Which are the causes of Leber Congenital Amaurosis?

Leber Congenital Amaurosis (LCA) is a rare genetic disorder that affects the development and function of the retina, leading to severe visual impairment or blindness from birth or early childhood. LCA is primarily caused by mutations in at least 18 different genes, each responsible for the production of proteins essential for normal vision.

1. RPE65 Gene Mutations: Mutations in the RPE65 gene are the most common cause of LCA, accounting for approximately 10-20% of cases. The RPE65 gene provides instructions for producing a protein that is crucial for the normal functioning of the retinal pigment epithelium (RPE), a layer of cells that support the photoreceptor cells in the retina.

2. Other Gene Mutations: Mutations in genes such as CRX, GUCY2D, AIPL1, CRB1, and SPATA7, among others, can also lead to LCA. These genes play vital roles in the development, maintenance, and function of photoreceptor cells in the retina.

3. Inheritance Patterns: LCA can be inherited in an autosomal recessive, autosomal dominant, or X-linked recessive manner. Autosomal recessive inheritance is the most common pattern, where both parents carry a single copy of the mutated gene but do not exhibit symptoms themselves. When both parents pass on the mutated gene, their child has a 25% chance of developing LCA.

4. Protein Dysfunction: The mutations in LCA-associated genes result in dysfunctional or absent proteins, disrupting the normal processes required for vision. These proteins are involved in various functions, including phototransduction (conversion of light into electrical signals), maintenance of photoreceptor structure, and transportation of molecules within the retina.

5. Retinal Degeneration: The impaired function of photoreceptor cells, specifically the rod cells responsible for vision in low light conditions, leads to progressive degeneration of the retina. The degeneration of the retina further contributes to the visual impairment experienced by individuals with LCA.

6. Variable Severity: The severity of LCA can vary widely among affected individuals, even within the same family. Some individuals may have minimal vision loss and retain some degree of visual function, while others may experience complete blindness.

While LCA is primarily a genetic disorder, it is important to note that not all cases are caused by known gene mutations. Researchers continue to investigate other potential causes and contributing factors to further understand the complexity of this condition.