Clinical characteristics.

LRRK2-related Parkinson disease (PARK-LRRK2) is characterized by initial motor features of bradykinesia and asymmetric tremor at rest or rigidity. Dystonia and gait abnormalities that may include freezing and postural instability may also be present. Onset is generally after age 50 years, although early onset (in the 20s) and late onset (in the 90s) have been described. PARK-LRRK2 is indistinguishable from Parkinson disease of unknown cause representing a simplex case (also referred to as "sporadic" Parkinson disease) on an individual basis. However, on average individuals with PARK-LRRK2 have slightly slower motor progression and better survival. Overall, nonmotor symptoms in PARK-LRRK2, especially REM sleep behavior disorder and cognitive decline, may occur at reduced frequency and the latter may progress more slowly compared to Parkinson disease of unknown cause. Melanoma is more common in individuals with Parkinson disease, including those with PARK-LRRK2.

Diagnosis/testing.

The diagnosis of PARK-LRRK2 is established in a proband with Parkinson disease and a heterozygous LRRK2 pathogenic variant identified by molecular genetic testing.

Management.

Treatment of manifestations: Symptomatic treatment of the motor features of parkinsonism is the same as for other known causes of Parkinson disease: pharmacologic replacement of dopamine, most commonly accomplished with the precursor of dopamine, levodopa, combined with carbidopa. Dopamine receptor agonists may also be used, as well as monoamine oxidase type B inhibitors, amantadine, adenosine receptor A2A antagonists, and/or anticholinergics. Dyskinesias may occur with therapy at similar or increased rates compared with Parkinson disease of unknown cause. Exercise is usually recommended. Physical, occupational, and voice therapy may be beneficial. Treatment of nonmotor manifestations – such as cognitive changes, constipation, depression, anxiety, urinary issues, sleep disorders, and orthostatic hypotension – should be addressed based on an individual basis; standard treatment of melanoma per dermatologist and oncologist.

Surveillance: At least annual evaluation (typically every three months) for both motor and nonmotor symptoms. Motor evaluation focuses on gait and frequency of falls, slowness of movement and dexterity, tremor, and rigidity. Evaluation for nonmotor signs and symptoms includes assessment of constipation, cognitive changes, mood disorder, impulse control disorders, other psychiatric disorders, urinary frequency, sexual dysfunction, sleep disturbance, and orthostatic hypotension. At least annual dermatologic evaluation for melanoma.

Agents/circumstances to avoid: Dopamine-blocking therapies may exacerbate parkinsonism.

Pregnancy management: While data is limited, most support treatment with levodopa and dopa decarboxylase inhibitors during pregnancy.

Genetic counseling.

PARK-LRRK2 is inherited in an autosomal dominant manner with reduced penetrance. To date, all individuals with PARK-LRRK2 whose parents have undergone molecular genetic testing have the disorder as the result of an LRRK2 pathogenic variant inherited from a parent. However, because the penetrance of PARK-LRRK2 is reduced, a high percentage of probands report unaffected parents. Each child of an individual with a heterozygous LRRK2 pathogenic variant has a 50% chance of inheriting the LRRK2 pathogenic variant. Once the causative LRRK2 pathogenic variant(s) has been identified in an affected family member, predictive testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.

Suggestive Findings

PARK-LRRK2 should be suspected in probands with the following clinical and imaging findings and family history. PARK-LRRK2 may not be distinguishable from other forms of Parkinson disease; suggestive findings include clinical findings of Parkinson disease, additional clinical findings, and features highly suggestive of but frequently not present in individuals with PARK-LRRK2.

Clinical findings of Parkinson disease

• Bradykinesia (slowness of movement) with decrements in speed or amplitude as movements are continued AND
• Resting tremor (4-6-Hz tremor in a fully resting limb) OR
• Rigidity OR
• Gait disturbances

Additional clinical findings

• Clear and dramatic beneficial response to dopaminergic therapy
• Levodopa-induced dyskinesias

Clinical findings highly suggestive of but not always present in individuals with PARK-LRRK2

• Multiple family members with Parkinson disease
• Slower progression of motor symptoms
• Less cognitive impairment for age
• Absence of REM sleep behavior disorder
• Absence of hyposmia
• Leg tremor at onset (infrequent but highly suggestive)

Imaging findings

• Brain CT and MRI are normal.

• DAT-SPECT, ¹⁸F-fluordopa-PET, or ¹⁸F-FDG-PET scans may be used to aid in diagnosis. Typically, there will be significant reduction in uptake of ¹⁸F-fluordopa on PET scan and in dopamine transporter on DAT-SPECT. Note: While ¹⁸F-fluordopa-PET and ¹⁸F-FDG-PET scans are usually abnormal, results may be normal early in the disease course.

• Cardiac metaiodobenzylguanidine (MIBG) scintigraphy tends to show less impaired MIBG cardiac uptake compared to Parkinson disease of unknown cause [Valldeoriola et al 2011, Tijero et al 2013].

Establishing the Diagnosis

The diagnosis of PARK-LRRK2 is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in LRRK2 identified by molecular genetic testing (see Table 1).

Note: (1) Per American College of Medical Genetics and Genomics / Association for Molecular Pathology variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous LRRK2 variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Other Testing

Biomarker findings. While not currently integrated into the diagnosis of Parkinson disease, synuclein-related assays (e.g., cerebrospinal fluid [CSF] synuclein seeding assays, synuclein immunofluorescence on skin biopsy) are tests used to support the clinical diagnosis of Parkinson disease. Error! Hyperlink reference not valid.Individuals with PARK-LRRK2 often have results on these tests consistent with a diagnosis of Parkinson disease. However, not all individuals with PARK-LRRK2 will have positive results on these assays [Kim et al 2024, Yuan et al 2024, Chahine et al 2025]. More than 30% of individuals with PARK-LRRK2 may not demonstrate abnormal CSF synuclein seeding [Siderowf et al 2023]. Thus, negative results on a synuclein assay cannot be used to rule out a diagnosis of PARK-LRRK2. This is a controversial area and is under active investigation [Sekiya et al 2025].

Clinical Description

LRRK2-related Parkinson disease (PARK-LRRK2) is characterized by manifestations of typical parkinsonism including bradykinesia (slowness of movement, decreased arm swing), resting tremor, and rigidity. Gait features including postural instability may be present. Although it may be clinically indistinguishable from Parkinson disease of unknown cause representing a simplex case (also referred to as "sporadic" Parkinson disease; see Nomenclature), the motor and cognitive manifestations of PARK-LRRK2 may be less frequent and milder than in sporadic Parkinson disease [Kestenbaum & Alcalay 2017, Ben Romdhan et al 2018, Saunders-Pullman et al 2018] (see Genotype-Phenotype Correlations). PARK-LRRK2 follows a slowly progressive course.

Onset. PARK-LRRK2 onset is insidious. The mean age of onset of PARK-LRRK2 is 58-62 years [Marder et al 2015, San Luciano et al 2017], similar to or slightly younger than individuals with Parkinson disease of unknown cause. While uncommon, some individuals have very early-onset disease (in the 20s); the range of disease onset is 28 to 95 years. Age at onset varies, even within the same family.

Prognosis. Overall survival is longer in those with PARK-LRRK2 compared to those with Parkinson disease of unknown cause [Lanore et al 2023, Thaler et al 2018].

Motor features. There is conflicting data regarding the predominant motor features specific to PARK-LRRK2. Some have reported more tremor at onset [Healy et al 2008, Marras et al 2011, Becker et al 2024], including leg tremor, while others have reported more gait-predominant features, postural instability, and rigidity at onset [Alcalay et al 2009, Gan-Or et al 2010]. Motor features are overall similar to Parkinson disease of unknown cause and includes bradykinesia (slowness of movement) and difficulty with dexterity. Tremor may occur at rest or during action, although tremor may not always be present. Motor features generally spread from unilateral to bilateral involvement.

• Gait abnormalities include slow walking, shuffling gait, lower-limb dystonia, freezing, and unsteadiness. Postural instability and gait difficulty may be slightly worse in individuals with PARK-LRRK2 [Alcalay et al 2013, Mirelman et al 2013], although a lower rate of falls has also been reported [Healy et al 2008, Brockmann et al 2011].
• Facial hypomimia (masking) is reported.
• Bulbar dysfunction including swallowing issues are often less prominent than in Parkinson disease of unknown cause, although extensive reports are limited.
• Dyskinesias often develop as a complication of dopaminergic therapy. Dyskinesias in individuals with PARK-LRRK2 occur at a similar or lower frequency than in those with Parkinson disease of unknown cause [Healy et al 2008], with no difference in prevalence or latency to dyskinesia [Yahalom et al 2012]. Females with PARK-LRRK2 have a higher incidence of dyskinesias than males [San Luciano et al 2017].
  Generally, slower progression of motor features is reported in those with PARK-LRRK2 compared to Parkinson disease of unknown cause [Ben Romdhan et al 2018, Saunders-Pullman et al 2018]. However, some older longitudinal studies do not support this finding [Yahalom et al 2014, Nabli et al 2015].

Nonmotor features. Nonmotor features may appear prior to the movement disorder or emerge with motor features [Alcalay et al 2015, Kestenbaum & Alcalay 2017, Gunzler et al 2018, Liu & Le 2020, Smith et al 2022].

• Cognitive decline can occur, including mild cognitive impairment and dementia. Cognition may be slightly less impaired in individuals with PARK-LRRK2 compared to individuals with Parkinson disease of unknown cause [Alcalay et al 2015, Somme et al 2015, Srivatsal et al 2015, Wise & Alcalay 2022]. Some studies have not found any significant differences in cognition between individuals with PARK-LRRK2 and those with Parkinson disease of unknown cause [Zheng et al 2015].
• Constipation is less severe in the Tunisian Berber cohort with PARK-LRRK2 [Trinh et al 2014a] compared to those with Parkinson disease of unknown cause. In a Chinese cohort there were no differences in constipation between individuals with PARK-LRRK2 and those with Parkinson disease of unknown cause [Song et al 2025].
• Hyposmia/anosmia. Olfaction is impaired to a lesser extent in those with PARK-LRRK2 compared to those with Parkinson disease of unknown cause [Vilas et al 2020, Saunders-Pullman et al 2022].
• Neuropsychiatric features. Depression, anxiety, and other neuropsychiatric features are reported [Brockmann et al 2011, Marras et al 2011, Shanker et al 2011]. There is possibly a slightly lower risk of depression in those with PARK-LRRK2 compared to those with Parkinson disease of unknown cause [Marras et al 2016], although this is not consistently reported.
• Genitourinary manifestations may include sexual dysfunction, urinary frequency, and incontinence.
• Sleep problems include poor sleep quality, excessive daytime sleepiness, sleep fragmentation, early awakening, and insomnia [Pont-Sunyer et al 2015]. Sleep-onset insomnia may occur more frequently in those with PARK-LRRK2, although the frequency of excessive daytime sleepiness may not differ [Pont-Sunyer et al 2015].
  REM sleep behavior disorder is less frequent in individuals of Ashkenazi Jewish and Tunisian Berber ancestry with the LRRK2 p.Gly2019Ser pathogenic variant [Saunders-Pullman et al 2014, Trinh et al 2014a] and in individuals of Spanish ancestry with LRRK2 pathogenic variants p.Gly2019Ser, p.Arg1441Cys, and p.Arg1441Gly [Pont-Sunyer et al 2015] compared to those with Parkinson disease of unknown cause.
• Orthostatic hypotension may be less severe in individuals with PARK-LRRK2 compared to those with Parkinson disease of unknown cause. Heart rate variability may be normal in individuals with PARK-LRRK2 (i.e., less impaired than in those with Parkinson disease of unknown cause) [Visanji et al 2017] and there may be less sympathetic denervation and orthostasis [Quattrone et al 2008, Tijero et al 2013].

Risk of malignancy

• Melanoma. An association between melanoma and Parkinson disease of any etiology has been reported [Huang et al 2015, Dalvin et al 2017]. Compared to individuals without Parkinson disease, those with Parkinson disease due to any cause have a 3.8-fold increased likelihood of having a preexisting melanoma [Dalvin et al 2017]. The rate of melanoma in individuals with PARK-LRRK2 who have a heterozygous p.Gly2019Ser pathogenic variant is similar or increased compared to the risk of melanoma in individuals with other forms of Parkinson disease [Agalliu et al 2015, Agalliu et al 2019].
• Non-skin cancer, especially leukemia, colon cancer, and breast cancer, may be increased in individuals with a heterozygous pathogenic variant in LRRK2, although not all studies support this association [Agalliu et al 2015, Warø & Aasly 2017, Agalliu et al 2019, Wang et al 2023].

Prognosis. Overall survival is longer in those with PARK-LRRK2 compared to those with Parkinson disease of unknown cause [Lanore et al 2023, Thaler et al 2018].

Atypical Parkinson disease phenotypes. For a small number of individuals with an LRRK2 pathogenic variant, clinical features and/or pathology support an atypical parkinsonian syndrome. These atypical phenotypes include progressive supranuclear palsy (PSP; the pathologic hallmark of which is the accumulation of abnormally phosphorylated tau protein, specifically 4-repeat [4R] tau isoforms), multiple system atrophy, corticobasal syndrome, amyotrophic lateral sclerosis-like phenotype, and frontotemporal dementia [Zimprich et al 2004a, Ross et al 2006, Dächsel et al 2007, Chen-Plotkin et al 2008, Santos-Rebouças et al 2008, Lee et al 2018b, Blauwendraat et al 2019]. Frontotemporal dementia and other LRRK2-related atypical parkinsonian syndromes have variable clinical manifestations but overall tend to be associated with more severe cognitive and motor phenotypes (see also Neuropathology).

Neuropathology. The majority of individuals with PARK-LRRK2 exhibit typical pathologic features also seen in Parkinson disease of unknown cause including neuronal loss and gliosis in the substantia nigra and the presence of intracytoplasmic inclusions (Lewy bodies) [Ross et al 2006, Poulopoulos et al 2012, Kalia et al 2015]. However, a significant subset of individuals with PARK-LRRK2, and up to one third of those with the p.Gly2019Ser pathogenic variant, have substantia nigra dopaminergic neuronal loss and gliosis without accompanying Lewy body inclusions [Wise et al 2024]. The pathology correlates with the extent of nonmotor clinical features including cognitive impairment/dementia, anxiety, and orthostatic hypotension [Kalia et al 2015]. The absence of Lewy bodies is associated with a motor phenotype with preserved cognition and fewer nonmotor features.

Atypical pathology has also been reported in a minority of individuals with PARK-LRRK2 atypical phenotypes (e.g., dementia early in the disease course). Of particular note, three out of six individuals with atypical Parkinson disease and a heterozygous LRRK2 pathogenic variant identified in a large brain bank series were found to have pathology suggestive of PSP or pre-PSP with tau-positive neurons, neuropil threads, and tufted astrocytes [Blauwendraat et al 2019]. Additional series have reported pathologic features in those with PARK-LRRK2 that are more typical of Alzheimer disease including amyloid plaques with amyloid beta protein, tau containing neurofibrillary tangles, and TDP-43 inclusions [Henderson et al 2019, Agin-Liebes et al 2023].

Biallelic LRRK2 pathogenic variants. Individuals homozygous for LRRK2 pathogenic variant p.Gly2019Ser are not phenotypically different from those with a heterozygous p.Gly2019Ser pathogenic variant [Ishihara et al 2006, Ben Romdhan et al 2018]. In addition, isolated nigral degeneration without significant Lewy body presence has been seen in postmortem brains of individuals homozygous for either LRRK2 p.Gly2019Ser or p.Arg1441His pathogenic variants [Takanashi et al 2018, Wise et al 2024].

Codominant pathogenic variants in LRRK2 and GBA1. Individuals with an LRRK2 p.Gly2019Ser pathogenic variant and a heterozygous GBA1 pathogenic variant have a less severe clinical phenotype than individuals with a GBA1 pathogenic variant alone, and the phenotype of those with LRRK2 p.Gly2019Ser and a GBA1 pathogenic variant is more similar to those with PARK-LRRK2 than individuals with PARK-GBA1 [Yahalom et al 2019, Omer et al 2020, Ortega et al 2021], with one study demonstrating slower cognitive decline in those with codominant pathogenic variants in LRRK2 and GBA1 [Ortega et al 2021].

Genotype-Phenotype Correlations

Differences in phenotype have been observed for the rarer pathogenic LRRK2 variants as compared to the most common LRRK2 pathogenic variant p.Gly2019Ser [Domingo & Klein 2018].

• p.Arg1441Gly. Individuals with the p.Arg1441Gly pathogenic variant may be more likely to have excessive tremor than those with pathogenic variant p.Gly2019Ser, although they may also present with bradykinesia [Paisán-Ruíz et al 2004, Mata et al 2005b]. However, one systematic review found more frequent tremor in individuals with p.Gly2019Ser compared to those with p.Arg1441Gly [Trinh et al 2018].
• p.Arg1441. Individuals with a pathogenic variant at residue 1441 (p.Arg1441Gly, p.Arg1441Cys, p.Arg1441His, p.Arg1441Ser) have more frequent motor fluctuations compared to individuals with pathogenic variant p.Gly2019Ser [Trinh et al 2018].
• p.Tyr1699Cys. Individuals with pathogenic variant p.Tyr1699Cys may present with wide clinical variability. This pathogenic variant was identified in affected individuals in a large Korean family; clinical features were similar to those of Parkinson disease of unknown cause, although intrafamilial clinical variability was described [Kim et al 2012]. Atypical presentations initially reported include dementia and amyotrophy [Zimprich et al 2004a] (Family A) or behavior disorder characterized by depression and anxiety [Khan et al 2005] (Lincolnshire kindred).
• p.Leu1795Phe. Individuals with pathogenic variant p.Leu1795Phe may lack tremor on presentation and have significant and early dyskinesia and motor fluctuations, frequent orthostatic hypotension (83%) and urinary dysfunction (83%), and less REM sleep behavior disorder and dementia [Ostrozovicova et al 2025]; some may present with features of typical Parkinson disease [Lange et al 2025].
• p.Gly2385Arg. Individuals with the p.Gly2385Arg pathogenic variant appear to have greater motor impairment as well as more motor fluctuations compared to individuals with idiopathic Parkinson disease and individuals with pathogenic variant p.Gly2019Ser [Marras et al 2016]. Note: The estimated penetrance of p.Gly2385Arg is low, at roughly 10% by age 80 years [Wang et al 2022]. The p.Gly2385Arg pathogenic variant has conflicting classifications of pathogenicity and has been reclassified in the Human Gene Mutation Database [Stenson et al 2020] as disease causing. However, the pathogenicity is not firmly established, and this variant is included in ClinVar as benign.

Modifying LRRK2 risk alleles. One study showed increased motor progression for individuals heterozygous for LRRK2 risk variants p.Arg1628Pro or p.Ser1647Thr over a four-year period compared to individuals without these variants [Oosterveld et al 2015]. To date, these variants have not been associated with autosomal dominant Parkinson disease.

Penetrance

p.Gly2019Ser. Penetrance of LRRK2 pathogenic variants is age dependent and may vary based on pathogenic variant. The most common LRRK2 pathogenic variant, p.Gly2019Ser, is a founder variant in both Eastern European (Ashkenazi) Jewish and North African Berber populations. A recent study using two large online databases estimated LRRK2 p.Gly2019Ser penetrance at 24% by age 80 years [Kmiecik et al 2025]. Prior studies have estimated penetrance at 42%-45% [Hulihan et al 2008, Lee et al 2017a], and 25%-30% in Ashkenazi Jewish individuals [Ozelius et al 2006, Goldwurm et al 2007, Marder et al 2015]. Penetrance in individuals homozygous for LRRK2 p.Gly2019Ser appears to be similar to that of heterozygotes [Ishihara et al 2006].

Other variants. High penetrance was reported for some of the rarer LRRK2 pathogenic variants [Lee et al 2017a]:

• The p.Arg1441Cys pathogenic variant has been associated with penetrance of 95% by age 75 years [Haugarvoll et al 2008, Klein & Westenberger 2012] in a group primarily including familial PARK-LRRK2 and penetrance of 80% by age 80 years in another study [Ruiz-Martínez et al 2010].
• A study of one family with PARK-LRRK2 and the p.Ile2020Thr pathogenic variant estimated 70% penetrance by age 70 years [Funayama et al 2002].

Nomenclature

Alternate nomenclature for PARK-LRRK2 includes the following:

• PARK8, which refers to the chromosomal region of 12q12 linked to disease in a large Japanese Parkinson disease kindred [Funayama et al 2002]
• "Dardarin," the Basque word for "tremor," has been used to refer to PARK-LRRK2 caused by the pathogenic variant p.Arg1441Gly.

Prevalence

A study of inherited forms of Parkinson disease in the United States, Canada, and Dominican Republic reported an overall 2.4% prevalence of LRRK2 pathogenic variants [Cook et al 2024]. A parallel study in Europe, the Middle East, and North and South America found a similar prevalence of 2.9% [Westenberger et al 2024].

PARK-LRRK2 causes approximately 1% of simplex Parkinson disease in the US (i.e., single occurrences in a family) and approximately 5%-6% of familial Parkinson disease. There is no difference in the number of males and females affected, compared to 60% male and 40% female for Parkinson disease of unknown cause [Gan-Or et al 2015, San Luciano et al 2017].

• A founder effect exists for certain pathogenic variants, such as p.Gly2019Ser (North African Berber and Ashkenazi Jewish populations). The pathogenic variant p.Gly2019Ser has been seen in many parts of the world, including Asia, but is most common in Europe, the Middle East, and North and South America [Simpson et al 2022, Kmiecik et al 2024].
• A founder effect exists for the p.Arg1441Gly pathogenic variant in the Basque population.
• Pathogenic variant p.Arg1441Cys may be more common in the southern Italian and Belgian populations.
• Pathogenic variant p.Leu1795Phe may be present in 2% of individuals with Parkinson disease in Central Europe, and may represent the most common LRRK2 pathogenic variant in this population [Ostrozovicova et al 2025].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with PARK-LRRK2, the evaluations summarized in Table 2 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

The treatment of individuals with PARK-LRRK2 does not differ from that of Parkinson disease of unknown cause and should be tailored to the individual (see also Parkinson Disease Overview). Supportive care to improve quality of life, maximize function, and reduce complications is recommended with referral to a neurologist with training in movement disorders, a rehabilitation medicine specialist, psychiatrist, sleep medicine specialist, gastroenterologist, urologist, and pain medicine specialist as indicated (see Table 3).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 4 are recommended.

Agents/Circumstances to Avoid

Dopamine-blocking therapies (both typical and atypical dopamine-blocking psychiatric medications as well as dopamine blockers for gastrointestinal causes) may exacerbate parkinsonism in individuals with PARK-LRRK2 and should be avoided when possible.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

While the data are restricted to case reports and registries, most support treatment with levodopa and dopa decarboxylase inhibitors during pregnancy [Seier & Hiller 2017, Young et al 2020].

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

LRRK2 encodes leucine-rich repeat serine/threonine-protein kinase 2 (LRRK2). LRRK2 is a fusion of Rab (Roc), COR, and kinase (MAPK) domains, and LRRK2 pathogenic variants are overall postulated to exert their effects through augmentation of kinase activity and RAB GTPase interactors, although full pathogenesis has not been elucidated [West & Schwarzschild 2023]. Hence, the development of specific kinase inhibitors offers an attractive therapeutic target for neuroprotection in asymptomatic and affected LRRK2 heterozygotes, as well as for Parkinson disease of unknown cause [Niotis et al 2022, Jennings et al 2023, Müller 2023, West & Schwarzschild 2023, Maayan Eshed & Alcalay 2025]. A number of inhibitors are being developed; however, selectivity, specificity, and delivery into the central nervous system remain difficult issues to address [West & Schwarzschild 2023]. While LRRK2 kinase inhibition had been associated with pulmonary complications in rodents and non-human primates [Herzig et al 2011, Baptista et al 2013, Fuji et al 2015], more recent data suggest that this effect is reversible and that toxicity is not significant; no pulmonary complications were observed in initial trials with the kinase inhibitor BIIB122 [Jennings et al 2023]. Trials of oral small-molecule kinase inhibitors (BIIB122, NCT05348785; FB-418, NCT05995782; WXWH-0226) as well as molecules that cause LRRK2 protein degradation (ARV-102) are ongoing [Maayan Eshed & Alcalay 2025].

Additional treatments being explored include intrathecal antisense oligonucleotides (BIIB094, NCT03976349), proteolysis-targeting chimeras (PROTacs), and targeted gene therapy.

Trials for PARK-LRRK2 can be viewed at ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe.

Mode of Inheritance

LRRK2-related Parkinson disease (PARK-LRRK2) is inherited in an autosomal dominant manner with reduced penetrance.

Risk to Family Members

Parents of a proband

• To date, all individuals with PARK-LRRK2 whose parents have undergone molecular genetic testing have the disorder as the result of an LRRK2 pathogenic variant inherited from a parent. However, because the penetrance of PARK-LRRK2 is reduced, a high percentage of probands report unaffected parents.
• Biallelic LRRK2 pathogenic variants have been identified in some individuals with PARK-LRRK2 [Ishihara et al 2006, Ben Romdhan et al 2018]. It is likely that both parents of an individual with biallelic LRRK2 pathogenic variants are heterozygous for an LRRK2 pathogenic variant. (See Clinical Description, Biallelic LRRK2 Pathogenic Variants).
• The probability that an asymptomatic parent with an LRRK2 pathogenic variant will develop manifestations of PARK-LRRK2 increases with age.
• Molecular genetic testing of the parents of the proband can establish their genetic status and inform family risk assessment.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant. (De novo pathogenic variants have not been reported but remain a possibility. Some sites within LRRK2 may be highly mutable – notably, the arginine codon at residue 1441, in which four sometimes recurring amino acid changes have been reported to be pathogenic [Mata et al 2016].)
  • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• A proband may appear to be the only affected family member because of failure to recognize the disorder in family members, reduced penetrance, early death of a parent before the onset of symptoms, or late onset of the disease in an affected parent. Therefore, de novo occurrence of an LRRK2 pathogenic variant cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the LRRK2 pathogenic variant.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If one parent of the proband is known to have an LRRK2 pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%. A sib who inherits an LRRK2 pathogenic variant may or may not develop manifestations of PARK-LRRK2; the penetrance of LRRK2 pathogenic variants is age dependent and may vary based on pathogenic variant (see Penetrance).
• The probability that an asymptomatic heterozygous sib will develop manifestations of PARK-LRRK2 increases with age.
• If both parents of the proband are known to be heterozygous for an LRRK2 pathogenic variant, the risk to the sibs of inheriting one or two pathogenic variants is 75%. Note: This is a rare occurrence but more likely in populations with higher prevalence of LRRK2 pathogenic variants (see Prevalence). Individuals homozygous for LRRK2 pathogenic variant p.Gly2019Ser are not phenotypically different from those with a heterozygous p.Gly2019Ser pathogenic variant [Ishihara et al 2006, Ben Romdhan et al 2018].

Offspring of a proband. Each child of an individual with a heterozygous LRRK2 pathogenic variant has a 50% chance of inheriting the LRRK2 pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has an LRRK2 pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

Predictive testing (i.e., testing of asymptomatic at-risk individuals)

• Predictive testing for at-risk relatives is possible once the LRRK2 pathogenic variant has been identified in an affected family member.
• Such testing should be performed in the context of formal genetic counseling and is not useful in predicting age of onset, severity, type of manifestations, or rate of progression in asymptomatic individuals.
• Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.

Predictive testing in minors (i.e., testing of asymptomatic at-risk individuals younger than age 18 years) for typically adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality should be discussed in the context of formal genetic counseling. The autonomy of the minor is a primary concern and consideration should be given to delay of predictive genetic testing until the at-risk individual is capable of informed decision making.

In a family with an established diagnosis of PARK-LRRK2, it is appropriate to consider testing of symptomatic individuals regardless of age.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

Prenatal Testing and Preimplantation Genetic Testing

Once the causative LRRK2 pathogenic variant(s) has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

LRRK2 encodes leucine-rich repeat serine/threonine-protein kinase 2 (LRRK2), which is a member of the ROCO protein superfamily [Usmani et al 2021]. LRRK2 has six conserved domains (ankyrin repeat, leucine-rich repeat, Roc, COR, kinase, and WD40) [Bosgraaf & Van Haastert 2003, Mata et al 2006]. The COR domain may mediate interactions between LRRK2's GTPase and kinase [Usmani et al 2021].

LRRK2 pathogenic variants have been identified throughout the gene including in the ROC, COR, kinase, and WD40 domains. LRRK2 is known to both phosphorylate and be regulated by Rab GTPases, which are considered "master regulators" of the secretory and endocytic pathways [Usmani et al 2021, Alessi & Pfeffer 2024].

The function of LRRK2 both in health and in the pathogenesis of Parkinson disease is not well understood. Abnormal LRRK2 is posited to mediate effects through phosphorylation of the subset of Rab GTPases [Alessi & Pfeffer 2024]. LRRK2 has been implicated in a number of different cellular pathways, especially endosomal-lysosomal function autophagy, mitochondrial dysfunction, immune signaling, microglial motility, synaptic vesicle trafficking, and Wnt signal transduction pathways [Berwick & Harvey 2011, Berwick & Harvey 2012, Friedman et al 2012, Gómez-Suaga & Hilfiker 2012, Tong et al 2012, Bravo-San Pedro et al 2013, Howlett et al 2017, Lee et al 2017b, Pan et al 2017, Verma et al 2017, Alessi & Pfeffer 2024]. LRRK2 may also affect cellular organelles including the mitochondria and cytoskeleton, as well as the trans-Golgi network and retromer complex [Usmani et al 2021, Maayan Eshed & Alcalay 2025]. While LRRK2 is primarily cytosolic, many interactions are membrane associated [Alessi & Pfeffer 2024].

Mechanism of disease. While the mechanism is still not fully elucidated, extensive data support that LRRK2 pathogenic variants exert their effects through overactivity of the LRRK2 kinase regardless of the domain affected by the variant (reviewed by Usmani et al [2021]).

LRRK2-specific laboratory technical considerations. Penetrance of LRRK2 pathogenic variants is age dependent and may vary based on pathogenic variant and population ethnicity (including ancestral background and country of origin) [Hentati et al 2014]. In addition, some disease-associated LRRK2 variants are common in specific populations. Therefore, interpretation of LRRK2 variants requires careful review of all relevant literature.

Note: LRRK2 variant p.Gly2385Arg has conflicting classifications of pathogenicity and has been reclassified in Human Gene Mutation Database [Stenson et al 2020] as disease causing. However, the pathogenicity is not firmly established and the variant is included in ClinVar as benign. The penetrance is very low: approximately 2% by age 70 years and around 10% by age 80 years [Wang et al 2022].

Reported risk factor variants (which are not associated with mendelian disease) include p.Arg1628Pro and p.Ser1647Thr [Oosterveld et al 2015].

Author Notes

Dr Saunders-Pullman is the Bachmann-Strauss Chair of Neurology at Mount Sinai. Her research interests focus on the clinical-genetic spectrum of Parkinson disease and dystonia, including the study of biomarkers and molecular pathways implicated in Parkinson disease. Ms Raymond is a genetic counselor and clinical research manager. The authors have no financial disclosures.

Acknowledgments

Current research is supported through the National Institutes of Health (NINDS U01-NS107016-01A1U01 U01-NS094148-02), Silverstein Foundation for GBA1 Parkinson's, the Bigglesworth Family Foundation, the Michael J Fox Foundation, and the Empire Clinical Research Investigator Program.

We are grateful to the individuals involved in our research, including the many scientists, clinicians, and most especially the people with Parkinson disease and their families who have graciously contributed to research.

Author History

Sonya Elango, MS; Icahn School of Medicine at Mount Sinai / Mount Sinai Beth Israel (2019-2025)
Matthew Farrer, PhD; University of British Columbia (2006-2019)
Ilaria Guella, PhD; University of British Columbia (2014-2019)
Deborah Raymond, MS (2019-present)
Owen A Ross, PhD; Mayo Clinic (2006-2019)
Rachel Saunders-Pullman, MD, MPH (2019-present)
Jeremy T Stone, BSc; Mayo Clinic (2006-2010)
Joanne Trinh, BSc; University of British Columbia (2014-2019)
Adina Wise, MD (2025-present)

Revision History

• 4 December 2025 (sw) Comprehensive update posted live
• 24 October 2019 (ma) Comprehensive update posted live
• 11 December 2014 (me) Comprehensive update posted live
• 13 September 2012 (me) Comprehensive update posted live
• 29 April 2010 (me) Comprehensive update posted live
• 2 November 2006 (me) Review posted live
• 6 July 2006 (mf) Original submission

Literature Cited

• Agalliu I, Ortega RA, Luciano MS, Mirelman A, Pont-Sunyer C, Brockmann K, Vilas D, Tolosa E, Berg D, Warø B, Glickman A, Raymond D, Inzelberg R, Ruiz-Martinez J, Mondragon E, Friedman E, Hassin-Baer S, Alcalay RN, Mejia-Santana H, Aasly J, Foroud T, Marder K, Giladi N, Bressman S, Saunders-Pullman R. Cancer outcomes among Parkinson's disease patients with leucine rich repeat kinase 2 mutations, idiopathic Parkinson's disease patients, and nonaffected controls. Mov Disord. 2019;34:1392–8. [PMC free article: PMC6754269] [PubMed: 31348549]
• Agalliu I, San Luciano M, Mirelman A, Giladi N, Waro B, Aasly J, Inzelberg R, Hassin-Baer S, Friedman E, Ruiz-Martinez J, Marti-Masso JF, Orr-Urtreger A, Bressman SB, Saunders-Pullman R. Higher frequency of certain cancers in LRRK2 G2019S mutation carriers with Parkinson disease: a pooled analysis. JAMA Neurology. 2015;72:58–65. [PMC free article: PMC4366130] [PubMed: 25401981]
• Agin-Liebes J, Hickman RA, Vonsattel JP, Faust PL, Flowers X, Utkina Sosunova I, Ntiri J, Mayeux R, Surface M, Marder K, Fahn S, Przedborski S, Alcalay RN. Patterns of TDP-43 deposition in brains with LRRK2 G2019S mutations. Mov Disord. 2023;38:1541-5. [PMC free article: PMC10524857] [PubMed: 37218402]
• Alcalay RN, Mejia-Santana H, Mirelman A, Saunders-Pullman R, Raymond D, Palmese C, Caccappolo E, Ozelius L, Orr-Urtreger A, Clark L, Giladi N, Bressman S, Marder K, et al. Neuropsychological performance in LRRK2 G2019S carriers with Parkinson's disease. Parkinsonism Relat Disord. 2015;21:106–10. [PMC free article: PMC4306614] [PubMed: 25434972]
• Alcalay RN, Mejia-Santana H, Tang MX, Rosado L, Verbitsky M, Kisselev S, Ross BM, Louis ED, Comella CL, Colcher A, Jennings D, Nance MA, Bressman S, Scott WK, Tanner C, Mickel SF, Andrews HF, Waters CH, Fahn S, Cote LJ, Frucht SJ, Ford B, Rezak M, Novak K, Friedman JH, Pfeiffer R, Marsh L, Hiner B, Siderowf A, Caccappolo E, Ottman R, Clark LN, Marder KS. Motor phenotype of LRRK2 G2019S carriers in early-onset Parkinson disease. Arch Neurol. 2009;66:1517–22. [PMC free article: PMC2837584] [PubMed: 20008657]
• Alcalay RN, Mirelman A, Saunders-Pullman R, Tang MX, Mejia Santana H, Raymond D, Roos E, Orbe-Reilly M, Gurevich T, Bar Shira A, Gana Weisz M, Yasinovsky K, Zalis M, Thaler A, Deik A, Barrett MJ, Cabassa J, Groves M, Hunt AL, Lubarr N, San Luciano M, Miravite J, Palmese C, Sachdev R, Sarva H, Severt L, Shanker V, Swan MC, Soto-Valencia J, Johannes B, Ortega R, Fahn S, Cote L, Waters C, Mazzoni P, Ford B, Louis E, Levy O, Rosado L, Ruiz D, Dorovski T, Pauciulo M, Nichols W, Orr-Urtreger A, Ozelius L, Clark L, Giladi N, Bressman S, Marder KS. Parkinson disease phenotype in Ashkenazi Jews with and without LRRK2 p.Gly2019Ser mutations. Mov Disord. 2013;28:1966–71. [PMC free article: PMC3859844] [PubMed: 24243757]
• Alessi DR, Pfeffer SR. Leucine-rich repeat kinases. Annu Rev Biochem. 2024;93:261-87. [PubMed: 38621236]
• Artusi CA, Dwivedi A, Romagnolo A, Pal G, Kauffman M, Mata I, Patel D, Vizcarra JA, Duker A, Marsili L, Cheeran B, Woo D, Contarino MF, Verhagen L, Lopiano L, Espay AJ, Fasano A, Merola A. Association of subthalamic deep brain stimulation with motor, functional, and pharmacologic outcomes in patients with monogenic Parkinson disease: a systematic review and meta-analysis. JAMA Netw Open. 2019;2:e187800. [PMC free article: PMC6484599] [PubMed: 30707228]
• Baptista MA, Dave KD, Frasier MA, Sherer TB, Greeley M, Beck MJ, Varsho JS, Parker GA, Moore C, Churchill MJ, Meshul CK, Fiske BK. Loss of leucine-rich repeat kinase 2 (LRRK2) in rats leads to progressive abnormal phenotypes in peripheral organs. PLoS One. 2013;8:e80705. [PMC free article: PMC3828242] [PubMed: 24244710]
• Becker N, Shah S, Raymond D, Rawal M, Katsnelson V, Leaver K, Bressman S, Saunders-Pullman R, Young C, Yang M. Contribution of genetics to onset of PD with leg tremor [Abstract]. Mov Disord. 2024;39.
• Ben Romdhan S, Farhat N, Nasri A, Lesage S, Hdiji O, Ben Djebara M, Landoulsi Z, Stevanin G, Brice A, Damak M, Gouider R, Mhiri C. LRRK2 G2019S Parkinson's disease with more benign phenotype than idiopathic. Acta Neurol Scand. 2018;138:425–31. [PubMed: 29989150]
• Berwick DC, Harvey K. LRRK2 functions as a Wnt signaling scaffold, bridging cytosolic proteins and membrane-localized LRP6. Hum Mol Genet. 2012;21:4966–79. [PMC free article: PMC3709196] [PubMed: 22899650]
• Berwick DC, Harvey K. LRRK2 signaling pathways: the key to unlocking neurodegeneration? Trends Cell Biol. 2011;21:257–65. [PubMed: 21306901]
• Blauwendraat C, Pletnikova O, Geiger JT, Murphy NA, Abramzon Y, Rudow G, Mamais A, Sabir MS, Crain B, Ahmed S, Rosenthal LS, Bakker CC, Faghri F, Chia R, Ding J, Dawson TM, Pantelyat A, Albert MS, Nalls MA, Resnick SM, Ferrucci L, Cookson MR, Hillis AE, Troncoso JC, Scholz SW. Genetic analysis of neurodegenerative diseases in a pathology cohort. Neurobiol Aging. 2019;76:214.e1–214.e9. [PMC free article: PMC6391207] [PubMed: 30528841]
• Bosgraaf L, Van Haastert PJ. Roc, a Ras/GTPase domain in complex proteins. Biochim Biophys Acta. 2003;1643:5–10. [PubMed: 14654223]
• Bravo-San Pedro JM, Niso-Santano M, Gómez-Sánchez R, Pizarro-Estrella E, Aiastui-Pujana A, Gorostidi A, Climent V, López de Maturana R, Sanchez-Pernaute R, López de Munain A, Fuentes JM, González-Polo RA. The LRRK2 p.Gly2019Ser mutant exacerbates basal autophagy through activation of the MEK/ERK pathway. Cell Mol Life Sci. 2013;70:121–36. [PMC free article: PMC11113213] [PubMed: 22773119]
• Bressman S, Saunders-Pullman R. When to start Levodopa therapy for Parkinson's disease. N Engl J Med. 2019;380:389–90. [PubMed: 30673551]
• Brockmann K, Srulijes K, Hauser AK, Schulte C, Csoti I, Gasser T, Berg D. GBA-associated PD presents with nonmotor characteristics. Neurology. 2011;77:276–80. [PubMed: 21734182]
• Chahine LM, Lafontant DE, Choi SH, Iwaki H, Blauwendraat C, Singleton AB, Brumm MC, Alcalay RN, Merchant K, Nudelman KNH, Dagher A, Vo A, Tao Q, Venuto CS, Kieburtz K, Poston KL, Bressman S, Gonzalez-Latapi P, Avants B, Coffey C, Jennings D, Tolosa E, Siderowf A, Marek K, Simuni T; Parkinson’s Progression Markers Initiative. LRRK2-associated parkinsonism with and without in vivo evidence of alpha-synuclein aggregates: longitudinal clinical and biomarker characterization. Brain Commun. 2025;7:fcaf103. [PMC free article: PMC11925012] [PubMed: 40114783]
• Chen-Plotkin AS, Yuan W, Anderson C, McCarty Wood E, Hurtig HI, Clark CM, Miller BL, Lee VM, Trojanowski JQ, Grossman M, Van Deerlin VM. Corticobasal syndrome and primary progressive aphasia as manifestations of LRRK2 gene mutations. Neurology. 2008;70:521–7. [PMC free article: PMC3619720] [PubMed: 17914064]
• Cook L, Verbrugge J, Schwantes-An TH, Schulze J, Foroud T, Hall A, Marder KS, Mata IF, Mencacci NE, Nance MA, Schwarzschild MA, Simuni T, Bressman S, Wills AM, Fernandez HH, Litvan I, Lyons KE, Shill HA, Singer C, Tropea TF, Vanegas Arroyave N, Carbonell J, Cruz Vicioso R, Katus L, Quinn JF, Hodges PD, Meng Y, Strom SP, Blauwendraat C, Lohmann K, Casaceli C, Rao SC, Ghosh Galvelis K, Naito A, Beck JC, Alcalay RN. Parkinson's disease variant detection and disclosure: PD GENEration, a North American study. Brain. 2024;147:2668-79. [PMC free article: PMC11292896] [PubMed: 39074992]
• Dächsel JC, Ross OA, Mata IF, Kachergus J, Toft M, Cannon A, Baker M, Adamson J, Hutton M, Dickson DW, Farrer MJ. Lrrk2 p.Gly2019Ser substitution in frontotemporal lobar degeneration with ubiquitin-immunoreactive neuronal inclusions. Acta Neuropathol. 2007;113:601–6. [PubMed: 17151837]
• Dalvin LA, Damento GM, Yawn BP, Abbott BA, Hodge DO, Pulido JS. Parkinson disease and melanoma: confirming and reexamining an association. Mayo Clin Proc. 2017;92:1070–9. [PMC free article: PMC5682925] [PubMed: 28688464]
• Domingo A, Klein C. Genetics of Parkinson disease. Handb Clin Neurol. 2018;147:211–27. [PubMed: 29325612]
• Friedman LG, Lachenmayer ML, Wang J, He L, Poulose SM, Komatsu M, Holstein GR, Yue Z. Disrupted autophagy leads to dopaminergic axon and dendrite degeneration and promotes presynaptic accumulation of α-synuclein and LRRK2 in the brain. J Neurosci. 2012;32:7585–93. [PMC free article: PMC3382107] [PubMed: 22649237]
• Fuji RN, Flagella M, Baca M, Baptista MA, Brodbeck J, Chan BK, Fiske BK, Honigberg L, Jubb AM, Katavolos P, Lee DW, Lewin-Koh SC, Lin T, Liu X, Liu S, Lyssikatos JP, O'Mahony J, Reichelt M, Roose-Girma M, Sheng Z, Sherer T, Smith A, Solon M, Sweeney ZK, Tarrant J, Urkowitz A, Warming S, Yaylaoglu M, Zhang S, Zhu H, Estrada AA, Watts RJ. Effect of selective LRRK2 kinase inhibition on nonhuman primate lung. Sci Transl Med. 2015;7:273ra15. [PubMed: 25653221]
• Funayama M, Hasegawa K, Kowa H, Saito M, Tsuji S, Obata F. A new locus for Parkinson's disease (PARK8) maps to chromosome 12p11.2-q13.1. Ann Neurol. 2002;51:296–301. [PubMed: 11891824]
• Gaig C, Vilas D, Infante J, Sierra M, García-Gorostiaga I, Buongiorno M, Ezquerra M, Martí MJ, Valldeoriola F, Aguilar M, Calopa M, Hernandez-Vara J, Tolosa E. Nonmotor symptoms in LRRK2 G2019S associated Parkinson's disease. PLoS One. 2014;9:e108982. [PMC free article: PMC4201457] [PubMed: 25330404]
• Gan-Or Z, Bar-Shira A, Mirelman A, Gurevich T, Kedmi M, Giladi N, Orr-Urtreger A. LRRK2 and GBA mutations differentially affect the initial presentation of Parkinson disease. Neurogenetics. 2010;11:121–5. [PubMed: 19458969]
• Gan-Or Z, Leblond CS, Mallett V, Orr-Urtreger A, Dion PA, Rouleau GA. LRRK2 mutations in Parkinson disease; a sex effect or lack thereof? A meta-analysis. Parkinsonism Relat Disord. 2015;21:778–82. [PubMed: 25962553]
• Goetz CG, Nutt JG, Stebbins GT. The Unified Dyskinesia Rating Scale: presentation and clinimetric profile. Mov Disord. 2008;23:2398–403. [PubMed: 19025759]
• Goldwurm S, Zini M, Mariani L, Tesei S, Miceli R, Sironi F, Clementi M, Bonifati V, Pezzoli G. Evaluation of LRRK2 p.Gly2019Ser penetrance: relevance for genetic counseling in Parkinson disease. Neurology. 2007;68:1141–3. [PubMed: 17215492]
• Gómez-Suaga P, Hilfiker S. LRRK2 as a modulator of lysosomal calcium homeostasis with downstream effects on autophagy. Autophagy. 2012;8:692–3. [PubMed: 22441017]
• Gunzler SA, Riley DE, Chen SG, Tatsuoka CM, Johnson WM, Mieyal JJ, Walter EM, Whitney CM, Feng IJ, Owusu-Dapaah H, Mittal SO, Wilson-Delfosse AL. Motor and non-motor features of Parkinson's disease in LRRK2 G2019S carriers versus matched controls. J Neurol Sci. 2018;388:203-7. [PMC free article: PMC5908224] [PubMed: 29627023]
• Haugarvoll K, Rademakers R, Kachergus JM, Nuytemans K, Ross OA, Gibson JM, Tan EK, Gaig C, Tolosa E, Goldwurm S, Guidi M, Riboldazzi G, Brown L, Walter U, Benecke R, Berg D, Gasser T, Theuns J, Pals P, Cras P, De Deyn PP, Engelborghs S, Pickut B, Uitti RJ, Foroud T, Nichols WC, Hagenah J, Klein C, Samii A, Zabetian CP, Bonifati V, Van Broeckhoven C, Farrer MJ, Wszolek ZK. Lrrk2 R1441C parkinsonism is clinically similar to sporadic Parkinson disease. Neurology. 2008;70:1456–60. [PMC free article: PMC3906630] [PubMed: 18337586]
• Healy DG, Falchi M, O'Sullivan SS, Bonifati V, Durr A, Bressman S, Brice A, Aasly J, Zabetian CP, Goldwurm S, Ferreira JJ, Tolosa E, Kay DM, Klein C, Williams DR, Marras C, Lang AE, Wszolek ZK, Berciano J, Schapira AH, Lynch T, Bhatia KP, Gasser T, Lees AJ, Wood NW. International LRRK2 Consortium. Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson's disease: a case-control study. Lancet Neurol. 2008;7:583–90. [PMC free article: PMC2832754] [PubMed: 18539534]
• Henderson MX, Sengupta M, Trojanowski JQ, Lee VMY. Alzheimer's disease tau is a prominent pathology in LRRK2 Parkinson's disease. Acta Neuropathol Commun. 2019;7:183. [PMC free article: PMC6858668] [PubMed: 31733655]
• Hentati F, Trinh J, Thompson C, Nosova E, Farrer MJ, Aasly JO. LRRK2 parkinsonism in Tunisia and Norway: a comparative analysis of disease penetrance. Neurology. 2014;83:568–9. [PMC free article: PMC4142000] [PubMed: 25008396]
• Herzig MC, Kolly C, Persohn E, Theil D, Schweizer T, Hafner T, Stemmelen C, Troxler TJ, Schmid P, Danner S, Schnell CR, Muelle M, Kinzel B, Grevot A, Bolognani F, Stirn M, Kuhn RR, Kaupmann K, van der Putten PH, Rovelli G, Shimshek DR. LRRK2 protein levels are determined by kinase function and are crucial for kidney and lung homeostasis in mice. Hum Mol Genet. 2011;20:4209–23. [PMC free article: PMC3188995] [PubMed: 21828077]
• Howlett EH, Jensen N, Belmonte F, Zafar F, Hu X, Kluss J, Schüle B, Kaufman BA, Greenamyre JT, Sanders LH. LRRK2 p.Gly2019Ser-induced mitochondrial DNA damage is LRRK2 kinase dependent and inhibition restores mtDNA integrity in Parkinson's disease. Hum Mol Genet. 2017;26:4340–51. [PMC free article: PMC5886254] [PubMed: 28973664]
• Huang P, Yang XD, Chen SD, Xiao Q. The association between Parkinson's disease and melanoma: a systematic review and meta-analysis. Transl Neurodegener. 2015;4:21. [PMC free article: PMC4631109] [PubMed: 26535116]
• Hulihan MM, Ishihara-Paul L, Kachergus J, Warren L, Amouri R, Elango R, Prinjha RK, Upmanyu R, Kefi M, Zouari M, Sassi SB, Yahmed SB, El Euch-Fayeche G, Matthews PM, Middleton LT, Gibson RA, Hentati F, Farrer MJ. LRRK2 Gly2019Ser penetrance in Arab-Berber patients from Tunisia: a case-control genetic study. Lancet Neurol. 2008;7:591–4. [PubMed: 18539535]
• Ishihara L, Warren L, Gibson R, Amouri R, Lesage S, Durr A, Tazir M, Wszolek ZK, Uitti RJ, Nichols WC, Griffith A, Hattori N, Leppert D, Watts R, Zabetian CP, Foroud TM, Farrer MJ, Brice A, Middleton L, Hentati F. Clinical features of Parkinson disease patients with homozygous leucine-rich repeat kinase 2 p.Gly2019Ser mutations. Arch Neurol. 2006;63:1250–4. [PubMed: 16966502]
• Jennings D, Huntwork-Rodriguez S, Vissers MFJM, Daryani VM, Diaz D, Goo MS, Chen JJ, Maciuca R, Fraser K, Mabrouk OS, van de Wetering de Rooij J, Heuberger JAAC, Groeneveld GJ, Borin MT, Cruz-Herranz A, Graham D, Scearce-Levie K, De Vicente J, Henry AG, Chin P, Ho C, Troyer MD. LRRK2 inhibition by BIIB122 in healthy participants and patients with Parkinson's disease. Mov Disord. 2023;38:386-98. [PubMed: 36807624]
• Kalia LV, Lang AE, Hazrati LN, Fujioka S, Wszolek ZK, Dickson DW, Ross OA, Van Deerlin VM, Trojanowski JQ, Hurtig HI, Alcalay RN, Marder KS, Clark LN, Gaig C, Tolosa E, Ruiz-Martínez J, Marti-Masso JF, Ferrer I, López de Munain A, Goldman SM, Schüle B, Langston JW, Aasly JO, Giordana MT, Bonifati V, Puschmann A, Canesi M, Pezzoli G, Maues De Paula A, Hasegawa K, Duyckaerts C, Brice A, Stoessl AJ, Marras C. Clinical correlations with Lewy body pathology in LRRK2-related Parkinson disease. JAMA Neurol. 2015;72:100–5. [PMC free article: PMC4399368] [PubMed: 25401511]
• Kestenbaum M, Alcalay RN. Clinical features of LRRK2 carriers with Parkinson's disease. Adv Neurobiol. 2017;14:31–48. [PubMed: 28353277]
• Khan NL, Jain S, Lynch JM, Pavese N, Abou-Sleiman P, Holton JL, Healy DG, Gilks WP, Sweeney MG, Ganguly M, Gibbons V, Gandhi S, Vaughan J, Eunson LH, Katzenschlager R, Gayton J, Lennox G, Revesz T, Nicholl D, Bhatia KP, Quinn N, Brooks D, Lees AJ, Davis MB, Piccini P, Singleton AB, Wood NW. Mutations in the gene LRRK2 encoding dardarin (PARK8) cause familial Parkinson's disease: clinical, pathological, olfactory and functional imaging and genetic data. Brain. 2005;128:2786–96. [PubMed: 16272164]
• Kim A, Martinez-Valbuena I, Keith JL, Kovacs GG, Lang AE. Misfolded alpha-synuclein seeding is detected in suspected LRRK2-Parkinson's disease without immunohistochemically detectable alpha-synuclein pathology. Mov Disord. 2024;39:218-20. [PubMed: 37986700]
• Kim JS, Cho JW, Shin H, Lee WY, Ki CS, Cho AR, Kim HT. A Korean Parkinson's disease family with the LRRK2 p.Tyr1699Cys mutation showing clinical heterogeneity. Mov Disord. 2012;27:320–4. [PubMed: 22162019]
• Klein C, Westenberger A. Genetics of Parkinson's disease. Cold Spring Harb Perspect Med. 2012;2:a008888. [PMC free article: PMC3253033] [PubMed: 22315721]
• Kmiecik MJ, Holmes MV, Fontanillas P, Riboldi GM, Schneider RB, Shi J, Guan A, Tat S, Micheletti S, Stagaman K, Gottesman J, Hinds DA, Tung JY; 23andMe Research Team; Aslibekyan S, Norcliffe-Kaufmann L. Genetic modifiers of Parkinson's disease: a case-control study. Ann Clin Transl Neurol. 2025. Epub ahead of print. [PMC free article: PMC12698958] [PubMed: 40926580]
• Kmiecik MJ, Micheletti S, Coker D, Heilbron K, Shi J, Stagaman K, Filshtein Sonmez T, Fontanillas P, Shringarpure S, Wetzel M, Rowbotham HM, Cannon P, Shelton JF, Hinds DA, Tung JY, andMe Research T, Holmes MV, Aslibekyan S, Norcliffe-Kaufmann L. Genetic analysis and natural history of Parkinson's disease due to the LRRK2 G2019S variant. Brain. 2024;147:1996-2008. [PMC free article: PMC11146432] [PubMed: 38804604]
• Kuusimäki T, Korpela J, Pekkonen E, Martikainen MH, Antonini A, Kaasinen V. Deep brain stimulation for monogenic Parkinson disease: a systematic review. J Neurol. 2020;267:883–97. [PMC free article: PMC7109183] [PubMed: 30659355]
• Lanore A, Casse F, Tesson C, Courtin T, Menon PJ, Sambin S, Mangone G, Mariani LL, Lesage S, Brice A, Elbaz A, Corvol JC; French Clinicians Network for Parkinson's Disease Genetics (the PDG Group). Differences in survival across monogenic forms of Parkinson's disease. Ann Neurol. 2023;94:123-32. [PubMed: 36905164]
• Lange LM, Levine K, Fox SH, Marras C, Ahmed N, Kuznetsov N, Vitale D, Iwaki H, Lohmann K, Marsili L, Espay AJ, Bauer P, Beetz C, Martin J, Factor SA, Higginbotham LA, Chen H, Leonard H, Nalls MA, Mencacci NE, Morris HR, Singleton AB, Klein C, Blauwendraat C, Fang ZH; Global Parkinson’s Genetics Program (GP2). The LRRK2 p.L1795F variant causes Parkinson's disease in the European population. NPJ Parkinsons Dis. 2025;11:58. [PMC free article: PMC11937388] [PubMed: 40133296]
• Leaver K, Miravite J, Dilli C, Sa B, Ortega RP, Moran E, Kopell B, Okun MS, Foote KD, Shanker V, Bressman SB, Saunders-Pullman RJ. Longitudinal outcomes of LRRK2 gene mutation parkinsonism undergoing either subthalamic nucleus (STN) or globus pallidus internus (GPi) deep brain stimulation (DBS): a multigroup comparison. 2019. American Academy of Neurology 2019 Annual Meeting, May 4-10.
• Lee AJ, Wang Y, Alcalay RN, Mejia-Santana H, Saunders-Pullman R, Bressman S, Corvol JC, Brice A, Lesage S, Mangone G, Tolosa E, Pont-Sunyer C, Vilas D, Schüle B, Kausar F, Foroud T, Berg D, Brockmann K, Goldwurm S, Siri C, Asselta R, Ruiz-Martinez J, Mondragón E, Marras C, Ghate T, Giladi N, Mirelman A, Marder K. Penetrance estimate of LRRK2 p.Gly2019Ser mutation in individuals of non-Ashkenazi Jewish ancestry. Mov Disord. 2017a;32:1432–8. [PMC free article: PMC5656509] [PubMed: 28639421]
• Lee H, James WS, Cowley SA. LRRK2 in peripheral and central nervous system innate immunity: its link to Parkinson's disease. Biochem Soc Trans. 2017b;45:131–9. [PMC free article: PMC5652224] [PubMed: 28202666]
• Lee JM, Kim TW, Park SS, Han JH, Shin MS, Lim BV, Kim SH, Baek SS, Cho YS, Kim KH. Treadmill exercise improves motor function by suppressing Purkinje cell loss in Parkinson disease rats. Int Neurourol J. 2018a;22:S147–55. [PMC free article: PMC6234730] [PubMed: 30396264]
• Lee K, Nguyen KD, Sun C, Liu M, Zafar F, Saetern J, Flierl A, Tetrud JW, Langston JW, Dickson D, Schüle B. LRRK2 p.Ile1371Val mutation in a case with neuropathologically confirmed multi-system atrophy. J Parkinsons Dis. 2018b;8:93–100. [PubMed: 29480226]
• Liu X, Le W. Profiling non-motor symptoms in monogenic Parkinson's disease. Front Aging Neurosci. 2020;12:591183. [PMC free article: PMC7661846] [PubMed: 33192488]
• Maayan Eshed G, Alcalay RN. Precision medicine in Parkinson's disease. Neurol Clin. 2025;43:365-81. [PubMed: 40185526]
• Marder K, Wang Y, Alcalay RN, Mejia-Santana H, Tang MX, Lee A, Raymond D, Mirelman A, Saunders-Pullman R, Clark L, Ozelius L, Orr-Urtreger A, Giladi N, Bressman S. Age-specific penetrance of LRRK2 p.Gly2019Ser in the Michael J. Fox Ashkenazi Jewish LRRK2 Consortium. Neurology. 2015;85:89–95. [PMC free article: PMC4501942] [PubMed: 26062626]
• Marras C, Alcalay RN, Caspell-Garcia C, Coffey C, Chan P, Duda JE, Facheris MF, Fernández-Santiago R, Ruíz-Martínez J, Mestre T, Saunders-Pullman R, Pont-Sunyer C, Tolosa E, Waro B, et al. Motor and nonmotor heterogeneity of LRRK2-related and idiopathic Parkinson's disease. Mov Disord. 2016;31:1192–202. [PubMed: 27091104]
• Marras C, Schüle B, Munhoz RP, Rogaeva E, Langston JW, Kasten M, Meaney C, Klein C, Wadia PM, Lim SY, Chuang RS, Zadikof C, Steeves T, Prakash KM, de Bie RM, Adeli G, Thomsen T, Johansen KK, Teive HA, Asante A, Reginold W, Lang AE. Phenotype in parkinsonian and nonparkinsonian LRRK2 G2019S mutation carriers. Neurology. 2011;77:325–33. [PMC free article: PMC3140802] [PubMed: 21753163]
• Mata IF, Davis MY, Lopez AN, Dorschner MO, Martinez E, Yearout D, Cholerton BA, Hu SC, Edwards KL, Bird TD, Zabetian CP. The discovery of LRRK2 p.R1441S, a novel mutation for Parkinson's disease, adds to the complexity of a mutational hotspot. Am J Med Genet B Neuropsychiatr Genet. 2016;171:925–30. [PMC free article: PMC5028305] [PubMed: 27111571]
• Mata IF, Taylor JP, Kachergus J, Hulihan M, Huerta C, Lahoz C, Blazquez M, Guisasola LM, Salvador C, Ribacoba R, Martinez C, Farrer M, Alvarez V. LRRK2 R1441G in Spanish patients with Parkinson's disease. Neurosci Lett. 2005b;382:309–11. [PubMed: 15925109]
• Mata IF, Wedemeyer WJ, Farrer MJ, Taylor JP, Gallo KA. LRRK2 in Parkinson's disease: protein domains and functional insights. Trends Neurosci. 2006;29:286–93. [PubMed: 16616379]
• Mirelman A, Heman T, Yasinovsky K, Thaler A, Gurevich T, Marder K, Bressman S, Bar-Shira A, Orr-Urtreger A, Giladi N, Hausdorff JM, et al. Fall risk and gait in Parkinson's disease: the role of the LRRK2 p.Gly2019Ser mutation. Mov Disord. 2013;28:1683–90. [PubMed: 24123150]
• Müller T. DNL151, DNL201, and BIIB094: experimental agents for the treatment of Parkinson's disease. Expert Opin Investig Drugs. 2023;32:787-92. [PubMed: 37755071]
• Nabli F, Ben Sassi S, Amouri R, Duda JE, Farrer MJ, Hentati F. Motor phenotype of LRRK2-associated Parkinson's disease: a Tunisian longitudinal study. Mov Disord. 2015;30:253–8. [PubMed: 25487881]
• Niotis K, West AB, Saunders-Pullman R. Who to enroll in Parkinson Disease Prevention Trials? The case for genetically at-risk cohorts. Neurology. 2022;99:10-18. [PMC free article: PMC12393001] [PubMed: 35970585]
• Olanow CW, Stocchi I. Levodopa: a new look at an old friend. Mov Disord. 2018;33:859–66. [PubMed: 29178365]
• Omer N, Giladi N, Gurevich T, Bar-Shira A, Gana-Weisz M, Goldstein O, Kestenbaum M, Cedarbaum JM, Orr-Urtreger A, Mirelman A, Thaler A. A possible modifying effect of the G2019S mutation in the LRRK2 gene on GBA Parkinson's disease. Mov Disord. 2020;35:1249-53. [PubMed: 32353202]
• Oosterveld LP, Allen JC, Ng EY, Seah SH, Tay KY, Au WL, Tan EK, Tan LC. Greater motor progression in patients with Parkinson disease who carry LRRK2 variants. Neurology. 2015;85:1039–42. [PubMed: 26311745]
• Ortega RA, Wang C, Raymond D, Bryant N, Scherzer CR, Thaler A, Alcalay RN, West AB, Mirelman A, Kuras Y, Marder KS, Giladi N, Ozelius LJ, Bressman SB, Saunders-Pullman R. Association of dual LRRK2 G2019S and GBA variations with Parkinson disease progression. JAMA Netw Open. 2021;4:e215845. [PMC free article: PMC8060834] [PubMed: 33881531]
• Ostrozovicova M, Tamas G, Atputhavadivel A, Dusek P, Grofik M, Han V, Holly P, Jech R, Kalinova K, Klivenyi P, Kovacs N, Kulcsarova K, Kurca E, Lackova A, Lee H, Lewis P, Magocova V, Marekova M, Murphy D, Nagano A, Necpal J, Pinter D, Rabajdova M, Ruzicka E, Serranova T, Smilowska K, Soos K, Straka I, Svorenova T, Valkovic P, Zarubova K, Gdovinova Z, Houlden H, Rizig M, Skorvanek M; CEGEMOD consortium. Prevalence and clinical characteristics of the LRRK2 p.L1795F variant in central Europeans with early-onset and familial Parkinson's disease. Mov Disord Clin Pract. 2025;12:1132-9. [PMC free article: PMC12371444] [PubMed: 40119633]
• Ozelius LJ, Senthil G, Saunders-Pullman R, Ohmann E, Deligtisch A, Tagliati M, Hunt AL, Klein C, Henick B, Hailpern SM, Lipton RB, Soto-Valencia J, Risch N, Bressman SB. LRRK2 p.Gly2019Ser as a cause of Parkinson's disease in Ashkenazi Jews. N Engl J Med. 2006;354:424–5. [PubMed: 16436782]
• Paisán-Ruíz C, Jain S, Evans EW, Gilks WP, Simon J, van der Brug M, Lopez de Munain A, Aparicio S, Gil AM, Khan N, Johnson J, Martinez JR, Nicholl D, Carrera IM, Pena AS, de Silva R, Lees A, Marti-Masso JF, Perez-Tur J, Wood NW, Singleton AB. Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease. Neuron. 2004;44:595–600. [PubMed: 15541308]
• Pan PY, Li X, Wang J, Powell J, Wang Q, Zhang Y, Chen Z, Wicinski B, Hof P, Ryan TA, Yue Z. Parkinson's disease-associated LRRK2 hyperactive kinase mutant disrupts synaptic vesicle trafficking in ventral midbrain neurons. J Neurosci. 2017;37:11366–76. [PMC free article: PMC5700420] [PubMed: 29054882]
• Park J, Cheon SM, Lee MJ, Rhu DW, Yoo D. Comparison of impact of various exercise modalities on Parkinson's disease. J Mov Disord. 2025;18:222-30. [PMC free article: PMC12301928] [PubMed: 40230226]
• Pont-Sunyer C, Iranzo A, Gaig C, Fernández-Arcos A, Vilas D, Valldeoriola F, Compta Y, Fernández-Santiago R, Fernández M, Bayés A, Calopa M, Casquero P, de Fàbregues O, Jaumà S, Puente V, Salamero M, José Martí M, Santamaría J, Tolosa E. Sleep disorders in parkinsonian and nonparkinsonian LRRK2 mutation carriers. PLoS One. 2015;10:e0132368. [PMC free article: PMC4503402] [PubMed: 26177462]
• Poulopoulos M, Levy OA, Alcalay RN. The neuropathology of genetic Parkinson's disease. Mov Disord. 2012;27:831-42. [PMC free article: PMC3383342] [PubMed: 22451330]
• Quattrone A, Bagnato A, Annesi G, Novellino F, Morgante L, Savettieri G, Zappia M, Tarantino P, Candiano IC, Annesi F, Civitelli D, Rocca FE, D'Amelio M, Nicoletti G, Morelli M, Petrone A, Loizzo P, Condino F. Myocardial 123metaiodobenzylguanidine uptake in genetic Parkinson's disease. Mov Disord. 2008;23:21–7. [PubMed: 17975812]
• Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24. [PMC free article: PMC4544753] [PubMed: 25741868]
• Ross OA, Toft M, Whittle AJ, Johnson JL, Papapetropoulos S, Mash DC, Litvan I, Gordon MF, Wszolek ZK, Farrer MJ, Dickson DW. Lrrk2 and Lewy body disease. Ann Neurol. 2006;59:388–93. [PubMed: 16437559]
• Ruiz-Martínez J, Gorostidi A, Ibañez B, Alzualde A, Otaegui D, Moreno F, López de Munain A, Bergareche A, Gómez-Esteban JC, Martí Massó JF. Penetrance in Parkinson's disease related to the LRRK2 R1441G mutation in the Basque country (Spain). Mov Disord. 2010;25:2340–5. [PubMed: 20721916]
• San Luciano M, Wang C, Ortega R, Giladi N, Marder K, Bressman S, Saunders-Pullman R, et al. Sex differences in LRRK2 G2019S and idiopathic Parkinson's disease. Ann Clin Transl Neurol. 2017;4:801–10. [PMC free article: PMC5682117] [PubMed: 29159192]
• Santos-Rebouças CB, Abdalla CB, Baldi FJ, Martins PA, Corrêa JC, Gonçalves AP, Cunha MS, Borges MB, Pereira JS, Laks J, Pimentel MM. Co-occurrence of sporadic parkinsonism and late-onset Alzheimer's disease in a Brazilian male with the LRRK2 p.p.Gly2019Ser mutation. Genet Test. 2008;12:471–3. [PubMed: 19072560]
• Saunders-Pullman R, Mirelman A, Alcalay RN, Wang C, Ortega RA, Raymond D, Mejia-Santana H, Orbe-Reilly M, Johannes BA, Thaler A, Ozelius L, Orr-Urtreger A, Marder KS, Giladi N, Bressman SB, et al. Progression in the LRRK2-asssociated Parkinson disease population. JAMA Neurol. 2018;75:312–9. [PMC free article: PMC5885854] [PubMed: 29309488]
• Saunders-Pullman R, Mirelman A, Wang C, Alcalay R, San Luciano M, Ortega R, Raymond D, Mejia-Santana H, Ozelius LO, Clark L, Orr-Utreger A, Marder K, Giladi N, Bressman SB. Olfactory identification in LRRK2 G2019S mutation carriers: a relevant marker? Ann Clin Transl Neurol. 2014;1:670–8. [PMC free article: PMC4241794] [PubMed: 25493281]
• Saunders-Pullman R, Ortega RA, Wang C, Raymond D, Elango S, Leaver K, Urval N, Katsnelson V, Gerber R, Swan M, Shanker V, Alcalay RN, Mirelman A, Brumm MC, Mejia-Santana H, Coffey CS, Marek K, Ozelius LJ, Giladi N, Marder KS, Bressman SB. Association of olfactory performance with motor decline and age at onset in people with Parkinson disease and the LRRK2 G2019S variant. Neurology. 2022;99:e814-e823. [PMC free article: PMC9484727] [PubMed: 35995594]
• Seier M, Hiller A. Parkinson's disease and pregnancy: an updated review. Parkinsonism Relat Disord. 2017;40:11–7. [PubMed: 28506531]
• Sekiya H, Franke L, Hashimoto Y, Takata M, Nishida K, Futamura N, Hasegawa K, Kowa H, Ross OA, McLean PJ, Toda T, Wszolek ZK, Dickson DW. Widespread distribution of α-synuclein oligomers in LRRK2-related Parkinson's disease. Acta Neuropathol. 2025;149:42. [PMC free article: PMC12395563] [PubMed: 40314842]
• Shanker V, Groves M, Heiman G, Saunders-Pullman R, Ozelius L, Palmese C, Raymond D, Bressman SB. Mood and cognition in leucine-rich repeat kinase 2 G2019S Parkinson's disease. Mov Disord. 2011;26:1875–80. [PMC free article: PMC3972755] [PubMed: 21611978]
• Siderowf A, Concha-Marambio L, Lafontant DE, Farris CM, Ma Y, Urenia PA, Nguyen H, Alcalay RN, Chahine LM, Foroud T, Galasko D, Kieburtz K, Merchant K, Mollenhauer B, Poston KL, Seibyl J, Simuni T, Tanner CM, Weintraub D, Videnovic A, Choi SH, Kurth R, Caspell-Garcia C, Coffey CS, Frasier M, Oliveira LMA, Hutten SJ, Sherer T, Marek K, Soto C, Parkinson's Progression Markers I. Assessment of heterogeneity among participants in the Parkinson's Progression Markers Initiative cohort using alpha-synuclein seed amplification: a cross-sectional study. Lancet Neurol. 2023;22:407-17. [PMC free article: PMC10627170] [PubMed: 37059509]
• Simpson C, Vinikoor-Imler L, Nassan FL, Shirvan J, Lally C, Dam T, Maserejian N. Prevalence of ten LRRK2 variants in Parkinson's disease: a comprehensive review. Parkinsonism Relat Disord. 2022;98:103-13. [PubMed: 35654702]
• Smith LJ, Lee CY, Menozzi E, Schapira AHV. Genetic variations in GBA1 and LRRK2 genes: Biochemical and clinical consequences in Parkinson disease. Front Neurol. 2022;13:971252. [PMC free article: PMC9416236] [PubMed: 36034282]
• Somme JH, Molano Salazar A, Gonzalez A, Tijero B, Berganzo K, Lezcano E, Fernandez Martinez M, Zarranz JJ, Gómez-Esteban JC. Cognitive and behavioral symptoms in Parkinson's disease patients with G2019S and R1441G mutations of the LRRK2 gene. Parkinsonism Relat Disord. 2015;21:494–9. [PubMed: 25840672]
• Song T, Zhou X, Wang C, Wu H, Yan X, Guo J, Tang B, Lei L, Xu Q; Parkinson's Disease & Movement Disorders Multicenter Database and Collaborative Network in China (PD‐MDCNC). Clinical features and progression of Parkinson's disease with LRRK2 variants: a prospective study. Ann Clin Transl Neurol. 2025;12:34-42. [PMC free article: PMC11752092] [PubMed: 39529459]
• Srivatsal S, Cholerton B, Leverenz JB, Wszolek ZK, Uitti RJ, Dickson DW, Weintraub D, Trojanowski JQ, Van Deerlin VM, Quinn JF, Chung KA, Peterson AL, Factor SA, Wood-Siverio C, Goldman JG, Stebbins GT, Bernard B, Ritz B, Rausch R, Espay AJ, Revilla FJ, Devoto J, Rosenthal LS, Dawson TM, Albert MS, Mata IF, Hu SC, Montine KS, Johnson C, Montine TJ, Edwards KL, Zhang J, Zabetian CP. Cognitive profile of LRRK2-related Parkinson's disease. Mov Disord. 2015;30:728–33. [PMC free article: PMC4397146] [PubMed: 25650144]
• Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L, Hayden M, Heywood S, Millar DS, Phillips AD, Cooper DN. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting. Hum Genet. 2020;139:1197-207. [PMC free article: PMC7497289] [PubMed: 32596782]
• Takanashi M, Funayama M, Matsuura E, Yoshino H, Li Y, Tsuyama S, Takashima H, Nishioka K, Hattori N. Isolated nigral degeneration without pathological protein aggregation in autopsied brains with LRRK2 p.R1441H homozygous and heterozygous mutations. Acta Neuropathol Commun. 2018;6:105. [PMC free article: PMC6192197] [PubMed: 30333048]
• Thaler A, Kozlovski T, Gurevich T, Bar-Shira A, Gana-Weisz M, Orr-Urtreger A, Giladi N, Mirelman A. Survival rates among Parkinson's disease patients who carry mutations in the LRRK2 and GBA genes. Mov Disord. 2018;33:1656–60. [PubMed: 30288804]
• Tijero B, Gómez Esteban JC, Somme J, Llorens V, Lezcano E, Martinez A, Rodríguez T, Berganzo K, Zarranz JJ. Autonomic dysfunction in parkinsonian LRRK2 mutation carriers. Parkinsonism Relat Disord. 2013;19:906–9. [PubMed: 23764467]
• Tong Y, Giaime E, Yamaguchi H, Ichimura T, Liu Y, Si H, Cai H, Bonventre JV, Shen J. Loss of leucine-rich repeat kinase 2 causes age-dependent bi-phasic alterations of the autophagy pathway. Mol Neurodegener. 2012;7:2. [PMC free article: PMC3296570] [PubMed: 22230652]
• Trinh J, Amouri R, Duda JE, Morley JF, Read M, Donald A, Vilarino-Guell C, Thompson C, Szu Tu C, Gustavsson EK, Sassi SB, Hentati E, Zouari M, Farhat E, Nabli F, Hentati F, Farrer MJ. A comparative study of Parkinson's disease and leucine-rich repeat kinase 2 p.p.Gly2019Ser parkinsonism. Neurobiol Aging. 2014a;35:1125–31. [PubMed: 24355527]
• Trinh J, Zeldenrust FMJ, Huang J, Kasten M, Schaake S, Petkovic S, Madoev H, Grünewald A, Almuammar S, König I, Lill CM, Lohmann K, Klein C, Marras C. Genotype-phenotype relations for the Parkinson's disease genes SNCA, LRRK2, VPS35: MDSGene systematic review. Mov Disord. 2018;33:1857–70. [PubMed: 30357936]
• Usmani A, Shavarebi F, Hiniker A. The cell biology of LRRK2 in Parkinson's disease. Mol Cell Biol. 2021;41:e00660-20. [PMC free article: PMC8088268] [PubMed: 33526455]
• Valldeoriola F, Gaig C, Muxi A, Navales I, Paredes P, Lomena F, De la Cerda A, Buongiorno M, Ezquerra M, Santacruz P, Marti MJ, Tolosa E. 123I-MIBG cardiac uptake and smell identification in parkinsonian patients with LRRK2 mutations. J Neurol. 2011;258:1126-32. [PMC free article: PMC3101340] [PubMed: 21221623]
• Verma M, Callio J, Otero PA, Sekler I, Wills ZP, Chu CT. Mitochondrial calcium dysregulation contributes to dendrite degeneration mediated by PD/LBD-associated LRRK2 mutants. J Neurosci. 2017;37:11151–65. [PMC free article: PMC5688524] [PubMed: 29038245]
• Vilas D, Tolosa E, Quintana M, Pont-Sunyer C, Santos M, Casellas A, Valldeoriola F, Compta Y, Martí MJ, Mullol J. Olfaction in LRRK2 linked Parkinson's disease: is it different from idiopathic Parkinson's disease? J Parkinsons Dis. 2020;10:951-8. [PubMed: 32310189]
• Visanji NP, Bhudhikanok GS, Mestre TA, Ghate T, Udupa K, AlDakheel A, Connolly BS, Gasca-Salas C, Kern DS, Jain J, Slow EJ, Faust-Socher A, Kim S, Azhu Valappil R, Kausar F, Rogaeva E, William Langston J, Tanner CM, Schüle B, Lang AE, Goldman SM, Marras C. Heart rate variability in leucine-rich repeat kinase 2-associated Parkinson's disease. Mov Disord. 2017;32:610–4. [PubMed: 28071824]
• Wang P, Cui P, Luo Q, Chen J, Tang H, Zhang L, Chen S, Ma J. Penetrance of Parkinson disease LRRK2 G2385R-associated variant in the Chinese population. Eur J Neurol. 2022;29:2639-44. [PubMed: 35608967]
• Wang Y, Gao J, Xiong Y, Kang Z. LRRK2 G2019S promotes the development of colon cancer. The Journal of Immunology. 2023;210:161.12-.12.
• Warø BJ, Aasly JO. Exploring cancer in LRRK2 mutation carriers and idiopathic Parkinson's disease. Brain Behav. 2017;8:e00858. [PMC free article: PMC5853627] [PubMed: 29568677]
• West AB, Schwarzschild MA. LRRK2-targeting therapies march through the valley of death. Mov Disord. 2023;38:361-5. [PMC free article: PMC11076002] [PubMed: 36942368]
• Westenberger A, Skrahina V, Usnich T, Beetz C, Vollstedt EJ, Laabs BH, Paul JJ, Curado F, Skobalj S, Gaber H, Olmedillas M, Bogdanovic X, Ameziane N, Schell N, Aasly JO, Afshari M, Agarwal P, Aldred J, Alonso-Frech F, Anderson R, Araujo R, Arkadir D, Avenali M, Balal M, Benizri S, Bette S, Bhatia P, Bonello M, Braga-Neto P, Brauneis S, Cardoso FEC, Cavallieri F, Classen J, Cohen L, Coletta D, Crosiers D, Cullufi P, Dashtipour K, Demirkiran M, de Carvalho Aguiar P, De Rosa A, Djaldetti R, Dogu O, Dos Santos Ghilardi MG, Eggers C, Elibol B, Ellenbogen A, Ertan S, Fabiani G, Falkenburger BH, Farrow S, Fay-Karmon T, Ferencz GJ, Fonoff ET, Fragoso YD, Genc G, Gorospe A, Grandas F, Gruber D, Gudesblatt M, Gurevich T, Hagenah J, Hanagasi HA, Hassin-Baer S, Hauser RA, Hernandez-Vara J, Herting B, Hinson VK, Hogg E, Hu MT, Hummelgen E, Hussey K, Infante J, Isaacson SH, Jauma S, Koleva-Alazeh N, Kuhlenbaumer G, Kuhn A, Litvan I, Lopez-Manzanares L, Luxmore M, Manandhar S, Marcaud V, Markopoulou K, Marras C, McKenzie M, Matarazzo M, Merello M, Mollenhauer B, Morgan JC, Mullin S, Musacchio T, Myers B, Negrotti A, Nieves A, Nitsan Z, Oskooilar N, Oztop-Cakmak O, Pal G, Pavese N, Percesepe A, Piccoli T, Pinto de Souza C, Prell T, Pulera M, Raw J, Reetz K, Reiner J, Rosenberg D, Ruiz-Lopez M, Ruiz Martinez J, Sammler E, Santos-Lobato BL, Saunders-Pullman R, Schlesinger I, Schofield CM, Schumacher-Schuh AF, Scott B, Sesar A, Shafer SJ, Sheridan R, Silverdale M, Sophia R, Spitz M, Stathis P, Stocchi F, Tagliati M, Tai YF, Terwecoren A, Thonke S, Tonges L, Toschi G, Tumas V, Urban PP, Vacca L, Vandenberghe W, Valente EM, Valzania F, Vela-Desojo L, Weill C, Weise D, Wojcieszek J, Wolz M, Yahalom G, Yalcin-Cakmakli G, Zittel S, Zlotnik Y, Kandaswamy KK, Balck A, Hanssen H, Borsche M, Lange LM, Csoti I, Lohmann K, Kasten M, Bruggemann N, Rolfs A, Klein C, Bauer P. Relevance of genetic testing in the gene-targeted trial era: the Rostock Parkinson's disease study. Brain. 2024;147:2652-67. [PMC free article: PMC11292909] [PubMed: 39087914]
• Wise A, Ortega RA, Raymond D, Cervera A, Thorn E, Leaver K, Russell DS, Bressman SB, Crary JF, Saunders-Pullman R. Multiple sclerosis in LRRK2 G2019S Parkinson's disease and isolated nigral degeneration in a homozygous variant carrier. Front Neurol. 2024;15:1450654. [PMC free article: PMC11340503] [PubMed: 39175765]
• Wise AH, Alcalay RN. Genetics of cognitive dysfunction in Parkinson's disease. Prog Brain Res. 2022;269:195-226. [PubMed: 35248195]
• Yahalom G, Greenbaum L, Israeli-Korn S, Fay-Karmon T, Livneh V, Ruskey JA, Roncière L, Alam A, Gan-Or Z, Hassin-Baer S. Carriers of both GBA and LRRK2 mutations, compared to carriers of either, in Parkinson's disease: risk estimates and genotype-phenotype correlations. Parkinsonism Relat Disord. 2019;62:179–84. [PubMed: 30573413]
• Yahalom G, Kaplan N, Vituri A, Cohen OS, Inzelberg R, Kozlova E, Korczyn AD, Rosset S, Friedman E, Hassin-Baer S. Dyskinesias in patients with Parkinson's disease: effect of the leucine-rich repeat kinase 2 (LRRK2) G2019S mutation. Parkinsonism Relat Disord. 2012;18:1039–41. [PubMed: 22703868]
• Yahalom G, Orlev Y, Cohen OS, Kozlova E, Friedman E, Inzelberg R, Hassin-Baer S. Motor progression of Parkinson's disease with the leucine-rich repeat kinase 2 G2019S mutation. Mov Disord. 2014;29:1057–60. [PubMed: 24903616]
• Young C, Phillips R, Ebenezer L, Zutt R, Peall KJ. Management of Parkinson's disease during pregnancy: literature review and multidisciplinary input. Mov Disord Clin Pract. 2020;7:419-30. [PMC free article: PMC7197310] [PubMed: 32373659]
• Yuan Y, Wang Y, Liu M, Luo H, Liu X, Li L, Mao C, Yang T, Li S, Zhang X, Gao Y, Xu Y, Yang J. Peripheral cutaneous synucleinopathy characteristics in genetic Parkinson's disease. Front Neurol. 2024;15:1404492. [PMC free article: PMC11094647] [PubMed: 38751879]
• Zheng Y, Pei Z, Liu Y, Zhou H, Xian W, Fang Y, Chen L, Wu Q. Cognitive impairments in LRRK2-related Parkinson's disease: a study in Chinese individuals. Behav Neurol. 2015;2015:621873. [PMC free article: PMC4544948] [PubMed: 26346174]
• Zimprich A, Biskup S, Leitner P, Lichtner P, Farrer M, Lincoln S, Kachergus J, Hulihan M, Uitti RJ, Calne DB, Stoessl AJ, Pfeiffer RF, Patenge N, Carbajal IC, Vieregge P, Asmus F, Muller-Myhsok B, Dickson DW, Meitinger T, Strom TM, Wszolek ZK, Gasser T. Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron. 2004a;44:601–7. [PubMed: 15541309]