Leber congenital amaurosis (LCA) is a very severe form of congenital blindness due to hereditary retinal dystrophy. It was first identified by Theodore Leber in 1869, and is diagnosed early in infancy or at birth. The child has absolutely no vision or very little, and there is no electrical activity on the electroretinogram (ERG). However, the fundus of the eye, or the inner aspect of the retina viewed through the pupillary opening, appears normal. It is now becoming clear that some cases of LCA are not as severe as described above. It was Waardenburg who first reported the birth of normal children to parents with LCA, and this showed that the mode of inheritance and the action of the genes was not uniform.

Genetic Nature of LCA

LCA accounts for 5% of all congenital genetic retinal dystrophies. About 22 genes have been identified so far and mapped to their chromosomal location. It is transmitted in an autosomal recessive manner, which means both copies of the defective gene must be present in each cell for the disease to manifest.

The first gene connected to LCA was isolated in 1995 and was named LCA1 and is localized on chromosome 17p13. It causes mutations in retGC1, the gene responsible for the form of guanylate cyclase, which is unique to photoreceptors. This is a critical component of the visual process, because it helps the light receptors in the retina to recover to the dark or non-excited state following their stimulation by light. Its defect causes severe dystrophy of both cones and rods (the two types of light receptors in the retina) in fetal life, leading to congenital blindness and it is stationary at birth.

Another mutation was reported in 1997, namely, RPE65. This is a gene which encodes retinal pigment epithelium, and is vital for metabolizing vitamin A. This molecule is the inactive form of rhodopsin, one of the two visual pigments in the eye which trap light and become excited as a result. This mutation causes progressive rather than stationary severe rod-cone dystrophy.

The third gene CRX has been reported to be responsible for the development of light receptors. These three genes are responsible for a little more than a quarter of all cases. The important fact to be grasped about these three genes is that they all produce an identical syndrome, but act in completely different ways.

Clinical Features

LCA is characterized by blindness, nystagmus, absent or sluggish pupillary responses, photophobia, keratoconus and high hyperopia.

A typical sign of this syndrome, and a few other genetic diseases associated with congenital blindness, is Franceschetti’s oculodigital sign, where the infant pokes, rubs and presses the eyes. The retina may or may not show abnormalities, because a few children who initially look normal show pigmentary defects similar to that seen in retinitis pigmentosa.

An ERG typically shows no detectable signal or an extremely subnormal signal. Visual acuity is 20/400 or even less, that means the affected child can see only at the distance of 20 feet away what others with normal vision see at 400 feet.

Diagnosis and Management

The diagnosis of LCA is made upon clinical findings, but genetic testing is now available to test for 17 genes known to cause this syndrome, which account for just over 50% of all cases and include the following:

• GUCY2D or LCA1
• RPE65 or LCA2
• SPATA7 or LCA3
• AIPL1 or LCA4
• LCA5
• RPGRIP or LCA6

Management is largely supportive, and is aimed at helping the child live as normally as possible. This includes optimizing vision, using vision aids, and providing chances to gain good education and employment. The children should be trained not to rub their eyes as this may lead to enophthalmos (sinking in of the eyes into the sockets) in some cases. A careful follow-up is mandatory to assess vision, correct refractive errors such as short-sightedness or long-sightedness, lazy eye, and cataract development.

Genetic counseling is offered to the parents to help them understand the risk of transmission. At each conception, the child may have LCA (25%), may be a carrier having the disease gene but not showing any signs of visual defect (50%), or may be genetically normal (25%). Prenatal and family testing may also be offered if the disease gene is identified.