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PubMed This is a summary of 7 peer-reviewed journal articles Updated
Medical Genetics

The Biology and Genetics of Aicardi Syndrome

At a Glance

Aicardi syndrome is a brain-eye malformation syndrome that usually affects girls and appears to arise from a new genetic change, not one inherited from a parent. No single gene is confirmed, and MRI helps show the varied brain-development abnormalities.

Understanding the biology of Aicardi syndrome is like looking at a complex map of early development where several paths were reshaped very early on. It is not just a condition that affects one part of the brain; rather, it is a brain-eye malformation syndrome that begins during the first few months of pregnancy [1][2]. While we are still learning the exact “why,” researchers have developed several theories about how this condition starts and why it primarily affects girls.

The Genetic Mystery: Why Mostly Females?

One of the most striking features of Aicardi syndrome is its female predominance. For years, the leading scientific theory has been the X-linked dominant, male-lethal model [3].

Humans have two sex chromosomes: females typically have two X chromosomes (XX), and males have one X and one Y (XY). The theory suggests that the genetic change causing Aicardi syndrome occurs on the X chromosome. Because girls have two X chromosomes, the “healthy” X can often compensate enough to allow the baby to develop, though with the malformations we see in Aicardi syndrome [3]. In boys, who have only one X chromosome, the theory suggests that this genetic change is so severe that it is usually fatal before birth [4][2].

While this theory is widely accepted, it remains a hypothesis because no single “Aicardi gene” has been definitively confirmed as of 2025 [4][3]. Interestingly, rare cases have been reported in boys, particularly those with Klinefelter syndrome (who have an XXY chromosome pattern) [3].

A “De Novo” Event

In almost every case, Aicardi syndrome is a de novo event, which means the genetic change is newly arising [3]. This means the genetic change happened by chance in the sperm or egg, or very shortly after conception. It was not inherited from either parent, and parents typically do not carry the genetic change themselves [4][5]. Because it is a random, newly arising event, the risk of it happening again in a future pregnancy is considered low [5].

However, the risk is not literally zero because of possibilities such as germline mosaicism (where a small percentage of a parent’s reproductive cells carry the variant). Families are strongly encouraged to meet with a formal genetic counselor before making reproductive decisions. Genetic testing in Aicardi syndrome is often used primarily to rule out other neurodevelopmental disorders rather than to confirm Aicardi with a single test [4].

A Broader View of Brain Development

While “agenesis of the corpus callosum” (a missing connection between the brain’s halves) is a hallmark of the syndrome, imaging like an MRI shows that Aicardi syndrome affects the brain’s architecture much more broadly [1]. It involves a disruption of how brain cells move and organize themselves during fetal growth.

Key findings often seen on a brain MRI include:

  • Polymicrogyria: This means “many small folds.” Instead of the normal large, deep folds on the brain’s surface, the brain develops many tiny, irregular folds. In one prenatal study of referred cases, this was seen in up to 94% of cases [1].
  • Heterotopia: This occurs when gray matter (brain cells) gets “stuck” in the wrong place while migrating to the brain’s surface. About 88% of children in the same prenatal study had these misplaced cells [1].
  • Intracranial Cysts: Many children (up to 95% in some studies) have fluid-filled sacs near the brain’s fluid-filled chambers (ventricles) or between the brain’s hemispheres [1][6]. The significance of a cyst depends heavily on its size, type, location, and effect on surrounding structures.
  • Brain Asymmetry: One side of the brain may be noticeably smaller or shaped differently than the other [1].

These findings show that Aicardi syndrome is a global disruption of brain development. It is important to remember that MRI findings vary substantially between individuals, and not every child will have all of these malformations [7][2]. The combination of these malformations is what leads to the neurological challenges, such as seizures and developmental delays, that children with this syndrome experience.

Common questions in this guide

Is there a confirmed gene that causes Aicardi syndrome?
No single gene has been definitively confirmed as the cause of Aicardi syndrome. The leading explanation involves a change on the X chromosome, but genetic testing is often used to look for other conditions that can resemble Aicardi syndrome rather than to confirm it with one definitive test.
Why does Aicardi syndrome mostly affect girls?
The leading theory involves a change on the X chromosome. Girls usually have two X chromosomes, so an unaffected copy may allow survival, while boys usually have one X chromosome and the change may be fatal before birth. Rare boys with Klinefelter syndrome, which includes two X chromosomes, have also been reported.
Could Aicardi syndrome be inherited or happen again in another pregnancy?
Almost every case is de novo, meaning the genetic change arises in the sperm, egg, or shortly after conception rather than being passed down from a parent. Recurrence risk is considered low, but not zero because germline mosaicism can occur. A genetic counselor can review family-specific risk before another pregnancy.
What might a brain MRI show in a child with Aicardi syndrome?
The hallmark is agenesis of the corpus callosum, meaning the connection between the brain’s two halves is missing. MRI may also show many small brain folds, misplaced gray matter, fluid-filled cysts, or differences in brain size and shape. Findings vary, so not every child has all of these changes.
Do brain cysts in Aicardi syndrome always need treatment?
No, a cyst does not automatically require surgery. Its importance depends on its size, type, location, and effect on nearby structures, so the care team may recommend monitoring or ask a neurosurgeon to consider intervention when appropriate.
What does a variant of uncertain significance mean in Aicardi syndrome testing?
It means a DNA change was found, but there is not enough evidence to know whether it affects health. A variant of uncertain significance does not by itself confirm Aicardi syndrome or prove that a parent passed it on. The genetics team interprets the result alongside the child’s clinical findings and imaging.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Since Aicardi syndrome is often 'genetically unresolved,' what specific genetic tests have been performed, and were any 'variants of uncertain significance' found?
  2. 2.Can you explain the specific brain malformations found on my child's MRI, such as polymicrogyria or heterotopia, and how they might affect her development?
  3. 3.Given the theory of de novo mutations, what are the chances of this condition recurring in a future pregnancy?
  4. 4.Are there any signs of intracranial cysts, and if so, do they require monitoring or intervention by a neurosurgeon?

Questions For You

Tap a prompt to share your answer — we'll use it plus this page's context to start a tailored conversation.

References

References (7)
  1. 1

    Prenatal diagnosis of Aicardi syndrome based on a suggestive imaging pattern: A multicenter case-series.

    Pomar L, Ochoa J, Cabet S, et al.

    Prenatal diagnosis 2022; (42(4)):484-494 doi:10.1002/pd.6085.

    PMID: 34984691
  2. 2

    A De Novo Mutation in TEAD1 Causes Non-X-Linked Aicardi Syndrome.

    Schrauwen I, Szelinger S, Siniard AL, et al.

    Investigative ophthalmology & visual science 2015; (56(6)):3896-904 doi:10.1167/iovs.14-16261.

    PMID: 26091538
  3. 3

    Aicardi syndrome, an unsolved mystery: Review of diagnostic features, previous attempts, and future opportunities for genetic examination.

    Wong BKY, Sutton VR

    American journal of medical genetics. Part C, Seminars in medical genetics 2018; (178(4)):423-431 doi:10.1002/ajmg.c.31658.

    PMID: 30536540
  4. 4

    Aicardi Syndrome Is a Genetically Heterogeneous Disorder.

    Ha TT, Burgess R, Newman M, et al.

    Genes 2023; (14(8)) doi:10.3390/genes14081565.

    PMID: 37628618
  5. 5

    Exome Sequencing Fails to Identify the Genetic Cause of Aicardi Syndrome.

    Lund C, Striano P, Sorte HS, et al.

    Molecular syndromology 2016; (7(4)):234-238 doi:10.1159/000448367.

    PMID: 27781033
  6. 6

    Microphthalmia and Infantile Spasms Leading to the Diagnosis of Aicardi Syndrome: A Case Report and Literature Review of a Rare Entity.

    Amanallah MR, Chraa M, Louhab N, Balili K

    Cureus 2025; (17(12)):e99822 doi:10.7759/cureus.99822.

    PMID: 41573467
  7. 7

    Agenesis of the Corpus Callosum and Aicardi Syndrome: A Neuroimaging and Clinical Comparison.

    Govil-Dalela T, Kumar A, Agarwal R, Chugani HT

    Pediatric neurology 2017; (68()):44-48.e2 doi:10.1016/j.pediatrneurol.2016.12.002.

    PMID: 28214165

This page explains Aicardi syndrome biology, genetics, and MRI findings for education; it is not medical advice. A genetic counselor and your child’s care team can interpret results and discuss pregnancy planning.

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