INTRODUCTION

PINK1-related Parkinson’s disease (PARK-PINK1) is the second most common cause of early-onset Parkinson’s disease (EOPD) after PRKN-related Parkinson’s disease, with the former accounting for nearly 4%–5% of autosomal-recessive cases and 1%–2% of sporadic cases. PINK1 variants account for approximately 1%–7% of the cases of EOPD in Caucasians [1-5], 8.9% in Japanese individuals [6], 3.7% in patients of Chinese origin [7] and 1.8% in the Indian population [8]. PINK1 is a 581 amino acid protein that contains an N-terminal mitochondrial targeting sequence and a conserved serine/threonine kinase domain (amino acids 156-509) [9]. Drosophila knockout models have revealed the neuroprotective nature of this protein, which is ubiquitously present in the human brain [10]. Protein phosphorylation is likely to play an important role in Parkinson’s disease (PD) pathogenesis, and PINK1 may participate either by directly phosphorylating or binding key cellular proteins that govern neuronal survival [10]. PARK-PINK1 usually presents with asymmetric parkinsonism, often with lower limb dystonia, slow progression, a good response to levodopa and early motor complications. Atypical presentations with spasticity are rare (<2%) [11]. The Indian literature concerning the phenotypic and genotypic spectrum is scarce. Very few studies such as case reports, mutational analyses [8,12] or family studies [13] are available. In this retrospective chart review, we aimed to describe the clinical and genetic profiles of seven cases of PINK1-related movement disorders to add to the literature. We also compared the findings in our cohort with those from the Movement Disorder Society Genetic mutation (MDSgene) database (https://www.mdsgene.org/d/40/g/4) of patients with PARK-PINK1.

MATERIALS & METHODS

This was a retrospective study by the National Institute of Mental Health and Neurosciences, India. We screened our database of approximately 350 patients with parkinsonism who had undergone exome sequencing to identify those individuals with parkinsonism and/or dystonia who carried biallelic disease-causing variants in the PINK1 gene. The available demographics, clinical history and examination results, investigations (including imaging and genetic data), and treatment details were extracted from the hospital records and tabulated. The study was approved by the National Institute of Mental Health and Neurosciences Institute Ethics Committee (No. NIMH/DO/IEC [BS & NS DIV]/2022-23). Written informed consent was obtained from the patients for their participation in the study, the recording of videos and the publication in print or online of the findings.

RESULTS

A total of 7 patients (four females) were recruited for the study; the median age at onset was 33 years (range: 20–49 years), the median age at presentation was 43 years (range: 28–53 years), and the median duration of illness was 4 years (range: 1–20 years). All patients had an early onset of symptoms (<50 years at onset). None of the patients had a positive family history. However, consanguineous parentage was noted in 3 patients (42.9%) (Table 1).

Clinical features

Tremor was the most common symptom at onset (4 patients, 57.1%), followed by abnormal posturing (2 patients, 28.6%) and slowness (1 patient, 14.3%). All patients had asymmetrical symptoms at onset, with upper-limb onset in 3 patients (42.9%), lower-limb onset in 3 patients (42.9%) and neck symptoms in the remaining patient (14.3%). Parkinsonism was noted in 6 patients (85.7%, with dystonia in 4 patients), and isolated generalized dystonia was noted in the remaining patients (14.3%). Among the 6 patients with parkinsonism, five had a tremor-dominant phenotype with rest tremors, whereas one had an akinetic-rigid phenotype (Supplementary Videos 1 and 2 in the online-only Data Supplement). Among the 5 patients had dystonia (four with parkinsonism and one with isolated dystonia) and all of them had lower-limb involvement with or without the involvement of other regions.

Additionally, 2 patients presented with hypometric saccades and pyramidal signs upon neurological examination. The nonmotor symptoms (NMS) included anxiety (1 patient), depression with suicidal ideation (1 patient), impulse-control disorder (1 patient), restless leg syndrome (1 patient) and rapid eye movement sleep behaviour disorder (RBD) (1 patient). None of the patients had cognitive impairments.

Imaging

The results of three-tesla magnetic resonance imaging of the brain were normal in all patients, with no significant mineralization. One patient (patient 4) underwent F18-DOPA-PET, which revealed left-side predominant reduced uptake in the bilateral putamen, which was supported by the right-side dominant clinical presentation.

Variant spectrum

Exome sequencing identified disease-causing biallelic variants in all patients: these variants were homozygous in five and compound heterozygous in two (Figure 1). Eight unique variants were identified, including two previously reported missense variants (c.1466T>C:p.Leu489Pro and c.1225G>A:p.Gly409Arg), one previously reported exon-5 deletion variant and five novel variants comprised of two small deletions with frameshift variants (c.867delA:p.Ala291ProfsTer28 and c.548_549delAG:p.Glu183GlyfsTer114), two in-frame deletion variants (c.823_825del:p. Ile275del and c.1097_1099del:p.Asn367del), and one stop-gain variant (c.1208G>A:p.Trp403Ter). All eight variants were likely pathogenic according to the American College of Medical Genetics criteria [14]. There were no additional variants of interest in the Parkinsonian genes. Among the total parkinsonism cohort, none carried a single heterozygous pathogenic/likely pathogenic variant in the PINK1 gene.

Treatment response

All patients with parkinsonism had a good levodopa response. The median Movement Disorder Society Unified Parkinson’s Disease Rating Scale Part III OFF score was 34 (range: 19–54), and the ON score was 9.5 (range: 2–16), with a median improvement of 76% (range: 54%–94%). The median levodopa equivalent daily dose was 575 mg (range: 300–900). Motor fluctuations were present in four-sixths patients (66.7%), with levodopa-induced choreiform dyskinesia observed in all patients. None of our patients underwent deep brain stimulation.

Literature review

We conducted a comprehensive search across the publicly accessible medical database PubMed, employing the specific medical subject headings: “PINK1”, “parkinsonism”, “young-onset Parkinson’s disease”, and “early-onset Parkinson’s disease” to identify relevant studies. We subsequently screened the titles and abstracts of these studies. We also searched the MDSgene database to identify PARK-PINK1 cases (Supplementary Table 1 in the online-only Data Supplement). We compared our current study data from patients from our centre with the PARK-PINK1 data of the MDSgene cohort available at mdsgene.org. The median age at onset of our cohort was similar to that of the MDSgene cohort (33 years vs. 32 years). More than 90% of the MDSgene cohort had EOPD, compared to all of the patients in our cohort. In addition, both cohorts were similar with respect to tremors being the most common symptom at onset, with rest tremors observed in the majority of the patients and dystonia in approximately half of the patients. NMS were less common, while almost all patients were responsive to levodopa.

DISCUSSION

In this study, we provide the detailed clinical spectrum and treatment response in seven patients with PINK1-related parkinsonism and/or dystonia, and we expand the known genotypic spectrum by reporting five novel likely pathogenic variants. The clinical details of the current cohort were in line with our current understanding of PARK-PINK1 as per the available literature [11,15]. PARK-PINK1 commonly presents as early-onset parkinsonism, often tremor dominant, with or without lower limb predominant dystonia, and less frequent NMS. The levodopa response is usually robust, and patients often develop early motor fluctuations and levodopa-induced chorea in early disease stages. Atypical parkinsonism presentation is very rare in PARK-PINK1. Notably, 1 patient had isolated generalized dystonia, and this phenotype, although rare, has been reported multiple times as dopa-responsive lower limb-predominant dystonia [16].

NMS were reported by all but one of the subjects. Although some studies have reported that the frequency of NMS is similar between patients with PARK-PINK1 and idiopathic PD [17], several studies have shown a higher incidence of NMS in patients with PARK-PINK1 [18-21]. Hyposmia has been reported as a common symptom in PARK-PINK1 patients [19]. Mood disorders are known to be associated with the PINK1 phenotype [22-24]. Depression was found to be the most common symptom in one study [25]. In our cohort, 1 subject had anxiety, and 1 subject had impulse control disorder and depression with suicidal ideation. Cognition is usually not impaired in individuals with PINK1-associated PD, as shown in multiple studies [21,26-28]. Mild cognitive deficits, however, have been shown in some studies [6,29]. In a recent systematic review, the incidence of cognitive dysfunction was shown to be relatively greater in PARK-PINK1 patients (29.4%), and executive function and attention were the most affected domains [25]. In our cohort, we did not find any cognitive deficits. Autonomic dysfunction is not commonly observed in PARK-PINK1 patients [11,15,30]. Even though autonomic dysfunction has been reported in 45%–48% of patients [11,15], this proportion is among those in whom this feature was mentioned, and in the majority of patients (70%–80%), this information was missing, suggesting that this may not be an accurate representation of autonomic dysfunction in PARK-PINK1. Sleep disorders are common in patients with PARK-PINK1 [31]. In a multicentric study of 350 RBD patients, Gan-Or et al. [32] reported an association between heterozygosity for the PINK1 p.Gly411Ser variant and RBD.

All 7 subjects underwent whole-exome sequencing, which revealed the presence of biallelic likely pathogenic variants. We reviewed the literature from the past 20 years (Supplementary Table 1 in the online-only Data Supplement) to identify previously reported cases of PARK-PINK1 worldwide and their phenotypic presentations [33]. In India, the p.Phe385Ser, p.Tyr404Ter, p. Gln267Ter, and c.959+1G>A variants have been described [8,12,13,34]. No specific genotypic‒phenotypic correlation could be identified because numerous variants have been previously reported. Our patients were found to have five previously unreported novel variants. Notably, homozygosity for one novel in-frame deletion variant (c.1097_1099:p.Asn367del) was identified in two unrelated patients with no apparent familial relationship or shared ethnic origin, suggesting the possibility of a distant founder effect.

In conclusion, PINK1-associated early-onset parkinsonism usually presents as an asymmetric-onset tremor-dominant disorder with a good levodopa response. Early motor fluctuations and lower limb dystonia are common. NMS such as mood and sleep disorders, are common. We described six novel variants in the PINK1 gene.

Supplementary Materials

Video 1.

Video of patient 2 demonstrating the akinetic rigid parkinsonism phenotype with generalized dystonia in the OFF state and significant improvement in bradykinesia, dystonia, gait and postural instability along with lower limb predominant levodopa-induced choreiform dyskinesia in the ON state.

Video 2.

Video of patient 3 demonstrating proximal predominant rest tremors, bradykinesia and dystonia in the OFF state with significant improvement in bradykinesia, tremors and gait along with lower limb predominant levodopa-induced choreiform dyskinesia in the ON state.

Notes

Conflicts of Interest

The authors have no financial conflicts of interest.

Funding Statement

The study was partially funded by Department of Biotechnology, Government of India (BT/PR26428/MED/12/783/2017).

Author Contributions

Conceptualization: Aravind Gunasekaran, Vikram V Holla, Pramod Kumar Pal. Data curation: Aravind Gunasekaran, Vikram V Holla, Prashant Phulpagar, Sneha D Kamath. Formal analysis: Aravind Gunasekaran, Vikram V Holla. Funding acquisition: Nitish Kamble, Ravi Yadav, Babylakshmi Muthusamy, Pramod Kumar Pal. Investigation: Aravind Gunasekaran, Vikram V Holla, Prashant Phulpagar, Babylakshmi Muthusamy. Methodology: all authors. Project administration: Vikram V Holla, Prashant Phulpagar, Nitish Kamble, Ravi Yadav, Babylakshmi Muthusamy, Pramod Kumar Pal. Resources: Vikram V Holla, Nitish Kamble, Ravi Yadav, Babylakshmi Muthusamy, Pramod Kumar Pal. Supervision: Ravi Yadav, Babylakshmi Muthusamy, Pramod Kumar Pal. Validation: Nitish Kamble, Ravi Yadav, Babylakshmi Muthusamy, Pramod Kumar Pal. Visualization: Vikram V Holla, Pramod Kumar Pal. Writing—original draft: Aravind Gunasekaran, Vikram V Holla. Writing—review & editing: Prashant Phulpagar, Sneha D Kamath, Nitish Kamble, Ravi Yadav, Babylakshmi Muthusamy, Pramod Kumar Pal.

Acknowledgments

None

Figure 1.

The variant spectrum identified in the PINK1 gene in the current cohort (transcript ID: NM_032409). The novel variants are in bold. CH, compound heterozygous; HOM, homozygous.

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