Aicardi syndrome

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Aicardi syndrome is a rare disorder that occurs primarily in women and girls. Aicardi syndrome has typically been characterized by the presence of three main features:

Although many affected individuals will have all three of these features, some people with Aicardi syndrome will have only two. Besides these main features, people with Aicardi syndrome typically have additional signs and symptoms.

The folds and grooves on the surface of the brain often do not develop properly in people with Aicardi syndrome. Additional abnormalities that can occur in affected individuals include a difference in the size or shape between the two halves of the brain, cysts in the brain, enlargement of the fluid-filled cavities (ventricles) near the center of the brain, and clusters of cells that are not in the correct location (heterotopias).

Infantile spasms are the most common type of seizure in infants with Aicardi syndrome. However, as they age, many people with Aicardi syndrome will develop additional types of seizures, some of which may not respond well to medication.

People with Aicardi syndrome typically have developmental delays and intellectual disabilities, which can range from mild to severe. For most affected individuals, developmental delays and intellectual disabilities fall within the moderate to severe range.

Chorioretinal lacunae are considered to be a characteristic feature of Aicardi syndrome. However, additional eye abnormalities may also occur. The structure that carries information from the eye to the brain (optic nerve) can be underdeveloped (hypoplasia) or have a gap or hole (coloboma). Another eye abnormality that can occur is called microphthalmia, which is a birth defect in which one or both eyes do not fully develop and are abnormally small. The eye abnormalities in individuals with Aicardi syndrome can cause vision loss.

Some people with Aicardi syndrome have differences between the right and left sides of the face (facial asymmetry), a short area between the upper lip and the nose (philtrum), a flat nose with an upturned tip, large ears, and sparse eyebrows. Other features of this condition include small or malformed hands; spinal and rib abnormalities that lead to progressive abnormal curvature of the spine (scoliosis); and gastrointestinal problems, such as constipation or diarrhea, gastroesophageal reflux, and difficulty feeding.

The number and severity of the signs and symptoms seen in people with Aicardi syndrome can vary. Affected individuals with severe signs and symptoms may not survive past childhood, while those with milder features can survive into adulthood.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

The cause of Aicardi syndrome is unknown. Because it occurs almost exclusively in women and girls, researchers believe that Aicardi syndrome is caused by changes in a gene on the X chromosome. Genetic changes that cause disease are called pathogenic variants.

People normally have 46 chromosomes in each cell. Two of the 46 chromosomes, known as X and Y, are called sex chromosomes because they help determine whether a person will develop male or female sex characteristics. Females typically have two X chromosomes (46,XX), and males have one X chromosome and one Y chromosome (46,XY).

Early in embryonic development in females, one of the two X chromosomes is permanently inactivated in cells other than egg and sperm cells. This process is called X-inactivation. X-inactivation ensures that females, like males, have only one active copy of the X chromosome in each body cell. X-inactivation usually occurs randomly, so that each X chromosome is active in about half the body's cells. Sometimes, however, X-inactivation is not random. This is called skewed X-inactivation.

Skewed X-inactivation sometimes occurs when there is a pathogenic variant in one of the X chromosomes in each cell. Skewed X-inactivation has been identified in some women and girls with Aicardi syndrome. This could explain why some people with Aicardi syndrome are more severely affected than others. Skewed X inactivation also supports the idea that the condition is caused by a pathogenic variant in a gene on the X chromosome. However, the gene that contains this variant has not been identified.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

Nearly all known cases of Aicardi syndrome are sporadic, which means that they occur in people with no history of the disorder in their family.

Researchers suspect that the pathogenic variants that cause Aicardi syndrome typically occur as random (de novo) events during the formation of eggs or sperm in an affected individual's parent or during early embryonic development.

Although this condition primarily affects women and girls, cases of men and boys with Aicardi syndrome have been reported.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

Aicardi syndrome is a very rare disorder. It occurs in about 1 in 105,000 to 167,000 newborns in the United States. Researchers estimate that there are approximately 4,000 affected individuals worldwide.

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.

Infantile spasms · Very frequent (99-80%)

Infantile spasms represent a subset of "epileptic spasms". Infantile Spasms are epileptic spasms starting in the first year of life (infancy).

Intellectual disability, moderate · Very frequent (99-80%)

Moderate intellectual disability (ID) is defined as a type of ID characterized by moderately sub-average adaptive functioning and intellectual functioning, with an intelligence quotient (IQ) the range of 35-49.

Intellectual disability, severe · Very frequent (99-80%)

Severe intellectual disability (ID) is defined as a type of ID characterized by severely sub-average adaptive functioning and intellectual functioning, with an intelligence quotient (IQ) the range of 20-34.

Moderate global developmental delay · Very frequent (99-80%)

A moderate delay in the achievement of motor or mental milestones in the domains of development of a child.

Pachygyria · Very frequent (99-80%)

Pachygyria is a malformation of cortical development with abnormally wide gyri with sulci 1,5-3 cm apart and abnormally thick cortex measuring more than 5 mm (radiological definition). See also neuropathological definitions for 2-, 3-, and 4-layered lissencephaly.

Partial agenesis of the corpus callosum · Very frequent (99-80%)

A partial failure of the development of the corpus callosum.

Polymicrogyria · Very frequent (99-80%)

Polymicrogyria is a congenital malformation of the cerebral cortex characterized by abnormal cortical layering (lamination) and an excessive number of small gyri (folds).

Other findings in the same source

From: Orphanet

Additional reported features include Severe global developmental delay (Very frequent (99-80%)); Bifid ribs (Frequent (79-30%)); Block vertebrae (Frequent (79-30%)); Butterfly vertebrae (Frequent (79-30%)); EEG abnormality (Frequent (79-30%)); Hemiplegia/hemiparesis (Frequent (79-30%)); Hypertonia (Frequent (79-30%)); Hypotonia (Frequent (79-30%)); Microcephaly (Frequent (79-30%)); Microphthalmia (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 Aicardi syndrome is Clinical Genetics, with a clinical geneticist as the relevant type of clinician. Paediatrician (children) or physician (adults), with clinical geneticist referral.

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.

• Does the exact genetic or chromosome finding explain the observed features?
• Would a genetic counsellor help the family understand the result?
• Which organ-specific assessments are appropriate for this particular diagnosis?

Treatment discussions and follow-up

Where the source describes treatments, these are an overview of possible care, not a prescription for an individual. Ask which option applies to the confirmed diagnosis, what benefit is expected, what adverse effects to watch for and how progress will be assessed. Availability, approvals and local practice can differ from the country described in the source.

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.