Objective: To describe a genetically proven DYT-PRKRA (DYT16) case with documented loss of presynaptic dopamine transporters.

Background: DYT-PRKRA is an autosomal recessive disorder combining generalized dystonia and parkinsonism. Homozygous variant c.665C>T (p.Pro222Leu) in exon 7 of PRKRA gene is the most frequent causative mutation. Since the first description in 2008, other pathogenic variants of PRKRA were described and the clinical phenotype was also expanded, ranging from severe childhood-onset combined dystonia-parkinsonism to moderate adult-onset isolated dystonia. Most patients derive no clinical benefit from currently available drugs, including levodopa. In vivo nigrostriatal degeneration has not been previously described in DYT-PRKRA.

Method: Case report and review of the literature.

Results: A 27-year-old Portuguese woman presented to the neurology clinic due to progressive worsening of childhood-onset unsteadiness of gait, slowness of movements and writing difficulty. There was no relevant medical or family history. Examination showed right upper limb and left hand dystonia, right sided writer’s cramp, micrography, and cervical and left limb rigidity and bradykinesia. Routine laboratory tests and brain MRI were unremarkable. Presynaptic nigrostriatal dopamine transporter SPECT was performed, disclosing marked symmetric loss of presynaptic dopamine transporters in both putamina. Levodopa was started with clinical improvement. Genetic testing revealed the c.665C>T (p.Pro222Leu) homozygous mutation in exon 7 of PRKRA gene, hence diagnostic of DYT-PRKRA. Despite clinical improvement with levodopa, the patient decided to stop treatment in order to get pregnant. So far, there is no apparent clinical worsening.

Conclusion: We present a genetically confirmed DYT-PRKRA case of childhood-onset generalized dystonia and parkinsonism, improved under levodopa. Interestingly, in vivo nigrostriatal degeneration was seen using presynaptic dopamine transporter SPECT. These findings suggest that DYT-PRKRA could in fact belong to the group of early onset neurodegenerative complex dystonia-parkinsonism disorders, and also that treatment with levodopa should be considered in these patients. Given the scarce evidence regarding nigrostriatal degeneration in DYT-PRKRA we suggest that clinicians and researchers should consider probing this hypothesis.

References: [1] Camargos S, Scholz S, Simón-Sánchez J, Paisán-Ruiz C, Lewis P, Hernandez D, et al. DYT16, a novel young-onset dystonia-parkinsonism disorder: identification of a segregating mutation in the stress-response protein PRKRA. Lancet Neurol. Elsevier; 2008 Mar;7(3):207–15. [2] dos Santos CO, da Silva-Júnior FP, Puga RD, Barbosa ER, Azevedo Silva SMC, Borges V, et al. The prevalence of PRKRA mutations in idiopathic dystonia. Park Relat Disord. 2018;48:93–6. [3] de Carvalho Aguiar P, Borges V, Ferraz HB, Ozelius LJ. Novel compound heterozygous mutations in PRKRA cause pure dystonia. Mov Disord. 2015;30(6):877–8. [4] Zech M, Castrop F, Schormair B, Jochim A, Wieland T, Gross N, et al. DYT16 revisited: Exome sequencing identifies PRKRA mutations in a European dystonia family. Mov Disord. 2014;29(12):1504–10. [5] Quadri M, Olgiati S, Sensi M, Gualandi F, Groppo E, Rispoli V, et al. PRKRA Mutation Causing Early-Onset Generalized Dystonia-Parkinsonism (DYT16) in an Italian Family. Mov Disord. 2016;31(5):765–7.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/nigrostriatal-degeneration-in-dyt-prkra-new-insights-on-a-rare-disorder/