Leber Congenital Amaurosis ~ Overview
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Leber congenital amaurosis (LCA) is a genetic condition that causes severe loss of vision at birth or early childhood. LCA causes childhood blindness in 1:33,330 people. Recent scientific discoveries have helped us better understand LCA and clinical trials testing therapies for some types of LCA have begun.
Early Symptoms
The symptoms of LCA are often noticed very early in a child’s life – in the first weeks or months after birth. The parents may observe that the child does not focus on things in his/her environment. They may note that their child has “wobbly” back and forth eye movements called nystagmus. Some children may press or push on their eyes with their fingers or fist.
Medical Description
LCA is caused by a genetic mutation in one of several different genes. Each mutation has somewhat different characteristics. During an eye exam, the retina of a small child with LCA may not look different than a normal retina however further testing will reveal that the light-sensing cells in the retina called photoreceptors are not sending electrical signals to the brain correctly. This can be measured by an instrument called an electroretinogram.
Children with LCA usually have severe vision loss of 20/400 or worse. (A person with 20/400 vision can see at 20 feet what a person with normal vision can see at 400 feet). Some children may have only light/dark perception or rarely, no vision at all.
Children with some vision may have other symptoms such as night blindness or light sensitivity. They also may be far-sighted.
There are rare genetic syndromes that mimic LCA vision loss in young children. These include Alström syndrome, Batten disease, Joubert syndrome, and peroxisomal diseases (Zellweger syndrome or Refsum disease). Children with these conditions have vision loss similar to LCA, along with other physical/mental disabilities.
A child diagnosed with true LCA (not one of the syndromes above) may, in rare cases, be more vulnerable to kidney disease than other children. However, compared to the general population, they do not have a greater risk of either intellectual disabilities or autism.
Genetic Causes
Mutations in at least 15 different genes are known to cause LCA. Thirteen of these have been named LCA types 1-13:
|
Type |
Gene |
% of cases |
|
LCA 1 |
GUCY2D |
12 |
|
LCA 2 |
RPE65 |
6 |
|
LCA 3 |
SPATA7 |
Unknown |
|
LCA 4 |
AIPL1 |
5 |
|
LCA 5 |
Lebercillin |
2 |
|
LCA 6 |
RPGRIP1 |
4 |
|
LCA 7 |
CRX |
1 |
|
LCA 8 |
CRB1 |
10 |
|
LCA 9 |
Unknown |
Unknown |
|
LCA 10 |
CEP290 |
15 |
|
LCA 11 |
IMPDH1 |
8 |
|
LCA 12 |
RD3 |
0.1 |
|
LCA 13 |
RDH12 |
3 |
Mutations in the LRAT, MERTK1 and TULP1 genes can also cause LCA.
Diagnosis
An ERG (electroretinography) is the most important test for diagnosing LCA. This test will rule out other cause of early vision loss. OCT (optical coherence tomography) which makes digital images of the retinal layers may also be suggested.
ERG testing may be done on one or both eyes. Drops are put in the eye and the child must stay in a dark room for at least 30 minutes. Large contact lenses are inserted into the eye and it is exposed to flashes of light. This can be done under anesthesia, if need-be. The eye’s electrical response to light is measured. Children with LCA usually have no detectable electrical response from either the rod or cone photoreceptors. This is important for the diagnosis, but it does not mean that the photoreceptors are dead.
To rule out the syndromes mentioned earlier, other testing may also be recommended.
Genetic testing gives a definitive diagnosis of LCA, if a mutation listed on page 1 is found. In 25-30% of cases the genetic cause cannot yet be determined. Ongoing research continues to identify new genetic mutations.
Treatment
No treatments are currently approved for LCA however research is very hopeful. Both gene and drug therapy are giving positive results in human trials of patients with specific mutations. Some types of LCA are associated with cataracts and changes to the cornea. It may be possible to treat these conditions and restore some vision. It is important for people with LCA to be monitored regularly for any changes.
What to Expect
LCA vision loss varies from child to child but remains stable over time in 75% of cases. About 15% of children will have progressive vision loss, while 10% may experience some modest, often temporary, improvement.
Research
Clinical trials of treatments for two genetic types of LCA have begun.
1) Gene Therapy for RPE65 mutations
In 2007, the first clinical trial of a gene therapy for defects in the RPE65 gene began. Since then about 30 people have been treated in clinical trials; all appear to have had at least some benefit, with no serious side effects. Trials are ongoing. To learn more see the FFB gene therapy fact sheet.
2) Drug therapy for RPE65 and LRAT
These two genetic mutations impair the ability of the retina to convert vitamin A into a substance necessary for vision called 11-cis-retinal. In this clinical trial, sponsored by the Canadian company QLT Inc., participants take an oral retinoid called QLT091001. This trial began at the Montreal Children’s Hospital of the McGill University Health Centre under the direction of Dr. Robert Koenekoop; recently several other trial sites have opened in the US and Europe. Some information about the preliminary outcomes for people with LCA was released in 2011.
Gene therapies for other genetic types of LCA are also being developed. Therapies for GUCY2D, AIPL1, and RPGRIP1 mutations have now been demonstrated in animal studies. Additional research teams, including Canadian experts led by Dr. Robert Molday, are targeting other genes. It is anticipated that more clinical trials will start in the next few years.
Updated March 21, 2012: Reviewed by Dr. Robert Koenekoop, Clinician-Scientist and Retinal Specialist, Montreal Children’s Hospital, McGill University Health Centre.