Retinal Dystrophies

Continuing Education Activity

Retinal dystrophies (RD) are a group of degenerative disorders of the retina with clinical and genetic heterogeneity. Common presentations include color blindness or night blindness, peripheral vision abnormalities, and subsequent progression to complete blindness in progressive conditions. This activity describes the various entities that fall under the spectrum of retinal dystrophies and highlights the role of genetic testing and counseling in the management of patients with this condition.


  • Describe the differential diagnosis of various disease conditions that are collectively termed as retinal dystrophies.
  • Describe the role of electrophysiology and other diagnostic tests in diagnosing retinal dystrophies.
  • Outline current treatment and recent advances in the field of inherited retinal dystrophies.
  • Describe the role of genetic testing and genetic counseling in the management of retinal dystrophy.


Retinal dystrophies (RD) are a group of degenerative disorders of the retina with clinical and genetic heterogeneity. Common presentations include color blindness or night blindness, peripheral vision abnormalities, and subsequent progression to complete blindness in progressive conditions. Multiple causative gene defects have been identified. To date, over 270 genes are known to be associated with different phenotypes of retinal dystrophies. Besides, mutations within the same gene have been associated with different phenotypes, even within different individuals of the same family—these genes code for proteins involved in photoreceptors and other retinal cellular units and phototransduction.


Rods and cone photoreceptors are the main cellular units responsible for visual phototransduction. Phototransduction is a process by which light signals are converted into action potential within the retina and facilitate the brain's perception of an image. During this process, light-sensitive pigments are generated and recycled. RD occurs due to abnormalities in photoreceptors as well as defects in phototransduction.

Depending on the type of photoreceptors affected, retinal dystrophies can be subdivided into rod-dominated diseases, cone-dominated diseases, and generalized form, which involves both rods and cones. Cases may be syndromic and non-syndromic, 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 non-syndromic varieties, which affect only the retina.


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

History and Physical

Rod dystrophies: Rod dominated dystrophies include rod and rod-cone dystrophies, where either rod photoreceptors are predominantly affected, or rod photoreceptors are the first affected. This includes Retinitis pigmentosa (RP) and Congenital stational night blindness (CSNB).

Retinitis pigmentosa: It is the most commonly seen retinal dystrophy. RP 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 RD, it may be sporadic or inherited in an autosomal dominant (AD), autosomal recessive (AR), or x- linked recessive (XLR) pattern. AD is the most common form, and XLR is the least common but most severe form. Non-syndromic and syndromic forms are reported.

Nyctalopia is a constant feature, although it is not pathognomic of RP. Most cases do not report night vision problems until the ocular disease is in an advanced stage. Patients also notice an insidious progressive loss of peripheral field of vision. In most cases, the inferior retina is affected first. Hence superior field losses are commonly seen. Visual field loss, coupled with night vision problems, makes these patients prone to accidents, especially at night.  In typical RP, the rate of progression of visual field loss is usually slow, and usually 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 such as cystoid macular edema, epiretinal membrane, or development of retinal pigment epithelial defects (RPE) in macular or fovea.[2] Color vision remains unaffected until the later stages of the disease in most cases.

Fundus appearance of RP classically includes a triad of retinal vessel attenuation, waxy pallor of the optic disc, and bone spicule intraretinal pigmentation. Patients with very early RP without fundus pigmentary abnormalities are termed as RP sine pigmento. This is no longer considered as a subtype of RP as it is a stage of RP through which some patients pass. Fine dust-like pigment cells are noted in the vitreous cavity; these are released from the degeneration of RPE.

Phenotypic variants, based on retinal involvement are sectoral retinitis pigmentosa, pericentral RP, and unilateral or extremely asymmetric RP. Sectoral RP is characterized by pigmentary changes limited to one or two quadrants with limited visual field changes, good electroretinogram (ERG) responses, and minimal progression with time. True sector RP can be autosomal dominant or recessive. Sporadic cases are, however, common and may possibly result from non-genetic 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 and encroach the central field of vision early, causing greater disability. Unilateral RP is typically an acquired condition and is commonly referred to as diffuse unilateral neuroretinitis. However, extremely asymmetric RP is an entity with a genetic association.

Congenital Stationary Night Blindness: CSNB is a non-progressive form of night blindness. Various inheritance patterns (autosomal dominant, autosomal recessive, or X-linked) are now recognized. CSNB is further categorized as- CSNB with normal fundus and abnormal fundus.

Some cases of CSNB with normal fundi present with reduced vision ( 20/50) and no history of night blindness. CSNB with abnormal fundi includes two entities: Oguchi disease and fundus albipunctatus.

In Oguchi disease, the Mizuo Nakamura phenomenon is classically observed. In this variant, golden sheen over the retina is noted with an unusually dark macula on exposure to light. However, the retina appears normal after prolonged dark adaptation. Color vision and visual acuity are normal in these cases. Histopathological studies suggest the presence of an abnormal layer between outer segments of photoreceptors and RPE. 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. Color vision and visual acuity are usually normal.

Cone disorders: Cone dominated diseases can be further subdivided into diseases with early-onset 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: It is an autosomal recessive condition with patients presenting with poor visual acuity since birth,  photosensitivity, and poor color discrimination.  Photosensitivity is due to poor visual acuity in bright lights, instead of actual light intolerance. It has two subtypes- Complete and incomplete achromatopsia. Cases with complete achromatopsia, also known as rod monochromats, usually have visual acuity less than 20/200. Incomplete or atypical forms retain a visual acuity between 20/80- 20/200. Color vision is completely absent in complete achromatopsia cases. Pendular nystagmus may be present but usually improves with age. Fundus examination is usually 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; however, peripheral fields are usually normal or mildly constricted. Characteristically, these are non-progressive changes.

Cone Monochromatism: It is an X linked recessive congenital disorder where two of the three cone systems are absent or significantly affected. The most common variety is blue cone monochromatism, in which both red and green cone systems are completely absent. Visual acuity in affected individuals ranges from 20/80 to 20/200. Clinical signs and symptoms resemble achromatopsia cases. They can perceive blue color.[3] 

Cone rod dystrophy (CRD): It is usually misdiagnosed as RP with more involvement of cones than rods. Patients present with the early loss of vision and color vision abnormalities with subsequent peripheral field constriction. 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 includes disorders like Leber congenital amaurosis.

Leber congenital amaurosis (LCA)It is a group of disorders due to a mutation in at least 16 different genes, all presenting with severe visual impairment or blindness from infancy and extinguished ERG. Most patients show either a normal fundus appearance or subtle RPE changes and retinal vascular attenuation. Eye rubbing, also known as the oculo-digital sign is a common association. Keratoconus is seen in 29% of cases.[4] This association is not just a consequence of eye rubbing but may be due to other genetic factors. Complicated cases have systemic features. Cases with deafness, renal anomalies, hepatic dysfunction, skeletal abnormalities have been reported. Mental retardation is reported in around 20% of cases. The most common inheritance pattern is autosomal recessive. Patients with RPE65 or CRB1 gene mutations have progressive vision loss with age, with the prognosis being slightly better in those with onset after infancy.


Visual field analysis: In rod dominated disorders, peripheral visual field loss is a common occurrence. Initially, mild constriction of peripheral fields is seen, which progress gradually over the years to tunnel vision.  The visual field changes are usually symmetric in both eyes. In progressive diseases such as RP, regular field assessments are mandatory, especially if the patient is driving a motor vehicle. All patients with RP have to 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.

In cone-dominated disorders, peripheral field constriction is rarely seen and, if present remains stable over the years. 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 in the paracentral region between 5 and 30 degrees from fixation and involve the periphery in later stages.

Color vision: Retinitis pigmentosa patients maintain good color discrimination until advanced stages when cones get 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 pseudoisochromatic 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, have preservation of Tritan color discrimination, which can be tested on higher-order color tests like Berson plates.

Electrophysiology: Full-field ERG is a sensitive test for diagnosis. In the early stages of RP, 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, the reduction of scotopic responses in the early stages is a pointer towards the diagnosis of retinitis pigmentosa. The differentiating feature of achromatopsia and blue monochromatism is that in the latter, a cone signal can be obtained using blue light flash on a yellow background. Cases with Leber congenital amaurosis are known to have profoundly abnormal or extinguished ERG.

ERG also is essential in differentiating RP 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.

Optical coherence tomography: Spectral-domain OCT provides valuable information for diagnosis and monitoring progression of the disease. In retinitis pigmentosa, thinning of retinal layers, especially outer retinal layers, is commonly seen. The thinning progresses towards the macula and shows the sparing of foveal layers till advanced stages.[5] OCT is also useful in detecting cystoid macular edema (CME) and epiretinal membrane. It can eliminate the need for fundus fluorescein angiography for detecting CME.

No changes in OCT are noted in cases of CSNB with normal fundi. In Fundus Albipunctatus, hyperreflective deposits are noted over RPE corresponding to retinal flecks observed clinically.[6] Optical coherence tomography in achromatism may show changes ranging from disruption of inner /outer segment receptors in the subfoveal region to hyperreflective cavity in the cone layer of foveola and foveal hypoplasia in some cases.[7]

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 cystoid macular edema benefit from topical or systemic carbonic anhydrase inhibitors.[8]

Patients with night vision problems benefit from night vision aid or commonly used devices like a flashlight. Cases with cone dystrophies with photosensitivity benefit from tinted lenses, particularly orange or red lenses, since rod photoreceptors are less sensitive to orange and red lights. Red tinted soft contact lenses are an alternative to glasses. Low vision aids may help in enhancing visual acuity.

Gene therapy: 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 amount of therapeutics to be administered.

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 US FDA approved subretinal injection of voretigene neparvovec for RPE65 associated Leber congenital amaurosis.[9]

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. For reasons similar to gene therapy, the retina is a good target for stem cell therapy. Moreover, the limited size of the retina requires smaller quantities of therapeutic tissue compared to other organs. Several trials are ongoing which mostly focus on diseases like age-related macular degeneration, Stargardt disease, glaucoma, and retinitis pigmentosa.

Retinal prostheses: These are devices that replace phototransduction within the eyes of individuals lacking photoreceptors in diseases such as retinitis pigmentosa. Normally photoreceptors contain light-sensitive pigments that trigger phototransduction, which generate neuronal signals in presence of light stimuli. These signals are processed by the middle layers of the retina before they reach ganglion cells. These retinal ganglion cells, that form the optic nerve, then transmit these signals to the visual cortex. In cases where the outer retinal layer/ photoreceptors are lost, retinal prosthesis transmits the signals to inner layers for the phototransduction pathway to be completed.

In 2013, USFDA approved Argus II retinal prosthesis for late-stage retinitis pigmentosa. Currently, many other retinal prostheses are under trial worldwide with an aim at exploring use in conditions like severe age-related macular degeneration, cone-rod dystrophy, choroideremia. Argus II is composed of 60 electrodes that are implanted epiretinally. It has three external and three 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, internal processing unit which is within a casing which is sutured to the sclera.

Currently, it is indicated in cases of retinitis pigmentosa who are > 25 years of age, with light perception or worse vision and a previous history of useful form vision. Patients must also be highly motivated for post-op clinic follow up and rehabilitation. Complications reported include retinal detachment, choroidal effusion, hypotony, endophthalmitis, and implant dislocation.[10]

As new therapies continue to be discovered, there is an ever-increasing need for the clinicians to recognize the clinical characteristics to determine whether the patients may benefit from a certain treatment.

Genetic consultation: Once the diagnosis of retinitis pigmentosa or other retinal dystrophies is suspected, genetic counseling must be arranged. The consultation aims to confirm the diagnosis and mode of inheritance. It involves history taking and 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, 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 made aware of the risk of transmission of the disease 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 the autosomal recessive disease has a small risk of transmitting the disease to his offsprings, depending on the carrier state of a 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.

Differential Diagnosis

Each phenotype of retinal dystrophy 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 a must.

Retinitis pigmentosa must be differentiated from other acquired conditions causing retinal pigmentation such as 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 RP. ERG in quinine overdose has a negative configuration, affecting b wave more than a wave.[11] Pigmented paravenous retinochoroidal atrophy also manifest with retinal pigmentation along the retinal veins. It is mostly an incidental finding and has been associated with tuberculosis, syphilis, rubeola, and meningoencephalitis. ERG responses in these conditions are only mild to moderate abnormal. Occasionally, traumatic retinopathy and diffuse unilateral subacute neuroretinitis (DUSN) can be misdiagnosed as unilateral RP.

Advanced cases of choroideremia, Stargardt macular dystrophy, 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. Electrophysiological characteristics of most diseases can help narrow the diagnosis in case of phenotypically similar conditions.


Retinitis pigmentosa, Leber congenital amaurosis, cone-rod dystrophies are generally progressive in nature. Early age of onset is usually associated with poor prognosis in RP and LCA. However, conditions like congenital stationary night blindness and achromatism are non-progressive. Proper counseling regarding the disease and its progression can help the patient and family cope with the challenges.


RP progresses at a varied rate, depending on the inheritance pattern and age of onset, from peripheral constriction of fields to tunnel vision and gradually losing vision loss. Early-onset of visually significant cataract is common. Risk factors associated with cataract surgery are more in cases with retinal dystrophy compared to the general population, which include zonular weakness, capsular phimosis, early onset of posterior capsule opacification, and cystoid macular edema.[12]

Deterrence and Patient Education

The diagnosis of retinal dystrophy causes a lot of anxiety to the patient and their family. Patients on knowing the diagnosis are often apprehensive about losing their vision, adding to psychological stress. Except for LCA, most conditions are usually slowly progressive, and some have a stationary course.

Another misconception is that these retinal dystrophies are 'not treatable.' These are incurable. However, supportive treatments, such as low vision assessment, support services, and visual rehabilitation can improve a patient's lifestyle to a great extent.

Enhancing Healthcare Team Outcomes

An interdisciplinary team approach involving ophthalmologists, geneticists, and genetic nurse counselors providing patient care would lead to the best outcomes. While an ophthalmologist primarily makes the clinical diagnosis, the clinical genetics team plays a vital role in ordering specific genetic testing and counseling the patient and family members regarding diagnosis, prognosis, and probability of inheritance of the gene defect in future generations. An up- to- date refraction, low visual aids, visual rehabilitation, and support services are essential steps in the management of any retinal dystrophy. 

Article Details

Article Author

Harshika Chawla

Article Editor:

Vishal Vohra


2/15/2021 8:59:03 AM

PubMed Link:

Retinal Dystrophies



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