Loss‐of‐Function Mutations in NR4A2 Cause Dopa‐Responsive Dystonia Parkinsonism

Abstract

impaired superior colliculus activation, by fMRI, in cervical dystonia and their relatives with abnormal TDTs response to looming visual stimuli. 10 We consider that further interrogation of the role of superior collicular processing in cervical dystonia is warranted. References1. Albanese A, Bhatia K, Bressman SB, et al. Phenomenology and classification of dystonia: a consensus update. Mov Disord 2013;28:863-873. 2. Williams L, McGovern E, Kimmich O, et al. Epidemiological, clinical and genetic aspects of adult onset isolated focal dystonia in Ireland. Eur J Neurol 2017;24:73-81. 3. Ceballos-Baumann AO, Passingham RE, Warner T, Playford ED, Marsden CD, Brooks DJ. Overactive prefrontal and underactive motor cortical areas in idiopathic dystonia. Ann Neurol 1995;37:363-372. 4. Huang YZ, Rothwell JC, Lu CS, Wang J, Chen RS. Restoration of motor inhibition through an abnormal premotor-motor connection in dystonia. Mov Disord 2010;25:696-703. 5. Levy LM, Hallett M. Impaired brain GABA in focal dystonia. Ann Neurol 2002;51:93-101. 6. Tisch S, Limousin P, Rothwell JC, et al. Changes in blink reflex excitability after globus pallidus internus stimulation for dystonia. Mov Disord 2006;21:1650-1655. 7. Bradley D, Whelan R, Kimmich O, et al. Temporal discrimination thresholds in adult-onset primary torsion dystonia: an analysis by task type and by dystonia phenotype.

Movement disorders associated with chromosomal aberrations diagnosed in adult patients

“…Recently, two patients have been reported with loss-of-function variants in NR4A2 and mild intellectual disability with dystonia-parkinsonism in early adulthood [20]. On the molecular level, the haploinsufficiency caused by deletion in our patient should result in a dosage effect similar to the frameshift mutations in the two patients described recently [20]. This case further strengthens the hypothesis that parkinsonism is a part of the clinical picture associated with NR4A2 dysfunction.…”

“…Deletions encompassing NR4A2 alone, or with GPD2, have been found in a few patients with intellectual disability, epilepsy, language impairment and/or dysmorphic features. Recently, two patients have been reported with loss-of-function variants in NR4A2 and mild intellectual disability with dystonia-parkinsonism in early adulthood [20]. On the molecular level, the haploinsufficiency caused by deletion in our patient should result in a dosage effect similar to the frameshift mutations in the two patients described recently [20].…”

Early‐Onset Parkinsonism Is a Manifestation of the PPP2R5D p.E200K Mutation

“…The clinical courses of all three patients are notable for mild intellectual disability and early‐onset parkinsonism, with onset from ages 25 to 40 years and variable rates of progression. This phenotype of stable intellectual disability during childhood with subsequent adult‐onset parkinsonism has been described with mutations in only a few genes previously 8,11 . All PPP2R5D p.E200K cases demonstrated levodopa responsiveness with motor fluctuations; two were complicated by impulse control disorders.…”

“…This phenotype of stable intellectual disability during childhood with subsequent adult-onset parkinsonism has been described with mutations in only a few genes previously. 8,11 All PPP2R5D p.E200K cases demonstrated levodopa responsiveness with motor fluctuations; two were complicated by impulse control disorders. Incidence of the PPP2R5D neurodevelopmental disorder is estimated at 2.32 to 2.87 per 100,000 births.…”

“…4 Genomic DNA was extracted from whole blood. Whole exome sequencing (WES) and Sanger confirmations 4,7,8 and neuropathologic analysis 9 were performed as previously described.…”