Combined molecular characterization and dopa-responsive treatment in two patients with NR4A2-associated intellectual developmental disorder.
Liang N, Li T, Deng Y
Two children with NR4A2 variants show significant improvements in speech and motor function when treated with levodopa. This study confirms that dopa-responsive features in NR4A2-related disorders can be effectively managed with this medication.
- Levodopa therapy improves linguistic competence and motor function in NR4A2 patients.
- Two pediatric cases showed marked clinical improvement after starting levodopa treatment.
- Three of nineteen previously reported NR4A2 cases also responded favorably to dopaminergic treatment.
- RNA analysis reveals that specific NR4A2 variants cause pathogenic exon skipping.
Expanding the Clinical Spectrum of NR4A2-Related Disorder: A Systematic Literature Review and Case Series.
Borden C, Nasir MB, Roberts MB, Palange L, Wang X
This study expands the known clinical features of NR4A2-related disorder by reviewing existing cases and adding two new ones, revealing that the condition affects more than just neurodevelopment. It identifies a broader range of symptoms including seizures, movement disorders, and extra-neurologic issues like craniofacial and metabolic anomalies.
- The review includes 32 patients with 31 unique pathogenic NR4A2 variants.
- 93% of patients have intellectual disability or developmental delay.
- Language impairment affects 63% and seizures affect 41% of the cohort.
- Movement disorders are present in 31% of reported cases.
- Extra-neurologic anomalies occur in nearly half of patients, including metabolic issues.
NR4A2 as a Novel Target Gene for Developmental and Epileptic Encephalopathy: A Systematic Review of Related Disorders and Therapeutic Strategies.
Gabaldon-Albero A, Mayo S, Martinez F
This review consolidates clinical data from reported NR4A2 cases to define the typical phenotype, highlighting developmental delay, language disorders, movement issues, and epilepsy as core features. It recommends NR4A2 testing as a first-tier option for children with developmental and epileptic encephalopathy.
- Developmental delay and intellectual disability are universal findings in NR4A2-related syndrome.
- Language disorders affect at least 42% of patients, impacting expressive and receptive skills.
- Movement disorders like dystonia or ataxia occur in 37% of cases, often appearing later.
- Epilepsy is present in 42% of patients and can be drug-resistant.
- The authors propose NR4A2 as a primary gene to test for developmental encephalopathy.
Two novel heterozygous truncating variants in NR4A2 identified in patients with neurodevelopmental disorder and brief literature review.
Song X, Xu W, Xiao M, Lu Y, Lan X, Tang X, Xu N, Yu G, Zhang H, Wu S
This study identifies two new genetic mutations in the NR4A2 gene that cause neurodevelopmental disorders characterized by developmental delay, language impairment, and ADHD. The findings confirm that different types of NR4A2 mutations lead to varying severity of symptoms, reinforcing the link between specific genetic changes and clinical outcomes.
- Two novel de novo NR4A2 mutations cause neurodevelopmental disorders with developmental delay and ADHD.
- One mutation causes aberrant splicing and truncated protein, reducing overall expression levels.
- The other mutation produces a shorter protein but unexpectedly increases its expression level.
- Results confirm NR4A2 as a disease-causing gene where different domains affect symptom severity.
NR4A2 and Dystonia with Dopa Responsiveness.
Winter B, Krämer J, Meinhardt T, Berner D, Alt K, Wenzel M, Winkelmann J, Zech M
This paper establishes that mutations in the NR4A2 gene cause a form of dystonia that responds well to levodopa treatment. It confirms that children with this genetic variant can experience significant symptom relief from standard Parkinson's medications.
- NR4A2 mutations are a known cause of dopa-responsive dystonia.
- Patients with these variants show positive clinical responses to levodopa.
- This finding guides treatment decisions for affected children.
NR4A2 Mutations Can Cause Intellectual Disability and Language Impairment With Persistent Dystonia-Parkinsonism.
Jesús S, Hinarejos I, Carrillo F, Martínez-Rubio D, Macías-García D, Sánchez-Monteagudo A, Adarmes A, Lupo V, Pérez-Dueñas B, Mir P, Espinós C
Mutations in the NR4A2 gene cause a specific syndrome characterized by intellectual disability, language impairment, and persistent dystonia-parkinsonism. This study defines the clinical phenotype associated with these genetic variants in human patients.
- NR4A2 mutations directly cause intellectual disability and significant language impairment.
- Patients exhibit persistent dystonia and parkinsonism alongside cognitive deficits.
- This paper establishes a clear genotype-phenotype link for NR4A2-related syndrome.
De novo variants of NR4A2 are associated with neurodevelopmental disorder and epilepsy.
Singh S, Gupta A, Zech M, Sigafoos AN, Clark KJ, Dincer Y, Wagner M, Humberson JB, Green S, van Gassen K, Brandt T, Schnur RE, Millan F, Si Y, Mall V, Winkelmann J, Gavrilova RH, Klee EW, Engleman K, Safina NP, Slaugh R, Bryant EM, Tan WH, Granadillo J, Misra SN, Schaefer GB, Towner S, Brilstra EH, Koeleman BPC
This study identifies NR4A2 as a confirmed cause of neurodevelopmental disorders and epilepsy in humans, describing the specific clinical features associated with these genetic variants. It provides direct evidence linking de novo mutations in this gene to developmental delay, hypotonia, and seizures in patients.
- NR4A2 variants cause neurodevelopmental disorder and epilepsy in human patients.
- Six of nine patients presented with developmental delay and hypotonia.
- Six of nine patients experienced epilepsy alongside other symptoms.
- Variants include missense, loss-of-function, and splicing defects.
- The study confirms NR4A2 is a causative disease gene.
Loss-of-Function Mutations in NR4A2 Cause Dopa-Responsive Dystonia Parkinsonism.
Wirth T, Mariani LL, Bergant G, Baulac M, Habert MO, Drouot N, Ollivier E, Hodžić A, Rudolf G, Nitschke P, Rudolf G, Chelly J, Tranchant C, Anheim M, Roze E
Loss-of-function mutations in the NR4A2 gene cause a form of dystonia and parkinsonism that responds to levodopa treatment. This study identifies specific genetic variants in two patients who developed these movement disorders after childhood intellectual disability.
- NR4A2 mutations cause early-onset dystonia and parkinsonism in humans.
- Patients had mild intellectual disability before developing movement symptoms.
- Brain imaging was normal, but scans showed dopaminergic denervation.
- The condition is treatable with levodopa (dopa-responsive).
- Symptoms can appear years after initial neurodevelopmental signs.
Heterozygous loss of function of NR4A2 is associated with intellectual deficiency, rolandic epilepsy, and language impairment.
Ramos LLP, Monteiro FP, Sampaio LPB, Costa LA, Ribeiro MDO, Freitas EL, Kitajima JP, Kok F
This case report identifies a de novo loss-of-function mutation in the NR4A2 gene as the cause of intellectual disability, rolandic epilepsy, and language impairment in a patient. It confirms that heterozygous mutations in this specific gene can lead to this distinct clinical triad.
- A de novo NR4A2 loss-of-function mutation causes the observed symptoms.
- The phenotype includes intellectual deficiency, rolandic epilepsy, and language impairment.
- NR4A2 is highly intolerant to loss-of-function variants (pLi = 1.0).
- This finding reinforces NR4A2's role in 2q23q24 microdeletion syndrome.
NR4A2 haploinsufficiency is associated with intellectual disability and autism spectrum disorder.
Lévy J, Grotto S, Mignot C, Maruani A, Delahaye-Duriez A, Benzacken B, Keren B, Haye D, Xavier J, Heulin M, Charles E, Verloes A, Dupont C, Pipiras E, Tabet AC
This study identifies four children with de novo deletions of the NR4A2 gene who all present with neurodevelopmental disorders, including intellectual disability, developmental delay, and autism spectrum disorder. The findings confirm that having only one functional copy of NR4A2 causes these conditions with high penetrance.
- Four patients had de novo deletions involving the NR4A2 gene.
- All patients exhibited neurodevelopmental disorders.
- Symptoms include intellectual disability and autism spectrum disorder.
- NR4A2 haploinsufficiency causes these conditions with high penetrance.
Haploinsufficiency of NR4A2 is associated with a neurodevelopmental phenotype with prominent language impairment.
Reuter MS, Krumbiegel M, Schlüter G, Ekici AB, Reis A, Zweier C
This study confirms that losing one copy of the NR4A2 gene causes a specific neurodevelopmental profile characterized by severe language and speech impairments alongside mild cognitive challenges. It provides direct human evidence linking NR4A2 haploinsufficiency to these symptoms, distinguishing them from broader intellectual disability.
- A de novo deletion of only the NR4A2 gene causes this specific phenotype.
- Severe language and speech impairment are the primary clinical features.
- Cognitive impairment is present but typically mild compared to language deficits.
- This finding supports NR4A2 haploinsufficiency as the direct cause of these symptoms.
Microdeletion 2q23.3q24.1: exploring genotype-phenotype correlations.
Milani D, Sabatini C, Manzoni FM, Ajmone PF, Rigamonti C, Malacarne M, Pierluigi M, Cavani S, Costantino MA
This case report describes a 13-year-old girl with a genetic deletion on chromosome 2 that includes the NR4A2 gene, linking this specific genomic change to developmental delay and behavioral disorders. The authors identify NR4A2 as a likely contributor to the neurological symptoms observed in this patient.
- A 13-year-old girl has a de novo deletion on chromosome 2q23.3q24.1.
- The deletion includes the NR4A2 gene, which is expressed in neuronal cells.
- Clinical features include mild developmental delay and behavioral disorders.
- This case helps define the neurological impact of losing the NR4A2 gene.
Clinical improvement of the aggressive neurobehavioral phenotype in a patient with a deletion of PITX3 and the absence of L-DOPA in the cerebrospinal fluid.
Derwińska K, Mierzewska H, Goszczańska A, Szczepanik E, Xia Z, Kuśmierska K, Tryfon J, Kutkowska-Kaźmierczak A, Bocian E, Mazurczak T, Obersztyn E, Stankiewicz P
L-DOPA treatment reduces aggressive behavior and improves attention and sleep in a patient with a PITX3 deletion who lacks L-DOPA in their cerebrospinal fluid. This case demonstrates that dopamine pathway supplementation can mitigate neurobehavioral symptoms associated with specific genetic deletions affecting midbrain dopamine neuron development.
- A 17-year-old male with a PITX3 deletion showed absent CSF L-DOPA and severe behavioral issues.
- L-DOPA therapy mildly reduced aggression and improved attention span and sleep quality.
- PITX3 regulates dopamine neuron development, linking its loss to neurotransmitter deficits.
- This is direct human evidence of clinical response to dopamine precursor therapy.
An 8.9 Mb 19p13 duplication associated with precocious puberty and a sporadic 3.9 Mb 2q23.3q24.1 deletion containing NR4A2 in mentally retarded members of a family with an intrachromosomal 19p-into-19q between-arm insertion.
Lybaek H, Ørstavik KH, Prescott T, Hovland R, Breilid H, Stansberg C, Steen VM, Houge G
This study identifies a specific microdeletion on chromosome 2q that removes the NR4A2 gene in family members with intellectual disability, providing direct human genetic evidence linking NR4A2 loss to neurodevelopmental issues. It also documents a separate chromosomal duplication associated with precocious puberty, though this finding does not involve NR4A2.
- A 3.9 Mb deletion on chromosome 2q removes NR4A2 in relatives with intellectual disability.
- This confirms NR4A2 haploinsufficiency contributes to the neurodevelopmental phenotype.
- An unrelated 19p duplication caused precocious puberty but did not involve NR4A2.
- Gene expression analysis showed limited impact from the duplication, excluding it as a cause for early puberty.
Mutations in NR4A2 associated with familial Parkinson disease.
Le WD, Xu P, Jankovic J, Jiang H, Appel SH, Smith RG, Vassilatis DK
This study identifies specific mutations in the NR4A2 gene that reduce its activity and are linked to familial Parkinson's disease. These genetic changes lower NR4A2 mRNA levels and disrupt the transcription of tyrosine hydroxylase, a key enzyme for dopamine production. The findings confirm that NR4A2 dysfunction contributes to dopaminergic failure in humans.
- Two specific NR4A2 mutations reduce gene expression in affected individuals.
- Mutations impair transcription of tyrosine hydroxylase, critical for dopamine synthesis.
- Ten familial Parkinson's patients carried these mutations; controls did not.
- Clinical features and age of onset matched typical Parkinson's disease.
- This is human genetic evidence linking NR4A2 directly to dopaminergic dysfunction.