Imaging Evidence of Nigrostriatal Degeneration in DYT‐PRKRA

Short abstract

https://onlinelibrary.wiley.com/page/journal/23301619/homepage/mdc312941-sup-v001.htm

DYT‐PRKRA (DYT16) is a rare autosomal‐recessive disorder typically combining generalized dystonia and parkinsonism.1 The homozygous variant, c.665C > T (p.Pro222Leu), in exon 7 of the PRKRA gene is the most common cause.2 There is no convincing evidence that DYT‐PRKRA is a neurodegenerative condition.

A 27‐year‐old right‐handed Portuguese female reported stuttering speech, unsteady gait, and slow movements since the age of 4 years, unrelated to trauma, fever, or other precipitants. During childhood and adolescence, she performed poorly at sports and failed three school years because of learning disability. She completed high school, but lost successive jobs because of slowness of movement, particularly with the left hand, which prevented skilled accomplishment of manual tasks. She also reported small handwriting. Her medical record was otherwise unremarkable with nonconsanguineous parents nor other relevant family history.

The patient came to our movement disorders clinic at the age of 24. We observed dysphemia, hypophonia, mild hypomimia, and sialorrhea. There was mild rigidity of both upper limbs and neck, mild bradykinesia of the right hand, and micrography, but no tremor; subtle right‐hand dystonia was noted. Laboratory testing, including copper and ceruloplasmin, was normal, as was brain MRI (1.5 Tesla). Neuropsychological assessment showed mild executive dysfunction. Dopamine transporter single‐photon emission computed tomography with ioflupane I‐123 (DaTSCAN) disclosed marked bilateral loss of striatal presynaptic dopamine transporters (Figure 1). She was not being treated and was then prescribed levodopa up to 400 mg/day, with improvement of motor symptoms and overall quality of life (Video 1). Genetic testing excluded parkin gene mutations and revealed homozygous c.665C > T (p.Pro222Leu) mutations in exon 7 of the PRKRA gene, thus confirming the diagnosis of DYT‐PRKRA (previously DYT16). Meanwhile, the patient wanted to become pregnant and was weaned off l‐dopa after discussing this issue.

Figure 1.

DaTSCAN. Marked bilateral loss of presynaptic dopamine transporters is seen in the striatum, with clear putaminal predominance.

Camargos et al. described the typical clinical features and the most common causative gene mutation of DYT‐PRKRA in 2008.1 Since then, <20 cases have been reported in the literature, with some phenotypic variability and other associated gene mutations.3, 4 Most reported DYT‐PRKRA patients have not improved under dopaminergic or anticholinergic therapy.1, 2, 3, 4 Because of lack of evidence, including both in vivo and postmortem data, the disorder cannot be classified as neurodegenerative.5

We present a patient with DYT‐PRKRA bearing marked bilateral loss of striatal presynaptic dopamine transporters, suggesting that nigrostriatal neurodegeneration could be a feature of the disease, which is in accordance with recent in vitro experimental evidence.6 To the best of our knowledge, this is the first case of DYT‐PRKRA with documented nigrostriatal degeneration in vivo. Thus, one could hypothesize that DYT‐PRKRA belongs to the group of early‐onset neurodegenerative complex dystonia‐parkinsonism disorders. Our observation also suggests that it is worth trying l‐dopa therapy in these patients, given that clinical improvement could be achieved. We hope that our findings will prompt others to report further cases, in order to confirm the neurodegenerative nature of DYT‐PRKRA.

Author Roles

(1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique.

M.J.P.: 1A, 1B, 1C, 3A, 3B

A.O.: 1B, 1C, 3B

M.J.R.: 3B

J.M.: 1C, 3A, 3B

Disclosures

Ethical Compliance Statement

A written informed patient consent was obtained for this work. The authors confirm that the approval of an institutional review board was not required for this work. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

Funding Sources and Conflicts of Interest

The authors report no sources of funding and no conflicts of interest.

Financial Disclosures for previous 12 months

Maria João Pinto received financial support to attend meetings from Allergan, Bial, Biogen, Eisai, and Novartis. Ana Oliveira received advisor honoraria from Zambon; she received financial support to attend meetings from Allergan, Bial, Boston Scientific, Ipsen, Medtronic, and Zambon. Maria José Rosas received financial support to attend meetings from Allergan, Bial, and Zambon. João Massano received advisor honoraria from AbbVie, Bial, Merck Sharp & Dohme, and Zambon; he received financial support to speak or attend meetings from Bial, Boston Scientific, GE Healthcare, and Medtronic.

Supporting information

Video 1 Patient under l‐dopa 400 mg daily (first segment) and 1 year after l‐dopa was stopped, and already with ongoing pregnancy (second segment). In segment 1, there is mild bradykinesia on finger tapping of the right hand (MDS‐UPDRS definitions) and mild bradykinesia on pronation‐supination movements of the left hand; gait is normal. In segment 2, there is subtle finger dystonia on the right side and slight bradykinesia on finger tapping and mild bradykinesia on pronation‐supination movements of hands; micrography is evident. Lower limbs are unaffected at both time points (not shown). Unfortunately, we do not have the video of the patient before l‐dopa was prescribed; interestingly, symptoms seem to have remained milder after l‐dopa was stopped.