CEP290-Related Leber Congenital Amaurosis (LCA10)

Introduction

CEP290

Leber Congenital Amaurosis Type 10 (LCA10) is a rare, inherited eye disorder that causes severe vision loss from birth. It is the result of mutations in the CEP290 gene, which is critical for the normal function of cells in the retina. This document provides an in-depth, scientifically accurate explanation of the condition, covering its genetic basis, clinical symptoms, diagnostic methods, management strategies, and current research efforts. The aim is to present a clear and evidence-based narrative for families, patients, and professionals seeking to understand this complex disorder.

The CEP290 Gene and Its Role

Gene Location and Function

The CEP290 gene, also known as Centrosomal Protein 290, is found on the long arm of chromosome 12 at position 12q21.32. Spanning approximately 93,000 base pairs, it encodes a protein that is vital to the structure and function of centrosomes and cilia, which are microscopic structures present in almost every cell type. In the retina, cilia are particularly important for photoreceptor cells—the specialized light-detecting cells that allow vision. These cilia connect the inner and outer segments of photoreceptors, ensuring that proteins and other molecules are transported correctly to maintain visual function.

When the CEP290 gene is mutated, the resulting protein is faulty or absent, and this disrupts the ability of photoreceptor cells to function properly. Over time, this leads to the progressive degeneration of these cells and a significant loss of vision. The gene is sometimes referred to by other names in scientific literature, including KIAA0373, LCA10, JBTS5, BBS14, and NPHP6. These alternate names reflect its involvement in different ciliopathies—disorders linked to defects in ciliary function.

Understanding LCA10

What is LCA?

Leber Congenital Amaurosis (LCA) is a group of inherited retinal diseases that cause severe visual impairment detectable at or soon after birth. It is a leading cause of childhood blindness globally. Each subtype of LCA is caused by mutations in a different gene, and these subtypes vary in severity, inheritance patterns, and molecular mechanisms.

The Specifics of LCA10

LCA10 refers to the subtype specifically associated with mutations in the CEP290 gene. One of its distinctive features is that, despite severely reduced or absent visual function, the physical structure of the retina—particularly the central region known as the fovea—is often relatively preserved. This structural preservation is significant because it suggests that the retina retains some degree of integrity, making it a promising candidate for emerging treatments aimed at restoring or improving vision.

Epidemiology

Although rare, LCA overall affects an estimated 1 in 30,000 to 1 in 80,000 live births worldwide and accounts for approximately 20% of all cases of childhood blindness. Among these, LCA10 is the most prevalent subtype, representing up to 30% of LCA cases.

In the United States, a specific mutation, known as c.2991+1655A>G (also referred to as IVS26), is present in around 77% of individuals with LCA10. This mutation profile, however, is not consistent globally. In Asian populations and other regions, different mutations within CEP290 are more common, underscoring the importance of considering population genetics when interpreting diagnostic results or designing targeted therapies.

Causes of LCA10

Mutations in the CEP290 gene impair the normal production or function of the protein it encodes. The most frequent pathogenic variant, c.2991+1655A>G, alters the splicing of the gene’s RNA transcript. This mutation creates an abnormal splice site within a non-coding region of the gene (an intron), which leads to the insertion of a “cryptic exon” into the messenger RNA. The resulting protein is truncated and unable to support the maintenance of photoreceptor cell function.

Although CEP290 is active in many tissues, the retina is particularly vulnerable to this dysfunction. Photoreceptors rely heavily on precise protein trafficking between their inner and outer segments, and disruption of this process leads to the rapid onset of visual symptoms seen in affected infants.

Symptoms

The primary symptom of LCA10 is profound vision loss that is evident from birth. Infants often display nystagmus, which are involuntary, side-to-side eye movements that develop as the visual system attempts to compensate for the lack of functional vision. In many cases, the pupils have a reduced or absent light reflex, meaning they do not constrict properly in response to light. Severe hyperopia, or farsightedness, is common, and many children exhibit photophobia, an extreme sensitivity to light that can cause discomfort.

As children grow, some develop keratoconus, a progressive thinning and bulging of the cornea that further distorts vision. Another frequently observed behavior is the oculo-digital sign, where children press or rub their eyes, a response thought to be linked to sensory stimulation in the absence of normal vision. Visual engagement, such as maintaining eye contact or tracking objects, is often limited or absent.

In a subset of patients, the condition extends beyond the eye. Because CEP290 is expressed in other organs, some children exhibit additional systemic symptoms. These may include delays in motor or speech development, neurological features associated with Joubert syndrome such as cerebellar malformations or ataxia, and, in rare cases, kidney or liver abnormalities consistent with broader ciliopathies.

Testing and Diagnosis

Diagnosis of LCA10 requires a combination of clinical evaluation, advanced imaging, and genetic testing.

Ophthalmologic assessments often begin with electroretinography (ERG), which measures the retina’s electrical response to light. In LCA10, this response is typically absent, confirming a severe functional impairment of photoreceptors. Optical coherence tomography (OCT) imaging is then used to visualize the structure of the retina in detail, and many patients show preservation of the central retina despite profound functional loss. Over time, fundus examinations may reveal white deposits or pigmentary changes in the retina, signs of progressive degeneration.

Genetic testing is essential for a definitive diagnosis. Multi-gene panels designed for inherited retinal diseases can detect mutations in the CEP290 gene, allowing for precise identification of the causative variant. Confirming the genetic basis also facilitates accurate genetic counseling for families and helps identify candidates for clinical trials or experimental therapies.

Differentiating LCA10 from other conditions with early-onset vision loss is important. Disorders such as achromatopsia, congenital stationary night blindness, albinism, neuronal ceroid lipofuscinosis, and Zellweger spectrum disorder can present with overlapping clinical features but have distinct molecular causes and prognoses.

Treatment and Management

At present, there is no established cure for LCA10. Management focuses on supporting visual function, addressing complications, and optimizing quality of life from early childhood. Low-vision aids such as magnifiers or tinted glasses can enhance residual vision and reduce discomfort from light sensitivity. Refractive errors, particularly hyperopia, are often corrected with prescription glasses. When structural complications arise, such as keratoconus or cataracts, targeted medical or surgical interventions may be required.

For children, early developmental support is essential. Sensory-based educational strategies, including tactile and auditory learning tools, help maximize developmental outcomes and independence.

Emerging Therapies

Significant research is underway to develop treatments that target the underlying genetic defect. One promising approach is antisense oligonucleotide therapy. The drug sepofarsen (QR-110) is designed to modify the RNA transcript by removing the cryptic exon, thereby enabling production of a functional CEP290 protein. Clinical trials have shown that some patients experience improvements in visual acuity and mobility when treated with this therapy.

Another groundbreaking strategy involves genome editing. The CRISPR-Cas9 therapy known as EDIT-101 aims to directly excise the deep intronic mutation c.2991+1655A>G, restoring normal gene function. Early-phase trials indicate that the therapy is safe and can lead to measurable improvements in light sensitivity and visual performance, particularly in younger patients whose retinal structure is still relatively intact.

Prognosis

Without treatment, LCA10 results in lifelong, profound visual impairment. However, the structural preservation of the central retina in many patients offers hope for future therapies, as interventions are more likely to succeed when the retinal architecture remains relatively undamaged. Prognosis is influenced by the specific mutation involved, the age at which therapeutic intervention begins, and the presence of additional systemic symptoms, such as those seen in Joubert syndrome. Early diagnosis allows for timely access to supportive services and participation in clinical trials, which may significantly improve long-term outcomes.家族に対しての保因者検査や出生前診断（遺伝カウンセリング）も選択肢になります。

Helpful Terms

A gene is a segment of DNA that contains the instructions for building proteins, inherited from both parents. A gene mutation is a change in this sequence that prevents proper protein production, leading to disease. CEP290 is the specific gene implicated in LCA10, responsible for producing a protein critical to the function of photoreceptors in the retina.

Autosomal recessive inheritance means that both parents carry one copy of the mutated gene but do not show symptoms themselves. A child must inherit two copies—one from each parent—to be affected.

The retina is the light-sensitive layer at the back of the eye that captures visual information, while photoreceptor cells within it detect light and transmit signals to the brain. Cilia are tiny, hair-like projections on many types of cells, including photoreceptors, that play essential roles in cell communication and protein transport. Other terms often associated with LCA10 include photophobia (heightened sensitivity to light), keratoconus (corneal thinning and distortion), and the oculo-digital sign (eye rubbing or pressing).

References

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