Introduction
Parkinson’s disease (PD) is a progressive neurodegenerative disorder that predominantly affects individuals in their 60s, with prevalence increasing with age, impacting 1% to 2% of those over 65 (Ascherio & Schwarzschild, 2016; Van Den Eeden et al., 2003). Early-onset PD (EOPD) has been variably defined, with the maximal age ranging from 40 to 60 years, until expert consensus in 2022 set the threshold at motor symptom onset before 50 (Mehanna et al., 2022), which accounts for approximately 3% to 7% of PD cases (Mehanna & Jankovic, 2019). Genetic factors are strongly associated with EOPD, with the likelihood of detecting genetic mutations increasing as the age of onset decreases (Blauwendraat et al., 2020). In North Africa, specific mutations, such as the LRRK2 G2019S mutation, are prevalent among PD patients (El Otmani et al., 2023), although their precise relationship with EOPD has not been thoroughly investigated.
Subthalamic nucleus deep brain stimulation (STN-DBS) is a well-established treatment for managing motor and non-motor complications, as well as reducing the need for dopaminergic medication in advanced stages of PD (Deuschl et al., 2006). Emerging evidence supports its efficacy in EOPD (Krause et al., 2022) compared to late-onset PD patients (Knipe et al., 2011; Kumar et al., 2005). While STN-DBS appears particularly effective in patients carrying the LRRK2 G2019S mutation (Leaver et al., 2022) including motor ratings and levodopa-equivalent daily dose (LEDD), data specifically focusing on EOPD patients with these mutations remain limited, with no previous studies investigating this relationship.
This study aims to fill this gap by exploring the impact of the LRRK2 G2019S mutation on the clinical outcomes of EOPD patients undergoing STN-DBS, in a Moroccan cohort.

Materials and Methods

Study design and population
This prospective study was conducted at the University Hospital of Ibn Rochd in Casablanca, Morocco. The study included patients diagnosed with EOPD, defined in our cohort as disease onset at age 45 or younger—a threshold established before the 2022 consensus, which later set the cutoff at motor symptom onset before age 50—who underwent STN-DBS between June 2007 and June 2023. Participants were selected according to the UK PD Society Brain Bank diagnostic criteria (Hughes et al., 1992). Eligibility for DBS was determined based on the CAPSIT-PD criteria (Defer et al., 1999), which included an acute levodopa challenge test demonstrating improvement greater than 50% in motor symptoms measured by the unified PD rating scale (UPDRS) III, a neuropsychological assessment with a Moroccan version of the Mattis scale exceeding a score of 140, a favorable psychiatric status evaluated preoperatively by a psychiatrist to rule out contraindication (with depression assessed using the Montgomery–Åsberg depression rating scale [MADRS] scale), and preoperative MRI findings showing no substantial atrophy, signal abnormalities, or structural lesions. All patients provided informed consent before their inclusion in the study, and the local ethics committee approved the research.
Genomic DNA was extracted from saliva samples using the Oragene-DNA kit. Genotyping for LRRK2 mutations was performed using TaqMan SNP genotyping assays, with polymerase chain reaction (PCR) and real-time detection. Based on genetic results, patients were divided into two groups: Those who tested positive for the LRRK2 G2019S mutation (carriers) and those who did not (non-carriers). The non-carriers did not have any known monogenic mutations, including PARKIN, PINK1, DJ-1, or GBA.

Surgical procedure
A stereotactic neurosurgical implantation of leads into the STN was performed under local anesthesia. Precise coordinates for targeting the dorsolateral part of the STN were calculated using a 1.5-T brain MRI. During the procedure, three recording microelectrodes were inserted, and neuronal activity was recorded starting from 10 mm above the target. After placing the DBS leads, we assessed the effect of the stimulation current while the patient was awake, monitoring for motor improvements and side effects. Postoperative CT scans were conducted to identify complications. Pulse generators were implanted on the same day or shortly thereafter, and programming of the DBS device began 2 to 4 weeks post-surgery, with adjustments made during follow-up visits.

Data collection and statistical analysis
We collected demographic and clinical data for all patients. Motor symptoms were evaluated before surgery and reassessed one year after surgery. A genetic study was conducted in conjunction with the surgical procedure, with some analyses completed up to 18 months before the procedure. To ensure a standardized evaluation of post-surgical outcomes, we established a one-year follow-up period. The primary outcome measures included improvements in motor function, evaluated using the UPDRS Part III during OFF periods, as well as a reduction in dyskinesia and motor fluctuations based on specific UPDRS IV items.
Additionally, a decrease in the levodopa equivalent daily dose (LEDD) was calculated using the conversion formulae proposed by Tomlinson et al. (2010). Improvements were quantified by calculating the percentage change between pre- and post-surgery scores. This was achieved by subtracting the initial value from the final value, dividing the result by the initial value, and then multiplying by 100. Any complications related to DBS surgery or device implantation were also recorded.
Data were analyzed using SPSS software, version 21 (Armonk, NY: IBM Corp). Descriptive statistics were used to summarize demographic and clinical characteristics of the study population. Continuous variables were expressed as Mean±SD, while categorical variables were presented as frequencies and percentages. The normality of continuous variables was assessed using the Shapiro-Wilk test. Depending on the distribution, comparisons between LRRK2 mutation carriers and non-carriers were performed using t-tests for normally distributed data and the Mann-Whitney U test for non-normally distributed data. For categorical variables, the chi-square test was used, or the Fisher exact test when expected counts were low. A P<0.05 was considered statistically significant.

Results

Sociodemographic and clinical characteristics
Seventeen EOPD patients who underwent STN-DBS were included, selected from a cohort of 62 PD patients who underwent surgery at our center. Of these, 10 (58.8%) carried the LRRK2 G2019S mutation. The mean age at disease onset was 37.9 years, and the majority of the sample were females (64.7%). The mean age at surgery was 49.6 years, with an average disease duration of 11.7 years. In terms of clinical presentation, motor fluctuations were present in 88.2% of the patients, and dyskinesia affected 94.1%. The akinetic-rigid PD subtype was the most common (47.1%), followed by mixed type (41.2%) and tremor-dominant type (11.8%). The mean daily dosage of levodopa was 894 mg. All patients were on dopa therapy, 16 out of 17 were on dopamine agonists, 5 were on trihexyphenidyl, and 12 used amantadine. Nearly one-quarter of the patients (23.5%) were on antidepressants. Table 1 presents the demographic and clinical characteristics of the sample.
When comparing carriers and non-carriers, LRRK2 G2019S patients were more likely to present with the mixed PD subtype. In contrast, non-carriers were predominantly affected by the akinetic-rigid or tremor-dominant subtypes (P=0.011). No other significant differences were found in the demographic or clinical characteristics between the two groups, as shown in Table 1.



Stimulation settings
We used three stereotactic trajectories (central, internal, and posterior) for all patients to measure electrophysiological activity. The central trajectory was selected for 7 of 10 mutation carriers and 5 of 7 non-carriers, as it provided the longest neuronal recording and the most significant improvement. Regarding DBS settings, in the LRRK2 G2019S group, 15 leads were used in monopolar stimulation and 5 in bipolar stimulation, with an average voltage of 2.3V (range: 1.7–2.9) at one year. Among the non-carriers, 11 leads were used in monopolar stimulation and 3 in bipolar stimulation, with an average voltage of 2.4V (range: 1.4–3.2) at one year.

Clinical outcomes one year after DBS
After one year of STN-DBS, both LRRK2 G2019S mutation carriers and non-carriers demonstrated significant improvements in motor symptoms, with no significant difference between LRRK2 carriers and non-carriers. The mean improvement in UPDRS III score was 61.3% for the overall cohort. Improvements in dyskinesia and motor fluctuations were also comparable between the two groups, with an overall improvement of 77.1% and 83.8%, respectively. The reduction in LEDD was also notable. The overall cohort achieved a mean decrease of 60.6%. Table 2 provides an overview of these improvements observed in both patient groups.
All patients reported improvements in their QoL and expressed satisfaction with the treatment outcomes. One patient experienced a hardware-related infection 18 months post-surgery, necessitating device replacement a year later. No other significant complications were reported in the cohort.



Discussion
This study demonstrates that STN-DBS is an effective intervention for managing motor symptoms and reducing medication needs in EOPD patients. However, our findings indicate that the LRRK2 G2019S mutation does not alter DBS outcomes, with no significant difference observed in motor function (P=0.922), dyskinesias (P=0.454), fluctuations (P=0.158), or LEDD reduction (P=0.580) when comparing carriers to non-carriers at one year after DBS. Our series is the first to examine the effect of DBS specifically on EOPD linked to the LRRK2 G2019S mutation. While previous studies (Leaver et al., 2022; Perju-Dumbrava et al., 2012; Sayad et al., 2016) have compared DBS outcomes in patients carrying the LRRK2 G2019S mutation, they focused on all PD patients and did not specifically target EOPD. Moreover, performing such advanced procedures in Morocco, a developing country with healthcare challenges, including workforce shortages and limited access to DBS specialists (Daghi et al., 2025), is a significant accomplishment.
Both LRRK2 mutation carriers and non-carriers demonstrated significant improvements in motor function, consistent with previous reports on the efficacy of DBS in EOPD (Krause et al., 2022). A review of 12 studies comparing DBS responses across various forms of PD, including carriers of LRRK2, PRKN, and GBA mutations, found that DBS effectively controls motor symptoms regardless of the patient's genetic status or age at onset (Rizzone et al., 2019). While these studies confirmed the overall effectiveness of DBS, they also noted some differences in the response to DBS based on genetic factors. However, the very long-term effects of DBS remain uncertain among EOPD patients carrying the mutations.
While LRRK2 mutations are the most common genetic cause of familial and sporadic PD in our region (El Otmani et al., 2023), it is still unclear whether this translates into differential DBS eligibility. In one study, patients with EOPD carrying LRRK2, GBA, or PRKN mutations were more frequently found in the DBS group compared to the non-DBS group (26.5% vs 16.8%; P=0.02) (Pal et al., 2016), suggesting a potential link between these mutations and eligibility for DBS. Our results align with this, as the prevalence of LRRK2 mutations in our group was approximately 58%, which is notably higher than the 41% previously reported among PD patients in our country or any other reported prevalence globally (Bouhouche et al., 2017; El Otmani et al., 2023). As well, the higher prevalence of LRRK2 mutations in our DBS group (58%) compared to the 5.1% reported in a previous study (Pal et al., 2016) confirms regional genetic differences, possibly driven by a founder effect in this area (El Otmani et al., 2023).
Approximately two-thirds of our DBS patients were female (64.7%), with a higher prevalence reported among the LRRK2 group (80%). A previous meta-analysis investigating gender differences in patients carrying the LRRK2 mutation confirms these findings (Chen et al., 2020). This may be due to earlier onset and faster progression in LRRK2-PD females, with evidence showing a 5-year earlier onset in this subgroup (Trinh et al., 2014). However, other studies have found no significant gender differences in LRRK2 mutation prevalence (Gan-Or et al., 2015).
Multiple studies have shown that patients with a younger age at disease onset tend to exhibit better long-term outcomes, particularly in motor and axial symptoms (Shalash et al., 2014). In our study, STN-DBS resulted in significant improvements, with a 77.1% reduction in dyskinesia and an 83.8% reduction in motor fluctuations. These results surpass the 66.7% and 50% reductions reported in a previous local study and exceed outcomes from other STN-DBS studies across the African region (Daghi et al., 2024). Additionally, the reduction in LEDD in our cohort was 60.6%, slightly higher than the 51.72% reduction reported in a previous study from Rabat (Rahmani et al., 2018). All our patients reported satisfaction with the treatment, with only one patient experiencing an infection. These favorable outcomes are likely linked to the younger age at surgery (mean 49.6 years), as younger patients generally respond better to DBS, compared to older ages reported in Rabat and other studies (Daghi et al., 2024; Rahmani et al., 2018). 
This study has several limitations. The sample size was relatively small, and the cohort was monocentric, which restricts the generalizability of our findings. Additionally, since the last surgical interventions and genetic studies were conducted up to 18 months ago, the follow-up period was limited to one year post-surgery. As a result, this timeframe may not adequately capture the long-term durability of DBS effects in EOPD patients. Future studies with larger, multicenter cohorts and longer follow-up periods are needed to confirm these results and to assess the long-term durability of DBS in this patient population. Moreover, while we did not evaluate other variants associated with EOPD, such as PARKIN or GBA, their potential influence on DBS outcomes warrants further exploration.

Conclusion
In conclusion, STN-DBS effectively manages motor complications and reduces medication needs in EOPD, irrespective of whether patients carry the LRRK2 G2019S mutation. At one year post-surgery, our patients experienced a 61.3% improvement in motor function, with reductions of 77.1% in dyskinesia and 83.8% in motor fluctuations, respectively, and a 60.6% decrease in daily medication doses.

Ethical Considerations

Compliance with ethical guidelines
The patients were fully informed about this research and gave consent to its publication.

Funding
This research did not receive any grant from funding agencies in the public, commercial, or non-profit sectors.

Authors' contributions
Conceptualization: Hicham EL Otmani, Bouchra EL Moutawaki, Mohammed Abdoh Rafai, Nadia Tahiri Jouti, and Abdelhakim Lakhda; Methodology: Hicham EL Otmani, Mohamed Daghi, and Suzanne Lesage; Investigation: Mohamed Daghi, Maha Abdallaoui and Suzanne Lesage; Validation: Bouchra EL Moutawaki, Mohammed Abdoh Rafai, Nadia Tahiri Jouti, Suzanne Lesage, and Abdelhakim Lakhda; Formal analysis: Mohamed Daghi; Data curation: Hicham EL Otmani, Mohamed Daghi, and Maha Abdallaoui; Project administration, Hicham EL Otmani, and Suzanne Lesage. Writing the original draft: Hicham EL Otmani and Mohamed Daghi; Review and editing: Hicham EL Otmani, Nadia Tahiri Jouti, and Suzanne Lesage, Abdelhakim Lakhda; Supervision: Hicham EL Otmani, Suzanne Lesage, and Abdelhakim Lakhdar; 

Conflict of interest
The authors declared no conflict of interest.

Acknowledgments
The authors gratefully acknowledge the invaluable contributions of the clinical, surgical, and laboratory teams involved in the genetic analyses and deep brain stimulation procedures. Their technical expertise and commitment were essential to the successful completion of this work.





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