Patients who develop Parkinson's disease (PD) between 21 and 50 years of age are defined as having young-onset PD (YOPD). Autosomal recessive biallellic mutations in PRKN cause up to 15% of YOPD in familial cohorts. In addition to developing parkinsonism typically in their 30s, PRKN-PD is characterized by exquisite sensitivity to levodopa, with early-onset levodopa-induced dyskinesia (LID) and slow motor progression. 1 While foot dystonia may occur prior to levodopa therapy, brief, variable orofacial or cervical dystonic movements have not been reported. 2 Patient 1 (Fig. 1A, III-9, proband), a 46-year-old right-handed man, developed abductor spasmodic dysphonia around the age of 24 and noticed a right leg rest tremor aged 35, which progressed to involve all limbs by the age of 46. His dopamine transporter (DaT) scan showed bilaterally reduced dopaminergic uptake in the striatum (Fig. 1B). His tremor was managed with biperiden 1 mg twice a day. He had never been prescribed any dopaminergic therapy or neuroleptics. His neurological examination at age 46 (Video 1) revealed intermittent orofacial and eyebrow movement exacerbated by speech and when performing rapid alternating hand movements. Genetic testing showed pathogenic variants c. 823C>T (p. Arg275Trp, rs34424986) in exon 7 and deletion of exon 8 in PRKN. Subsequently, the same compound heterozygous PRKN pathogenic variants were found in his affected siblings described below (III-1, III-4, III-8). After 25 years of motor symptoms, the patient's parkinsonism has progressed slowly and is managed with mirapexin 0. 78 mg once daily. His mother and maternal grandmother both developed Parkinson's disease in their 70s, but neither had genetic testing. Patient 2 (Fig. 1A, III-1), a 58-year-old right-handed man, presented with subtle parkinsonism after being recruited as an “unaffected” sibling of the proband (III-9) for a research study. He reported right foot cramping from the age of 53. At age 58, prior to commencing dopaminergic therapy, he had symmetrical mild rigidity and mild bradykinesia affecting both arms with right hand and foot dystonia. He was noted to have increased dystonic facial movements present at rest, while talking and gesticulating (Video 1 and 2). His speech was normal. A DaTscan aged 59 demonstrated moderate reduction in dopaminergic uptake bilaterally (Fig. 1B). The patient died at age 66 from sequelae of a malignancy of unclear primary origin with vertebral metastases diagnosed at age 64. His parkinsonism had not progressed from the time of PD diagnosis and he did not report any nonmotor symptoms. Patient 3 (Fig. 1A, III-6) was a 51-year-old right-handed man who also attended our department as a healthy familial control for the study. He denied any subjective parkinsonian symptoms and had never taken dopaminergic or neuroleptic therapy. On examination (Video 2), he had alternating intermittent variable anterocollis and laterocollis bilaterally. The varied movement was more prominent at rest than with action and speaking. He also had intermittent bilateral eyebrow movement. His head movement was more consistent with an intermittent alternating dystonia as he had no torticollis in the primary position. He had moderate bradykinesia of the right hand and mild bradykinesia of the left. His speech was normal. Genetic testing confirmed the same compound heterozygous pathogenic variants in PRKN found in his siblings (III-1, III-9). At 10 year follow-up the patient reports mild levodopa-responsive parkinsonism and no non-motor symptoms. Biallelic pathogenic variants in the PRKN gene classically cause a restricted nigropathy without Lewy bodies. Clinically, PRKN-PD is typically distinguished by lower limb dystonia, early levodopa-induced leg dyskinesias, sleep benefit with diurnal variation, and cognitive sparing late in its disease course. However, the phenotype demonstrates heterogeneity, including features such as hyperreflexia, autonomic dysfunction, peripheral neuropathy, and behavioral changes. 2 Spasmodic dysphonia and torticollis have recently been reported in levodopa-naïve PRKN-PD, 3 but our patients’ variable orofacial and neck movements have not been described in the literature. Intriguingly, early isolated orofacial dystonia is reported in DJ-1. 4 The different and specific distribution of pathology distinguishing PRKN-PD from gene-negative YOPD could inform why their dystonia differs in anatomical distribution and severity, typically first affecting the lower limbs in PRKN-PD. The sensorimotor nigrostriatal loop passes through the caudal putamen, which has somatotopic organization, with the foot represented dorsally, the face represented ventrally and the hand in the intermediate zone. 5 The dorsal putamen is predominantly innervated by the ventrolateral tier of substantia nigra pars compacta (SNc), which is disproportionately degenerated in PRKN-PD. 6 Patchy, selective dopaminergic denervation could therefore target the dorsal putamen first in PRKN-PD, giving rise to early leg and foot dystonia with diurnal variation in this population. Perhaps instead in these particular patients, the ventral putamen is more severely affected earlier, resulting instead in orofacial and cervical dystonic movements. Alternatively, dystonic movements such as those reported may be overlooked in similar PRKN-PD patients given their brief, variable and subtle character. Since its identification in Japan in 1998, the clinicopathological description of PRKN-PD has continued to expand. We report three levodopa-naïve PRKN-PD patients with variable alternating orofacial and cervical dystonia. The physician should look closely for any signs of parkinsonism, and genetic testing for PRKN pathogenic variants should be considered in dopamine-naïve patients who develop hyperkinetic facial movements. (1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (*not applicable) ; (3) Manuscript Preparation: A. Writing of the first draft, B. Review and Critique. A. G.: 1B, 1C, 3A A. R.: 1B, 1C, 3A J. M. C. K.: 1B, 1C, 3B J. I.: 1B, 1C, 3B D. A. O.: 1B, 1C, 3B C. F.: 1B, 1C, 3B T. L.: 1A, 1B, 3B We would like to thank the patients involved for kindly contributing their time and effort to taking part in this study. Ethical Compliance Statement: The authors confirm that the approval of an institutional review board was not required for this work. Written informed patient consent was obtained 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 Conflict of Interest: No specific funding was received for this work. However, TL has grant funding from the JPND EU grant, Health Research Board Ireland, Michael J. Fox Foundation, and the Irish Institute of Clinical Neuroscience. Financial Disclosures for the Previous 12 Months: TL has grant funding from the JPND EU grant, Health Research Board Ireland, Michael J. Fox Foundation, and the Irish Institute of Clinical Neuroscience. Author disclosures are available in the Supporting Information. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. Data S1. COIdisclosure. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Gallagher et al. (Mon,) studied this question.