The retinal dystrophies are a large group of heterogeneous conditions characterized by deteriorating vision in both eyes due to degeneration of the photoreceptors (cones and rods) in the retina. Central vision and color vision are primarily controlled by the cones, while peripheral vision and night vision are controlled by the rods. An individual’s clinical features or course may infer information regarding which cells are most affected or when. Most retinal dystrophies are genetic, with autosomal dominant, autosomal recessive, and X-linked forms reported. Retinal dystrophies can be either non-syndromic (isolated) or syndromic in nature. The non-syndromic retinal dystrophies include early-onset forms such as Leber congenital amaurosis, rod-cone dystrophies such as retinitis pigmentosa, cone-rod dystrophies, and macular dystrophies such as Stargardt or Best vitelliform macular dystrophy (Nash et al., 2015). Retinal dystrophy can also be a feature of a genetic syndrome, such as Usher disease, Batten disease, and Bardet-Biedl syndrome (Chiang et al., 2015).
Over 200 genes have been associated with retinal dystrophies. While significant genetic and clinical overlap have been noted, these conditions have varying prognoses and management strategies. Next generation sequencing for non-syndromic retinal dystrophy genes has been proposed as an effective tool for decreasing cost and increasing detection rate among affected individuals (Bowne et al., 2011; Fu et al., 2013; Shah et al., 2020). Multi-gene panel testing is supported by the American Academy of Ophthalmology as the most effective testing strategy for non-syndromic retinal dystrophies (Stone et al., 2012; Duncan et al., 2016). Evaluation for copy number variation is important as well, as about 3% – 9% of cases are due to deletions, duplications or other copy number variants (Jespersgaard et al., 2019; Zampaglione et al., 2020). Comprehensive multi-gene retinal dystrophy panels of over 200 genes have been able to identify inconsistencies between initial clinical diagnoses and genetic results, which may necessitate revision of the clinical diagnosis (Huang et al., 2014). Genetic diagnoses are more likely to be established in individuals whose initial disease symptoms occur before 30 years of age, and inconclusive genetic testing is more frequent among those with atypical fundus features or autoimmune diseases (Birtel et al., 2019). It is important to target genetic testing based on clinical details and family history when possible, given the challenges associated with variants of uncertain significance that are frequently detected from larger sequencing tests (Di Resta et al., 2018).
Accurate diagnosis and genotype data is important for the optimal treatment and management of persons with retinal dystrophies. Testing may identify an underlying syndromic diagnosis in some cases, leading to additional treatments or surveillance recommendations (Duncan et al., 2016). In addition, treatment decisions may be impacted by genetic results. For example, some studies suggest that high dose vitamin A may slow the progression of retinitis pigmentosa, and Vitamin A is frequently recommended for individuals with inherited retinal disease (Berson et al., 2004). However, Vitamin A is specifically contraindicated for individuals with Stargardt disease and other ABACA4-related macular dystrophies as it may actually accelerate disease progression in these individuals (Radu et al., 2008). Targeted gene therapies have also become more promising in recent years. Clinical trials are ongoing for several inherited retinal diseases; however, challenges still exist for others, including difficulty developing gene-specific treatments due to the genetic heterogeneity of these conditions (Duncan et al., 2016; Fortuny and Flannery, 2018; Amato et al., 2021; Martinez Velazquez and Ballios, 2021).
Select retinal dystrophies are discussed below:
Retinitis pigmentosa
Retinitis pigmentosa (RP) causes progressive vision loss due to abnormalities of the photoreceptors or the retinal pigment epithelium. In typical RP, individuals first experience difficulty seeing at night, progressing to total “night blindness” and often loss of peripheral vision. For some individuals with RP, loss of central vision occurs late in the course of the disease, while other individuals retain a very small area of good central vision throughout their lives. Total blindness is uncommon in typical RP. RP is usually nonsyndromic, but about 20-30% of patients with RP have a syndromic form that is also associated with extra-ocular abnormalities (Verbakel et al., 2018). Usher syndrome, which is also associated with variable hearing loss and balance problems, is one of the more common syndromic forms of RP. Other syndromes associated with RP include Joubert Syndrome, Bardet-Biedl syndrome, and systemic metabolic and mitochondrial disorders, which can be associated with risks for renal disease and cardiac dysfunction, among other features.
Pathogenic/likely pathogenic (P/LP) variants in over 60 genes are known to cause RP, but over 100 genes are suspected to be involved. No single gene accounts for the majority of RP cases, but some more commonly affected genes include USH2A, RPGR, EYS, ABCA4, PRPF31, RP1, RP2, CYP4V2, and RHO (Huang et al., 2018; Verbakel et al., 2018). Multiple modes of inheritance are associated with RP genes, including autosomal dominant, autosomal recessive, X-linked and rarely, forms of digenic inheritance have been reported (Fahim et al., 2017). In addition, specific genes can exhibit variable inheritance. For instance, P/LP variants within the RHO gene can cause autosomal dominant and autosomal recessive RP (Nash et al., 2015). Further complicating the inheritance, both de novo P/LP variants and incomplete penetrance are observed.
Testing of all genes known to be associated with RP identifies a P/LP variant in up to 69% of persons with RP (Birtel et al., 2019). Targeted genetic testing for patients with RP is complicated by locus heterogeneity, limited ability to predict genotype from a phenotype, and the complex and variable inheritance patterns observed. Still, genetic testing through multi-gene panels often allows for precise identification of the inheritance pattern and leads to more accurate risk assessment and reproductive decision-making for affected persons and their families.
Accurate diagnosis and genotype data is important for the optimal treatment and management of persons with retinal dystrophies. Testing may identify an underlying syndromic diagnosis in some cases, leading to additional treatments or surveillance recommendations (Duncan et al., 2016) as well as impact treatment options and eligibility. In late 2017, the FDA granted approval of Luxturna (voretigene neparvovec), a gene therapy that introduces a functioning copy of the RPE65 gene directly into the retina. This one-time treatment can improve functional vision for patients with RPE65 mediated retinal dystrophy who still have viable retinal cells. Genetic testing is necessary prior to initiation of this expensive treatment, as it is only indicated for individuals with biallelic P/LP variants in the RPE65 gene (Russell et al., 2017). RPE65 accounts for approximately 3.1% of retinitis pigmentosa cases overall (Huang et al., 2018).
Cone-rod dystrophy
Cone-rod dystrophy (CRD) is a term used to describe a group of inherited retinal dystrophies in which both the cones and the rods are affected, leading to progressive vision loss. In cone-rod dystrophy, the cones are affected to a greater degree than the rods, therefore, affected individuals typically experience difficulties with color vision, central vision, and light sensitivity first. Later in the course of the disease, as the rods become more significantly affected, peripheral vision loss and night vision difficulties become more apparent. Cone-rod dystrophies tend to demonstrate early onset and are often syndromic. The clinical diagnosis of cone-rod dystrophy relies upon documentation of loss of photoreceptor function by electroretinography (ERG), often in conjunction with multifocal ERG testing (Hamel 2007).
Cone-rod dystrophy can be inherited in a dominant, recessive, or X-linked pattern. When a specific genetic etiology is not apparent based on clinical evaluation, panel testing is useful given the number of genes associated with inherited eye diseases. Some of the more common genes associated with CRD include ABCA4, PRPH2, and BEST1 (Birtel et al., 2018). Identifying a genetic etiology is important to determine best medical management, as syndromic etiologies may necessitate changes in clinical management such as increased screening for other medical concerns. Multi-gene panel testing is again supported in this population with a diagnostic yield reported to be as high as 74% (Birtel et al., 2018).
Leber Congenital Amaurosis (LCA)
Leber congenital amaurosis (LCA) causes progressive, severe visual impairment beginning in infancy or early childhood. LCA is part of a group of inherited disorders caused by abnormalities of some of the light-sensitive layers of the retina, including the rods, cones, and retinal pigment epithelium (RPE). LCA has a prevalence between 1 in 33,000 to 1 in 81,000 and accounts for approximately 5% of inherited retinal disease (Kumaran et al., 2017). Children and adults with LCA often have nystagmus, photophobia, high hyperopia, keratoconus, and the Franceschetti’s oculo-digital sign which includes frequent eye poking, pressing, and rubbing (Kumaran et al., 2017). Visual acuity is rarely better than 20/400. The clinical diagnosis of LCA relies upon documentation of cellular loss of the photoreceptors through ERG testing. Though most cases of LCA occur in otherwise normal infants, any non-ocular symptom and signs should be investigated for syndromic retinal dystrophy or neurometabolic disease. Renal involvement can be seen in some subtypes of LCA/early onset severe retinal disease (Kumaran et al., 2017).
LCA is typically inherited in an autosomal recessive manner, although it can sometimes be inherited as an autosomal dominant condition. Up to 28 genes have been associated with the development of LCA and account for 70-80% of cases (Kumaran et al., 2017; Kondkar and Abu-Amero, 2019). CEP290, GUCY2D, and NMNAT1 are some of the most common causative genes (Duijkers et al., 2018; Thompson et al., 2017). CRX, IMPDH1, and OTX2 are the genes associated with the autosomal dominant form of LCA (Thompson et al., 2018).
When a specific genetic etiology is not apparent based on clinical evaluation or family history, panel testing is useful given the number of genes associated with LCA. In addition to identifying syndromic etiologies, gene-specific therapies have emerged in the treatment of inherited retinal diseases such as LCA. P/LP RPE65 variants account for approximately 7% of LCA cases and as discussed with retinitis pigmentosa, there is an FDA approved gene therapy, Luxturna, available to LCA patients with this causative gene (Thompson et al., 2017). Clinical trials for gene therapies for other forms of inherited retinal disease are also in progress, including antisense oligonucleotide therapy for CEP290-associated LCA (Duijkers et al., 2018; Thompson et al., 2018).
Achromatopsia
Achromatopsia is an autosomal recessive condition associated with reduced visual acuity, pendular nystagmus, photophobia, a small central scotoma, eccentric fixation, and impaired color discrimination (Hirji et al., 2018). Hyperopia is common. Nystagmus typically develops shortly after birth, followed by the development of photophobia. There are two categories of achromatopsia: complete and incomplete. In complete achromatopsia, none of the three types of cone photoreceptors function (Hirji et al., 2018). In incomplete achromatopsia, which is less common, one or more cone types may partially function (Hirji et al., 2018). The symptoms of incomplete achromatopsia are similar to complete achromatopsia but generally less severe (Hirji et al., 2018).
There are currently 6 genes known to be associated with achromatopsia: CNGA3, CNGB3, GNAT2, PDE6C, ATF6, and PDE6H. The CNGB3 gene accounts for the majority of P/LP variants in Caucasian individuals (60%), and up to 80% of patients with Israeli, Palestinian, or Chinese ancestry have P/LP variants in CNGA3. P/LP variants in PDE6H lead to the incomplete form of achromatopsia, but certain P/LP variants in GNAT2 and CNGA3 are associated with a very mild form of incomplete achromatopsia as well, and are difficult to distinguish (Kohl et al., 2018).
Treatment for achromatopsia is typically based on symptoms, but knowing the potential for disease progression can be useful in medical and personal management of vision concerns (Kohl et al., 2018). Additionally, early clinical trials with gene therapy have shown promise in the treatment of achromatopsia and further research is ongoing (Kohl et al., 2018, DiCarlo et al., 2018, Hirji et al., 2018; Fischer et al., 2020).
Choroideremia
Choroideremia (CHM) is an X-linked condition characterized by progressive chorioretinal degeneration. Males are more severely affected, typically presenting first with night blindness, progressing to peripheral visual field loss in their 40’s. Central vision is usually maintained until age 50-70. Cataracts may be present in about 31% of affected males. Carrier females are generally asymptomatic, but later-onset vision loss is possible. Funduscopic examination in carrier females often shows patchy chorioretinal atrophy, which is caused by random X-inactivation (MacDonald et al., 2003).
In general, a diagnosis of choroideremia may be suspected based on clinical examination in an affected male, especially with a characteristic appearance of the fundus with chorioretinal degeneration beginning in the mid-periphery, progressing to marked loss of the retinal pigment epithelium and choriocapillaris, and preservation of the deep choroidal vessels (MacDonald et al., 2015). Genetic testing is necessary to confirm a diagnosis. CHM is inherited as an x-linked condition due to P/LP variants in the CHM (REP1) gene.
Beyond providing accurate diagnosis, confirmation of a CHM P/LP variant may also impact eligibility for relevant clinical trials. There are currently no specific therapeutic interventions for CHM, however gene therapy is under development for AAV2-REP1, which is an adeno-associated viral vector designed to produce functional REP1 inside the eye (Edwards et al, 2016; Imani et al., 2018). Initial results of these clinical trials are promising in maintaining/improving vision of affected patients and demonstrating sustained improvements to visual acuity, while also demonstrating an acceptable safety profile (Xue et al., 2018; Lam et al., 2018; Fischer et al., 2020). Robot-assisted infusion of the vector is being developed to improve consistency and safety. Antisense oligonucleotide therapy has also been proposed as a treatment for CHM caused by a specific P/LP variant known to cause aberrant splicing (Garanto et al., 2018).
Retinoschisis
X-linked juvenile retinoschisis is a rare inherited condition that causes blindness or poor vision in affected boys. Onset is typically in the first decade of life, and can occur as early as 3 months. Vision often worsens throughout childhood and adolescence but then remains stable until middle age. X-linked retinoschisis is caused by P/LP variants in the RS1 gene. In males with an RS1 P/LP variant, penetrance is complete, though there is variability in the severity of symptoms both within and across affected families. Carrier females are asymptomatic but may be ascertained through a detailed retinal exam or genetic testing (Tsang and Sharma, 2018).
Treatment for retinoschisis may include surgery, although this approach is complex. Affected and at risk boys should have annual evaluation by a pediatric ophthalmologist or retina specialist until age 10 (Sieving et al., 2014). Clinical trials involving gene therapy are underway, with initial results that have been promising (Rao et al., 2018; Cukras et al., 2018).
Macular Dystrophy
Macular dystrophy is a type of inherited retinal degeneration that primarily affects the macula, which is the region of the retina that is important for sharp central vision and color vision. As with most forms of inherited retinal degeneration, both eyes are typically affected. Multiple forms of inherited macular dystrophy have been identified, with autosomal dominant, autosomal recessive, and X-linked forms reported. Multiple genes have been reported with inherited macular dystrophies. There is considerable clinical and genetic overlap of macular dystrophy with other retinal dystrophies such as retinitis pigmentosa and cone-rod dystrophy, and sometimes the diagnosis or classification for a particular patient may change with disease progression or molecular test results (Birtel et al., 2018). Details about some of the more common forms of macular dystrophy are provided below:
Stargardt Macular Dystrophy
Stargardt macular dystrophy is the most common inherited macular dystrophy in both adults and children, with a prevalence of 1:8,000-10,000 (Tanna et al., 2017). Stargardt disease is a slowly progressive macular dystrophy with onset generally in late childhood to early adulthood. Characteristic presentation includes progressive and bilateral decreased central visual acuity and night vision problems. Some individuals with Stargardt disease may also have impaired color vision. In most people with Stargardt disease, lipofuscin accumulates in cells underlying the macula. The spectrum of variability in Stargardt disease is broad. Treatment for this disease is typically focused on visual support and adaptation, and photoprotection. Recent data suggests that individuals with ABCA4-associated Stargardt disease may progress more rapidly with vitamin A exposure and thus supplements containing this vitamin should be avoided (Radu et al., 2008). Stargardt disease is diagnosed using family history information and a variety of tests, including visual acuity and visual field testing, fundus autofluorescence (FAF), fluorescein angiography, optical-coherence tomography (OCT), and electroretinography (ERG).
P/LP variants in the ABCA4 gene account for ~90% of cases of Stargardt macular dystrophy. ABCA4-related Stargardt macular dystrophy is considered to be an autosomal recessive form of the condition. Both sequence variants and deletions have been reported within the ABCA4 gene (Bax, 2015). P/LP in ELOVL4 and PROM1 have also been associated with Stargardt disease; however, less commonly and typically associated with an autosomal dominant form of the condition. Determining the gene associated with Stargardt disease helps to determine recurrence risk for family members as both autosomal recessive and dominant forms are known. Disease severity may be able to be predicted based on type of mutation (Di Iorio et al., 2018). In addition, confirmation of the genetic mutation can impact treatment decision-making for these patients, especially with regard to Vitamin A supplementation, as described above (Radu et al., 2008).
Clinical presentation of Stargardt macular dystrophy may overlap with cone rod dystrophy, with some individuals with a clinical diagnosis of Stargardt disease are later found to have cone-rod dystrophy. Clarifying a diagnosis through molecular diagnostic testing may assist in planning for vision interventions. Clinical trials for gene replacement, stem cell therapy, and pharmacological approaches are underway (Tanna et al., 2017).
Vitelliform Dystrophies
Vitelliform dystrophies are a group of macular degenerative diseases characterized by round yolk-like yellow lesions in the macula in fundus exam. A prevalence study in a midwestern American population estimated the prevalence for vitelliform dystrophies to be 1 in 5500 (Dalvin et al., 2016). Although most forms of vitelliform dystrophies are idiopathic in nature, there are some inherited forms of vitelliform dystrophies including Best disease and some pattern dystrophies.
Best vitelliform macular dystrophy (VMD) (also known as bestrophinopathies) is a slowly progressive macular dystrophy with onset generally in childhood to late teens. Characteristic presentation includes progressive decreased central visual acuity and metamorphopsia, while peripheral vision and dark adaptation is often stable. Retinal findings typically do not manifest until ages 5-10 years. Both expression and age of onset are variable, and though penetrance is generally complete, some individuals can remain asymptomatic (MacDonald et al., 2013). Other genetic modifiers may influence disease penetrance in some families with inherited BEST1 P/LP variants (Nguyen et al., 2018).
Diagnosis of Best VMD is based on clinical examination, including fundus appearance, electrooculogram (EOG), and family history. Best VMD has a distinctly identified macular lesion. BEST1 (VMD2) is the only known gene associated with Best VMD, although this gene has also been associated with other retinal dystrophies such as Cone-Rod dystrophy. Both autosomal dominant and autosomal recessive inheritance of BEST1 P/LP variants have been reported, and inheritance depends on the type of variant (Tian et al, 2014). Management of Best VMD includes vision aids, direct laser photocoagulation and anti-vascular growth factors (anti-VEGF) therapy (MacDonald et al., 2013). In addition, smoking is not advised for individuals who have Best VMD and annual ophthalmologic examinations are recommended as surveillance for all individuals who have the condition.