Pallidal Deep Brain Stimulation for Tremor Control in a Child with Juvenile DNAJC6-Associated Parkinsonism

Introduction

Juvenile DNAJC6-associated Parkinson’s disease is a rare autosomal recessive, early-onset neurodegenerative disorder characterized by parkinsonian features including bradykinesia, resting tremor, rigidity, and postural instability [1]. In addition, affected individuals frequently exhibit developmental delay, intellectual disability, epilepsy, dystonia, and neuropsychiatric symptoms, which may precede the onset of parkinsonism [2]. The disease course is often rapidly progressive and commonly associated with a poor or absent response to pharmacological treatment [3].

The DNAJC6 gene encodes a brain-specific isoform of auxilin, a protein that plays a critical role in clathrin-mediated synaptic vesicle recycling [4].

In this report, we describe a child with juvenile parkinsonism caused by a novel DNAJC6 variant who underwent bilateral globus pallidus internus deep brain stimulation (GPi-DBS), resulting in marked tremor improvement.

Case Report

We present a 15-year-old female, born to healthy, non-consanguineous parents with no family history of neurological disorders. Pre- and perinatal history was unremarkable. During infancy, she exhibited muscular hypotonia and a significant speech delay. She did not crawl but achieved independent walking at 13 months and subsequently reached all further motor milestones. At 3.5 years of age, she was first diagnosed with autism spectrum disorder, although this diagnosis was not confirmed later.

At 10 years of age, she developed an irregular, medium-frequency, medium-amplitude tremor affecting the right arm and leg, accompanied by painful muscular spasms of the arms that improved with gabapentin. Over time, she experienced increasing difficulties with chewing and swallowing, excessive drooling, delayed bowel and bladder emptying and progressive speech impairment. A vertical gaze palsy emerged, followed by worsening bradykinesia, hypomimia and postural instability.

Metabolic investigations revealed mildly reduced cerebrospinal fluid dopamine metabolites (homovanillic acid and 5-hydroxyindoleacetic acid). EEG and brain MRI were unremarkable. She was clinically diagnosed with juvenile parkinsonism. Chromosomal microarray analysis identified a deletion at 16q24.1, and whole-exome sequencing revealed a novel homozygous splice-site variant in DNAJC6 (c.543+1G>A), confirming the diagnosis at age 14 years.

This variant affects a canonical donor splice site and is predicted to disrupt normal splicing, resulting in aberrant transcript processing. Given that loss of function is a known disease mechanism for DNAJC6 [2], this variant constitutes very strong evidence of pathogenicity (PVS1) according to ACMG criteria [5] and has not been previously reported.

Over time tremor worsened, increasing in frequency and amplitude and presenting whole body distribution. Unfortunately, formal neurophysiological characterization of the tremor was not performed.

Levodopa–carbidopa therapy was initiated, but the patient exhibited marked drug sensitivity. Although levodopa effectively controlled the tremor, its benefit was short-lived: as soon as the drug effect wore off, tremor promptly re-emerged. Critically, any attempt to increase the dose to prolong or stabilize this response immediately triggered severe levodopa-induced dyskinesias (LID). In addition and particularly at night, prolonged compulsive pacing occurred with higher dosages of levodopa as possible manifestation of akathisia. Despite multiple treatment adjustments, including off-label administration of levodopa/carbidopa via gastrointestinal pump (4.7 mg/kg/day), the LID became intolerable. Dopamine agonists (oral and transdermal) and amantadine were ineffective, while trihexyphenidyl provided only transient benefit. Nitrazepam and dronabinol were used to improve sleep and relieve muscle cramps, and clonazepam was administered during severe tremor exacerbations, with transient benefit.

The alternating hyperkinetic and hypokinetic states became the dominant clinical feature, reflecting severe motor fluctuations and substantial therapeutic challenges (Video 1). The patient also developed recurrent vomiting and significant weight loss, necessitating gastrostomy followed by jejunostomy. Gastroscopy revealed severe gastroparesis.

Due to progressive clinical deterioration and refractory motor fluctuations, bilateral GPi-DBS was performed at 14 years of age. Surgery was carried out under general anesthesia in a single stage, using a frame-based approach with intraoperative microelectrode recordings, and stimulation was activated immediately postoperatively. A dramatic and sustained reduction in tremor was observed, persisting throughout the entire follow-up period. LID initially resolved and independent ambulation was transiently restored but did not persist beyond the first months postoperatively; pharmacological therapy could nonetheless be reduced (Video 2).

Electrode localization is shown using Lead-DBS v3 visualization (Figure 1) [6, 7]. Three months postoperatively, improvements were noted in Unified Parkinson’s Disease Rating Scale (UPDRS) and Caregiver Priorities and Child Health Index of Life with Disabilities (CPCHILD) scores (assessed under ongoing medication and active stimulation; Table 1).

Figure 1

Despite sustained tremor control, the patient’s overall condition progressively worsened. She developed severe, painful dystonia and worsening postural instability refractory to stimulation adjustments. Once stimulation was briefly turned off and led to a severe increase of dystonia, making it unlikely a stimulation induced effect but more likely a symptom of disease progression. Moreover, clear capsular effects following stimulation were noticed while testing with higher amplitude and lowest contacts. Therefore, only contacts 2–4 were used for continuous stimulation. Detailed description of all stimulation settings tried over time are shown in Table 2. Formal ON/OFF medication and ON/OFF stimulation assessments were not feasible given the severity of the patient’s condition, precluding objective quantification of the DBS effect in isolation. Nevertheless, the consistent and immediate recurrence of tremor upon reduction of stimulation parameters provides meaningful, if informal, evidence of a stimulation-dependent therapeutic effect. Progressive neuropsychiatric symptoms emerged, including pronounced abulia, reduced speech output, and emotional lability.

Continuous subcutaneous foslevodopa/foscarbidopa infusion (8–10 mg/kg/day) was initiated to avoid LID and gastrointestinal intolerance of oral treatment but yielded only transient benefit. Dyskinesias recurred even at low doses, accompanied by akathisia, leading to frequent falls and injuries. Pump therapy was discontinued, and clonidine with chloral hydrate (up to 0.6 µg/kg/hour) was introduced at night, resulting in modest improvement of dystonia and sleep.

Approximately one year after GPi-DBS, despite persistent tremor suppression, the patient exhibited severe disease progression with intractable dystonia and paroxysmal exacerbations, necessitating transfer to palliative care, a trajectory reflected in the 12-month CPCHILD scores (Table 1). Subsequent bilateral subthalamic nucleus (STN) DBS implantation did not result in clinical improvement.

Discussion

This case highlights the complexity of clinical and pharmacological management in juvenile DNAJC6-associated parkinsonism. Multiple phenotypes have been described, including parkinsonism-predominant [4], dystonia-predominant [8], dystonia–parkinsonism [3, 9], and generalized dystonia with tremor-dominant parkinsonism [10]. While many reported patients initially respond to levodopa, motor complications, dyskinesias, and behavioral symptoms often severely impair quality of life [9, 11].

Our patient harbored a novel DNAJC6 variant and exhibited a rapidly progressive, parkinsonism-predominant phenotype with severe tremor and profound levodopa intolerance.

Given the rapidly worsening clinical condition and the unsatisfactory pharmacological treatment, GPi-DBS was performed. Due to the significant dyskinesia observed in our patient, GPi-DBS was preferred over STN-DBS, as it may provide superior control of hyperkinetic symptoms [12].

To date, DBS experience in DNAJC6-associated disease remains extremely limited. Previously reported adult patients with early-onset DNAJC6-related parkinsonism showed good levodopa responsiveness but developed severe motor complications; surgical interventions included pallidotomy or STN-DBS with favorable outcomes [11, 13].

A recent report describes a 19-year-old female carrying a novel DNAJC6 mutation who presented predominantly with dystonia and showed only a poor response to pharmacological treatment, prompting bilateral GPi-DBS implantation [14]. In that case, GPi-DBS resulted in a marked and sustained improvement of dystonia as well as tremor, allowing for a substantial reduction of dopaminergic medication and leading to an overall functional benefit.

In contrast, the clinical presentation of our patient differed considerably. Parkinsonian features with severe, functionally disabling tremor initially predominated over dystonia and were accompanied by pronounced LID and extreme motor fluctuations. The most clinically meaningful effect of GPi-DBS in our case was a dramatic and sustained suppression of tremor, which persisted throughout the entire follow-up period and proved resistant to stimulation adjustments. This pronounced anti-tremor effect represents a relevant therapeutic achievement in DNAJC6-associated juvenile parkinsonism, a condition in which effective treatment options are exceedingly limited.

However, despite the robust tremor control, beneficial effects on other motor and non-motor symptoms—including LID, sleep disturbances, independent ambulation, and medication burden—were only transient and failed to translate into a sustained improvement in quality of life. Importantly, in contrast to the previously reported dystonia-predominant case [14], our patient did not experience meaningful or lasting improvement of dystonia following GPi-DBS. Dystonia subsequently progressed to become the dominant and most treatment-refractory feature, ultimately driving overall disease progression. Given this unfavorable course, additional bilateral STN-DBS was attempted; however, this intervention did not result in any clinical benefit.

This trajectory raises important considerations regarding surgical risk-benefit assessment in rapidly progressive dystonia-parkinsonism syndromes, where DBS may offer only palliative rather than disease-modifying benefit and procedural risks must be carefully weighed against uncertain therapeutic gain. In DNAJC6-associated parkinsonism, published DBS experience remains extremely limited and outcomes appear heterogeneous and phenotype-dependent. While refractory tremor would likely have further compromised our patient’s quality of life in the absence of intervention, the overall disease trajectory was not altered, underscoring the importance of transparent shared decision-making with patients and families before proceeding with surgery.

In conclusion, this case demonstrates that DNAJC6-associated juvenile parkinsonism can follow a devastating course refractory to standard medical therapies. While GPi-DBS may provide effective and sustained tremor control, it does not modify overall disease progression and should be regarded as a palliative intervention. Nevertheless, given the scarcity of published data on DBS outcomes in juvenile DNAJC6-related parkinsonism, our experience suggests that GPi-DBS can be considered a viable therapeutic option specifically for tremor control, while emphasizing the need for realistic prognostic counseling regarding overall disease progression.

Ethics and Consent

The patient’s respective pre- and post-operative data were included from the longitudinal, retrospective GEPESTIM registry (DRKS813–168), approved by the ethics committee of the University of Cologne (13–168).

Patient’s legal caregivers gave informed consent to participate in the study before taking part.

Patient’s legal caregivers provided written informed consent, including consent for anonymous publication of clinical information and video.

Financial Disclosures

Dr. Thiel reports grants from Deutsche Forschungsge-meinschaft in EJPRD Call 2023 for GNAO1-EU project and Grant of the GNAO1-Gemeinsam nicht allein e.V. for the trial ZINCGNAO1. Dr. Thiel serves as an unpaid chair of YEPNS (Young European Pediatric Neurology Society).

Dr. Barbe reports grants from DFG CRC 1252, DFG CRC 1451, and OPEL (Medtronic) research grant. He has received payment or honoraria for lectures, presentations, or educational events from Medtronic, Boston Scientific, Abbott, FomF, desitin, UCB, Bial, Apothekerverband Köln e.V., BDN, Ever Pharma, and Esteve. Dr. Barbe serves on Data Safety Monitoring Boards or Advisory Boards for IQWIG, Medtronic, Esteve, Boston Scientific, and Abbvie. He holds an unpaid leadership role as Co-chair of the Speech and Swallowing Disorder Group of the International Movement Disorder Society.

Dr. Koy reports support from Dr. Rita and Dr. Hans Günther Herfort Grant. She has received grants from Boston Scientific, which partly sponsored a clinical trial where she was PI (2014–2024), and from Dr. Rita and Dr. Hans Günther Herfort Grant. Dr. Koy serves as a member of the steering committee of the SIG Pediatric Movement Disorders.