Retinal dystrophy

In this article:

• What are retinal dystrophies?
• Rod and rod-cone dystrophies
• Retinitis pigmentosa
• Congenital stationary night blindness
• Cone and cone-rod dystrophies
• Progressive cone and cone-rod dystrophies
• Achromatopsia
• Generalised non-syndromic RDs
• Leber congenital amaurosis
• Choroideremia
• Zellweger spectrum disorder (ZSD)
• Causes and risk factors
• Symptoms
• Diagnosis
• Vision test
• Visual field analysis
• Color vision test
• Optical coherence tomography (OCT)
• Electrophysiology test (ERG)
• Retinal photography
• Blood test
• Genetic consultation
• How it can be prevented?
• References

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What are retinal dystrophies?

Retinal dystrophies (RD) are a group of degenerative disorders of the retina with clinical and genetic heterogeneity. Most commonly known diseases of this group are:

• color blindness or night blindness,
• peripheral vision abnormalities,
• retinal dystrophy due to other eye diseases

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 vision mechanisms through photoreceptors and other retinal cellular units and phototransduction.

The exact incidence of retinal dystrophies is unknown, but the most common form, retinitis pigmentosa, affects around 1 in 5000 individuals worldwide. 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.

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Rod and rod-cone 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

Phenotypic variant determination based on retinal involvement are:

1. Sectoral retinitis pigmentosa, 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.
2. Pericentral RP. 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.
3. Unilateral or extremely asymmetric RP. 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.

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.

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
• Fundus albipunctatus.

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Cone and cone-rod dystrophies

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.

Cone rod dystrophy (CRD) 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.

Progressive cone and cone-rod dystrophies

Progressive cone and cone-rod dystrophies are a clinically and genetically heterogeneous group of inherited retinal diseases characterised by cone photoreceptor degeneration, which may be followed by subsequent rod photoreceptor loss. These disorders typically present with progressive loss of central vision, colour vision disturbance and photophobia.

Considerable progress has been made in elucidating the molecular genetics and genotype-phenotype correlations associated with these dystrophies, with mutations in at least 30 genes implicated in this group of disorders. The most common disease-associated genes: GUCA1A, PRPH2, ABCA4 and RPGR.

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 achromatopsia
• 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.

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Generalised non-syndromic RDs

This group of diseases has a confirmed mutation and inheritance mode of a vision loss but does not have any other organs involved.

Leber congenital amaurosis

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. 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.

RPE65-related Leber congenital amaurosis / early-onset severe retinal dystrophy (RPE65-LCA/EOSRD) is a severe inherited retinal degeneration (IRD) with a typical presentation between birth and age five years. While central vision varies, the hallmark of this disorder is the presence of severe visual impairment with a deceptively preserved retinal structure.

Vision is relatively stable in the first decade of life, but begins to decline in adolescence. Most affected individuals are legally blind (visual acuity 20/200 and/or visual fields extending <20 degrees from fixation) by age 20 years. After age 20 years, visual acuity declines further and by the fourth decade all affected individuals are legally blind and many have complete loss of vision (i.e., no light perception). Milder disease phenotypes have been described in individuals with hypomorphic alleles.

Choroideremia

Choroideremia (CHM) is characterized by progressive chorioretinal degeneration in affected boys, and milder signs in heterozygous (carrier) girls. Typically, symptoms in affected males evolve from night blindness to peripheral visual field loss, with central vision preserved until late in life. Although carrier females are generally asymptomatic, signs of chorioretinal degeneration can be reliably observed with fundus autofluorescence imaging, and – after age 25 years – with careful fundus examination.

CHM is inherited in an X-linked manner. Affected males transmit the pathogenic variant to all of their daughters and none of their sons. Heterozygous females have a 50% chance of transmitting the variant in each pregnancy: males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be carriers and will usually not be symptomatic. Once the CHM pathogenic variant has been identified in an affected family member, carrier testing for at-risk female relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing for choroideremia are possible.

Zellweger spectrum disorder (ZSD)

It is a genetic disease ranging from severe to mild. While individual phenotypes were described in the past before the biochemical and molecular bases of this spectrum were fully determined, the term “ZSD” is now used to refer to all individuals with a defect in one of the ZSD-PEX genes regardless of phenotype.

Examples of disease described are:

• Zellweger syndrome (ZS)
• Neonatal adrenoleukodystrophy (NALD)
• Infantile Refsum disease (IRD)

Individuals with ZSD usually come to clinical attention in the newborn period or later in childhood. Affected newborns are hypotonic and feed poorly. They have distinctive facies, congenital malformations (neuronal migration defects associated with neonatal-onset seizures, renal cysts, and bony stippling (chondrodysplasia), and liver disease that can be severe. Infants with severe ZSD are significantly impaired and typically die during the first year of life, usually having made no developmental progress.

Individuals with intermediate/milder ZSD do not have congenital malformations, but rather progressive sensory loss (secondary to retinal dystrophy and sensorineural hearing loss), neurologic involvement (ataxia, polyneuropathy, and leukodystrophy), liver dysfunction, adrenal insufficiency, and renal oxalate stones. While hypotonia and developmental delays are typical, intellect can be normal. Some have osteopenia; almost all have ameleogenesis imperfecta in the secondary teeth.

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Causes and risk factors

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. Retinal dystrophy occurs due to abnormalities in photoreceptors as well as defects in phototransduction.

Cases may be:

• Syndromic. Syndromic cases have clinical features that extend to multisystemic involvement
• Non-syndromic, which affect only the retina.
• Sporadic, where no associated disease or gene can be found
• Familial. Inheritance patterns could be autosomal dominant, autosomal recessive or X-linked.

Depending on the type of photoreceptors affected, retinal dystrophies can be subdivided into:

• Rod-dominated diseases
• Cone-dominated diseases
• Generalized form, which involves both rods and cones.

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Symptoms

While all retinal dystrophy forms affect vision, the symptoms and progression of the disease are different.

Nyctalopia (night time blindness) is a constant symptom presenting in a later stages of the retinitis pigmentosa. Patients also notice subtle progressive loss of peripheral vision. In most cases, the inferior retina is affected first. Upper visual field losses are common.

Visual field loss, coupled with night vision problems, makes these patients prone to accidents, especially at night. The rate of progression of visual loss is usually slow, so 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 macular edema, epiretinal membrane, or development of retinal pigment epithelial defects (RPE) in macular or fovea. Color vision remains unaffected until the later stages of the disease in most cases.

Progressive cone rod dystrophy disorders typically present with progressive loss of central vision, colour vision disturbance and photophobia.

Cone monochromatism (color blindness) 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 people ranges from 20/80 to 20/200. Clinical signs and symptoms resemble achromatopsia cases. They can see blue color.

Syndromic diseases usually are associated with many malformations and other organ involvement.

In Oguchi disease, for example, 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.

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Diagnosis

People with complains of vision problems usually see a primary care doctor who refers them to the Ophthalmologist. You can compare eye doctors by their special skills and diseases they treat.

On the first appointment a thorough family and health history will be discussed, followed by an eye exam. Many situations call for the use of multiple tests including genetic testing that can be done only in the research centers.

Vision test

A simple visual acuity test can predict a diagnosis, as not all retinal dystrophies will have reduction of the visual acuity.

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 retinitis pigmentosa, regular field assessments are mandatory, especially if the patient is driving a motor vehicle.

All patients with retinitis pigmentosa have to restrict night driving and eventually stop driving as the disease progresses. Regular field assessments help 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 test

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. So, higher-order color tests may be required for diagnosis.

Optical coherence tomography (OCT)

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. OCT is also useful in detecting cystoid macular edema and epiretinal membrane. It can eliminate the need for fundus fluorescein angiography for detecting CME.

In Fundus Albipunctatus, hyperreflective deposits are noted over retinal epithelial pigment, corresponding to retinal flecks observed clinically. 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.

Electrophysiology test (ERG)

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 retinitis pigmentosa from disorders like cone-rod dystrophy where marked reduction or absence of cone ERG responses in the presence of less reduction in rod responses are seen.

Retinal photography

Fluorescence lifetime imaging ophthalmoscopy (FLIO) is an emerging technology, which enables the time-resolved in-vivo measurement of fluorescence emitted by endogenous fluorophores within the retina. The decay time of the fluorescence is a characteristic parameter for fluorescent molecules and their environment, and therefore FLIO is a promising tool to detect and assess varying metabolic states of different areas in the retina.

The system is based on a confocal scanning laser ophthalmoscope with an implemented real-time eye tracking system. The fluorophores are excited by picosecond laser pulses and the fluorescence emission is detected using time correlated single photon counting (TCSPC) technology.

Fundus appearance of retinitis pigmentosa 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.

Blood test

Blood test is usually ordered for the genetic testing. It can be also used to identify nutritional deficiencies causing eye problems,

The diagnosis of choroideremia is established in a male proband with suggestive findings and a hemizygous pathogenic variant in CHM identified by molecular genetic testing.

USH2A mutations are an important cause of retinitis pigmentosa (RP) with or without congenital sensorineural hearing impairment.

The diagnosis of ZSD is established in a proband with the suggestive clinical and biochemical findings above by identification of biallelic pathogenic variants in one of the 13 known ZSD-PEX genes. One PEX6 variant, p.Arg860Trp, has been associated with ZSD in the heterozygous state due to allelic expression imbalance dependent on allelic background.

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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.

In autosomal recessive diseases when both parents are carriers, each child has a 25% risk of inheritance. If only one parent is a carrier of the gene none of the children will be affected. In the areas with known predominance of genetic traits consanguineous marriages must be avoided.

All families will benefit from a referral to support services. This is particularly important when dealing with issues like vocational rehabilitation training and schooling for a visually impaired child.

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How it can be prevented?

Currently, retinal dystrophies are not preventable or curable. But supportive treatment can improve the quality of life to people with this vision problem. Major options to consider in all cases include visual aids and cataract surgery when indicated.

Patients with night vision problems benefit from counselling about dangers of fall and car accidents. people with color blindness 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.

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References

RetinalDystrophies. Chawla H, Vohra V.2021 Feb 15. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan–.PMID: 33232049 Free Books & Documents. Review.

Progressive cone and cone-rod dystrophies: clinical features, molecular genetics and prospects for therapy. Gill JS, et al. Br J Ophthalmol. 2019. PMID: 30679166 Free PMC article. Review.

Zellweger Spectrum Disorder. Steinberg SJ, Raymond GV, Braverman NE, Moser AB.2003 Dec 12 [updated 2020 Oct 29]. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mirzaa G, Amemiya A, editors. GeneReviews^® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2021.PMID: 20301621 Free Books & Documents. Review.

Retinitis Pigmentosa. O’Neal TB, Luther EE.2021 Aug 11. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan–.PMID: 30137803 Free Books & Documents. Review.

Fluorescence Lifetime Imaging Ophthalmoscopy (FLIO). Bernstein P, Dysli C, Fischer J, Hammer M, Katayama Y, Sauer L, Zinkernagel MS.2019 Aug 14. In: Bille JF, editor. High Resolution Imaging in Microscopy and Ophthalmology: New Frontiers in Biomedical Optics [Internet]. Cham (CH): Springer; 2019. Chapter 10.PMID: 32091850 Free Books & Documents. Review.