic heterogeneity, and mutations can cause various diseases, including:

• Autosomal recessive Stargardt disease
• Fundus flavimaculatus (autosomal recessive, AR)
• Cone rod dystrophy 3 (AR)
• Retinitis pigmentosa 19 (AR)
• Early onset severe retinal dystrophy (AR)
• Age-related macular degeneration 2 (autosomal dominant, AD)

Pigmented paravenous retinochoroidal atrophy or pigmented paravenous chorioretinal atrophy also manifests with retinal pigmentation along the retinal veins. Retinal pigmentation is mainly an incidental finding associated with tuberculosis, syphilis, rubeola, and meningoencephalitis. ERG responses in these conditions are only mild to moderate abnormal.

Occasionally, traumatic retinopathy and DUSN can be misdiagnosed as unilateral retinitis pigmentosa. Retinitis pigmentosa may be asymmetric initially; hence, long-term follow-up is needed before diagnosing unilateral retinitis pigmentosa. In all cases of so-called unilateral retinitis pigmentosa or unilateral pigmentary retinopathy (UPR), other causes of pigmentary retinopathy must be excluded. Other causes of pigmentary retinopathy (pseudo-retinitis pigmentosa) include:

• Drugs, including phenothiazines (thioridazine), chloroquine, hydroxychloroquine
• Trauma, including traumatic retinopathy, siderosis, and retinal detachment
• Infections including toxoplasmosis, rubella, syphilis, tuberculosis, retinitis including cytomegaloviral retinitis and acute retinal necrosis, measles
• Inflammations, including acute zonal occult outer retinopathy, DUSN, healed posterior uveitis, and severe retinal vasculitis,
• Retinal detachment may spontaneously resolve (self-settled retinal detachment), giving an appearance of pigmentary retinopathy [113]
• Autoimmune retinopathy (AIR) can be nonparaneoplastic (npAIR), including CAR, MAR, PON, and BDUMP, or paraneoplastic (pAIR)

Advanced cases of choroideremia, Stargardt macular dystrophy, and cone-rod dystrophy are usually misdiagnosed as retinitis pigmentosa. Retinitis punctata albescens and fundus albipunctatus have overlapping fundus images. Patients with fundus albipunctatus are usually asymptomatic, and fundus findings are incidental. Rarely, they may complain of night blindness early in childhood without progression. However, retinitis punctata albescens is a progressive disease with worse symptoms and a reduction in the field of vision over time. However, fundus albipunctatus and retinitis punctata albescens might denote a spectrum of diseases caused by the same or similar mutations of genes, including RLBP1.[114] Mutations in RLBP1 may result in multiple phenotypes, including:

• Fundus albipunctatus (AD, AR)
• Retinitis punctata albescens(AD, AR)
• Newfoundland rod-cone dystrophy
• Bothnia retinal dystrophy (AR)

 Electrophysiological characteristics of most diseases can help narrow the diagnosis in phenotypically similar conditions.

Prognosis

Retinitis pigmentosa, Leber congenital amaurosis, and cone-rod dystrophies are generally progressive. Early age of onset is usually associated with poor prognosis in retinitis pigmentosa and LCA. However, conditions like congenital stationary night blindness and achromatism are nonprogressive.[115] Proper counseling regarding the disease and its progression can help the patient and family cope with the challenges. Retinal pattern dystrophies and the 'Best disease' usually have good visual prognoses.[28] The life expectancy of people with retinal dystrophy is generally normal except for syndromic cases or cases with systemic disease.

Complications

Retinitis pigmentosa progresses at a varied rate, depending on various parameters, including the gene involved, family history, and age of onset, from peripheral constriction of fields to tunnel vision and gradual vision loss. Early onset of visually significant cataracts is common. Risk factors associated with cataract surgery are more prevalent in cases with retinal dystrophy than in the general population, including zonular weakness, capsular phimosis, early onset of posterior capsule opacification, and cystoid macular edema.[116] The intraretinal hyporefective spaces on macular OCT in retinitis pigmentosa, gyrate atrophy, X-linked retinoschisis, and Goldmann-Favre disease may not cause a petaloid leak on fundus fluorescein angiography and is better termed as "foveoschisis" or maculoschisis.[71][63][71] Vertical tissue bridges are seen on OCT. These cases may respond to topical, including dorzolamide or oral acetazolamide carbonic anhydrase inhibitors. Defects in color and peripheral vision may cause challenges during driving or moving. People with vision loss from retinal dystrophies may experience depression, which can include feelings of sadness, loss of interest, fatigue, weight loss or gain, and low energy.[117]