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Cone/Cone-rod dystrophy: for patients


Overview

Cone dystrophy and cone-rod dystrophy describe a group of inherited retinal dystrophies caused by genetic changes in one of the 35 genes identified so far that primarily affects the normal function of cone photoreceptor cells in the retina. As a result, these cells degenerate over time and eventually die, leading to sight loss. Combined together, these two conditions affect 1 in 20,000 to 100,000 people worldwide. [1,2]

There are two types of photoreceptor cells in humans, known as rods and cones. The cones are responsible for central (reading) vision, along with helping us to see colour and objects in detail under bright light. Rods are responsible for vision in dim light and peripheral vision (side vision). Only the cone cells undergo degeneration in cone dystrophy while both rods and cones are affected in cone-rod dystrophies.

A microscopic view of the cells in the retina. The cone-shaped and rod-shaped photoreceptors are situated deepest and supported by the RPE cells. Other cells above the photoreceptors are responsible for transmitting electrical signals to the brain to generate vision.
Microscopic view of the cells in the retina: The rod and cone photoreceptors are at the bottom supported by the retinal pigment epithelium. The other cell types above the photoreceptors relay electrical signals to the brain

Hence, patients tend to notice issues with their central and colour vision initially, while those with cone-rod dystrophy will also notice difficulties seeing in dim light (night blindness) and having problems seeing with their peripheral vision. They may end up bumping into things appearing at either side of their vision. Symptoms usually begin in childhood up to early adulthood with progressive deterioration of visual function over time. However, the onset of symptoms, severity of sight impairment, rate of disease progression and inheritance pattern vary among patients depending on the causative gene.

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The condition

Symptoms

1) Visual

Symptoms usually begin in childhood up to early adulthood. The main initial symptoms of cone and cone-rod dystrophies are:

  • Blurred vision/decreased sharpness of vision (known as visual acuity), which cannot be improved entirely by glasses
  • Problems with recognising colours
  • Increased sensitivity to light (known as photophobia)

Patients may also experience other symptoms which include:

  • Nystagmus (involuntary movements of the eyes)
  • Extreme short-sightedness (unable to see far) which requires glasses to improve

In patients affected by cone-rod dystrophies, they may also experience night blindness and blind spots in their peripheral (side) vision along with the aforementioned issues.

A person driving a car with normal peripheral vision is able to see the girl in a red dress on the left. If the driver has a loss of peripheral vision, the same girl is not noticeable.
Peripheral vision loss

Visual function tends to deteriorate over time, with cone-rod dystrophy patients generally experiencing a faster rate of decline compared to those affected by cone dystrophy. Most affected individuals are certified blind by mid-adulthood.[3] The severity of sight impairment, accompanying symptoms and progression of the condition vary between patients depending on the causative gene.

In addition, the appearance of the retina can be quite varied among patients but the macula is usually the first site of involvement, correlating with initial central vision disturbance (blurred vision/decreased visual acuity) experienced by most patients. The retina may also display abnormal pigment changes due to the death of the photoreceptor cells over time.

2) Systemic (other body systems)

Cone/cone-rod dystrophy can occur on their own or may form part of a syndrome where other organs in the body are also affected. Often in these conditions, visual loss is one of the first symptoms noted by parents or patients. Some notable examples include:

Cause

The retina is a complex structure comprised of different type of cells working smoothly together to help us see. 35 genes so far have been implicated to cause cone/cone-rod dystrophies, accounting for 60% of the cases.[4] This means that more genes are yet to be identified. The genes associated with cone/cone-rod dystrophies provide instructions to make proteins vital to the healthy development and functioning of retinal cells.[4] A defect in any of these genes disrupt the smooth working of the retina and leads to sight loss.

How is it diagnosed?

1) Eye examination

An ophthalmologist is able to diagnose someone with cone/cone-rod dystrophy based on the presenting symptoms, clinical examination and performing an electro-diagnostic test of the retina called electroretinogram (ERG). The ERG is used to assess the overall function of the photoreceptor cells in the retina. The cone function is severely reduced in both cone and cone-rod dystrophies, but the rod function is preserved in cone dystrophy while it is less severely affected than cones in cone-rod dystrophy. Doctors may also use special cameras to take pictures of the retina to assess the health and integrity of the different retinal cells.

Genetic testing can help confirm the diagnosis by identifying mutations in one of the 35 genes associated with cone/cone-rod dystrophy.

2) General medical assessment

Occasionally, cone-rod dystrophy may be the first feature of conditions that affect other parts of the body such as Bardet-Biedl and Alström syndrome. Thus, some children may be referred to a paediatrician and other specialists for further assessment, which may include but not limited to:

  • General physical examination including assessment of height, weight (BMI), head circumference and overall development
  • Blood tests
  • MRI (magenetic resonance imaging) of the brain
  • Hearing assessment
  • Heart tracing (knonw as electrocardiogram) and ultrasound of the heart (echocardiogram)
  • Ultrasound of the kidney and liver (if indicated)

How is it inherited?

1) Autosomal recessive (AR) inheritance

Most cases are inherited in this manner, with changes in the ABCA4 gene being most common. In this type of inheritance, two faulty copies of a gene are required to have the condition. Both parents are usually unaffected carriers (who only carry one faulty copy of the gene) while the patient has two faulty gene copies (one faulty copy inherited from each parent). This means that every newborn of the patient has the following risks regardless of gender:

  • 25% chance of being affected by cone/cone-rod dystrophy
  • 25% chance of being unaffected and not a carrier
  • 50% chance of being a carrier with no symptoms
If the mother has 1 copy of the faulty gene in her X chromosome (a carrier) while the father is unaffected, there is 50% chance that a daughter is a carrier and a 50% chance that a son is affected by the condition.
Autosomal recessive inheritance

2) Autosomal dominant inheritance

Only one copy of the faulty gene (inherited from either parent) is required to cause disease. This means that each newborn of the patient has a 50% chance of inheriting the condition regardless of gender. The most common causative gene inherited in this manner is GUCY2D.

The faulty gene copy is present in the father while the mother is not affected. Each newborn of this couple has a 50% chance to be affected by the condition.
Autosomal dominant inheritance

3) X-linked recessive inheritance

In this type of inheritance, the faulty gene is located on the X chromosome (determines our gender together with the Y chromosome). Males inherit the X chromosome from their mothers and the Y chromosome from their fathers. Females inherit one X chromosome from each parent.

As a result, males are usually affected in conditions inherited in an X-linked manner as they only have one X-chromosome containing the faulty gene copy. On the other hand, some cells in females contain the second functioning X chromosome and thus do not display any symptoms (heterozygous carrier). The most common gene responsible for cone/cone-rod dystrophy that is inherited in this manner is RPGR.

If the mother is a carrier and the father is healthy: 

  • Each son has a 50% chance of being affected
  • Each daughter has a 50% chance of being a carrier like the mother

If the father is affected and the mother is healthy: 

  • None of his sons will be affected
  • All of his daughters will be carriers
If a mother has 1 copy of the faulty gene in her X chromosome (a carrier) while the father is unaffected, there is 50% chance that a daughter is a carrier and a 50% chance that a son is affected by the condition.
X-linked recessive inheritance

4) No family history/sporadic

Up to 40% of cone/cone-rod dystrophy patients do not know of any other family members affected by the same condition.[4] This may be because their relatives are unaffected carriers and therefore do not show any symptoms. Genetic testing is the only method to find out how the condition is inherited in such situations, which ultimately be able to assist in family planning. Most sporadic cases turn out to be inherited in an autosomal recessive manner after genetic testing.[5]

If you or your child is affected by cone/cone-rod dystrophy, it is advisable to see a genetic counsellor to obtain more information and advice on inheritance and family planning options.

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Treatment

Is there any treatment?

There are no approved treatments for cone/cone-rod dystrophy at present. Current management is focused on alleviating symptoms and optimising remaining sight by treating the other eye conditions associated with cone/cone-rod dystrophy. These include:

  • Regular monitoring of visual function and prescribing glasses (if required)
  • Referral to low vision services
  • Encourage the use of visual aids and assistive technology
  • Tinted glasses/contact lenses for light sensitivity
  • Wearing hats/UV protected sunglasses and placing sunlight diffusers at the back window of cars to ease light sensitivity
  • A healthy diet consisting of fresh fruit and green leafy vegetables
  • Vitamin A supplementation should be avoided in those with ABCA4 mutations
  • Blue light screen protectors on mobile devices or computer screens*

*Current available evidence shows that blue light emitted from screens do not damage the retina but it can disrupt our sleep cycle. The screen protectors are used as a precautionary measure.

Systemic treatment

As some children with cone/cone-rod dystrophy may suffer from conditions affecting other parts of the body, they might need input from various specialists co-ordinated by a paediatrician. Furthermore, some may experience developmental delays due to deprivation of sight at such an early age, which can have a negative impact on early general development. Therefore, timely referral to practitioners familiar with developmental surveillance and intervention for children with visual impairment (VI), such as developmental paediatricians as well as a Qualified Teacher of children and young people with Visual Impairment (QTVI) is crucial to optimise their developmental potential.

The Developmental Journal for babies and young children with visual impairment (DJVI), developed by Great Ormond Street Hospital Developmental Vision team is a structured early intervention programme designed to track developmental and vision progress in children from birth to three years of age. It is mainly used by qualified healthcare professionals working in services providing support to babies and young children with VI in conjunction with the child’s parents. Children with VI may be referred to specialist services such as the developmental vision clinic in the Great Ormond Street Hospital for Children or other specialist developmental services for further management.

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Current research in cone/cone-rod dystrophy

Much of the current research is focused on finding out the remaining causative genes and understanding how the disease naturally progresses. Findings from ongoing trials in Stargardt disease could pave the way for the development of new therapies for one of the most common causes of cone-rod dystrophy. Other studies that may play similar roles include:

Related links

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Practical advice

Living with cone/cone-rod dystrophy

Patients are still able to lead fairly independent lives through maximising their available vision and having access to social support. Here are some ideas:

  • Using tinted glasses or contact lens when in bright lights, which will help reduce light sensitivity and improve visual sharpness
  • Getting in touch with the local education authority for access to qualified teachers for children with visual impairment (QTVI) and special educational needs co-ordinator (SENCO)
  • Preferential seating in classroom such as in the front row and away from windows
  • Registering your child as sight impaired (SI) or severely sight impaired (SSI) if eligible for access to social support and financial concessions
  • Getting in touch with national or local charities for advice and peer support

Related links

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Referral to a specialist centre

If you are based in the UK and would like to be seen in the nearest specialist centre for your eye condition, either to receive a more comprehensive genetic management or just to find out more about current research, you can approach your GP to make a referral or alternatively arrange for a private appointment. 

More information can be found in our “How to see a genetic eye specialist?” page

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Further information and support

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References

  1.  Roosing S, Thiadens AA, Hoyng CB, Klaver CC, den Hollander AI, Cremers FP. Causes and consequences of inherited cone disorders. Prog Retin Eye Res. 2014;42:1-26
  2.  Hamel CP. Cone rod dystrophies. Orphanet J Rare Dis. 2007;2:7
  3.  Thiadens AA, Phan TM, Zekveld-Vroon RC, et al. Clinical course, genetic etiology, and visual outcome in cone and cone-rod dystrophy. Ophthalmology. 2012;119(4):819-826
  4.  Gill JS, Georgiou M, Kalitzeos A, Moore AT, Michaelides M. Progressive cone and cone-rod dystrophies: clinical features, molecular genetics and prospects for therapy. Br J Ophthalmol. 2019;103(5):711-720
  5.  Birtel J, Eisenberger T, Gliem M, et al. Clinical and genetic characteristics of 251 consecutive patients with macular and cone/cone-rod dystrophy. Sci Rep. 2018;8(1):4824

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Updated on November 30, 2020
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