Objective: To report two patients with early-onset dystonia-parkinsonism as a result of loss-of-function mutations in nuclear receptor subfamily 4 group A member 2 (NR4A2).

Background: The group of dystonia genes is expanding, and mutations of these genes have been associated with various combined dystonia syndromes. Among the latter, the cause of some dystonia-parkinsonism cases remains unknown. NR4A2 encodes for Nur-related factor 1 (Nurr1), a transcription factor belonging to the steroid thyroid hormone and retinoid nuclear receptor superfamily (1) that has been implicated in the development (2) and the survival (3) of substantia nigra dopaminergic neurons. Variants in noncoding regions of NR4A2 have been suspected to represent susceptibility factors for autosomal dominantly inherited Parkinson’s disease (4). However, subsequent studies did not replicate the aforementioned finding (5, 6). Recently, de novo overlapping deletions encompassing NR4A2 were identified in patients with intellectual disability (7).

Method: Phenotypic characterization and exome sequencing were carried out in 2 families.

Results: The 2 patients reported here both had a history of mild intellectual disability in childhood and subsequently developed dystonia-parkinsonism in early adulthood with a very good response to levodopa. Brain magnetic resonance imaging was normal, and DATscan suggested bilateral dopaminergic denervation. Cerebrospinal fluid analysis in the first case  indicated dopaminergic dysfunction with low HVA (94 nmol/L; N = 115–488) and a reduced homovanillic acid/5-Hydroxyindoleacetic acid ratio (1.36; N > 1.44) consistent with the clinical phenotype of dystonia-parkinsonism. Two frameshift mutations in NR4A2 were identified: a pathogenic de novo insertion (NM_006186.3; c.326dupA) that has already been reported in another patient suffering from intellectual disability and epilepsy (8) in the first case and another likely pathogenic small insertion (NM_006186.3; c.881dupA) in the second.

Conclusion: NR4A2 haploinsufficiency mutations have been recently reported in neurodevelopmental phenotypes. Our findings indicate that dystonia and/or parkinsonism may appear years after the initial symptoms. Mutations in NR4A2 should be considered in cases with unexplained early-onset dystonia-parkinsonism with an excellent response to levodopa.

References: (1) Wang Z, Benoit G, Liu J, et al. Structure and function of Nurr1identifies a class of ligand-independent nuclear receptors. Nature 2003;423(6939):555–560. (2) Zetterström RH, Solomin L, Jansson L, Hoffer BJ, Olson L, Perlmann T. Dopamine neuron agenesis in Nurr1-deficient mice. Science 1997;276(5310):248–250. (3) Decressac M, Volakakis N, Björklund A, Perlmann T. NURR1 in Parkinson disease—from pathogenesis to therapeutic potential. Nat Rev Neurol 2013;9(11):629–636. (4) Le W-D, Xu P, Jankovic J, et al. Mutations in NR4A2 associated with familial Parkinson disease. Nat Genet 2003;33(1):85–89. (5) Hering R, Petrovic S, Mietz E-M, et al. Extended mutation analysis and association studies of Nurr1 (NR4A2) in Parkinson disease. Neurology 2004;62(7):1231–1232. (6) Ibáñez P, Lohmann E, Pollak P, et al. Absence of NR4A2 exon 1 mutations in 108 families with autosomal dominant Parkinson disease. Neurology 2004;62(11):2133–2134. (7) 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. (8) 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.

« Back to MDS Virtual Congress 2020

MDS Abstracts - https://www.mdsabstracts.org/abstract/loss%e2%80%90of%e2%80%90function-mutations-in-nr4a2-cause-dopa%e2%80%90responsive-dystonia-parkinsonism/