Leber congenital amaurosis (LCA) is a genetic condition with multiple causes, which causes severe reduction in vision from birth or early childhood onwards.
Diagnosis is made on the basis of family history, clinical and laboratory findings (including an electroretinogram, ERG), a careful search for other genetic anomalies, and genetic testing. These help to confirm the condition as well as to establish how severe it is.
Treatment
LCA is widely considered to be an incurable condition at present and therefore the major form of management for this condition is supportive. The parents should be directed to any program designed to help and integrate visually-impaired children to ensure that they grow up as normally as possible. In addition, any correctable factors such as refractive errors (usually hyperopia) or keratoconus should be treated and aids should be provided to help them utilize the available vision optimally. They should also be given opportunities to complete their studies to whatever level they are able to rise to, and to be gainfully and productively employed.
During early childhood, affected patients should be trained to stop poking or pressing on the eyeballs, which is a typical manifestation called the oculodigital sign of Franceschetti. Repeated attempts may be necessary to terminate this behavior. It is suspected to be associated with trauma to the cornea which may result in keratoconus, an abnormal axial curvature of the cornea which may further affect vision.
Affected individuals are to be followed up carefully. At each visit, the following should be looked for, in addition to other specific tests as indicated.
- Visual acuity and visual field
- Refractive errors
- Amblyopia or lazy eye
- Glaucoma
- Cataract
In a percentage of cases, vision actually improves in adolescence or early adulthood, and the ERG may need to be repeated in these patients.
Jackson story living with Leber's congenital amaurosis | Fight for Sight
Genetic Counseling
Since LCA is most often inherited in an autosomal recessive manner, both parents are carriers of one copy of the abnormal gene. One mutated copy from each parent is inherited by the child to cause the syndrome. In one known variant caused by CRX gene mutations, the inheritance is autosomal dominant. Only one mutated copy needs to be passed down to cause the condition. However, this is often a new mutation not present in either parent.
Parents of affected children should be offered genetic counseling to test relatives or family members who are at risk of transmitting the condition. Genetic counseling means the offering of information on the nature of the condition, the way it is inherited, and what consequences it entails on health and future development of the affected individual. This is intended to make decision-making easier.
Investigational Therapies
In experiments of dogs with blindness caused by mutation of the RPE65 gene, gene therapy has been used to restore gene function. Successful improvement in vision lasting for 5 years or more has been shown to result. This was followed by three trials of AAV-mediated gene therapy in humans, which showed no demonstrable adverse effects but also were not linked to significant improvement in dim or bright light vision.
The CEP290 mutation is another prospect for gene therapy, because of the sparing of cone cells (the light receptors responsible for bright light vision and visual acuity) at the fovea (the point of the retina where they are maximally concentrated) in this condition. This is seen in patients who have lost most of their vision, and is being studied to understand whether these cells can be rescued and used to restore vision in these patients.
Stem cell therapies are also being explored for their application in many fields, for example, their use to help replace the photoreceptors which are dysfunctional in LCA. This follows their use in patients suffering from retinal pigment epithelium disorders. Electronic retinal prostheses are also being studied, but the cost-benefit ratio is suboptimal at the present level of development, and safety risks are also being found. Thus, these are purely experimental at present with no application for therapy in LCA in the near future.
Further Reading