What Is Leber Congenital Amaurosis?
Leber congenital amaurosis (LCA) is a disorder of the eye. LCA affects the retina, which is the specific tissue in the eye which is responsible for detecting light 1.
Leber congenital amaurosis is a disorder people are born with due to a mutation in specific genes. Individuals with this disorder typically have a visual impairment that begins in infancy.
Generally, the visual impairment severe but consistent, however, it can worsen slowly over time.
In normal, undamaged eyes, the pupils normally 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 Leber congenital amaurosis. However, there is one FDA approved medication that uses an adeno-associated virus for gene therapy. This is only available for a specific type of LCA.
The Different Types of Leber Congenital Amaurosis
There are at least 13 types of LCA. The types are distinguishable by the gene that causes it, the pattern or type of vision loss and the various related eye abnormalities.
Mutations in the genes CEP290, CRB1, GUCY2D, and RPE65 are the most common causes of Leber congenital amaurosis.
Mutations in other genes cause a smaller percentage of this disorder. However, there is an unknown cause of LCA in approximately 30% of all cases.
- CEP290 Gene - This is the most common gene mutation associated with Leber congenital amaurosis. This mutation affects the production of CEP290 protein and reduces its levels in cells. This shortage affects the development of the retina and photoreceptors. Photoreceptors are the light-sensing cells in the retina. These photoreceptors contain cilia, which are filament-like structures. Lack of cilia is what causes severe visual impairment.
- CRB1 Gene - This gene mutation is the cause of approximately 9 to 13% of LCA cases. This leads to abnormally short and nonfunctional CRB1 proteins. The shortage of CRB1 protein affects the early development of the retina and makes the retina become unusually thick. This thickness is the cause for the severe visual impairments in early life in people with Leber congenital amaurosis.
- GUCY2D Gene - This gene mutation causes approximately 6 to 12% of all Leber congenital amaurosis conditions. This mutation causes abnormally short and nonfunctional production of the GUCY2D protein. The shortage in this protein stops photoreceptor cells from going into their dark state after being exposed to light.
- REP65 Gene - This gene mutation causes approximately 6 to 16% of all LCA conditions. This mutation causes a partial or total loss of RPE65 protein function. Due to this, there is a build-up of all-trans-retinal in the retinal pigment epithelium. This build-up blocks the visual cycle, causing visual impairment.
Other causes of Leber congenital amaurosis come from genes such as AIPL1, CRX, IMPDH1, IQCB1, LCA5, LRAT, NMNAT1, RD3, RDH12, RPGRIP1, SPATA7 and TULP1.
Signs & Symptoms of Leber Congenital Amaurosis
There are many symptoms that occur due to LCA.
These Leber congenital amaurosis key characteristics include but are not limited to 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.
- Enophthalmos - This happens when the eyeballs are dislocated backward due to loss of function of the orbital muscle.
- Abnormal retinal pigment - This is a thickening of the pigment layer of the retina.
- Hyperopia - Hyperopia is a condition in which nearby objects look blurry. This is also known as farsightedness
- Pupils may also expand and contract slower than normal when exposed to light. It is also possible that the pupils may not react at all when exposed to light.
- Keratoconus - This eye disease is progressive 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 thus distorts vision.
- Franceschetti's oculo-digital sign- This is also a key characteristic of Leber congenital amaurosis. This is often one of the first behaviors that a child with this disorder will express. The child will begin to poke, press or rub their eyes with a knuckle or finger. Children do this in an attempt to stimulate the retina to produce light. Many times, this behavior is the cause of enophthalmos or keratoconus.
What Is Vision Like for People With LCA?
With all of the complications and symptoms that can occur with this diagnosis, one can predict that vision will be impaired in some way for most, if not all, people with LCA. It can also be different for each type.
Some patients will have blurred vision while others have more noticeable malformities like being cross-eyed or having rapid uncontrollable eye movements.
Are There Other Physical Problems Associated With LCA?
Lastly, it is possible for delayed development, hearing loss, and intellectual disability to happen rarely in those with Leber congenital amaurosis.
These don’t always occur and there is no guarantee that Leber congenital amaurosis is the cause of them.
However, there have been instances where these symptoms are reported alongside the diagnosis of Leber congenital amaurosis.
Prevalence and Risk Factors of Leber Congenital Amaurosis
A common concern for parents is understanding who Leber congenital amaurosis affects. Those who are at risk for this disease inherit the gene abnormalities from their parents.
So, if their parents have the disease, the child may inherit it also. Leber congenital amaurosis prevalence is 1/50,000.
It occurs in 1/33,000 live births and is the cause of 5% of all retinal dystrophies and 20% of all blindness in school-aged children. This occurs equally in males and females.
Causes of Leber Congenital Amaurosis
The majority of Leber congenital amaurosis cases are caused by a genetic mutation. However, some cases have no definitive cause.
How Is LCA Inherited?
The big question most people have is whether or not this disorder is dominant or recessive. Leber congenital amaurosis is a recessive gene abnormality.
This means that parents have to be carriers of the gene mutation in order for the child to develop it. They do not need to have the disease in order to pass it to their children.
This also means that both parents must carry the gene mutation in order for a child to develop it. In most cases, the parents are unaware that they carry this gene until they have an affected child.
What Is an LCA Carrier?
An LCA carrier is someone who has an abnormal gene that does not affect them. A carrier is not symptomatic and is not diagnosed with this disease. However, it is possible for them to pass this gene to their child.
Will Your Next Child Have LCA?
Due to the fact that this is a recessive trait, both parents must have one abnormal gene to pass this to their child. If one parent is a carrier and the other is not, there is a 0% chance that your child will have Leber congenital amaurosis.
However, if both parents are carriers of this mutated gene, then there is a risk for the child to develop the disease. If both parents are carriers there is a 25% chance that the child will be born with two normal genes.
There is also a 50% chance that the child will have one normal and one abnormal gene, making the child a carrier of the disease. They would not, however, have the disease itself.
Finally, there is a 25% chance that the child will be born with two abnormal genes and will inherit the disease. So this means that there is a 1 in 4 chance that a child will develop Leber congenital amaurosis if both parents are carriers.
Diagnosis of Leber Congenital Amaurosis
It is hard to diagnose this in infants without genetic testing. This is because upon early examination, the retina initially looks very normal and degeneration occurs later as the disease progresses.
However, there are some tests doctors can do to help with a diagnosis.
This disease can be confirmed with an electroretinogram (ERG) 3. This 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 Leber congenital amaurosis 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.
Genetic testing can also be done to figure out exactly what genetic mutation has caused Leber congenital amaurosis. This can also help carriers figure out their risk of passing the abnormal gene to their children.
Treatment and Care Options for Leber Congenital Amaurosis
Treatment options for Leber congenital amaurosis can vary depending on the specific gene causing the condition.
Standard Therapies for LCA
For those with LCA caused by an RPE65 mutation, gene therapy is a possibility. Gene therapy is the process of replacing defective or non-functioning cells with new DNA 4.
The idea of gene therapy is to provide the body with a gene that can restore the affected retina.
Voretigene neparvovec-rzyl 5 is an FDA-approved gene therapy option for those with impaired RPE65 gene. This is an adeno-associated virus vector-based gene therapy that has been proven effective to improve visual function in those with Leber congenital amaurosis.
Investigational Therapies for LCA
The most common type of Leber congenital amaurosis is caused by gene CEP290. Although adeno-associated virus gene therapy does not work on this specific type of LCA, there are clinical trials to test the use of Leber congenital amaurosis CRISPR (clustered regularly interspaced short palindromic repeats) to use as gene therapy.
This is not approved by the FDA, however, these studies indicate that there may be use of it in the future.
Which Leber Congenital Amaurosis Patients Are Eligible for Gene Therapy Trials?
Many people do not know that gene therapy is available to them, even if they are eligible. The requirements for gene therapy is for patients to be at least 1 year of age.
Patients must be diagnosed with Leber congenital amaurosis and genetic testing must determine that there is a defect in both RPE65 genes.
Eligibility also requires that the patient has a specific amount of functional retina so that treatment can restore vision.
Children are the ones who will benefit from this treatment the most because they have the least amount of vision impairment from this disease.
Is There a Cure for Leber's Disease?
Unfortunately, there is no way to get rid of the mutated gene or completely cure Leber's disease. However, for one specific mutated gene, the RPE65 gene, there is a promising treatment option to help in restoring vision impairment.
What to Do Next: Living With LCA
Knowledge and support are key to living with a Leber congenital amaurosis diagnosis. There are plenty of services and assistive resources available to those living with this disorder.
If you need more up to date information on these services, visit the Foundation Fighting Blindness website.
How Do You Find out More About LCA?
If you need more support, you can join a Leber’s congenital amaurosis support group. Peer relationships with others who are going through the same thing can be very beneficial.
Other sites you may find helpful include:
The American Society of Retina Specialists
Sophia Sees Hope
Parents who have children with this disease may need a parent support group to help them better understand the disease and get advice on how to best care for their child.
Overall, becoming familiar with various resources and Leber congenital amaurosis foundations will empower you through the diagnosis of this disease.