Última actualización:
12/18/2024
Años publicados: 2024
NORD gratefully acknowledges Ben Darbro, MD, PhD, Medical Geneticist, University of Iowa, Ted Abel, PhD, Ted Abel Lab, University of Iowa, Lucy Langmack, PhD Candidate, Ted Abel Lab, University of Iowa, Joe Henry, Parent/Advocate and Kathryn Semerau, MS, CGC, Genetic Counselor, for the preparation of this report.
NR4A2-related neurodevelopmental disorder is a rare genetic disorder caused by certain changes (variants) in the NR4A2 gene. The condition is associated with a wide range of symptoms. These include developmental delay, intellectual disability and speech, communication, and movement disorders, among others. Many individuals with NR4A2-related neurodevelopmental disorder are also diagnosed with autism spectrum disorder. No two individuals are affected in exactly the same way and the severity of symptoms varies greatly. Treatment is based on specific symptoms with a focus on speech, social, motor and learning skills.
Individuals with NR4A2-related neurodevelopmental disorder may have the following signs and symptoms:
These symptoms are linked to brain regions that require NR4A2 gene expression to function properly.
Additional reported symptoms include:
Other less commonly reported features include feeding and sleeping difficulties and a distinctive facial appearance.
While clinicians and scientists have identified a core group of symptoms associated with NR4A2-related neurodevelopmental disorder, the condition is not fully understood at this time. Affected individuals who have disease-causing variants in the NR4A2 gene can present with some or most of these clinical features. Some are more severely affected by certain symptoms, while others are more mildly affected. For example, severity of intellectual disability has been reported to vary widely, even among affected individuals in the same family.
NR4A2-related neurodevelopmental disorder is caused by disease-causing (pathogenic) variants in the sequence of the NR4A2 gene. This can include a single change in the DNA sequence (i.e., missense, nonsense, splice site, or frameshift variant) or deletion of part or all of the gene and no other genes. All types of variants can affect the function of NR4A2. So far, the known variants that have caused NR4A2-related neurodevelopmental disorder have turned off a copy of the NR4A2 gene, causing a ‘loss-of-function’ of NR4A2.
To date, over 200 variants in NR4A2 have been reported in the Simons Foundation Autism Research Initiative (SFARI) Gene database, a part of the SPARK research study. Research is currently underway to understand how each variant in NR4A2 uniquely affects the resulting Nurr1 protein. This will help to more accurately predict the symptoms and prognosis of this disorder in an affected person.
The NR4A2 gene encodes a member of the steroid-hormone nuclear receptor family, known as nuclear receptor group 4a member 2 (Nr4A2/Nurr1). This gene contains instructions for making Nurr1 protein. Nurr1 determines when other genes are turned on (expressed) or off (repressed) in cells. NR4A2 is expressed predominantly in the central nervous system. For example, it is expressed in limbic regions and the ventral midbrain, including in dopamine neurons. These regions are especially important for memory, emotion and movement. Therefore, Nurr1 plays an important role in controlling the function of genes involved in the dopamine system.
Dopamine acts as a signal to regions of the brain that allow certain behaviors like movement, motivation and seeking out rewards. During development, NR4A2 helps establish the functions of these brain regions and the connections between them. Disease-causing (pathogenic) variants in NR4A2 might disrupt the genes that need to be turned on and off for normal development and this disruption can lead to the development of this neurodevelopmental disorder.
NR4A2-related neurodevelopmental disorder is usually caused by a new (de novo) change (variant) in the NR4A2 gene. A de novo change can occur early in development, for example, during the formation of an egg or sperm cell. A child may be the first in the family to have this type of change in their NR4A2 gene. In this case, no other family members will be affected. Very rare cases of NR4A2-related neurodevelopmental disorder are inherited as an autosomal dominant disorder from an affected parent. Dominant genetic disorders occur when only a single copy of a disease-causing gene variant is necessary to cause the disease. The gene variant can be inherited from either parent. The risk of passing the gene variant from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.
In summary, a single variant, either inherited or de novo, in NR4A2 can have a large effect on development and brain function, causing NR4A2-related neurodevelopmental disorder.
The first person with NR4A2-related neurodevelopmental disorder was reported in the medical literature in 2017. Now, nearly 30 people have been described with this condition, equally affecting males and females. As access to genetic testing and screening improves, it’s likely that many more diagnoses of this genetic condition will be reported.
A diagnosis of NR4A2-related neurodevelopmental disorder should be considered in a child with developmental delay, intellectual disability, speech and language impairments and/or motor impairments. It should also be considered in adults with unexplained dystonia-parkinsonism. Because these symptoms are common in many neurodevelopmental disorders, molecular genetic testing is needed for diagnosis. Gene panel tests that include NR4A2 may be considered, along with whole exome or whole genome sequencing.
There is no cure for NR4A2-related neurodevelopmental disorder. Each patient is treated for specific symptoms and their medical team can help facilitate decisions about the best treatment approach. Management of this condition can include the following:
Some individuals with NR4A2-related neurodevelopmental disorder are diagnosed with a movement disorder called dystonia-parkinsonism. Dystonia-parkinsonism affects certain muscle contractions, leading to abnormal postures and movements. All those described in the medical literature to date experienced this symptom onset in their mid-20s to early 30s. These individuals showed a favorable response to treatment with levodopa medication. A neurologist can diagnose and treat dystonia-parkinsonism. They can also screen adults with NR4A2-related neurodevelopmental disorder for symptoms of the movement disorder.
As of 2024, there are no ongoing clinical trials. Several labs around the world are dedicated to studying NR4A2 in the brain, but only a few are studying the effects of disease-causing (pathogenic) variants causing NR4A2-related neurodevelopmental disorder.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact: www.centerwatch.com
For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
Song X, Xu W, Xiao M, et al. Two novel heterozygous truncating variants in NR4A2 identified in patients with neurodevelopmental disorder and brief literature review. Front Neurosci. 2022;16:956429. Published 2022 Aug 3. doi:10.3389/fnins.2022.956429
Jesús S, Hinarejos I, Carrillo F, et al. NR4A2 mutations can cause intellectual disability and language impairment with persistent dystonia-parkinsonism. Neurol Genet. 2021;7(1):e543. Published 2021 Jan 21. doi:10.1212/NXG.0000000000000543
Winter B, Krämer J, Meinhardt T, et al. NR4A2 and dystonia with dopa responsiveness. Mov Disord. 2021;36(9):2203-2204. doi:10.1002/mds.28701
Singh S, Gupta A, Zech M, et al. De novo variants of NR4A2 are associated with neurodevelopmental disorder and epilepsy. Genet Med. 2020;22(8):1413-1417. doi:10.1038/s41436-020-0815-4
Wirth T, Mariani LL, Bergant G, et al. Loss-of-function mutations in NR4A2 cause dopa-responsive dystonia parkinsonism. Mov Disord. 2020;35(5):880-885. doi:10.1002/mds.27982
Guo H, Duyzend MH, Coe BP, et al. Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes. Genet Med. 2019;21(7):1611-1620. doi:10.1038/s41436-018-0380-2
Ramos LLP, Monteiro FP, Sampaio LPB, et al. Heterozygous loss of function of NR4A2 is associated with intellectual deficiency, rolandic epilepsy, and language impairment. Clin Case Rep. 2019;7(8):1582-1584. Published 2019 Jul 11. doi:10.1002/ccr3.2260
Lévy J, Grotto S, Mignot C, et al. NR4A2 haploinsufficiency is associated with intellectual disability and autism spectrum disorder. Clin Genet. 2018;94(2):264-268. doi:10.1111/cge.13383
Reuter MS, Krumbiegel M, Schlüter G, Ekici AB, Reis A, Zweier C. Haploinsufficiency of NR4A2 is associated with a neurodevelopmental phenotype with prominent language impairment. Am J Med Genet A. 2017;173(8):2231-2234. doi:10.1002/ajmg.a.38288
Leppa VM, Kravitz SN, Martin CL, et al. Rare inherited and de novo CNVs reveal complex contributions to ASD risk in multiplex families. Am J Hum Genet. 2016;99(3):540-554. doi:10.1016/j.ajhg.2016.06.036
Barge-Schaapveld DQ, Ofman R, Knegt AC, et al. Intellectual disability and hemizygous GPD2 mutation. Am J Med Genet A. 2013;161A(5):1044-1050. doi:10.1002/ajmg.a.35873
INTERNET
Simons Searchlight NR4A2 Community Parent Support Group https://www.facebook.com/groups/411122836052533/
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Aprende más https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/Asegurarse de que los pacientes y los cuidadores estén equipados con las herramientas que necesitan para vivir su mejor vida mientras manejan su condición rara es una parte vital de la misión de NORD.
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