GENE GUIDE

ARX-Related Syndrome

This guide is not meant to take the place of medical advice. Please consult with your doctor about your genetic results and health care choices. This Gene Guide was last updated in 2025. As new information comes to light with new research we will update this page. You may find it helpful to share this guide with friends and family members or doctors and teachers of the person who has ARX-Related Syndrome.
a doctor sees a patient

ARX-related syndrome is also called Partington syndrome, Proud syndrome, intellectual developmental disorder, X-linked 29, developmental and epileptic encephalopathy 1 (DEE1), hydranencephaly with abnormal genitalia, lissencephaly, X-linked 2, and Ohtahara syndrome. For this webpage, we will be using the name ARX-related syndrome to encompass the wide range of variants observed in the people identified.

ARX-related syndrome happens when there are changes in the ARX gene. These changes can keep the gene from working as it should.

The ARX gene is located on the X chromosome, which is one of the sex chromosomes. Males usually have the condition, but sometimes females have the condition, including the female biological parent.

Key Role

The ARX gene is important for development of the central nervous system (brain and spinal cord).

Symptoms

Because the ARX gene is important for brain activity, many people who have ARX-related syndrome have:

  • Developmental delay
  • Intellectual disability
  • Low muscle tone
  • High muscle tone
  • Movement disorders
  • Vision issues
  • Speech issues
  • Genital development issues
  • Seizures
  • Brain changes seen on magnetic resonance imaging (MRI)

ARX-related syndrome is a genetic condition, which means that it is caused by variants in genes. Our genes contain the instructions, or code, that tell our cells how to grow, develop, and work. Genes are arranged in structures in our cells called chromosomes. Chromosomes and genes usually come in pairs, with one copy from the mother’s egg, and one copy from the father’s sperm.

We each have 23 pairs of chromosomes. One pair, called the X and Y chromosomes, differs between biological males and biological females. Biological females have two copies of the X chromosome and all its genes, one inherited from their mother and one inherited from their father. Biological males have one copy of the X chromosome and all its genes, inherited from their mother, and one copy of the Y chromosome and its genes, inherited from their father.

In most cases, parents pass on exact copies of the gene to their child. But the process of making the sperm and egg is not perfect. A variant in the genetic code can lead to physical issues, developmental issues, or both.

The ARX gene is located on the X chromosome, therefore variants in this gene can affect biological males and biological females in different ways. Biological males who have variants in this gene will likely have ARX-related syndrome.

Biological females who have variants in this gene may or may not have symptoms of ARX-related syndrome. Biological females who have one working copy of the gene and one non-working copy are considered to be ‘carriers’. Even if a biological female does not have signs or symptoms of the syndrome, they can pass it along to their children.

X-linked dominant conditions

An X-linked dominant condition is caused by a variant in a gene on the X chromosome where only one copy of the altered gene is needed to cause a condition. Both males and females can be affected by X-linked dominant conditions.

ARX-related syndrome can result from a spontaneous variant in the ARX gene in the sperm or egg during development. When a brand new genetic variant happens in the genetic code it is called a ‘de novo’ genetic variant. The child can be the first in the family to have the gene variant.

De novo variants can take place in any gene. We all have some de novo variants, most of which don’t affect our health. But because ARX plays a key role in development, de novo variants in this gene can have a meaningful effect. Many parents who have had their genes tested do not have the ARX gene variant found in their child who has the syndrome.

In some cases, ARX-related syndrome is inherited. Biological females who inherit the ARX gene variant tend to have milder symptoms than those who have a de novo variant.

X-Linked Dominant Genetic Syndrome

Sex chromosomes
Non-carrier father
Non-carrier mother
Sex chromosomes
Genetic variant happens in X-chromosome in sperm or egg, or after fertilization
Non-carrier female
Female child with X-linked genetic condition
Male child with X-linked
genetic condition
Non-carrier
male

Why does my child have a change in the ARX gene?

No parent causes their child’s ARX-related syndrome. We know this because no parent has any control over the gene changes that they do or do not pass on to their children. Please keep in mind that nothing a parent does before or during the pregnancy causes this to happen. The gene change takes place on its own and cannot be foreseen or stopped.

Each family is different. A geneticist or genetic counselor can give you advice on the chance that this will happen again in your family.

The risk of having another child who has ARX-related syndrome depends on the genes of both biological parents.

  • For a biological female parent who does not have the same genetic variant found in their child, the chance of having another child who has the syndrome is on average 1 percent. This 1 percent chance is higher than the chance of the general population. The increased risk is due to the very unlikely chance that more of the mother’s egg cells or the father’s sperm cells carry the same genetic variant.
  • For a biological female parent who has the same ARX variant and is pregnant with a daughter, there is a 50 percent chance of passing on the same genetic variant and a 50 percent chance of passing on the working copy of the gene without the same ARX genetic variant.
  • If they are pregnant with a son, there is a 50 percent chance of passing on the same genetic variant and the syndrome.

For a symptom-free brother or sister of someone who has ARX-related syndrome, the sibling’s risk of having a child who has ARX-related syndrome depends on the sibling’s genes and their parents’ genes.

  • If neither parent has the same genetic variant causing ARX-related syndrome, the symptom-free sibling has a nearly 0 percent chance of having a child who would inherit ARX-related syndrome.
  • If the biological mother has the same genetic variant causing ARX-related syndrome, the symptom-free daughter has a 50 percent chance of also having the same genetic variant. If the symptom-free daughter has the same genetic variant as their sibling who has the syndrome, the symptom-free sibling’s chance of having a son who has ARX-related syndrome is 50 percent.

For a person who has ARX-related syndrome, the risk of having a child who has the syndrome is about 50 percent.

As of 2024, at least 120 people with ARX-related syndrome have been described in medical research.

People who have ARX-related syndrome may look different. Appearance can vary and can include some but not all of these features:

  • Small head size
  • Changes in facial features, which might not be the same in every person
  • Sideways curve of the spine, also called scoliosis

Scientists and doctors have only just begun to study ARX-related syndrome. At this point, there are no medicines designed to treat the syndrome. A genetic diagnosis can help people decide on the best way to track the condition and manage therapies. Doctors can refer people to specialists for:

  • Physical exams and brain studies
  • Genetics consults
  • Development and behavior studies
  • Other issues, as needed

A developmental pediatrician, neurologist, or psychologist can follow progress over time and can help:

  • Suggest the right therapies. This can include physical, occupational, speech, or behavioral therapy.
  • Guide individualized education plans (IEPs).

Specialists advise that therapies for ARX-related syndrome should begin as early as possible, ideally before a child begins school.

If seizures happen, consult a neurologist. There are many types of seizures, and not all types are easy to spot. To learn more, you can refer to resources such as the Epilepsy Foundation’s website: epilepsy.com/learn/types-seizures.

This section includes a summary of information from major published articles. It highlights how many people have different symptoms. To learn more about the articles, see the Sources and References section of this guide.

Females have two X chromosomes and two copies of the ARX gene. Females carrying a pathogenic or likely pathogenic ARX variant sometimes have medical features.

Usually, the X chromosome carrying the variant undergoes selective X inactivation. This is a random process where a cell chooses one X chromosome to silence gene expression. If the affected X chromosome is inactivated, this means that the ARX variant would be silenced or turned off. For some females, the unaffected X chromosome is inactivated, resulting in a person having more medical features.

The information below is divided by females and males.

Females with ARX-related syndrome

Researchers have suggested some links between the genetic variant in ARX and the type of medical features in males or females.

ARX gene within the amino acid region 320-380 as well as near the space between exons 4-5 appear (around amino acids 405-410) are more likely to be associated with severe/moderate condition in both females and males.

Both nonsense and missense variants near the beginning region of the protein before amino acid 40 or near the end of the protein after amino acid 520, appears to be associated with an unaffected in carrier females, but a more severe condition in males.

Some researchers suggest that de novo variants, brand new genetic variants in that person, might have a higher rate of medical features. Males with pathogenic or likely pathogenic ARX genetic variants always have medical features.

Learning

Fewer than one-half of females with ARX-related syndrome had developmental delays or intellectual disabilities. Some people had language delays or learning disabilities.

  • 33 out of 77 people had developmental delays or intellectual disabilities (43 percent)

The severity of intellectual disability (ID) varied among people:

  • 12 out of 33 people had mild ID (36 percent)
  • 2 out of 33 people had moderate ID (6 percent)
  • 13 out of 33 people had severe ID (39 percent)
  • 6 out of 33 people had ID severity that was not described (18 percent)
36%
12 out of 33 people had mild ID.
6%
2 out of 33 people had moderate ID.
39%
13 out of 33 people had severe ID.
18%
6 out of 33 people had ID severity that was not described.

Behavior

Females with ARX-related syndrome had behavioral challenges, such as autism without intellectual disability.

  • 5 out of 20 people had autism (25 percent)

Brain

Some females with ARX-related syndrome had seizures and brain changes seen on magnetic resonance imaging (MRI), such as agenesis of the corpus callosum or abnormal folding patterns of the brain.

  • 26 out of 76 people had seizures (34 percent)
  • 26 out of 39 people had brain changes seen on MRI (67 percent)
Human head showing brain outline
34%
26 out of 76 people had seizures.
67%
26 out of 39 people had brain changes seen on MRI.

Males with ARX-related syndrome

Researchers have suggested some links between the genetic variant in ARX and the type of medical features in males or females.

ARX gene within and flanking the amino acid region 320-380 as well as near the junction between exons 4-5 appear (around amino acids 405-410) are more likely to be associated with severe/moderate condition in both females and males.

Both nonsense and missense variants near the beginning region of the protein before amino acid 40 or near the end of the protein after amino acid 520, appears to be associated with an unaffected in carrier females, but a more severe condition in males.

Males with pathogenic or likely pathogenic ARX genetic variants always have medical features.

Learning

Males with ARX-related syndrome had developmental delays or intellectual disabilities.

  • 15 out of 15 people had developmental delays or intellectual disabilities (100 percent)

Brain

Males with ARX-related syndrome had neurological issues, such as lower than average muscle tone (hypotonia), smaller than average brain size (microcephaly), brain changes seen on magnetic resonance imaging (MRI), and seizures.

  • 5 out of 8 people had brain changes seen on MRI (63 percent)
  • 14 out of 15 people had seizures (93 percent)
63%
5 out of 8 people had brain changes seen on MRI.
93%
14 out of 15 people had seizures.

Other medical features

Males with ARX-related syndrome sometimes had ambiguous genitalia (where their genitalia does not look clearly male or female), feeding issues, and movement issues, such as involuntary muscle contractions (dystonia) and rigidity.

Where can I find support and resources?

Simons Searchlight

Simons Searchlight is an online international research program, building an ever growing natural history database, biorepository, and resource network of over 175 rare genetic neurodevelopmental disorders. By joining their community and sharing your experiences, you contribute to a growing database used by scientists worldwide to advance the understanding of your genetic condition. Through online surveys and optional blood sample collection, they gather valuable information to improve lives and drive scientific progress. Families like yours are the key to making meaningful progress. To register for Simons Searchlight, go to the Simons Searchlight website at www.simonssearchlight.org and click “Join Us.”

Sources and References

The content in this guide comes from published studies about ARX-related syndrome.

  • Akula, S. K., Quiroz, V., D’Gama, A. M., Chiu, M. Y., Koh, H. Y., Saffari, A., Zaman, Z., Tam, A., Srouji, R., … & Ebrahimi-Fakhari, D. (2024). The spectrum of movement disorders in young children with ARX-related epilepsy-dyskinesia syndrome. Annals of Clinical and Translational Neurology, 11(6), 1643-1647. https://pubmed.ncbi.nlm.nih.gov/38711225/
  • Arvio, M., Lähdetie, J., Koivu, H., Sohlberg, A., & Pekkonen, E. (2023). Manifestations of intellectual disability, dystonia, and Parkinson’s disease in an adult patient with ARX gene mutation c.558_560dup p.(Pro187dup). Case Reports in Genetics, 2023, 3636748. https://pmc.ncbi.nlm.nih.gov/articles/PMC9935879/
  • Gras, M., Heide, S., Keren, B., Valence, S., Garel, C., Whalen, S., Jansen, A. C., Keymolen, K., Stouffs, K., … & Héron, D. (2024). Further characterisation of ARX-related disorders in females due to inherited or de novo variants. Journal of Medical Genetics, 61(2), 103-108. https://pubmed.ncbi.nlm.nih.gov/37879892/
  • Iskandar, K., Herini, E. S., Triono, A., Hadiyanto, M. L., Nugrahanto, A. P., & Gunadi. (2023). Phenotypes of a female patient with novel de novo frameshift ARX variant identified by whole-exome sequencing: A case report. Annals of Medicine & Surgery (Lond), 85(2), 236-241. https://pmc.ncbi.nlm.nih.gov/articles/PMC9949785/
  • Li, C. L. (2024). Male-female phenotype correlation and dissociation related to mutations in the ARX gene. Journal of Medical Genetics, 61(11), 1068-1069. https://pubmed.ncbi.nlm.nih.gov/39313312/
  • Kwong, A. K., Chu, V. L., Rodenburg, R. J. T., Smeitink, J., & Fung, C. W. (2019). ARX-associated infantile epileptic-dyskinetic encephalopathy with responsiveness to valproate for controlling seizures and reduced activity of muscle mitochondrial complex IV. Brain & Development, 41(10), 883-887. https://pubmed.ncbi.nlm.nih.gov/31324350/
  • Shoubridge, C., Jackson, M., Grinton, B., Berkovic, S. F., Scheffer, I. E., Huskins, S., Thomas, A., & Ware, T. (2019). Splice variant in ARX leading to loss of C-terminal region in a boy with intellectual disability and infantile onset developmental and epileptic encephalopathy. American Journal of Medical Genetics Part A, 179(8), 1483-1490. https://pubmed.ncbi.nlm.nih.gov/31145546/
  • Zaker, E., Nouri, N., Movahedinia, M., Dadbinpour, A., & Vahidi Mehrjardi, M. Y. (2024). Type 1 early infantile epileptic encephalopathy: A case report and literature review. Molecular Genetics & Genomic Medicine, 12(2), e2412. https://pmc.ncbi.nlm.nih.gov/articles/PMC10891437/

Stay connected with Simons Searchlight

Join our newsletter to receive updates