What Is Leber Congenital Amaurosis?

Updated October 7, 2020

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A list of references is also included at the bottom of this article.

What Is Leber Congenital Amaurosis?

Leber congenital amaurosis (LCA) is a disorder of the eye affecting the retina, the part of the eye responsible for detecting light.

Leber congenital amaurosis is a disorder people are born with caused by a harmful change in several different genes. Individuals with this disorder typically have a visual impairment that begins in infancy.

What's in this Guide?

Disclaimer: Before You Read

It is important to know that your genes are not your destiny. There are various environmental and genetic factors working together to shape you. No matter your genetic makeup, maintain ideal blood pressure and glucose levels, avoid harmful alcohol intake, exercise regularly, get regular sleep. And for goodness sake, don't smoke.

Genetics is a quickly changing topic. Read More...

The visual impairment from LCA can be severe. It may remain consistent throughout life or worsen slowly over time.

In unaffected eyes, the pupils will expand and contract in response to the amount of light that enters the eyes. In patients with LCA, the eyes react to light slower than normal. Sometimes the eyes do not respond to light at all. 

There are few treatment options for LCA, and no cure. However, there are gene therapy clinical trials gaining momentum as research advances.

What are the Symptoms of Leber Congenital Amaurosis? 

The symptoms of LCA can vary depending on which gene is involved.

Severe vision impairment from infancy is the hallmark feature of LCA, but other problems with the eyes can occur as well. Some patients will have fairly stable vision throughout life, while others will experience a decline. 1

It’s not possible to predict what the specific symptoms will be when someone is first diagnosed. Some patients will have blurred vision while others have more noticeable features like being cross-eyed or having rapid uncontrollable eye movements. 

Some of the terminology used when describing disorders of the eyes can feel intimidating. The following list outlines some of the common findings in LCA, using both the medical term and a clarifying description. 2

  • Photophobia - This is a symptom in which a person experiences a high sensitivity to bright lights. With photophobia, discomfort in the eye occurs when exposed to light. 
  • Nystagmus - This is involuntary eye movement. Nystagmus may cause the eyes to move rapidly from side to side, up and down or in a circular motion. This can cause blurry vision. 
  • Cataracts - Cataracts are a clouding of the lens of the eyes. This makes it difficult to see and resembles looking through fogged up windows. 
  • Strabismus - This is when the eyes are not looking in the same direction at the same time, otherwise known as cross-eyed. 
  • Abnormal retinal pigment - This is a thickening of the pigment layer of the retina.
  • Hyperopia - This is a condition in which nearby objects look blurry. This is also known as farsightedness.
  • Keratoconus - This is a progressive eye disease, which means it gets worse over time. When keratoconus occurs, the normally round cornea begins to thin and turn into a cone-like shape. This cone-like shape deflects light when it enters the eye and distorts vision. 

The following table, adapted from Takkar (2018) 3, provides a high-level comparison of how LCA impacts a person across the most commonly involved genes.

 

Who is affected by Leber Congenital Amaurosis?

LCA is estimated to occur in 1 in every 33,000 live births. 4

It is the cause of 5% of all retinal dystrophies and 20% of all blindness in school-aged children. 5 This occurs equally in males and females.

What Causes Leber Congenital Amaurosis? 

The majority of Leber congenital amaurosis cases are caused by a genetic change. However, some cases have no definitive cause.

In general, LCA is caused by disruptions in genes that are involved in the formation of the retina in the eye. The genes play different roles in the retina development.

Some are responsible for moving proteins around throughout the eye, some create electrical signals that are sent to the brain, and others help form photoreceptors. 6 Since many genes are involved, the underlying cause for each can be different. This is why the symptoms of LCA can be so variable. 

The Different Types of Leber Congenital Amaurosis

There are currently thought to be 2 dozen genes that cause LCA and each can cause slightly different symptoms.

Over the years researchers continue to find new genes responsible for LCA. To date there seems to be 23 genes that can be involved. 7

Mutations in the genes CEP290, CRB1, GUCY2D, and RPE65 are the most common causes of LCA. 8

Mutations in other genes cause a smaller percentage of this disorder. However in some cases it’s not possible to discover the gene involved.

  • CEP290 gene - This is the most common gene mutation associated with LCA. This mutation affects the cilia that develop in the retina and photoreceptors. Cilia act as transporters to move proteins around. When the cilia don’t function properly, proteins don’t get moved into areas of the eye where they are needed. 9
  • CRB1 gene – Disruptions in this gene lead to short and nonfunctional CRB1 proteins. The shortage of CRB1 protein affects the early development of the retina and makes the retina become unusually thick, causing for the severe visual impairments in early life. 10
  • GUCY2D gene – When this gene is disrupted there is a shortage of the protein product, causing photoreceptor cells to have issues going into their dark state after being exposed to light. 11
  • RPE65 gene – This gene disruption causes a partial or total loss of RPE65 protein function. This creates a build-up of all-trans-retinal in the retinal pigment epithelium. This build-up blocks the visual cycle, causing visual impairment. 12

Other genes involved in LCA include, but are not limited to, AILP1, CRX, IMPDH1, LRAT, RD3, RDH12, RPGRIP1, SPATA7 and TULP1. 13

If I Have a Child With LCA, What Are the Chances That Future Children Will Have it as Well?

Most genes involved in LCA have an autosomal recessive inheritance pattern. 14 This means that it takes 2 non-working copies of the gene for a child to be affected.

In this kind of pattern, each parent must be a carrier for there to be a chance that a child will inherit the condition.

A carrier is someone who has a single non-working copy of the gene but is not personally affected. They wouldn’t be expected to show any symptoms of LCA.

If one parent is a carrier and the other is not a carrier, the chance that a child would be affected with LCA is very unlikely.

However, if both parents are carriers of a non-working gene, then there are a few possibilities for how a child could be affected.

  • If both parents are carriers there is a 25%, or 1 out of 4, chance that the child will be born with two working genes and be unaffected.
  • There is also a 50%, or 1 out of 2, chance that the child will have one working and one non-working gene, making the child a carrier of the disease. They would not have LCA or be expected to show any symptoms. This would make the child a carrier, just like their parents. 
  • Finally, there is a 25%, or 1 out of 4, chance that the child will be born with two non-working genes and will inherit LCA. 

Diagnosis of Leber Congenital Amaurosis 

In early examinations, sometimes the retina may look normal, with degeneration occurring later as the disease progresses.

Diagnosis of LCA can be complicated due to the different set of symptoms patients can have. One study reports that patients see an average of 7 ophthalmologists before finally receiving a diagnosis, usually not until their teenage years. 15

Some of the important aspects during an initial evaluation and clinical assessment are: 16

  • Detailed history of vision symptoms
    • What was the age of onset?
    • Are there affected family members?
    • Is there night blindness, light sensitivity, or troubles with color discrimination?
  • Looking at physical features that may be present
  • Imaging scans of the eye
    • Electroretinography (ERG)
    • Electrophysiologic

For imaging studies, an ERG can be useful in narrowing down whether or not a patient has LCA. ERG is a non-invasive test that measures the electrical circuit of the eye.

The retina's light-sensitive cells are assessed with an ERG while being stimulated. The test of someone with LCA will show a flat ERG, which indicates no retinal function.

Later on, the retina will show signs of a thinning, pale optic nerve and pigmentary changes that can be measured to diagnose the disease. 17

Regardless of the symptoms that are identified during an evaluation, the only way to confirm an LCA diagnosis is through genetic testing. Determining which gene is involved is critical to help understand the probable progression of the condition and identify which treatments have the best chance of success.

Knowing the genetic cause will also help a family plan for future pregnancies, or share risk status with other family members.

Treatment and Care Options for Leber Congenital Amaurosis

Treatment options for Leber congenital amaurosis can vary depending on the specific gene causing the condition. 

There is no cure for LCA, so treatments generally focus on lessening the impact of symptoms or attempting to slow the progression of vision loss. For those with poor vision, low vision aids are recommended to allow people to go about daily tasks as uninterrupted as possible. 18

With so many genes involved in causing LCA, treatment needs to take on a patient-specific approach. 19 Whether we’re looking at medications or gene therapy, there is not a one-size-fits-all model.

Recently there has been exciting advancements in gene therapy for LCA patients with a genetic change in the RPE65 gene. 20 Gene therapy hopes to deliver working copies of a gene into the cells of a patient and restore that missing function. 21

In 2017 the FDA approved the medication Luxturna based on phase III clinical trials that showed improvement after 1 year of use. 22, 23

For the latest news on clinical trials or research opportunities, you can visit the LCA Clinical Trials list from the National Institutes of Health. Before deciding to join a clinical trial or research study, it is very important that you work with your doctor to understand possible impacts or side effects that could occur.

Participating in research can be very rewarding for some individuals, and the risks and benefits must be carefully considered. 

Not all types of LCA are eligible for gene therapy trials, so this again stresses the need to have a confirmed diagnosis before determining a treatment plan.

Where can I get support if my family is affected by Leber Congenital Amaurosis?

The thought of living with impaired or no vision can be very scary for families recently diagnosed with LCA. 

Making connections with other families and learning from their experiences can be a solid source of support as you navigate this unexpected path. Support organizations have a wealth of knowledge on practical advice, topics to discuss with your doctor, and information about research.

The websites listed below offer various ways to get in touch with other families and become a part of the LCA community.

  • Curing Retinal Blindness Foundation
  • Sofia Sees Hope
  • Foundation Fighting Blindness
  • Fight For Sight
  • Retina UK

Referenced Sources

  1. Koenekoop, R. K. (2004). An overview of leber congenital amaurosis: a model to understand human retinal development. Survey of Ophthalmology, 49(4), 379–398. https://doi.org/10.1016/j.survophthal.2004.04.003
  2. American Foundation for the Blind. (n.d.). Eye Conditions. Retrieved July 26, 2020, from https://www.afb.org/blindness-and-low-vision/eye-conditions
  3. Takkar, B., Bansal, P., & Venkatesh, P. (2018). Leber's Congenital Amaurosis and Gene Therapy. Indian journal of pediatrics, 85(3), 237–242. https://doi.org/10.1007/s12098-017-2394-1
  4. Koenekoop, R. K. (2004). An overview of leber congenital amaurosis: a model to understand human retinal development. Survey of Ophthalmology, 49(4), 379–398. https://doi.org/10.1016/j.survophthal.2004.04.003
  5. Schappert-Kimmijser, J., Henkes, H. E., & Bosch, J. van den. (1959). Amaurosis Congenita (Leber). A.M.A. Archives of Ophthalmology, 61(2), 211–218. https://doi.org/10.1001/archopht.1959.00940090213003
  6. Genetics Home Reference. (n.d.). Leber congenital amaurosis. Genetics Home Reference. Retrieved July 26, 2020, from https://ghr.nlm.nih.gov/condition/leber-congenital-amaurosis
  7. Alkharashi, M., & Fulton, A. B. (2017). Available Evidence on Leber Congenital Amaurosis and Gene Therapy. Seminars in ophthalmology, 32(1), 14–21. https://doi.org/10.1080/08820538.2016.1228383
  8. Takkar, B., Bansal, P., & Venkatesh, P. (2018). Leber's Congenital Amaurosis and Gene Therapy. Indian journal of pediatrics, 85(3), 237–242. https://doi.org/10.1007/s12098-017-2394-1
  9. Cideciyan, A. V., & Jacobson, S. G. (2019). Leber Congenital Amaurosis (LCA): Potential for Improvement of Vision. Investigative Ophthalmology & Visual Science, 60(5), 1680–1695. https://doi.org/10.1167/iovs.19-26672
  10. Hollander, A. I. den, Heckenlively, J. R., van den Born, L. I., de Kok, Y. J. M., van der Velde-Visser, S. D., Kellner, U., Jurklies, B., van Schooneveld, M. J., Blankenagel, A., Rohrschneider, K., Wissinger, B., Cruysberg, J. R. M., Deutman, A. F., Brunner, H. G., Apfelstedt-Sylla, E., Hoyng, C. B., & Cremers, F. P. M. (2001). Leber Congenital Amaurosis and Retinitis Pigmentosa with Coats-like Exudative Vasculopathy Are Associated with Mutations in the Crumbs Homologue 1 (CRB1) Gene. The American Journal of Human Genetics, 69(1), 198–203. https://doi.org/10.1086/321263
  11. Boye S. E. (2014). Leber congenital amaurosis caused by mutations in GUCY2D. Cold Spring Harbor perspectives in medicine, 5(1), a017350. https://doi.org/10.1101/cshperspect.a017350
  12. Takkar, B., Bansal, P., & Venkatesh, P. (2018). Leber's Congenital Amaurosis and Gene Therapy. Indian journal of pediatrics, 85(3), 237–242. https://doi.org/10.1007/s12098-017-2394-1
  13. Chung, D. C., & Traboulsi, E. I. (2009). Leber congenital amaurosis: clinical correlations with genotypes, gene therapy trials update, and future directions. Journal of AAPOS : the official publication of the American Association for Pediatric Ophthalmology and Strabismus, 13(6), 587–592. https://doi.org/10.1016/j.jaapos.2009.10.004
  14. Koenekoop, R. K. (2004). An overview of leber congenital amaurosis: a model to understand human retinal development. Survey of Ophthalmology, 49(4), 379–398. https://doi.org/10.1016/j.survophthal.2004.04.003
  15. Weiss, A. H., & Biersdorf, W. R. (1989). Visual sensory disorders in congenital nystagmus. Ophthalmology, 96(4), 517–523. https://doi.org/10.1016/s0161-6420(89)32864-8
  16. Chung, D. C., & Traboulsi, E. I. (2009). Leber congenital amaurosis: clinical correlations with genotypes, gene therapy trials update, and future directions. Journal of AAPOS : the official publication of the American Association for Pediatric Ophthalmology and Strabismus, 13(6), 587–592. https://doi.org/10.1016/j.jaapos.2009.10.004
  17. Chung, D. C., & Traboulsi, E. I. (2009). Leber congenital amaurosis: clinical correlations with genotypes, gene therapy trials update, and future directions. Journal of AAPOS : the official publication of the American Association for Pediatric Ophthalmology and Strabismus, 13(6), 587–592. https://doi.org/10.1016/j.jaapos.2009.10.004
  18. Cideciyan, A. V., & Jacobson, S. G. (2019). Leber Congenital Amaurosis (LCA): Potential for Improvement of Vision. Investigative Ophthalmology & Visual Science, 60(5), 1680–1695. https://doi.org/10.1167/iovs.19-26672
  19. Koenekoop, R. K. (2004). An overview of leber congenital amaurosis: a model to understand human retinal development. Survey of Ophthalmology, 49(4), 379–398. https://doi.org/10.1016/j.survophthal.2004.04.003
  20. Chung, D. C., & Traboulsi, E. I. (2009). Leber congenital amaurosis: clinical correlations with genotypes, gene therapy trials update, and future directions. Journal of AAPOS : the official publication of the American Association for Pediatric Ophthalmology and Strabismus, 13(6), 587–592. https://doi.org/10.1016/j.jaapos.2009.10.004
  21. Koenekoop, R. K. (2004). An overview of leber congenital amaurosis: a model to understand human retinal development. Survey of Ophthalmology, 49(4), 379–398. https://doi.org/10.1016/j.survophthal.2004.04.003
  22. FDA Office of the Commissioner. (2020, March 24). FDA approves novel gene therapy to treat patients with a rare form of inherited vision loss. FDA. https://www.fda.gov/news-events/press-announcements/fda-approves-novel-gene-therapy-treat-patients-rare-form-inherited-vision-loss
  23. Russell, S., Bennett, J., Wellman, J. A., Chung, D. C., Yu, Z. F., Tillman, A., Wittes, J., Pappas, J., Elci, O., McCague, S., Cross, D., Marshall, K. A., Walshire, J., Kehoe, T. L., Reichert, H., Davis, M., Raffini, L., George, L. A., Hudson, F. P., Dingfield, L., … Maguire, A. M. (2017). Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial. Lancet (London, England), 390(10097), 849–860. https://doi.org/10.1016/S0140-6736(17)31868-8

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