Overview

Hereditary retinal dystrophies are a broad (and growing) group of hereditary disorders affecting the retina. About 150 children and 250 adults of working age are registered as blind or partially sighted as a result of these conditions.¹

Retinitis pigmentosa is perhaps the best known of them and is sometimes (inaccurately) used as a synonym for some of the other conditions in this category which are outlined below. See separate article Retinitis Pigmentosa for more information.

Diagnosis

Diagnosis of many of these conditions is made on clinical examination and subjective testing but has to be confirmed with electrodiagnostic tests. This is essential given the genetic implications and helps differentiate retinal disease from choroidal disease.

Subjective retinal tests

• Colour vision tests: the best known of these are the Ishihara's test plates which distinguish between red/green colour blindness. There are more sophisticated tests that can assess for yellow colour blindness, as well as help diagnose complex and subtle degrees of colour blindness.
• Dark adaptometry is useful in patients complaining of night blindness (nyctalopia) - a common complaint in these disorders.

• Fluorescein angiography provides a visual representation of changes in the retina and may help differentiate retinal from choroidal disease.
• Electroretinograms (ERGs) record the action potential produced by the retina in response to light and show typical patterns in dark (scotopic) and light (photopic) conditions. Deviations from normal waves assist diagnosis in a similar manner to an ECG.
• Electro-oculograms (EOGs) complement ERG measurements. They measure the standing potential between the electrically positive cornea and the electrically negative back of the eye. An abnormal EOG arises as a result of problems in the retinal pigment epithelium.

In describing inheritance patterns in this article, the following abbreviations are used:

• AD - autosomal dominant
• AR - autosomal recessive
• XL - X-linked

Management¹

Management of these patients revolves around early diagnosis and specialised genetic counselling in order to decrease morbidity through optimal preventative care. Treatment options for these conditions are limited and tend to be focused around optometric visual rehabilitation where possible (e.g. use of low vision aids, orientation and mobility training). However, as the responsible genes are being progressively identified, work is underway in the field of molecular and gene therapy. Currently, the highly specialised multidisciplinary services required to manage these patients have various availability throughout the UK with some areas having no access at all. Addressing this has been identified as one of a number of strategies that have been recommended in a recent report in order to improve the management and outcome of these patients.

Examples of hereditary retinal disorders

Stargardt's disease³

• Description - also known as juvenile macular dystrophy, this is the most common form of inherited macular degeneration along with fundus flavimaculatus (see below) and accounts for 7% of all retinal dystrophies.⁴
• Inheritance - mainly AR² but there is a rare AD variant.⁴
• Presentation⁵ - childhood (about six years old) to early adulthood: bilateral (usually) decreased central vision. This is often out of proportion to the clinical picture and these children may initially be labelled as malingerers.⁶ There is also progressive colour blindness.
• Prognosis - generally poor. Once vision drops below 6/12, progression is rapid and the visual prognosis is poor. However, active steps in visual rehabilitation can achieve and maintain some degree of independence.⁷

Fundus flavimaculatus²

• Description - sometimes considered to be a variant of Stargardt's disease due to the same gene being affected. However, this condition presents later and the macula may be spared.
• Inheritance - as for Stargardt's disease.
• Presentation - adulthood: may be discovered by chance or the patient may present with central visual deterioration. Deterioration in colour vision is often not noticed by the patient until later on. Peripheral and night vision are unaffected.
• Prognosis - tends to be better than in Stargardt's disease. Patients may remain asymptomatic for many years.

Juvenile Best's disease

• Description² - this rare condition is also known as vitelliform (macular) dystrophy. It is characterised by a macular lesion which grows over years, eventually to give rise to a characteristic round egg-yolk appearance and which may be later associated with a pseudo-hypopyon. There are distinct, identifiable stages in this disease.
• Inheritance - AD with variable penetrance.
• Presentation⁵ - changes occur in EOG readings in children before they are symptomatic or anything is seen clinically. Vision may remain normal or only be slightly decreased in childhood and teenage years when the 'egg-yolk lesion' is present.⁸ It is really only in the fifth decade that vision starts being significantly affected. Most individuals retain reading (and even driving) ability with vision in one eye.⁴
• Prognosis - declining visual acuity may be a reflection of macular scarring but other complications can add to this (e.g. macular hole formation or retinal detachment). Some patients go on to become legally blind.

Adult vitelliform foveomacular dystrophy (adult vitelliform degeneration)⁹

• Description - in this disease, there are bilateral, symmetrical lesions within the macula. They are similar to those of Best's disease but they are smaller, they present in adulthood and they do not progress.
• Inheritance - probably AD.
• Presentation - 40 to 50 years old: blurred vision ± distortion of images (metamorphopsia) which may be mild to the point that this condition is often discovered by chance.
• Prognosis - good, unless complications occur (such as neovascularisation of the underlying choroid).

Familial drusen (North Carolina macular dystrophy)²

• Description - this condition (with subtypes known as Doyne's honeycomb choroiditis or malattia levantinese)⁴ is thought by some to be the early form of age-related macular degeneration. It is characterised by well-defined creamy-yellow spots (drusen) over the macula, which can eventually extend widely over the posterior pole of the eye and around the optic disc.
• Inheritance - AD with full penetrance but variable expressivity.
• Presentation - the drusen only tend to become visually problematic around the fifth decade of life and patients then experience central visual decline.
• Prognosis - this is a progressive disease but peripheral vision is spared.

Bietti's crystalline dystrophy¹⁰

• Description - this condition is characterised by crystalline depositions in the peripheral cornea and the retina ± progressive retinal atrophy.
• Inheritance - XL or AR.
• Presentation - there is progressive visual loss in the third decade, particularly peripheral and night vision.
• Prognosis - the rate of progression varies between individuals.

Progressive cone dystrophies

• Description² - this heterogeneous group of rare disorders encompasses a range of problems from pure cone dysfunction to those with varying degrees of associated (but usually less severe) rod dysfunction. Many patients start with a pure cone problem which then progressively affects the rods over time.
• Inheritance - most are sporadic but AD, AR and XL inheritance is also known.
• Presentation⁶ - 10 to 30 years old: slow, progressive, bilateral visual loss (night vision better than day), photophobia, poor colour vision ± nystagmus. There may also be associated visual field defects.¹¹
• Prognosis - short-term, those with less rod involvement do well but, ultimately, the outlook is poor.

Alport's syndrome

• Description - this collagen type IV defect results in basement membrane abnormalities which manifest themselves through chronic renal failure ± sensorineural deafness. In the eye, there may be lenticonus (the lens' surfaces take on a conical shape), occasional corneal changes and foveal-sparing yellow flecks on the back of the retina.²
• Inheritance - XL dominant.
• Presentation - with renal problems ± deafness.
• Prognosis - visually: excellent.

Benign familial fleck retina⁵

• Description - this rare disorder manifests itself as benign pink-grey fovea-sparing irregularly-shaped lesions that densely cover the retina, extending to the far periphery.
• Inheritance - AR.²
• Presentation - asymptomatic, usually discovered by chance.
• Prognosis - excellent.

Leber's congenital amaurosis²

• Description - this is a rare multisystem disease:
  • Eyes - blindness or hypermetropia, keratoconus (cone-shaped cornea), keratoglobus (large cornea), early cataracts, nystagmus
  • Nervous system - learning disabilities, deafness, epilepsy
  • Other systems - renal and musculoskeletal abnormalities, endocrine dysfunction
• Inheritance - AR.
• Presentation - children are blind from birth or within the first few years of life. They exhibit the characteristic 'oculodigital syndrome': constant rubbing of the eyes results in orbital fat resorption and subsequent endophthalmos (eyes sunken into sockets).
• Prognosis - very poor. Trials are underway for gene therapy in selected patients depending on their genetic makeup (incorrectly identified patients may lead to treatment in some patients and lack of treatment in others; the work is ongoing).¹²

Congenital stationary night blindness⁵

• Description - this term covers various problems which may or may not be associated with abnormalities in the fundus. An example is gyrate atrophy, arising as a result of an AR defect of the mitochondrial enzyme orthinine aminotransferase resulting in hyperornithaemia.⁸
• Inheritance - depending on the subtype, may be AD, AR or XL.
• Presentation - nyctalopia as a result in a delay or an inability to achieve normal dark-adapted rod thresholds. There may be associated myopia, nystagmus and strabismus.
• Prognosis - there is no progression.

Congenital monochromatism²

• Description - this is the umbrella term used to describe various degrees of rod monochromatism or cone monochromatism.
• Inheritance - depending on subtype, AR or XL.
• Presentation - colour blindness: if colour vision is totally absent, the world is seen in shades of grey. There may be some colour perception in incomplete rod monochromatism. Cone monochromatism is associated with better visual acuity (6/6 to 6/9) than rod monochromatism (where this is complete, visual acuity is in the region of 6/60).
• Prognosis - there is no progression.

Hereditary macular dystrophies

There are a variety of other very rare macular dystrophies, most of which are inherited in an AD manner.

• Sorsby's pseudo-inflammatory macular dystrophy, North Carolina macular dystrophy and dominant cystoid macular oedema carry poor prognoses whereas butterfly macular dystrophy is a relatively innocuous condition (often found by chance) resulting in mild impairment of central vision.
• Pattern dystrophy is another example which presents with paracentral distortion and loss of visual acuity. It may also be asymptomatic. Little yellow flecks are seen throughout the fundus, with associated macular atrophy.

Document references

1. Moore T, Burton H; Genetic Ophthalmology in Focus: A Needs Assessment & Review of Specialist Services for Genetic Eye Disorders, April 2008.
2. Kanski J. Clinical Ophthalmology: A Systematic Approach (5th Ed) Butterworth Heinemann (2003)
3. RNIB; Stargadt's disease.
4. Denniston AKO, Murray PI. Oxford Handbook of Ophthalmology (OUP), 2008
5. Willshaw H, Scotcher S, Beatty S. A Handbook of Paediatric Ophthalmology, HE Willshaw (2000).
6. Kunimoto DY, Kanitkar KD, Makar MS; The Wills Eye Manual (4th Ed), Lippincott, Williams and Wilkins (2004)
7. Shah M, Zaman M, Khan MT, et al; Visual rehabilitation of patients with Stargardt's disease. J Coll Physicians Surg Pak. 2008 May;18(5):294-8. [abstract]
8. Jackson TL; Moorfields Manual of Ophthalmology, Mosby (2008)
9. Do P, Ferrucci S; Adult-onset foveomacular vitelliform dystrophy. Optometry 2006 Apr;77(4):156-66. [abstract]
10. National Eye Institute (US); Bietti's Crystalline Dystrophy. Last updated 2007.
11. Simunovic MP; Cone dystrophies. Optom today: 34-36, November 2005
12. Drack AV, Johnston R, Stone EM; Which Leber congenital amaurosis patients are eligible for gene therapy trials? J AAPOS. 2009 Oct;13(5):463-5. [abstract]

Internet and further reading

• Royal National Institute for the Blind (RNIB)
• Leber's Congenital Amaurosis, Contact a Family

Acknowledgements