GRAPHICAL ABSTRACT

INTRODUCTION

Parkinson disease (PD) is a chronic, progressive and complex neurodegenerative disorder that affects 1% of the population over the age of 60 [1]. The movement disorder of PD patients occurs due to the preferential loss of dopamine-secreting neurons within the substantia nigra and the presence of Lewy bodies [1]. The major clinical features of PD are motor symptoms (MS) and non-motor symptoms (NMS). Levodopa (L-DOPA) is the classic treatment for parkinsonism [1]. However, L-DOPA induces motor complications, such as dyskinesia and motor fluctuations, that affect the quality of life of PD patients [2]. Notably, this treatment response is variable between patients in appearance and intensity.

PD results from the failure of a neuronal mechanism triggered by defects in specific genes shaped by the environment over time [3]. Leucine-rich repeat kinase 2 (LRRK2) is the most common genetic cause of PD [3]. A broader role for LRRK2 has emerged following discoveries of the common G2019S kinase-enhancing mutation and risk variant at the LRRK2 locus in a significant number of idiopathic cases [3]. The frequencies of G2019S are highly variable between populations, and the highest carrier estimates for this mutation were reported in North African Arabs from Tunisia and Morocco [4]. Notably, the clinical features of patients carrying the mutation are variable, but the specific clinical differences remain elusive.

Because of the limited number of LRRK2-G2019S carriers worldwide and the paucity of related detailed clinical data, the pathogenic pathways of this mutation and its effects on the treatment course are not clear. The clinical outcomes of this mutation remain unclear, which is a significant barrier to our understanding of disease etiology and treatment management. A recent study suggested that disease-relevant changes in genetically linked forms of PD are reproduced in patients without genetic causes [5].

Therefore, in the absence of comprehensive genomic analyses and precise genotype-phenotype relationships between PD carriers of LRRK2-G2019S in North Africa, more in-depth analyses of the influence of this founder mutation during treatment assessment and the implementation of routine genetic diagnosis for personalized medicine are needed.

The present study investigated the clinical features, treatments and complications of PD in Tunisian patients according to their LRRK2-G2019S profile.

MATERIALS & METHODS

Study population

A longitudinal retrospective study was performed in the Department of Neurology at Razi University Hospital between 2002 and 2023. Subjects were diagnosed according to the clinical diagnostic criteria of the Movement Disorders Society for PD [6]. All patients underwent neurological examination by a movement disorder specialist and systematic brain imaging. We excluded all patients with parkinsonism of other origins.

Demographic and clinical data

Demographic, motor and neuropsychological data were collected at the first examination using standardized case-report forms. Age of onset (AOO) was defined as the age when the patient first had MS presumably attributable to PD. Motor signs were included. The Unified Parkinson’s Disease Rating Scale (UPDRS) Section III was used to rate the severity of MS [7]. Parkinsonian motor phenotypes were classified into three subgroups, tremor dominant, postural instability gait disorder (PIGD) or mixed, according to the formulas used for PD. Motor decline was considered two points of UPDRS-III scores during an interval of at least 6 months. The “on” and “off” scores were obtained using medication conditions, and “off” medication was defined as no dopaminergic treatment for at least 12 hours. Motor decline was calculated as the difference between the two scores divided by the number of months between the two tests. The response to L-DOPA was defined according to the Brain Bank Annual Assessment [8]. The levodopa equivalent dose (LED) per day was determined as previously described [9], and the acute levodopa challenge test was used to evaluate patient responsiveness [8]. A percentage greater than 30% was considered good responsiveness, and a percentage greater than 50% was classified as very good responsiveness.

Neuropsychological features were assessed to evaluate overall cognitive status at the first consultation. The techniques and tests used are described in detail in the Supplementary Materials (in the online-only Data Supplement). The Scales for Outcomes in Parkinson’s Disease-Autonomic Dysfunction was used to evaluate autonomic functions [10]. Other NMS, including hyposmia, rapid eye movement sleep behavior disorder (RBD), pain and fatigue, were also analyzed.

PD treatment data

Current treatments in Tunisia include dopaminergic agents, such as Modopar (L-DOPA and benserazide) and Sinemet (L-DOPA and carbidopa), dopaminergic agonists, such as pramipexole (Sifrol) and piribedil (Trivastal), anticholinergics, such as trihexyphenidyl (Parkizol/Artan) and biperidene (Akineton), antiepileptics (Depakine), glutamate receptor antagonists (amantadine), and adjuvants, such as entacapone (Comtan), a Catechol-O-Methyl Transferase inhibitor. The LED was calculated according to Schade et al. [11] and Nyholm and Jost [12].

Genetic analysis

Peripheral venous blood was collected from available participants in ethylenediaminetetraacetic acid-containing tubes. Genomic DNA was prepared using a QIAamp DNA Blood Mini Kit according to the manufacturer’s instructions (Qiagen GmbH, Hilden, Germany). Genomic DNA was extracted from peripheral leukocytes, and exon 41 of LRRK2 and the 15 bp fluctuating region were amplified by polymerase chain reaction using standard techniques. Sanger sequencing was performed using a 3500 Genetic Analyzer (The Applied Biosystems 3500; Thermo Fisher Scientific, Waltham, MA, USA).

Statistical analysis

We described demographic and clinical characteristics and LRRK2 genetic frequencies and assessed the relationships between the clinical variables and the LRRK2 genotype in the total cohort and between subgroups. Continuous variables are expressed as the means ± standard deviation or medians (1st quartile–3rd quartile). Fisher’s exact probability test for frequency tables was used for statistical analyses. Differences in proportions were analyzed using the chi-squared and Fischer’s exact tests. Multinomial logistic regression was used to model outcome variables according to LRRK2-G2019S mutation status. The associations of individual baseline characteristics with the present stages were evaluated using Cox proportional hazards regression analysis. A value of p < 0.05 was considered statistically significant. All statistical procedures and figures were generated using R software for Windows (RStudio version 4.1.1; PBC, Boston, MA, USA).

Ethics

The study was approved by the Ethics Committee of Razi University Hospital under the ID number 012019. All of the subjects conformed to the principles outlined in the Declaration of Helsinki and were informed of the purposes of the study. All subjects included in this study provided written consent (patients, their parents or caregivers).

RESULTS

We included 393 patients. The prevalence of patients with the LRRK2-G2019S mutation was 41.5%.

Demographic and baseline clinical features

Male predominance was noted in our total cohort, with a sex ratio of 1.09. We divided the PD patients according to LRRK2-G2019S status and found a significant difference in sex distribution (p = 0.008). PD was more frequently mutated in females than males (72 males vs. 91 females). Consanguinity was comparable between subgroups (p = 0.775), but a familial history of tremor was significantly more common in PD patients who were carriers of LRRK2 mutations (52.8% vs. 35.7% and p = 0.001). No differences were noted in smoking or alcohol consumption (Table 1).

The current age of the patients was comparable between the two groups (p = 0.165), but earlier PD onset was found in the mutated subgroup (57.79 vs. 60.10, p = 0.017).

The distribution of PD forms was significantly different between the two subgroups (adjusted-p < 0.001), and a high frequency of PIGD forms was found in carriers of the LRRK2 G2019S mutation compared to non-carriers (43.6% vs. 40.8%, respectively). Mixed forms were more frequently reported in the non-carriers of the LRRK2 mutation (26.9% vs. 22.7%, respectively). Asymmetric start times were more common in carriers of LRRK2 mutations (92.0% vs. 85.2%, adjusted-p < 0.001).

The difference in the initial UPDRS-III score between the two groups was slightly significant (adjusted-p = 0.087). Detailed data on initial treatments are summarized in Table 1. The percentage of patients who were LRRK2 G2019S carriers who received dopaminergic agonists was significantly greater than non-carriers (23.8% vs. 18.6%, respectively) (adjusted-p = 0.066). However, a greater percentage of non-carriers were receiving L-DOPA (65.5% vs. 60.0%, adjusted-p = 0.072).

Treatment and disease motor progression across PD subgroups

Detailed data on current treatments are summarized in Table 2. LED values were significantly greater in LRRK2-G2019S carriers compared to non-carriers (1055.77 vs. 913.61), with an adjusted-p < 0.001 (Table 2). We assessed the LED in our patients during follow-up (Figure 1B) to evaluate the changes in LED values according to the disease course. Notably, the mutated LED values were inferior to non-mutated patients during the first five years of the disease (340.00 vs. 368.05 for disease duration ≤2 years; and 559.85 vs. 631.08 for 3–5 years) and became greater during later stages according to LRRK2 status (1060.81 vs. 877.83 for 6–8 years and 1343.11 vs. 1290.67 for up to 9 years).

The UPDRS-III score at the last follow-up was significantly different between the PD subgroups, and higher scores were noted in the mutated patients compared to non-mutated patients (44.10 vs. 43.05, adjusted-p = 0.009) (Table 2). We observed a significant difference in the annual progression of the UPDRS-III score between the two subgroups. Greater annual progression was found in LRRK2-G2019S patients compared to non-LRRK2-G2019S patients (2.43 vs. 2.25). Notably, LRRK2 mutation carriers exhibited lower UPDRS-III scores in the early stages but progressed rapidly to align with non-LRRK2 patients (Figure 1A).

For motor complications, patients who were carriers of LRRK2 mutations experienced more dyskinesia during their last follow-up compared to non-carrier (52.8% vs. 35.6%, respectively, adjusted-p < 0.001). These complications were observed primarily in the late stages (up to 5 years) (Figure 1C and D). The frequency of motor fluctuations differed, and LRRK2 mutation carriers exhibited more complications compared to non-carriers (31.9% vs. 25.7%, respectively; adjusted-p < 0.001).

Non-motor findings between PD subgroups at the last follow-up

Detailed non-motor characteristics of the entire cohort stratified according to the LRRK2 mutation subgroup are summarized in Table 3. Notably, significant differences were found in the Mini-Mental State Examination (MMSE) score according to the LRRK2 profile (adjusted-p = 0.021). The prevalence of cognitive disorders was greater in the non-mutated subgroup, particularly for episodic memory (adjusted-p < 0.001), attentional (adjusted-p < 0.001) and dysexecutive disorders (adjusted-p = 0.038).

Assessment of neuropsychiatric symptoms (NPSs) revealed that LRRK2-G2019S mutation carriers had fewer sleep disturbances (adjusted-p < 0.001), hallucinations (adjusted-p = 0.004), depression (adjusted-p = 0.030), appetite and eating disorders (adjusted-p < 0.001), delirium (adjusted-p < 0.001), apathy (adjusted-p = 0.045), euphory (adjusted-p < 0.001), disinhibition (adjusted-p < 0.001), and aberrant motor behaviors (adjusted-p = 0.005).

The carriers of the mutation exhibited fewer dysautonomic signs, particularly hypersalivation (adjusted-p < 0.001), bowel and bladder disorders (adjusted-p = 0.009), orthostatic hypotension (adjusted-p < 0.001), sexual disorders (adjusted-p < 0.001), digestive disorders (adjusted-p < 0.001), hyperhidrosis (adjusted-p = 0.006), photosensitivity (adjusted-p = 0.044) and thermoregulation disorders (adjusted-p = 0.004). They had less hyposmia (adjusted-p < 0.001), RBD, fatigue and asthenia (adjusted-p < 0.001).

DISCUSSION

To the best of our knowledge, the present study is one of the largest cohort studies evaluating the impact of LRRK2-G2019S on clinical motor and non-motor characteristics and treatment complications in PD patients.

The LRRK2-G2019S mutation is the most common dominantly inherited cause of PD, and it accounts for up to 6% of familial cases and approximately 1.5% of sporadic cases worldwide [13]. The highest carrier estimates for this mutation have been reported in North African Arabian countries, namely Morocco and Tunisia (37% in patients with familial PD and 41% in sporadic cases) [14]. The present study reported a similar but slightly greater prevalence of LRRK2-G2019S carriers of approximately 41.5%. Our findings were lower than a previous Tunisian study with a 47.5% LRRK2-G2019S mutation frequency [15] but greater than another study that included a greater percentage of PD patients (35.5%) [16].

The analysis of our cohort according to LRRK2-G2019S mutation status confirmed and modified some previous demographic and clinical findings. We found a female predominance for this mutation with a sex-ratio of 0.79. Therefore, the predominance of PD in males observed previously did not include the G2019S mutation in LRRK2-related PD. A greater relative proportion of LRRK2 carriers in women (55.8% vs. 42.2%) vs. men (44.17% vs. 58.7%) was observed. Our findings corroborate a previous analysis [17] that suggested a relatively greater genetic load in women than men, particularly in Ashkenazi Jewish people [18]. However, another meta-analysis reported a lack of sex effects in LRRK2-associated PD patients [19]. Other studies, including the Tunisian study [16], observed a male predominance in LRRK2-G2019S patients [16,20]. Therefore, whether a sex preference exists for patients with LRRK2 mutations is not clear, and further comprehensive studies are needed to establish the impact of sex on disease penetrance.

We found an earlier onset in patients who were carriers of the mutation (p = 0.018), which is consistent with previous findings from a large LRRK2 series in different ethnic groups [13,15]. The penetrance of the G2019S mutation varies with age, and approximately 50% of people with this mutation develop PD symptoms by the age of 50 years [21,22].

The evaluation of motor features according to LRRK2 status revealed a severe phenotype among carriers of the mutation. These findings were explained by the greater frequency of PIGDs among carriers of the mutation, as reported previously and in our present study [23]. These findings were observed in a study of gait quantification in asymptomatic first-degree relatives of patients with PD who were carriers of the G2019S mutation [24]. They reported significantly greater gait variability under challenging conditions in asymptomatic G2019S mutation carriers compared to non-carriers [24]. This result suggests a relationship between a single mutation (LRRK2-G2019S) and specific motor features in PD patients. More recently, Mirelman et al. [25] performed a gait quantification study of Ashkenazi Jews who were PD carriers of the G2019S mutation. The author reported more carriers with the PIGD subtype of PD compared to non-carriers. These results and the results of our study, were explained by recent functional analysis using induced pluripotent stem cells (iPSCs) derived from PD-G2019S patients. The iPSC study revealed that the G2019S mutation significantly reduced the ratio of endogenous wild-type α-synuclein (αSyn) in the cytoplasm of intact neurons and promoted its accumulation, as well as pSer129 hyperphosphorylation [26]. The concentration of peripheral pSer192-αSyn may also contribute to gait impairment in PD patients [27]. Overall, we speculate that the high prevalence of PIGD in PD-G2019S patients was primarily due to the association of this mutation with the hyperphosphorylation of specific αSyn.

We also demonstrated that individuals with the mutation exhibited similar motor deficits in the early phases of the illness but experienced faster progression that resulted in greater motor impairment at the final assessment. These findings diverged from Healy et al. [13], who suggested a slower rate of progression. The accelerated progression observed in our cohort of LRRK2-G2019S patients is reinforced by the increased prevalence of PIGD phenotypes within this subgroup during the early stages of PD. The PIGD subtype is associated with faster progression and a poorer prognosis [28]. Our findings contradict the results of other Tunisian studies [16], which reported a similar or even milder phenotype in individuals carrying the LRRK2 mutation [15]. The disparate outcomes compared to previous Tunisian studies [15,16] may be attributed to the fact that the first study did not consider the adjustment of clinical parameters, and the second relied solely on a single assessment point.

During the final follow-up, LRRK2-related PD patients had a greater LED. However, they demonstrated greater L-DOPA dopa sensitivity, which was likely due to their increased susceptibility to motor fluctuations. They received a significantly greater dose of L-DOPA in combination therapy compared to the non-LRRK2 subgroup, which supports our previous observation of the severity of their condition.

Our study reported that the LRRK2-G2019S variant was associated with increased treatment doses, which resulted in increased motor complications. This result was explained by the established correlation between L-DOPA dose and dyskinesia [29,30] as well as the association of the LRRK2-G2019S variant with the occurrence of dyskinesia in North African PD patients [31]. Notably, the evaluation of disease kinetics revealed that these differences in treatment dose and motor complications primarily emerged in the later stages in LRRK2-G2019S patients. The follow-up of PD patients with LRRK2-G2019S revealed increased treatment doses and motor complications. These findings support the hypothesis that carriers of LRRK2-G2019S patients have altered specific neurodegenerative pathways [32,33].

We evaluated the non-motor features of our PD patients according to LRRK2 G2019S. Notably, our study revealed a distinctive feature, namely a lower manifestation of NMS in mutated patients than non-mutated patients.

For cognitive function, our data suggested that patients with LRRK2 mutations tended to be less affected overall, which is consistent with the literature [13,23]. However, the MMSE scores of LRRK2-G2019S patients were lower than non-carriers. This observation is intriguing, particularly because most of our LRRK2 mutation patients exhibited the PIGD subtype, which is typically associated with increased cognitive impairment. Therefore, we speculate that patients with mutations will develop early compensatory mechanisms that protect them from cognitive decline [13,23].

Our MMSE results may be overestimated because the use of the neuropsychiatric test (MMSE), which isa reliable battery for cognitive screening of PD patients, may lack sensitivity [34].

Our NPS findings indicated a lower prevalence of neuropsychiatric disorders. These observations are consistent with Alcalay et al. [23], who described better neuropsychological performance in LRRK2-G2019S patients. Although several studies suggested a greater likelihood of NPS in LRRK2-PD patients compared to idiopathic PD (iPD) [35,36], other studies proposed a decreased risk [37] or comparable prevalence rate [15,38]. Our observation contrasts with the results reported in neighboring Algeria, which suggested greater involvement of the limbic system among patients who were carriers of the mutation [35]. This variation could be clarified by the failure to consider AOO and disease duration as significant modulating factors in neuropsychological outcomes.

The observed infrequent dysautonomic involvement in our patients with LRRK2 mutations is consistent with previous studies [39]. However, the G2019S variant exhibited a similar profile to iPD [39], which suggests variability in pleomorphic histological features in patients with the LRRK2-G2019S mutation. We observed reduced olfactory impairment and fewer cases of RBD in patients with mutations, which is consistent with the literature [13,40]. This result indicates that the temporal characteristics of LRRK2-related pathology may not follow Braak’s staging schema.

Our study revealed several features that characterized PD patients with LRRK2-G2019S mutations, including an earlier AOO, a female predominance, fewer NMS, and a higher incidence of motor complications. Two additional factors influencing the clinical profile were the disease stage, wherein less motor impairment was observed at the early stage, and the AOO.

The findings of our study must be considered in light of the usual limitations of retrospective studies, such as incomplete data. However, the global clinical approach that we used, with the study of MS and NMS together in a large cohort of 393 patients, seems relevant for revealing the complete profile of LRRK2-G2019S carriers. Notably, the missing GBA screening data may be considered a limitation of this study because of the exclusion of potential confounders, especially because some variants were identified as specific in some similar populations.

In conclusion, our results are consistent with the incomplete penetrance of LRRK2-G2019S during the early PD phase, which revealed the main phenotypic differences between the two subgroups until the late stages of PD. Therefore, disease duration is a key step to standardizing comparisons and truly evaluating the effect of LRRK2-G2019S on PD features. Future studies are necessary to confirm our results when reliable biomarkers are developed.

Notes

Ethics Statement

Ethical approval was not required for this manuscript. Informed patient consent was not necessary or acquired for this work.

Supplementary Materials

Notes

Data Availability Statement

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.

Conflicts of Interest

The authors have no financial conflicts of interest.

Funding Statement

None

Author Contributions

Conceptualization: Riadh Gouider. Data curation: Guedi Ali Barreh, Youssef Abida, Ikram Sghaier, Alya Gharbi, Saloua Mrabet, Amira Souissi, Amina Nasri. Formal analysis: Guedi Ali Barreh, Ikram Sghaier. Funding acquisition: Riadh Gouider. Methodology: Mouna Ben Djebara, Imen Kacem, Youssef Abida, Ikram Sghaier. Supervision: Amina Gargouri-Berrechid, Imen Kacem, Riadh Gouider. Validation: Amina Gargouri-Berrechid, Imen Kacem, Riadh Gouider. Writing—original draft: Guedi Ali Barreh, Youssef Abida, Ikram Sghaier. Writing—review & editing: Imen Kacem, Sameh Trabelsi, Amina Gargouri-Berrechid, Riadh Gouider.

Acknowledgments

We thank all patients who gave their consent and participated in the present study. We are grateful to the technical assistance of the platform of sequencing in Faculty of Medicine of Tunis.

Figure 1.

Kinetics disease progression (motor symptom, treatment dose and motor complication) according to LRRK2 G2019S carriage. Patients Unified Parkinson’s Disease Rating Scale Section III score (A), levodopa equivalent dose (B) and motor complications (C: dyskinesia; D: motor fluctuation) according to G2019S-LRRK2 status (MUT: patients with the G2019S mutation in the leucine-rich repeat kinase 2 gene [LRRK2] and WT [wild type]: patients without the G2019S mutation) and disease duration. ^*p < 0.05.

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• Glutathione S-transferase polymorphisms (GSTM1/GSTT1) outcomes in clinical profile and treatment responsiveness among Tunisian cohort of Parkinson’s disease
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  Journal of Neural Transmission.2024;[Epub]     CrossRef

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