Genetic retinal disease

• Summary
• Retinitis Pigmentosa (RP)
• Cone-rod dystrophies (CRDs)
• Choroideremia
• Leber congenital amaurosis (LCA)
• Stargardt disease
• Best disease (Best vitelliform macular dystrophy, BVMD)
• Albinism
• Summary table
• References
• Author(s)

Summary

Inherited retinal disease (IRD) is the second most common cause of blindness in childhood, and the leading cause among working age adults in England and Wales. No effective treatment for IRDs exists, however, early gene therapy trials are showing promise.

Retinitis Pigmentosa (RP)

RP is the most common IRD. Also known as the rod-cone dystrophies (RCDs), RP is caused by primary loss of rod photoreceptors, and later in life, secondary loss of cone photoreceptors and degeneration of the retinal pigment epithelium (RPE). RP classically presents with night blindness + progressive visual loss. Its prevalence is 1 in 3000-5000.

Inheritance

RP is a collection of many genetic disorders; RP can be an isolated sporadic disorder, or inherited as autosomal dominant (AD), autosomal recessive (AR), or X-linked (XL). The following genes are most common for these different modes of inheritance:

• AD: RHO, RP1, PRPF31
• AR: USH2A
• XL: RPGR

Mutations in the RHO gene on chromosome 3, which codes for rhodopsin, are the commonest.

〜2% of mutations are in the RPE65 gene, but this is an important gene to remember as gene therapy trials targeting this gene are underway.

Presentation

• Tunnel vision (loss of peripheral vision) - it is rare to lose all vision bilaterally
• Nyctalopia (night blindness) - slow adjustment to dark, or inability to see in the dark
• Decreased visual acuity
• Bilateral involvement (may be asymmetric)

Diagnosis

Classic triad on fundoscopy:

• (1) retinal pigmentary changes (hypo- or hyperpigmentation e.g. bony spicules, pigment clumpings);
• (2) waxy disc pallor;
• (3) arteriolar attenuation

Optic disc drusen may also be found. The pigmentary changes occur in the mid-peripheral fundus (which is largely populated by rods). The fundus findings are often mostly symmetrical between the two eyes.

Other common fundoscopic signs:

• Vitreous cells
• Posterior subcapsular cataract
• Depigmentation + atrophy of the RPE
• Cystic macular lesions
• Refractive error e.g. astigmatism, myopia

Electroretinography (ERG):

ERG measures the electrical potential produced by rods and cones in response to a light stimulus and is vital in the diagnosis of RP.

• Elevated rod threshold on dark adaptation
• ± rod responses are reduced in a- and b-wave amplitude in early disease; non-detectable in advanced disease

Management

• Currently no effective management - vitamin A has been proposed as having possible benefit, but no clear evidence has been demonstrated from randomised controlled trials
• Gene therapy trials are under way, although given RP is a disease caused by heterogeneous genetic mutations, it will be challenging to target these various mutations using gene therapy
• Treatment of RP is a dynamic area of research, with other treatments being investigated, such as retinal prosthesis, and an implant called the Orion Visual Prosthesis System.

Cone-rod dystrophies (CRDs)

CRDs are a group of distinct IRDs, with various genetic causes, that belong to the pigmentary retinopathies group.

Unlike RP (aka rod-cone dystrophies), which involves primary loss of rod photoreceptors (and loss of cones in later life), CRDs involve primary loss of cone photoreceptors (or sometimes simultaneous loss of both rods + cones).

CRDs result in more rapid and severe deterioration in vision than RCDs, leading to earlier blindness.

They are estimated to affect 1 in 30,000-40,000 people.

Inheritance

There are over 30 different recognised CRDs with different genetic causes and patterns of inheritance (AR, AD and XL). Around 2/3 are inherited in an AR fashion.

CRDs usually occur on their own, but may also be part of syndromes (e.g. Spinocerebellar Ataxia Type 7, SCA7).

Clinical features

• In early childhood: decreased visual acuity + photophobia
• Later on, this is followed by: dyschromatopsia (impaired colour vision) and scotomas (blind spots) in the central visual field
• Decreased sensitivity in the central visual field is followed by peripheral visual loss + night blindness
• Patients may develop nystagmus in the late stages

Diagnosis

• History of early decreased of visual acuity + photophobia
• ERG is the key investigation, especially when patients are asymptomatic: hypovolted ERG traces with predominant cone involvement
• Fundoscopic changes in later disease

Choroideremia

Choroideremia is a rare X-linked chorioretinal dystrophy characterised by widespread progressive degeneration of the photoreceptors, RPE and choriocapillaris. The name ‘choroideremia’ arises from the almost total loss of the choroid, retina and RPE, which exposes the underlying white sclera. The Ancient Greek works “choroid” and “eremia” mean skin and barren land/desert respectively.

It is estimated to affect 1 in 50,000-100,000 people. There are estimated to be 〜500 affected males in the UK.

Inheritance

Due to its X-linked inheritance, men are predominantly affected, however women can rarely be affected too.

Choroideremia is caused by a mutation in the CHM gene encoding the REP-1 protein, which plays a role in intracellular vesicular trafficking.

Clinical features

• Nyctalopia, developing in the first decade of life
• Peripheral visual loss by the teenage years, with sparing of central vision until the 5th-7th decade of life
• Rapid deterioration of central vision in the 50s
• Deterioration in colour vision (due to degeneration of the macula) may occur before loss of visual acuity

There is significant variation in the severity of symptoms amongst affected males. Female carriers are generally asymptomatic, but some present with moderate nyctalopia and clinical features of RPE atrophy, chorioretinopathy and peripheral granular pigmentary atrophy.

Early fundoscopic signs are widespread pigment clumping in the RPE (which looks different from the bone-spicule pigment clumping in RP). Then well-defined regions of atrophy in the peripheries ensue, exposing the underlying sclera and choroidal vessels. The areas of atrophy advance towards the centre, sparing the fovea until the late stages of the disease, where foveal atrophy causes a deterioration in central and colour vision.

Investigations

• FA: areas of missing choriocapillaris appear hypofluorescent next to areas of perfused choriocapillaris
• Fundus autofluorescence: early loss of peripheral autofluorescence, followed by centripetal loss
• ERG: abnormal in early disease; the scotopic component (i.e. vision mediated by rods - vision at low light levels) decreases before the photopic component (i.e. vision mediated by cones - colour vision). In later stages, ERG is absent.
• OCT: inner retinal layers are preserved throughout the course of the disease
• Visual fields: peripheral vision lost before central

Management

• No effective treatments
• Gene therapy using viral vectors targeting the mutation in the CHM gene has shown promise in early trials

Leber congenital amaurosis (LCA)

LCA is a family of congenital retinal dystrophies that cause profound visual loss at a young age. It is the most severe retinal dystrophy, causing blindness by the age of 1 year in most patients. The prevalence is 2-3 per 100,000 births.

Various phenotypes exist (LCA1 to LCA19), and genes have been identified for 〜80% of cases. Mutations in 25 genes have been identified so far, coding for a diverse range of retinal functions. Most of these genes encode proteins only expressed in the retina or RPE. The most frequently mutated genes are:

• CEP290 (15% of cases)
• GUCY2D (12%)
• CRB1 (10%)
• RPE65 (8%)

Inheritance

• Autosomal recessive

Presentation

• Severely decreased visual acuity, usually present from birth
• Nystagmus
• Photophobia
• Sluggish or near-absent pupillary reflexes
• High hyperopia

Other features

• Keratoconus
• Olfactory dysfunction
• Mental retardation
• Stereotypical movements and behaviours

Diagnosis

• Diagnosis is clinical, based on history and examination
• Useful investigations: ERG (eletroretinography) and OCT (optical coherence tomography). ERG is severely subnormal or not detectable
• Molecular genetic testing
• The fundus looks normal in infants. In later life, abnormal fundus appearances occur, such as: chorioretinal degeneration + atrophy; “bone-spicule”-like pigmentation; subretinal flecks; “marbled” fundus; pigmented lesions at the level of the RPE; optic disc abnormalities

Management

• No effective treatment for LCA exists
• Refractive error should be corrected
• Gene therapy trials investigating correction of the defective RPE65 gene have shown promise

Stargardt disease

Stargardt disease (STGD) is the commonest juvenile inherited macular dystrophy. It is caused predominantly by an autosomal recessive mutation of the ABCA4 gene on the short arm of chromosome 1 (1p22.1). This causes widespread deposition of lipofuscin in the RPE with consequent impairment and death of photoreceptors.

Rarely, autosomal dominant transmission occurs through mutations in the PROM1 gene.

STGD affects 1 in 10,000 people, accounting for 7% of retinal degenerations.

Clinical features

STGD typically manifests in early childhood or adolescence, but later onset is also possible.

• Patients may be asymptomatic
• Bilateral central visual loss which is rapidly progressive, typically starting in adolescence. A classic history may describe reading difficulty in teenagers
• Colour vision abnormalities
• Photophobia
• Central scotomas
• Slow dark adaptation

Diagnosis

• Fundoscopy: normal in the early stage. As the disease progresses, a bull’s eye maculopathy - described as a ‘beaten bronze macula’ - with diffuse yellow-white flecks (due to the deposited lipofuscin) is seen
• Visual fields: central scotomas
• FA: “dark-choroid” sign is present in up to 62% of patients, due to blockage of fluorescence by lipofuscin deposition

Best disease (Best vitelliform macular dystrophy, BVMD)

Best disease is the second commonest inherited macular dystrophy involving the RPE, and is caused by an autosomal dominant mutation in the BEST1 gene, located on the long arm of chromosome 11 (11q12). This gene encodes the Best1 protein, which lies on the basolateral membrane of the RPE.

Clinical features

Best disease presents childhood or adolescence, and usually has a good visual prognosis. Despite the dramatic fundus appearances in Best disease, visual acuity is often minimally affected, and asymmetrical; in a minority of patients, visual acuity will become significantly reduced, but this is impossible to predict from fundoscopy.

Over time, patients typically experience a slow decline in visual acuity central scotoma, and metamorphopsia (visual distortion).

Diagnosis

• Fundoscopy: bilateral yellow ‘egg yolk’ appearance of the macula. Although one lesion is typical, around 1/3 of patients can have multiple lesions (’multifocal Best disease’).
• ERG: normal
• Electro-oculogram (EOG): abnormal, with a reduced Arden ratio (1.5 or less)

Albinism

Albinism is caused by deficiency of the pigment melanin, and in many patients, involves abnormalities in the optic tract and visual pathways to the brain. The name ‘albinism’ is derived from the Latin word “albus”, translated as “white”.

Albinism can be classified into two main groups:

• Oculocutaneous albinism (OCA), a systemic condition affecting the eyes, hair and skin. OCA is inherited in AR fashion, and is more common than ocular albinism
• Ocular albinism (OA), which is limited to the eye, and has XL inheritance. The mutation is in the GPR143 gene, which encodes the GPR143 protein. This protein controls the growth of melanosomes, intracellular structures which store the pigment melanin.

Clinical features

• Reduced visual acuity
• Photophobia. In OA, there is hypopigmentation of the iris and RPE. Pigmentation is important in filtering light, hence in OA there is excess scattering of light within the eye, producing photophobia
• Nystagmus
• Strabismus
• Difficulties with stereoscopic vision (combining vision from both eyes to perceive depth)
• Refractive errors
• Iris hypopigmentation

Management

• Limit sun exposure (patients with albinism are at increased risk of squamous cell and basal cell carcinomas) + wear sun screen
• Sunglasses (to help with photophobia)
• Treat refractive errors
• Eye muscle surgery may help with strabismus or nystagmus

Summary table

Here we have provided a summary table of key learning points of the genetic retinal diseases for the Duke-Elder exam.

References

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9. Yzer, Suzanne, et al. ‘Ocular and Extra-Ocular Features of Patients with Leber Congenital Amaurosis and Mutations in CEP290’. Molecular Vision, vol. 18, Feb. 2012, pp. 412–25. PubMed Central, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3283211/.
10. ‘What Is Stargardt Disease?’ American Academy of Ophthalmology, 27 May 2021, https://www.aao.org/eye-health/diseases/what-is-stargardt-disease.
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12. Palácios, Renato Menezes, et al. ‘Choroidal Thickness Using EDI-OCT in Adult-Onset Vitelliform Macular Dystrophy’. International Journal of Retina and Vitreous, vol. 2, no. 1, Feb. 2016, p. 5. BioMed Central, https://doi.org/10.1186/s40942-016-0031-1.
13. Johnson, Adiv A., et al. ‘Bestrophin 1 and Retinal Disease’. Progress in Retinal and Eye Research, vol. 58, May 2017, pp. 45–69. DOI.org (Crossref), https://doi.org/10.1016/j.preteyeres.2017.01.006.
14. Sreelatha, O. K., et al. ‘Albinism: Images in Ophthalmology’. Oman Journal of Ophthalmology, vol. 2, no. 1, Jan. 2009, p. 43. www.ojoonline.org, https://doi.org/10.4103/0974-620X.48423.

Author(s)

Jessica Mendall

Jessica is a final year medical student studying in London. She previously studied preclinical medicine in Oxford, intercalating in Systems Neuroscience and Molecular Pathology. She is particularly interested in Ophthalmology, medical education and clinical research.