GENE GUIDE

GRIA3-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 on 2024. 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 GRIA3-Related Syndrome.
a doctor sees a patient

GRIA3-related syndrome happens when there are changes in the GRIA3 gene. These changes can keep the gene from working as it should. The GRIA3 gene is located on the X chromosome. Males carrying the genetic variation are usually affected with the condition.

Key Role

The GRIA3 gene plays a key role in communication among brain cells. The GRIA3 gene codes for a unit of the AMPA receptor. The gene is called GRIA3, and the protein is called GluA3. 

Symptoms

Because the GRIA3 gene is important for brain activity, many people who have GRIA3-related syndrome have:

  • Intellectual disability
  • Global developmental delay
  • Sleep disturbances
  • Seizures
  • Muscle overactivity, also called hypertonia
  • Decreased muscle tone, also called hypotonia
  • Movement disorders

GRIA3-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, from the egg, and one copy from the father, from the 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 GRIA3 gene is located on the X chromosome, so 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 GRIA3-related syndrome. 

Biological females who have variants in this gene may or may not have symptoms of GRIA3-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 recessive conditions

Research shows that GRIA3-related syndrome is often the result of an inherited variant in GRIA3. This means that GRIA3-related syndrome happens because the genetic variant was passed down from a biological female parent. Biological females that carry the GRIA3 variant usually do not have symptoms, but sometimes they might. 

Sometimes it results from a spontaneous variant in the GRIA3 gene in the sperm or egg during development. When a brand new genetic variant happens in the genetic code is called a ‘de novo’ genetic variant. The child can be the first in the family to have the gene variant.

X-Linked Recessive Genetic Syndrome

Sex chromosomes
Non-carrier father
Carrier mother
Sex chromosomes
Non-carrier female
Carrier female
Male child with X-linked
genetic condition
Non-carrier
male

Why does my child have a change in the GRIA3 gene?

No parent causes their child’s GRIA3-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 predicted 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 GRIA3-related syndrome depends on the genes of both biological parents. 

  • Biological females who have a variant in the GRIA3 gene and are pregnant with a daughter have 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. 
  • If they are pregnant with a son, the child has a 50 percent chance of inheriting the genetic  variant and the syndrome. 

For a symptom-free brother or sister of someone who has GRIA3-related syndrome, the sibling’s risk of having a child who has GRIA3-related syndrome depends on the sibling’s genes and their parents’ genes. 

  • If neither parent has the same genetic variant causing GRIA3-related syndrome, the symptom-free sibling has a nearly 0 percent chance of having a child who would inherit GRIA3-related syndrome. 
  • If the biological mother has the same genetic variant causing GRIA3-related syndrome, and the symptom-free daughter has the variant, the symptom-free daughter’s chance of having a son who has GRIA3-related syndrome is 50 percent. 

For a person who has GRIA3-related syndrome, the risk of having a child who has the syndrome is about 50 percent.

As of 2024, at least 43 people with GRIA3-related syndrome have been identified in the medical literature.

People who have GRIA3-related syndrome might not look very different.

Scientists and doctors have only just begun to study GRIA3-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 GRIA3-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/…t-is-epilepsy/seizure-types

This section includes a summary of information from a major published article on GRIA3. To learn more about the article, see the Sources and references section of this guide.

Genetic variants in GRIA3-related syndrome result in either a gain of function of the GluA3 protein OR a loss of function of the GluA3 protein. It is not always obvious what the genetic variant in GRIA3 will do to the GluA3 protein. 

Understanding the variant consequence in general needs to be tested in the laboratory. Researchers have more recently begun to understand the differences for a loss of function variant and a gain of function GluA3 variant. We have summarized the general understanding of the differences in people.

GRIA3 gain of function variant, people tend to:

  • Be younger at the time seizures develop (around 1 month of age)
  • Have higher than average muscle tone
  • Have movement disorders
  • If female, have a gain of function variant

GRIA3 loss of function variant, people tend to:

  • Be older at the time seizures develop (around 16 months of age)
  • Have lower than average muscle tone
  • Have sleep disturbances
  • Have aggressive behaviors

There are few research publications on people with GRIA3-related syndrome. The information below includes 25 people.

All people had some level of developmental delay or intellectual disability. About one-half had seizures.

  • 9 out of 25 people had moderate intellectual disability (36 percent)
  • 15 out of 25 people had severe to profound intellectual disability (60 percent)
  • 12 out of 25 people had seizures (48 percent)
36%
9 out of 25 people had moderate intellectual disability.
60%
15 out of 25 people had severe to profound intellectual disability.
48%
12 out of 25 people had seizures.

For people taking seizure medication, about one-half were not able to find medication that controlled their seizures. Of the various seizure types people with GRIA3-related syndrome experienced, the most common was focal motor seizures. Several people experienced more than one seizure type. Seizure types included:

  • 6 out of 12 people had focal motor seizures (50 percent)
  • 4 out of 12 people had unknown onset motor seizures (33 percent)
  • 1 out of 12 people had focal impaired awareness seizures (8 percent)
  • 2 out of 12 people had atypical absence seizures (17 percent)
  • 5 out of 12 people had myoclonic seizures (42 percent)
  • 1 out of 12 people had generalized tonic-clonic seizures (8 percent)
  • 1 out of 12 people had atonic seizures (8 percent)

Almost everyone had muscle tone issues. About one-half had low muscle tone, and about one-half had high muscle tone. Movement disorders were common, with hyperekplexia (excessive startle response) or non-epileptic erratic myoclonus being the most common issues.

  • 12 out of 25 people had hypotonia (48 percent)
  • 11 out of 25 people had hypertonia (44 percent)
  • 15 out of 25 people had a movement disorder (60 percent)
48%
12 out of 25 people had hypotonia.
44%
11 out of 25 people had hypertonia.
60%
15 out of 25 people had a movement disorder.

About one-half of people had behavior issues, with some displaying aggressive behavior. About one-half of people had sleep disturbances, and a smaller portion of people had brain changes observed on magnetic resonance imaging (MRI).

  • 13 out of 25 people had sleep issues (52 percent)
  • 15 out of 25 people had behavior issues of any kind (60 percent)
  • 8 out of 25 people had aggressive outbursts or self-damaging behavior (32 percent)
  • 4 out of 18 people had brain changes on MRI (22 percent)

Where can I find support and resources?

CureGRIN Foundation

CureGRIN Foundation is dedicated to improving the lives of people around the world with GRI Disorders (GRIA, GRID, GRIK, and GRIN) and their families through research, education, and support. We work closely with scientists and the medical community to drive patient-centered research that will lead to treatments and cures. ​

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 GRIA3-related syndrome. Below you can find details about each study, as well as links to summaries or, in some cases, the full article.

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