Leber congenital amaurosis (CEP290)

Overview

Leber congenital amaurosis (LCA) is a group of rare inherited eye disorders that cause severe visual impairment very early in life. When LCA is caused by changes in the CEP290 gene, it is often referred to as LCA type 10 (LCA10). Individuals with LCA10 typically experience significant vision loss from birth or within the first few months of life [PMID:20301323].

This condition primarily affects the retina, the specialised tissue at the back of the eye that detects light and sends signals to the brain. The retina contains photoreceptor cells, rods and cones, which are essential for vision. In LCA10, these cells do not function correctly, leading to reduced vision and other eye-related symptoms.

Symptoms & clinical features

The main symptom of Leber congenital amaurosis due to CEP290 variants is severe vision impairment present from birth or very early infancy. This can manifest as poor visual responses, lack of attention to visual stimuli, or nystagmus (involuntary, repetitive eye movements) [PMID:20301323].

Other common signs include photophobia (sensitivity to light) and oculodigital reflex, where individuals press or rub their eyes with their fingers. Pupils may respond slowly or poorly to light. Over time, progressive degeneration of the retina can occur, leading to further decline in vision, though the initial severe impairment is present from a young age.

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Affected organs

Leber congenital amaurosis primarily affects the eyes, specifically the retina. The retina is a complex layer of tissue at the back of the eye that converts light into electrical signals, which are then sent to the brain to form images. In LCA10, the photoreceptor cells (rods and cones) within the retina, which are responsible for detecting light, are significantly impacted.

While LCA10 is primarily an eye condition, variants in CEP290 have also been associated with other conditions that can affect multiple organs, known as ciliopathies. However, the classic presentation of LCA10 is isolated to the eye.

Multiple body systems

Systemic involvement

Cellular impact

Mechanism at cellular level

Risks & severity

Leber congenital amaurosis caused by CEP290 variants typically presents with severe vision impairment from birth or early infancy. The degree of vision loss can vary but is generally profound, often leading to legal blindness. The condition is usually stable or slowly progressive after the initial severe onset.

While the severity of vision loss is high, the condition itself is not considered life-limiting. However, the visual impairment can significantly impact development and quality of life, requiring early intervention and support. The most common pathogenic variant in CEP290, known as c.2991+1655A>G, is often associated with the classic severe LCA phenotype [PMID:21729048].

Genetic causes

Leber congenital amaurosis (LCA) can be caused by pathogenic variants in several different genes. When it is caused by changes in the CEP290 gene, it is known as LCA type 10 (LCA10). The CEP290 gene provides instructions for making a protein called centrosomal protein 290.

This CEP290 protein is vital for the proper structure and function of cilia. Cilia are tiny, hair-like projections found on the surface of many cells, including the photoreceptor cells in the retina. In these cells, cilia play a crucial role in transporting molecules essential for light detection. Pathogenic variants in CEP290 can disrupt the normal function of these cilia, leading to the degeneration of photoreceptor cells and the severe vision loss characteristic of LCA10 [PMID:20301323].

• CEP290
  centrosomal protein 290
  The CEP290 gene provides instructions for a protein essential for the structure and function of cilia, microscopic cellular projections vital for sensory perception and cell signalling.

Inheritance pattern

Leber congenital amaurosis due to CEP290 variants is inherited in an autosomal recessive pattern. This means that an individual must inherit two copies of the altered CEP290 gene - one from each parent - to develop the condition.

If a person inherits only one copy of the altered gene, they are considered a carrier. Carriers typically do not show symptoms of LCA10 themselves but can pass the altered gene on to their children. If two carriers have a child, there is a 25% chance with each pregnancy that the child will inherit two altered copies of the gene and develop LCA10. There is also a 50% chance the child will be a carrier, and a 25% chance the child will inherit two unaffected copies of the gene.

Diagnosis & testing

The diagnosis of Leber congenital amaurosis caused by CEP290 variants is typically suspected based on clinical findings, such as severe vision impairment from infancy, nystagmus, and an abnormal or absent electroretinogram (ERG). An ERG measures the electrical activity of the retina in response to light.

Confirmation of the diagnosis relies on genetic testing. Genomic testing, often using a gene panel that includes CEP290 or whole exome sequencing, is used to identify pathogenic variants in the CEP290 gene. In the NHS Genomic Medicine Service, genetic testing for inherited retinal dystrophies such as LCA is available through specific pathways (e.g., R-code R85 for inherited retinal disease). Referral to a clinical genetics service or an ophthalmologist specialising in inherited eye conditions is usually the route for accessing such testing.

Management & lifestyle

While there is currently no cure for Leber congenital amaurosis due to CEP290 variants, management focuses on supporting individuals and optimising their visual function. This often involves early intervention programs, visual aids, and educational support tailored to children with severe visual impairment. Regular ophthalmological follow-up is important to monitor eye health and manage any secondary complications.

Research into potential therapies, including gene therapy, is ongoing for LCA caused by CEP290 variants. Some specific genetic changes in CEP290 may be amenable to emerging treatments, so genetic diagnosis is important for future potential therapeutic opportunities. Management plans are always individualised and should be discussed with a healthcare professional.

UK care pathway

In the UK, individuals suspected of having Leber congenital amaurosis or other inherited retinal dystrophies are typically referred by their GP, ophthalmologist, or paediatrician to a specialist service. This could be a clinical genetics service or an ophthalmology department with expertise in genetic eye conditions.

Genetic testing for inherited retinal diseases, including those caused by CEP290 variants, is available through the NHS Genomic Medicine Service. The testing is usually requested under specific R-codes, such as R85 for inherited retinal disease, which helps guide the laboratory analysis. Following diagnosis, individuals and their families often have access to genetic counsellors who can provide detailed information about the condition, inheritance patterns, and support resources.

Related conditions

Leber congenital amaurosis (LCA) is a group of conditions that share the common feature of severe, early-onset vision loss. While CEP290 is a common cause of LCA, many other genes can also lead to similar symptoms. For example, variants in GUCY2D, RPE65, and CRB1 can also cause LCA, each with slightly different clinical characteristics or potential therapeutic avenues.

Additionally, variants in CEP290 can sometimes cause a broader group of disorders known as ciliopathies, which affect multiple organ systems beyond the eye, such as Joubert syndrome or nephronophthisis. However, LCA due to CEP290 is often an isolated eye condition. Differentiating between these conditions requires careful clinical evaluation and genetic testing.

• Joubert syndrome
  Ciliopathy
  Shares 1 gene
• Meckel-Gruber syndrome
  Ciliopathy
  Shares 1 gene

Frequently asked questions