LRRK2 mutations in Parkinson disease

To determine the frequency of LRRK2 mutations in idiopathic Parkinson disease (PD), the authors studied 786 PD probands, 32 affected siblings, 1,044 unaffected siblings, and 278 unrelated controls. The authors designed allelic discrimination assays for nine LRRK2 mutations and identified these in six probands with PD, one affected sibling, one unaffected sibling, and one unrelated control. Thus LRRK2 mutations only rarely cause idiopathic PD.     

Genetic analysis of LRRK2 mutations in patients with Parkinson disease

In addition to the G2019S mutation in the leucine-rich repeat kinase 2 gene (LRRK2), which is particularly frequent in patients of Ashkenazi Jewish and Northern African origin, three amino acid substitutions (R1441C, R1441G, and R1441H), all at the same residue (R1441), have been identified as important genetic causes of Parkinson disease (PD). To evaluate the frequency of R1441C/G/H and G2019S mutations in the LRRK2 gene in North American patients with PD and to explore genotype-phenotype correlations, we screened 496 PD patients from North America. One Hispanic female was heterozygous for the LRRK2 R1441G mutation, and six other cases including 2 non-Jewish/non-Hispanic whites, 3 Ashkenazi Jewish, and 1 Hispanic, were found to be heterozygous for the LRRK2 G2019S mutation. G2019S mutation in the LRRK2 gene is a common mutation associated with PD in a North American population, especially in Jewish PD patients (10.7%), while the R1441C/G/H mutation occurs at a relatively low frequency in North Americans except possibly in Hispanics for R1441G. All six G2019S carriers shared a common haplotype with that observed in Europeans and North Africans. The clinical features of all seven cases with LRRK2 mutation were quite broad and included early and late disease onset. These finding may provide new insights into the cause and diagnosis of PD and have implications for genetic counseling.     

LRRK2 exon 41 mutations in sporadic Parkinson disease in Europeans

BACKGROUND: Mutations in leucine-rich repeat kinase 2 gene (LRRK2), particularly the G2019S mutation in exon 41, have been detected in familial and sporadic Parkinson disease (PD) cases. OBJECTIVES: To assess the frequency of LRRK2 exon 41 mutations in a series of sporadic PD cases from Europe and to determine the clinical features of LRRK2 mutation carriers. DESIGN: We analyzed European cases of sporadic PD for the presence of LRRK2 exon 41 mutations. These mutations were screened by denaturing high-performance liquid chromatography, and abnormal chromatograph traces were investigated by direct sequencing to determine the exact nature of the variants. Early-onset sporadic PD cases were also screened for parkin mutations. The haplotypes associated with the G2019S mutation were determined. The clinical characteristics of patients carrying LRRK2 mutations were detailed. SETTING: French Network for the Study of Parkinson Disease Genetics. Patients Three hundred twenty patients with apparently sporadic PD from Europe. MAIN OUTCOME MEASURES: Results of genetic analyses. RESULTS: We found the G2019S mutation in 6 patients and identified 2 new variants (Y2006H and T2031S) in 1 patient each. Their clinical features were similar to those of typical PD. All G2019S mutation carriers shared a common haplotype. CONCLUSIONS: The G2019S mutation is almost as frequent in sporadic cases (1.9%) as in previously reported familial cases (2.9%) in Europe and occurs in the same common founder. We identified 2 novel variants. Although the phenotype of LRRK2 mutation carriers closely resembles that of typical PD, the age at onset was younger (29 years in 1 patient) than previously described, and 3 patients were improved by deep brain stimulation.     

A clinic-based study of the LRRK2 gene in Parkinson disease yields new mutations

Referral-based studies indicate that a mutation (G2019S) in exon 41 of the LRRK2 gene might be a common cause of Parkinson disease (PD). The authors sequenced leucine-rich repeat kinase 2 (LRRK2) exons 31, 35, and 41 in 371 consecutively recruited patients with PD and found mutations in six (1.6%) subjects, including two heterozygous for new putative pathogenic variants (R1441H, IVS31 + 3A-->G). These data confirm the important contribution of LRRK2 to PD susceptibility in a clinic-based population.     

LRRK2 G2019S mutations are associated with an increased cancer risk in Parkinson disease

Leucine rich repeat kinase (LRRK2) G2019S mutations are presumed to cause PD through a toxic gain of function of the protein kinase. Small molecule kinase inhibitors have been developed for the treatment of certain cancers, and some antioncogenic agents such as sunitinib, may nonspecifically inhibit LRRK2. Few studies, however, have assessed cancer risk in LRRK2 mutation carriers. To explore this risk, we evaluated records of Ashkenazi Jewish (AJ) PD patients participating in genetic research. Charts were reviewed for 163 unrelated AJ PD patients, 31 of whom harbored the G2019S mutation. History of cancer was queried at baseline intake using a form reviewing medical conditions, and charts were reviewed for all follow‐up visits. 9/31 LRRK2 G2019S mutation carriers had nonskin cancers, whereas 15/132 without mutations had nonskin cancers, representing an almost threefold increased risk in this group (HR 2.9, 95% CI 1.3–6.6). Age at first nonskin cancer was younger in the LRRK2 carriers (56.0 years) than the noncarriers (62.0 years), but was not significant. 67% of the LRRK2 carriers had their cancer before the onset of PD, whereas only 40% of noncarriers developed their first nonskin cancer before onset of PD. While further evaluation is warranted, our findings indicate an increased risk of nonskin cancers in LRRK2 G2019S mutation carriers, which may be related to toxic gain of function of mutated LRRK2. © 2010 Movement Disorder Society     

Analysis of LRRK2 functional domains in nondominant Parkinson disease

A comprehensive sequence analysis of 29 exons that code for the functional domains of LRRK2 in 160 nondominant Parkinson disease (PD) patients was performed. Novel variant screening in a further 470 sporadic PD patients and 630 controls revealed two novel variants (R1067Q and IVS33 + 6 T>A), which are likely to be pathogenic in five patients. One patient presented initially with a typical essential tremor phenotype, expanding the phenotypic spectrum of LRRK2 mutations.     

LRRK2 mutations in Spanish patients with Parkinson disease: frequency, clinical features, and incomplete penetrance

BACKGROUND: Several pathogenic mutations in the LRRK2 gene have been implicated in familial and sporadic cases of Parkinson disease (PD). The R1441G mutation is frequent in Spanish patients of Basque ethnicity with PD, and the G2019S mutation is a common mutation found in several populations worldwide. OBJECTIVES: To determine the frequency of the LRRK2 G2019S and R1441G mutations in PD patients from the non-Basque northeast region of Spain (Catalonia), and to characterize their family history and clinical features. DESIGN: We screened patients for the presence of the LRRK2 R1441G and G2019S mutations. These LRRK2 mutations were detected by restriction endonuclease digestion, and samples with an abnormal electrophoresis pattern were sequenced to identify the exact nucleotide change. The clinical features and family history of patients with LRRK2 mutations were studied in detail. SETTING: The northeast region of Spain.Patients Three hundred two patients with PD. MAIN OUTCOME MEASURES: Onset age, clinical features, and family history of PD and LRRK2 mutations. RESULTS: The R1441G mutation was present in 0.7% of total PD cases. The G2019S mutation was found in 6.4% of familial and 3.4% of sporadic cases. Additionally, we found 1 patient with the R1441C mutation. Age at onset ranged from 33 to 78 years. Clinical features were not different from classic PD, except for 1 patient who presented with monosymptomatic leg rest tremor of 8 years' duration. In addition, a 91-year-old unaffected relative of a patient with the G2019S mutation was found to be a mutation carrier. CONCLUSIONS: The G2019S mutation frequency in PD patients from northeast Spain is similar to that reported in other European regions. The R1441G mutation is very uncommon in Catalonia. The presence of an aged unaffected G2019S mutation carrier supports the previously described occurrence of incomplete penetrance in PD patients with LRRK2 mutations.     

Autonomic failure as the initial presentation of Parkinson disease and dementia with Lewy bodies

The authors report the clinical and postmortem neuropathologic findings of two patients, one with Parkinson disease (PD) and one with dementia with Lewy bodies (DLB), both of whom initially sought treatment for isolated autonomic failure. These cases suggest that neurodegeneration in PD and DLB may begin outside the CNS in autonomic postganglionic neurons, a finding with potential diagnostic and therapeutic implications.     

LRRK2 mutations in a clinic-based cohort of Parkinson's disease

In the last decade, major breakthroughs in the understanding of genetic contributions to Parkinson's disease (PD) have been achieved. Recently, mutations in LRRK2 , encoding dardarin, have been found to be responsible for an autosomal dominant parkinsonism (OMIM 607060). We screened 311 subjects (cases: n  = 202, controls: n  = 109) for the three previously reported LRRK2 mutations. Our investigation revealed a sporadic case of PD with a heterozygous mutation G2019S (c.6055G>A). Here, we present the clinical phenotype of this patient and discuss the implications of genetic testing for the G2019S mutation in patients with sporadic PD.