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     

Cognitive dysfunction in Parkinson's disease related to the R1441G mutation in LRRK2

ObjectiveThe neuropsychological characteristics of patients with Parkinson's Disease (PD) associated with R1441G mutation in the LRRK2 gene (R1441G-PD) are not well known. The aim of this study was to examine the cognitive status and mood of R1441G-PD patients.MethodsThirty patients with R1441G-PD were compared with thirty idiopathic PD (i-PD) patients who were matched by age, sex, education, disease onset age and duration, using a comprehensive battery of neuropsychological test, and considering the Movement Disorder Society (MDS) criteria for the diagnosis of Mild Cognitive Impairment (PD-MCI) and dementia (PD-Dementia).ResultsThe mean scores in the depression and anxiety scales were similar in the two groups. Depressive symptoms were detected in 31.8% of R1441G-PD and 25% of i-PD patients and anxiety symptoms were evident in 4.5% and 15%, respectively, but the differences were not significant. The only neuropsychological test on which there was a significantly worse performance in the R1441G-PD group was the Boston naming test but the difference became not significant when Bonferroni's correction was applied. The prevalence of PD-MCI was 30% in both R1441G-PD and i-PD, with no differences in the number and type of domains altered given that executive function, memory and attention were mainly affected. PD-Dementia was diagnosed in 13.3% (n = 4) of R1441G-PD and 26.7% (n = 8) of i-PD patients (difference was not significant).ConclusionIn conclusion, significant differences were not detected between R1441G-PD and i-PD in cognitive, depression and anxiety scales, or PD-MCI and PD-Dementia prevalence, and the cognitive profile was identical in the two groups.     

Penetrance in Parkinson's disease related to the LRRK2 R1441G mutation in the Basque country (Spain)

The LRRK2 R1441G mutation was first identified in Basque families and it is responsible for 46% of familial Parkinson's disease (PD) and for 2.5% of sporadic PD in the PD population of Basque ascent. The aim of this study was to determine LRRK2 R1441G penetrance in PD in the Basque Country (Spain) to help in a more accurate genetic counseling. A total of 59 sibships containing 244 individuals, with a total of 40 PD‐affected relatives, were studied. Genetic testing for the R1441G mutation in the LRRK2 gene was performed in 133 individuals and was positive in 51% of them. Lifetime penetrance of R1441G mutations turned out to be 12.5% at 65 years to 83.4% at 80 years. No gender differences were found in penetrance. © 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.     

Olfactory deficits and cardiac 123I‐MIBG in Parkinson's disease related to the LRRK2 R1441G and G2019S mutations

It has been proposed that olfactory tests and metaiodobenzylguanidine cardiac scintigraphy may help diagnose idiopathic Parkinson's disease in the premotor phase. However, it is not clear what value these tests have in all patients with Parkinson's disease and, particularly, in those who carry mutations in LRRK2. The objective was to analyze olfactory dysfunction and the changes in cardiac I‐metaiodobenzylguanidine uptake in patients with Parkinson's disease carrying the R1441G and G2019S mutations in LRRK2, and in patients with Parkinson's disease with no known mutations. Patients with Parkinson's disease were screened for R1441G and G2019S LRRK2 gene mutations and classified as LRRK2 mutation carriers or noncarriers. A total of 190 patients with Parkinson's disease (44 LRRK2 mutation carriers) were tested for olfactory dysfunction using the Brief Smell Identification Test. Cardiac ¹²³I‐metaiodobenzylguanidine scintigraphy was performed on 90 patients with Parkinson's disease (27 LRRK2 mutation carriers). Thirty‐six percent of patients with LRRK2 mutations have hyposmia, compared to 75% of noncarrier patients with Parkinson's disease (P < .001). Sixty‐six percent of LRRK2 mutation carriers have low early metaiodobenzylguanidine uptake, compared to 86% of noncarriers (P = .048). Similarly, the heart/mediastinum ratio in delayed metaiodobenzylguanidine images appeared to differ between these groups of patients with Parkinson's disease, although these results did not reach statistical significance. The data obtained indicate that olfactory and cardiac impairment is less prevalent when Parkinson's disease is associated with mutations in LRRK2, although the underlying mechanisms for this difference remain unclear. Thus, such screening would be less useful to detect the premotor phase in asymptomatic relatives who carry mutations in LRRK2 than in cases not associated with LRRK2. © 2011 Movement Disorder Society     

Prevalence of cancer in Parkinson's disease related to R1441G and G2019S mutations in LRRK2

An inverse relationship between Parkinson's disease (PD) and cancer has been described. However, the association between cancers and genetic forms of PD, in particular the R1441G mutation in the LRRK2 gene, is not well known. The objective of this work was to analyze cancer prevalence in PD patients with R1441G or G2019S mutations in LRRK2, and in idiopathic PD (iPD). A total of 732 patients with PD (70 and 25 carriers of R1441G or G2019S mutations, respectively), and 177 controls, were linked using a population‐based cancer registry of the Spanish province of Gipuzkoa. Cancer prevalence was not significantly higher in PD‐G2019S carriers (20%) than in PD‐R1441G carriers (14.3%), iPD (13.8%), or controls (12.5%). With the exception of a high prevalence of hematological cancers (crude odds ratio of 7.1) in the R1441G group, specific cancer types were not increased in PD mutation carriers. In both the carrier and iPD groups, cancers were diagnosed after the onset of PD. PD patients had a similar prevalence of cancer to control subjects. There was no increased association between G2019S or R1441G mutations and any type of cancer. Although there was a higher prevalence of hematological cancers in the R1441G group, the low number of such cancers overall makes this finding of uncertain significance. There was a slightly higher but not statistically significant prevalence of non‐skin cancers in the G2019S group, suggesting that further study to evaluate the association should be undertaken prior to ascribing an increased cancer risk to this population. © 2013 International Parkinson and Movement Disorder Society     

R1514Q substitution in Lrrk2 is not a pathogenic Parkinson's disease mutation.

Mutations in LRRK2 were first reported as causing Parkinson's disease (PD) in late 2004. Since then, approximately a dozen LRRK2 substitutions have been identified that are believed to be pathogenic mutations. The substitution of adenine for guanine at nucleotide 4541 (4541G>A) in LRRK2 was recently reported. This substitution resulted in the replacement of an arginine at position 1514 with a glutamine (R1514Q). Although this substitution was not found in a large cohort of controls, its pathogenicity could not be verified. We have now genotyped the R1514Q substitution in a sample of 954 PD patients from 429 multiplex PD families. This substitution was identified in 1.8% of the PD patients; however, the majority of the PD sibships segregating this substitution were discordant for this putative mutation. In addition, the R1514Q substitution was detected in 1.4% of neurologically evaluated, control individuals. These data suggest that the R1514Q variant is not a pathogenic LRRK2 mutation. We believe it is imperative that the causative nature of any newly identified genetic variant be determined before it is included in any panel for diagnostic testing.     

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.     

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.     

Prevalence of the LRRK2 G2019S mutation in a UK community based idiopathic Parkinson's disease cohort

The LRRK2 G2019S mutation is the commonest genetic cause of Parkinson's disease (PD) identified to date, although estimates of its prevalence in idiopathic disease vary considerably. Our objectives were to determine G2019S mutation frequency in an unselected, community based cohort of idiopathic PD cases from the UK and to describe phenotypic characteristics among carriers. The mutation was present in two of 519 cases (0.4%) and none of 887 control individuals. The true prevalence of the mutation in idiopathic disease, its penetrance, and the phenotypic heterogeneity of associated cases have important implications for genetic screening in the clinical field.     

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.     

G2019S dardarin substitution is a common cause of Parkinson's disease in a Portuguese cohort.

LRRK2 mutations have recently been described in families with Parkinson's disease. Here we show that one of them (G2019S) is present in 6% (7 of 124) unrelated cases of disease in a clinic-based sample series from central Portugal, but not present in 126 controls from the same population. Thus, LRRK2 mutations appear to be a common cause of typical Parkinson's disease and as such will alter clinical practice.     

Fall risk and gait in Parkinson's disease: The role of the LRRK2 G2019S mutation

Patients with Parkinson's disease (PD) who carry the G2019S mutation (a glycine to serine substitution at amino acid 2019) in the leucine‐rich repeat kinase 2 (LRRK2) gene are generally believed to be clinically indistinguishable from patients with sporadic PD. There are, however, conflicting reports on the relationship between the mutation and the motor phenotype. We quantitatively compared gait and mobility in patients with PD carriers of the G2019S mutation to non‐carrier patients with PD to better understand the genotype‐phenotype relationship. Fifty patients with PD carriers of the G2019S LRRK2 mutation and 50 age, disease duration, and disease severity matched PD non‐carriers were studied. An accelerometer quantified gait under three walking conditions: usual‐walking, dual‐tasking, and fast‐walking. The Unified Parkinson's Disease Rating Scale classified patients into PD sub‐types and the Timed Up and Go quantified mobility and fall risk. In all three walking conditions, gait variability was larger and the walking pattern was less consistent among the PD mutation carriers (P < 0.016). The PD carriers also took longer to complete the Timed Up and Go (P = 0.011) and were more likely to report having fallen in the previous year (P = 0.018). 64% of the PD carriers were classified as belonging to the postural‐instability‐gait‐difficulty (PIGD) sub‐type compared to only 17% of the PD non‐carriers (P < 0.0001). Among patients with PD, the G2019S mutation in the LRRK2 gene is apparently associated with increased gait variability, an increased fall risk, and the PIGD sub‐type. Therapeutic approach specifically designed to delay gait disturbances and falls may be justified in patients who carry the G2019S mutation. © 2013 International Parkinson and Movement Disorder Society     

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.     

Mutations in LRRK2 other than G2019S are rare in a north american–based sample of familial Parkinson's disease

A total of 956 individuals with Parkinson's disease (PD) from 430 multiplex PD pedigrees were screened for 12 previously reported, pathogenic LRRK2 mutations: R793M, L1114L, I1371V, R1441C, R1441G, R1441H, Y1699C, M1869T, I2012T, I2020T, G2385R, and IVS31 +3G>A. Previous screening identified the LRRK2 G2019S mutation in 5% of our families. Only 1 of the 12 newly screened mutations, R1441C, was detected in a single family in our patient cohort. These results indicate that, although the G2019S mutation remains the most common mutation identified in familial PD patients, other mutations in LRRK2 are infrequent. © 2006 Movement Disorder Society     

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.