Leber congenital amaurosis

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Leber congenital amaurosis and early-onset severe retinal dystrophy (EOSRD) are part of a spectrum of inherited diseases that are characterized by severe visual impairment that occurs early in life. Leber congenital amaurosis typically refers to vision loss that occurs during the first year of life, while EOSRD typically refers to vision loss that occurs between the ages of 1 and 5 years. The word "amaurosis" comes from the Greek word for darkness and represents the severe vision loss that is associated with this condition. The visual impairment in people with Leber congenital amaurosis may worsen over time, depending on the specific underlying cause.

There are many types of Leber congenital amaurosis. This group of disorders primarily affects the specialized tissue at the back of the eye that detects light and color (retina). Although cases of Leber congenital amaurosis are rare, this group of disorders is among the leading genetic causes of severe vision loss in infants and is one of the most severe forms of inherited retinal disease.

Children with Leber congenital amaurosis often have additional vision problems, which can include an increased sensitivity to light (photophobia), involuntary movements of the eyes (nystagmus), and extreme farsightedness (hyperopia). In many affected individuals, the pupils, which usually expand and contract in response to the amount of light entering the eye, do not react normally to light. Instead, they expand and contract more slowly than normal, or they may not respond to light at all. Some children may also develop strabismus, which is a condition in which the eyes do not point in the same direction (misalignment). A form of strabismus in which one or both eyes turn inward (esotropia) is the most common type seen in children with Leber congenital amaurosis.

A specific behavior called Franceschetti's oculo-digital sign is a characteristic feature of Leber congenital amaurosis. This sign consists of individuals poking, pressing, and rubbing their eyes with a knuckle or finger. Poking the eyes often results in the sensation of flashes of light called phosphenes. Researchers suspect that this behavior may contribute to the appearance of deep-set eyes in affected children. Repeated eye rubbing or pressing may also increase the risk of developing keratoconus, a condition in which the clear front surface of the eye (cornea) becomes thinner and bulges outward. This can lead to blurred or distorted vision. As a result, frequent eye rubbing may be discouraged.

Children with Leber congenital amaurosis may benefit from early intervention programs and educational opportunities that are designed for children with visual impairment. These programs may help prevent the learning delays that can accompany vision loss.

When Leber congenital amaurosis occurs without additional signs and symptoms, it is called nonsyndromic Leber congenital amaurosis. Because signs and symptoms that are similar to those seen in people with Leber congenital amaurosis can also occur as part of a syndrome that affects other organs and tissues in the body, performing a careful clinical evaluation is an important part of the diagnostic process.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Genetic changes that cause disease are called pathogenic variants. Pathogenic variants in one of over 20 different genes can cause Leber congenital amaurosis. These genes are all necessary for normal vision and play a variety of roles in the development and function of the retina. For example, some of the genes that are associated with this disorder are essential for the normal development of light-sensing cells in the retina called photoreceptors. Other genes are involved in phototransduction, the process by which light entering the eye is converted into electrical signals that are transmitted to the brain. Still other genes play a role in the function of cilia, which are microscopic, finger-like projections that are found in many types of cells, including the retina's photoreceptors. These cilia are required for proper photoreceptor function.

Pathogenic variants in the genes that are associated with Leber congenital amaurosis disrupt the development or function of the retina, resulting in early vision loss. Pathogenic variants in the CEP290, CRB1, GUCY2D, and RPE65 genes are among the most common causes of Leber congenital amaurosis. The CEP290 gene plays a role in the function of cilia, while the CRB1 gene helps with the development of photoreceptor cells. The GUCY2D gene is important for phototransduction. The RPE65 gene plays an important role in the visual cycle, which is the process that helps recycle light-sensitive molecules that are needed for vision.

Despite advances in genetic testing, a pathogenic variant may not be found in 20 to 30 percent of all people with Leber congenital amaurosis. In these cases, the cause of the disorder is unknown.

When Leber congenital amaurosis occurs as part of a genetic syndrome, it is caused by pathogenic variants in the gene that is associated with that syndrome.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

Leber congenital amaurosis can be inherited in different ways, depending on the particular gene involved.

The condition is typically inherited in an autosomal recessive pattern, which means both copies of the gene in each cell must have a pathogenic variant to cause the disorder. The parents of an individual with an autosomal recessive condition each carry one copy of the altered gene, but they typically do not show signs and symptoms of the condition.

In some cases, Leber congenital amaurosis is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In most of these cases, a person with Leber congenital amaurosis inherits the pathogenic variant from a parent. Other cases result from a new (de novo) variant in the gene that occurs during the formation of reproductive cells (eggs or sperm) in an affected individual's parent or during early embryonic development. These affected individuals typically have no history of the disorder in their family.

When Leber congenital amaurosis occurs as part of a syndrome, it follows the inheritance pattern of that syndrome.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

Leber congenital amaurosis occurs in two to three in 100,000 newborns.

Reported clinical features and what the terms mean

The following findings are associated with this condition in Orphanet. They are not a checklist for diagnosing yourself, and they do not all occur in every affected person. Some are examination, imaging or laboratory findings that cannot be recognised at home.

The frequency labels describe how often a finding was reported among people with the condition in the source. They do not give the chance that a person with that symptom has the condition. Definitions below reproduce HPO terminology; they explain the term, not the likely severity in an individual.

Abnormality of retinal pigmentation · Very frequent (99-80%)

Any deviation from the normal pigmentation of the retina.

Abnormality of the optic disc · Very frequent (99-80%)

A morphological abnormality of the optic disc, i.e., of the portion of the optic nerve clinically visible on fundoscopic examination.

Severely reduced visual acuity · Very frequent (99-80%)

Severe reduction of the ability to see. On the 6m visual acuity scale, severe reduction is defined as less than 6/60 but at least 3/60. On the 20ft visual acuity scale, severe reduction is defined as less than 20/200 but at least 20/400. On the decimal visual acuity scale, severe reduction is defined as less than 0.1 but at least 0.05.

Abnormal electroretinogram · Frequent (79-30%)

Any abnormality of the electrical responses of various cell types in the retina as measured by electroretinography.

Abnormal full-field electroretinogram · Frequent (79-30%)

An anomaly observed by full-field electroretinogram (ffERG). The ffERG measures the light-induced electrical activity of the retina at the corneal surface. Specifically, the ffERG records the global or total retinal electrical response to a full-field (Ganzfield) light stimulus. Isolation of the rod and cone components has important diagnostic value in differentiating between various retinal diseases. Modifying the properties of the light-stimulus (wavelength, strength, and flicker rate) as well as the adaptive state of the retina can separate the rod and cone functions of the ffERG.

Abnormality of neuronal migration · Frequent (79-30%)

An abnormality resulting from an anomaly of neuronal migration, i.e., of the process by which neurons travel from their origin to their final position in the brain.

Aplasia/Hypoplasia of the cerebellar vermis · Frequent (79-30%)

Absence or underdevelopment of the vermis of cerebellum.

Cataract · Frequent (79-30%)

A cataract is an opacity or clouding that develops in the crystalline lens of the eye or in its capsule.

Other findings in the same source

From: Orphanet

Additional reported features include Encephalocele (Frequent (79-30%)); Eye poking (Frequent (79-30%)); Hemiplegia/hemiparesis (Frequent (79-30%)); Hypermetropia (Frequent (79-30%)); Hypotonia (Frequent (79-30%)); Keratoconus (Frequent (79-30%)); Nystagmus (Frequent (79-30%)); Photophobia (Frequent (79-30%)); Seizure (Frequent (79-30%)); Slow pupillary light response (Frequent (79-30%)). This is a selected summary, not a complete description of the condition.

Which doctor should you see?

The suggested department for discussing Leber congenital amaurosis is Ophthalmology, with a ophthalmologist as the relevant type of clinician. Ophthalmologist; paediatric services for children as appropriate.

Additional services that may be relevant, depending on the findings, include: Clinical Genetics.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• Which part of the eye or visual pathway is affected?
• What change in vision requires immediate contact with the eye service?
• What are the aims and alternatives of any proposed eye treatment?

Treatment discussions and follow-up

The material gathered for this draft does not provide a complete condition-specific treatment pathway for Leber congenital amaurosis. That gap does not mean that treatment is unavailable. A clinician needs to establish the diagnosis and review current guidance before recommending medicines, procedures, rehabilitation or other support.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.