Analysis of LRRK2 Gly2385Arg genetic variant in non-Chinese Asians.

A common LRRK2 missense variant, Gly2385Arg, has been found to be a genetic risk factor for Parkinson's disease (PD) in ethnic Chinese and Japanese. However, the presence of the variant in other non-Chinese Asian patients has not been fully clarified. We performed genetic analysis of the Gly2385Arg variant in 472 non-Chinese Asian subjects in Singapore (comprising of 166 PD and 306 controls of Malay/Indian ethnicity). The frequency of the heterozygous Gly2385Arg genotype was not significantly different in PD compared with controls (1.2% vs. 0.8%, odds ratio = 2.83, 95% CI 0.40, 20.2, P = 0.3). No subjects carried the homozygous genotype. Stratification by Malay and Indian ethnicity revealed that there were two carriers each among 98 (2.0%) Malay PD and 173 (1.2%) Malay controls (odds ratio = 1.78, 95% CI 0.25, 12.8, P = 0.6), but there were no carriers among 66 Indian PD and 133 Indian controls. We demonstrated that the Gly2385Arg variant could be detected in our Malay subjects. However, its frequency was much lower than the 8 to 10% prevalence previously reported in our Singaporean and Taiwanese Chinese PD population. The relevance of Gly2385Arg as a genetic risk factor may be restricted to selected Asian races, and more studies will be needed to confirm our observations.     

LRRK2 Gly2385Arg variant is a risk factor of Parkinson's disease among Han-Chinese from mainland China

Mutations in the gene encoding Leucine-rich repeat kinase 2 (LRRK2) have been recently linked with autosomal-dominant parkinsonism, and polymorphisms have been commonly associated with sporadic Parkinson's disease (PD). A p.2385G>R variant has been reported as a risk factor for PD in Taiwan, Singapore and Japan. Herein, we have assessed the frequency of this polymorphism among the ethnic Han-Chinese population in a case–control study. A total of 600 patients with PD and 334 unrelated healthy controls were genotyped using PCR-restriction fragment length polymorphism analysis. Hardy–Weinberg equilibrium of each group was calculated, and differences in genotype frequencies between groups were assessed by the Chi-square test. In the PD cohort, 70 patients (11.7%) were heterozygous and 1 (0.2%) was homozygous for the p.2385G>R variant. This was significantly more frequent than in the controls [3.3%, Odds ratio = 3.9, 95% confidence interval (CI) = 2.1–7.5, P <  0.01]. Clinically, the age of PD onset of the p.2385G>R carriers was lower than the non-carriers ( P =  0.01). Our study indicates that this LRRK2 p.2385G>R substitution contributes to the development of PD in ethnic Han-Chinese population, which may play important implications for future study on molecular genetics and pathogenesis of PD.     

Fatigue correlates with LRRK2 G2385R variant in Chinese Parkinson's disease patients

IntroductionFatigue is common in patients with Parkinson's disease (PD). The leucine-rich repeat kinase 2 (LRRK2) G2385R variant predisposes individuals to develop PD in China. The aim of this study was to evaluate whether the LRRK2 G2385R variant is associated with fatigue in patients with PD.MethodsFatigue was evaluated by the Parkinson Fatigue Scale (PFS) in 329 PD patients and 180 controls, a cut-off score of ≥3.3 was used to define the presence of fatigue. All the enrolled PD patients were assessed by a comprehensive battery of motor and non-motor questionnaires. PD patients were genotyped for the G2385R variant. Associations of fatigue with the clinical assessments and with the G2385R variant in PD patients were analyzed by logistic regression.ResultsFatigue frequency was 55.62%. A logistic regression model found that the female sex (OR = 10.477; 95%CI: 2.806–39.120; p < 0.001), motor function (OR = 1.060; 95%CI: 1.012–1.110; p = 0.013), sleep disturbance (OR = 0.943; 95%CI: 0.910–0.976; p = 0.001) and depression severity (OR = 0.843; 95%CI: 0.736–0.965; p = 0.013) collectively predict the presence of fatigue in PD patients. After adjustment for demographics and associated clinical factors, the G2385R variant was associated with an increased risk for the presence of fatigue (OR = 10.699; 95% CI = 2.387–47.958; p = 0.002) in the PD population in this study.ConclusionWe confirm that fatigue in PD patients is common, and we have strengthened the associations between fatigue and female sex, motor severity and non-motor symptoms, particularly depression and sleep disturbances. Overall, we found that carriers of the G2385R variant were more prone to fatigue than non-carriers in PD patients.     

Pathogenicity of LRRK2 P755L variant in Parkinson's disease

A heterozygous 2264C→T variant (P755L) in LRRK2 gene has been reported to be a likely pathogenic variant among ethnic Chinese patients with Parkinson's disease (PD). In a case control study, we performed genetic analysis of the P755L variant in an independent cohort of Chinese patients with PD and controls. The P755L variant was present in 4/204 (2.0%) of PD compared with 6/235 (2.6%) of controls (odds ratio = 0.76, 95% CI 0.23, 2.6, P = 0.76). All subjects carried the heterozygous genotype. Subset analysis in the group ≥65 years of age revealed a prevalence of 2.8% in PD compared with 3.1% in controls (odds ratio = 0.92, 95% CI 022, 3.7, P = 0.9), and in the group <65 years of age showed a 0% in PD versus 2.1% in controls (P = 0.2). The phenotype of patients with PD with the P755L variant was generally similar to other patients with PD and none of the carriers reported a positive family history. The lack of functional data, absence of segregation of the variant with disease, and the presence of the variant in apparently healthy individuals suggest that P755L is possibly a rare polymorphism in the Chinese population. Further validation of our findings in other populations would be important. © 2008 Movement Disorder Society     

A novel LRRK2 mutation in an Austrian cohort of patients with Parkinson's disease.

To investigate the frequency of mutations in the Leucine-Rich Repeat Kinase 2 gene (LRRK2) in a sample of Austrian Parkinson's disease (PD) patients, we sequenced the complete coding region in 16 patients with autosomal dominant PD. Furthermore, we sequenced exons 31, 35, and 41 additionally in 146 patients with idiopathic PD and 30 patients with dementia with Lewy bodies. Furthermore, all 192 patients were screened for 21 putative LRRK2 mutations. While the most common mutation G2019S and the risk variant G2385R were not found in our samples, we detected a novel missense mutation (S973N) in a patient with familial, late-onset and dopa-responsive PD.     

Analysis of 14 LRRK2 mutations in Parkinson's plus syndromes and late-onset Parkinson's disease.

The pleomorphic pathology of postmortem LRRK2-positive patients and the frequent association with late-onset Parkinson's disease (LOPD) symptoms suggest that LRRK2 mutations may play a role in Parkinson's Plus disorders and LOPD. Published studies primarily focus on the common G2019S mutation. Analysis of a spectrum of LRRK2 mutations in Parkinson's Plus disorders has yet to be reported. We investigated 14 leucine-rich repeat kinase 2 (LRRK2) mutations in a cohort of Parkinson's Plus disorders and LOPD. A total of 458 patients with progressive supranuclear palsy (PSP), multiple system atrophy (MSA), corticobasal ganglionic degeneration (CBGD), atypical Parkinsonism (AP), and LOPD were screened for 14 mutations that span exons 19 to 41 of the LRRK2 gene. Among the LOPD cases, 1 patient was found to harbor the R1441C mutation. He presented with typical features of PD at age of 58 years old and responded well to levodopa. We did not detect any of the 14 mutations in PSP, MSA, CBGD, and AP patients. We highlight the first case of LRRK2 R1441C mutation in late onset sporadic PD of non-European ancestry. Furthermore, extensive mutational screen found LRRK2 mutations to be rare among patients who presented with PSP, MSA, CBGD, and AP.     

High prevalence of LRRK2 mutations in familial and sporadic Parkinson's disease in Portugal.

Mutations in the Leucine-Rich Repeat Kinase 2 (LRRK2) gene are the most frequent known cause of Parkinson's disease (PD), but their prevalence varies markedly between populations. Here we studied the frequency and associated phenotype of four recurrent LRRK2 mutations (R1441C, R1441G, R1441H, and G2019S) in familial and sporadic PD from a single referral center in Lisbon, Portugal. Among 138 unrelated PD probands, we identified 9 heterozygous G2019S carriers (6.52%) and 1 heterozygous R1441H carrier (0.72%). The G2019S mutation was present in 4 of the 107 sporadic (3.74%) and in 5 of the 31 familial probands (16.1%). Mutations were not found among 101 Portuguese controls. The G2019S mutation was present on a single haplotype and displayed reduced penetrance. Heterozygous parkin gene mutations were also found in 2 G2019S-positive probands, but their pathogenic role is unclear. The clinical phenotype in patients with LRRK2 mutations was indistinguishable from that of typical PD, including impaired sense of smell. The G2019S mutation is a very common genetic determinant among the Portuguese patients with PD, and the R1441H mutation is also present in this population. These data have important implications for the diagnostic work-up and genetic counseling of patients with this disease in Portugal.     

Neuropathology of Parkinson's disease with the R1441G mutation in LRRK2

We report the neuropathological findings in a patient with Parkinson's disease (PD) associated with Basque R1441G‐LRRK2/dardarin mutation. The patient was a man with disease onset at 68 years of age, with unilateral rest tremor; the Parkinsonism was well controlled with medication for 15 years. He died at the age of 86, after 18 years of evolution. The neuropathological examination disclosed mild neuronal loss in the substantia nigra pars compacta without α‐synuclein, tau, LRRK2, or ubiquitin cytoplasmic inclusions. Lewy bodies and Lewy neurites were absent. This is the first neuropathological study of PD associated with brain with the R1441G mutation in LRRK2. © 2009 Movement Disorder Society     

Novel pathogenic LRRK2 p.Asn1437His substitution in familial Parkinson's disease

Genealogical investigation of a large Norwegian family (F04) with autosomal dominant parkinsonism has identified 18 affected family members over four generations. Genetic studies have revealed a novel pathogenic LRRK2 mutation c.4309 A>C (p.Asn1437His) that co‐segregates with disease manifestation (LOD = 3.15, θ = 0). Affected carriers have an early age at onset (48 ± 7.7 SD years) and are clinically asymmetric and levodopa responsive. The variant was absent in 623 Norwegian control subjects. Further screening of patients from the same population identified one additional affected carrier (1 of 692) with familial parkinsonism who shares the same haplotype. The mutation is located within the Roc domain of the protein and enhances GTP‐binding and kinase activity, further implicating these activities as the mechanisms that underlie LRRK2‐linked parkinsonism. © 2010 Movement Disorder Society     

G2019S LRRK2 mutation in familial and sporadic Parkinson's disease in Russia.

Among mutations associated with autosomal dominant and sporadic Parkinson's disease (PD) the G2019S substitution in the leucine-rich repeat kinase 2 (LRRK2) gene is the most frequently identified. To estimate its frequency in Russia, we analyzed 208 patients with PD from the Northwestern region of Russia. Of these, 51 patients were probands from families with PD compatible with autosomal dominant inheritance. The control group represented 161 subjects without neurological disorders settled in the same region. The frequency of the G2019S mutation was greater in familial PD (2 [3.9%] of 51) than in sporadic PD (1 [0.6%] of 157). In addition, this mutation was found in the proband's father, who also had PD, in 1 PD family, and in 1 carrier without signs of PD at age 40 in another PD family. All carriers were heterozygous for the G2019S mutation and reported the Ashkenazi Jewish origin. The mutation was not found in the control group.     

LRRK2 R1628P variant is a risk factor of Parkinson's disease among Han‐Chinese from mainland China

Mutations in LRRK2, the gene that encodes leucine‐rich repeat kinase 2 (LRRK2), are associated with autosomal dominant and sporadic forms of Parkinson's disease (PD) and are the most common genetic causes of PD. Recently, a R1628P variant has been reported as a risk factor for PD in Taiwan and Singapore. To determine the association of this variant and PD in the Han‐Chinese population from mainland China, we analyzed its frequency in a cohort of 600 patients and 459 unrelated healthy controls. Forty (6.7%) patients were heterozygous and 3 (0.5%) homozygous for the R1628P variant, which was significantly more frequent than in the controls [2.4% heterozygous and 0.0% homozygous, Odds ratio = 3.14, 95%CI: 1.60–6.17, P < 0.01]. Considering the age at onset, this difference was found only in late‐onset PD (older than 50) [Odds ratio = 3.76, 95% CI: 1.90–7.45, P < 0.01]. Our data confirms that the LRRK2 R1628P variant is associated with an increased risk to develop late onset PD in the ethnic Han‐Chinese population. © 2009 Movement Disorder Society     

Lack of G2019S LRRK2 mutation in a cohort of Taiwanese with sporadic Parkinson's disease.

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene have been shown to cause autosomal dominant and sporadic Parkinson's disease (PD). We report here the frequency of a common heterozygous mutation, 2877510G>A, which produces a glycine-to-serine amino acid substitution at codon 2019 in idiopathic Taiwanese PD. The extreme rarity of the G2019S mutation in our population suggests the occurrence of this mutation resulted from a common European founder.     

Neuropathology of Parkinson's disease associated with the LRRK2 Ile1371Val mutation.

Leucine-Rich Repeat Kinase 2 (LRRK2) gene mutations are the most common known cause of Parkinson's disease (PD), but neuropathological studies are available on very few patients with LRRK2 mutation. The reported findings range from Lewy body-positive pathology to different pathologies, including nigral degeneration without distinctive features, neuronal loss with only ubiquitin-positive inclusions, and tau-positive-only pathology. Here we report the first neuropathological study in an Italian PD case carrying a different LRRK2 mutation, Ile1371Val, and showing typical ubiquitin- and alpha-synuclein-positive Lewy body pathology. These findings support the concept that the neurodegeneration associated with LRRK2 mutations might be clinically and pathologically indistinguishable from typical PD.     

Recurrent LRRK2 (Park8) mutations in early-onset Parkinson's disease.

Mutations in LRRK2 (leucine-rich repeat kinase 2) have been associated with autosomal dominant Parkinson's disease (PD) and cluster in several 3' exons of the gene. The majority of mutations have been detected in late-onset cases (age at onset >50 years). We screened 5 of the 51 exons of LRRK2 that previously have been reported to harbor mutations in 98 early-onset and 42 late-onset PD patients. We identified two mutations (c.4321C>T, c.6055G>A) in three early-onset patients. Screening of an additional 220 early-onset PD patients for these mutations revealed another mutation carrier. In conclusion, LRRK2 mutations need to be considered also in early-onset PD.     

Comprehensive sequencing of the LRRK2 gene in patients with familial Parkinson's disease from North Africa

The LRRK2 gene is a key player in Parkinson's disease (PD), however prevalence and pathogenicity of LRRK2 variants remain to be investigated in ethnically diverse populations. Herein, we performed comprehensive sequencing of the LRRK2 gene in 92 Tunisian probands with familial PD. We then performed an association study using all identified variants in a series of 167 Lrrk2 p.G2019S‐negative patients with sporadic PD and 365 Lrrk2 p.G2019S‐negative healthy control subjects, all from the same Arab‐Berber ethnicity. We identified one novel coding substitution (p.M2408I) and 24 known coding changes. Only the Lrrk2 p.G2019S mutation segregated with disease within families and was found in 39% of familial probands. None of the variants displayed significant association with risk for sporadic PD, however a trend was observed for Lrrk2 p.Y2189C. The present study underscores the importance of the LRRK2 gene in the Tunisian PD population. © 2010 Movement Disorder Society     

Frequency and phenotypes of LRRK2 G2019S mutation in Italian patients with Parkinson's disease.

To evaluate the frequency of the LRRK2 G2019S mutation in Italy, we tested 1,072 probands with Parkinson's disease (PD; 822 sporadic and 250 familial): 20 patients (1.9%) carried the G2019S mutation, 11 patients (1.3%) were sporadic, and 9 (4.3%) had a positive family history. Considering only probands with autosomal dominant inheritance, the G2019S frequency raises to 5.2%. All presented a typical phenotype with variable onset and shared the common ancestral haplotype. Mutation frequency raised from 1.2% in early onset PD to 4.0% in late onset PD.