NR4A2-Related Syndrome
NR4A2-related syndrome is also called intellectual developmental disorder with language impairment and early-onset DOPA-responsive dystonia-parkinsonism. For this webpage, we will be using the name NR4A2-related syndrome to encompass the wide range of variants observed in the people identified.
What is NR4A2-related syndrome?
NR4A2-related syndrome happens when there are changes to the NR4A2 gene. These changes can keep the gene from working as it should.
Key Role
The NR4A2 gene plays a key role in the development of the brain. This gene is particularly important in brain cells that help control movement, emotion, and memory.
The NR4A2 gene makes a protein that is important for the dopamine pathway in the brain. The gene is called NR4A2, and the protein is called NURR1.
Symptoms
Because the NR4A2 gene is important in brain development and function, many people who have NR4A2-related syndrome have:
- Autism
- Intellectual disability
- Developmental delay
- Learning difficulties
- Speech and language issues
- Seizures
- Movement issues, such as dystonia, parkinsonism, or ataxia
- Brain changes seen on magnetic resonance imaging (MRI)
- Attention-deficit/hyperactivity disorder, or ADHD
- Anxiety
- Sleep issues
What causes NR4A2-related syndrome?
NR4A2-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. Every child gets two copies of the NR4A2 gene: one copy from their mother’s egg, and one copy from their father’s sperm. In most cases, parents pass on exact copies of the gene to their child. But the process of creating the egg or sperm is not perfect. A change in the genetic code can lead to physical issues, developmental issues, or both.
Sometimes a spontaneous variant happens in the sperm, egg or after fertilization. When a brand new genetic variant happens in the genetic code is called a ‘de novo’ genetic variant. The child is usually the first in the family to have the genetic 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 NR4A2 plays a key role in development, de novo variants in this gene can have a meaningful effect.
Research shows that NR4A2-related syndrome is often the result of a de novo variant in NR4A2. Many parents who have had their genes tested do not have the NR4A2 genetic variant found in their child who has the syndrome. In some cases, NR4A2-related syndrome happens because the genetic variant was passed down from a parent.
Autosomal dominant conditions
NR4A2-related syndrome is an autosomal dominant genetic condition. This means that when a person has the one damaging variant in NR4A2 they will likely have symptoms of NR4A2-related syndrome. For someone with an autosomal dominant genetic syndrome, every time they have a child there is a 50 percent chance they pass on the same genetic variant and a 50 percent chance they do not pass on the same genetic variant.
Autosomal Dominant Genetic Syndrome
Why does my child have a change in the NR4A2 gene?
No parent causes their child’s NR4A2-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.
What are the chances that other family members or future children will have NR4A2-related syndrome?
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 NR4A2-related syndrome depends on the genes of both biological parents.
- If neither biological parent has 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 increase in 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.
- If one biological parent has the same genetic variant found in their child, the chance of having another child who has the syndrome is 50 percent.
For a symptom-free brother or sister of someone who has NR4A2-related syndrome, the sibling’s risk of having a child who has NR4A2-related syndrome depends on the sibling’s genes and their parents’ genes.
- If neither parent has the same genetic variant causing NR4A2-related syndrome, the symptom-free sibling has a nearly 0 percent chance of having a child who would inherit NR4A2-related syndrome.
How many people have NR4A2-related syndrome?
As of 2024, at least 27 people with NR4A2-related syndrome have been identified in medical research. The first case of NR4A2-related syndrome was described in 2017.
Do people who have NR4A2-related syndrome look different?
People who have NR4A2-related syndrome generally do not look different.
How is NR4A2-related syndrome treated?
Scientists and doctors have only just begun to study NR4A2-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 NR4A2-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: www.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.
Behavior and development concerns linked to NR4A2-related syndrome
There are few research publications on people with NR4A2-related syndrome. The information below includes 26 people. The oldest person included was 57 years old.
Speech and Learning
Most people with NR4A2-related syndrome had speech delay or a language disorder and intellectual disability (ID). Language disorders included expressive and receptive language issues.
- 19 out of 21 people had speech delay or language disorder (91 percent)
- 23 out of 23 people had intellectual disability (100 percent)
The severity of ID varied among people:
- 11 out of 23 people had mild ID (48 percent)
- 6 out of 23 people had mild to moderate ID (26 percent)
- 6 out of 23 people had severe ID (26 percent)
Behavior
Many people with NR4A2-related syndrome had behavioral challenges, such as autism or features of autism, attention-deficit/hyperactivity disorder (ADHD), anxiety, mood swings, delusions, and hallucinations.
- 13 out of 20 people had behavior challenges (65 percent)
- 3 out of 20 people had autism (15 percent)
- 8 out of 20 people had hyperactivity (40 percent)
Brain
Some people with NR4A2-related syndrome had seizures. The age of seizure onset was between 5 months to 26 years old. Three people had seizures that could not be managed with medications. Some people had brain changes on magnetic resonance imaging (MRI).
- 9 out of 22 people had seizures (41 percent)
- 7 out of 19 people had brain changes seen on MRI (37 percent)
Medical and physical concerns linked to NR4A2-related syndrome
Mobility
People with NR4A2-related syndrome had delayed motor milestones and lower than average muscle tone. Movement issues were seen in people with NR4A2-related syndrome as young as 22 months, but most people with movement issues developed problems after the age of 16. Movement issues included ataxic gait, dystonia, parkinsonism, adult onset dystonia-parkinsonism, and choreoathetoid movements.
- 12 out of 25 people had delayed motor milestones (48 percent)
- 9 out of 15 people had lower than average muscle tone (60 percent)
- 8 out of 16 people had movement issues (50 percent)
Three people with movement issues caused by NR4A2-related syndrome took levodopa and/or dopaminergic agents to help with movement issues.
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 NR4A2-related syndrome. Below you can find details about each study, as well as links to summaries.
- Reuter MS. et al. American Journal of Medical Genetics Part A, 173, 2231-2234, (2017). Haploinsufficiency of NR4A2 is associated with a neurodevelopmental phenotype with prominent language impairment – www.ncbi.nlm.nih.gov/pubmed/28544326
- Lévy J. et al. Clinical Genetics, 94, 264-268, (2018). NR4A2 haploinsufficiency is associated with intellectual disability and autism spectrum disorder – www.ncbi.nlm.nih.gov/pubmed/29770430
- Gabaldon-Albero, A., Mayo, S., & Martinez, F. (2024). NR4A2 as a novel target gene for developmental and epileptic encephalopathy: A systematic review of related disorders and therapeutic strategies. International Journal of Molecular Sciences, 25(10). https://pubmed.ncbi.nlm.nih.gov/38791237/
- Song, X., Xu, W., Xiao, M., Lu, Y., Lan, X., Tang, X., Xu, N., Yu, G., Zhang, H., & Wu, S. (2022). Two novel heterozygous truncating variants in NR4A2 identified in patients with neurodevelopmental disorder and brief literature review. Frontiers in Neuroscience, 16, 956429. https://pubmed.ncbi.nlm.nih.gov/35992907/
- Winter, B., Krämer, J., Meinhardt, T., Berner, D., Alt, K., Wenzel, M., Winkelmann, J., & Zech, M. (2021). NR4A2 and dystonia with dopa responsiveness. Movement Disorders, 36(9), 2203-2204. https://pubmed.ncbi.nlm.nih.gov/34155693/