Genetic characteristics of leucine-rich repeat kinase 2 (LRRK2) associated Parkinson's disease

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the progressive and selective degeneration of nigrostriatal dopaminergic neurons. The discovery of at least six PD-causing genes in predominantly early-onset forms of the disorder has cemented a genetic component to the etiology. Notably, the discovery of mutations in the LRRK2 gene in patients presenting with typical 'sporadic' PD with ages at onset in their sixties and seventies has shifted paradigms in the field of PD research. The G2019S mutation in LRRK2 has been found in diverse populations worldwide and usually resides on a common haplotype revealing that many of these individuals share a common ancestor, probably of Middle Eastern origin. The only validated coding susceptibility alleles for PD, G2385R and R1628P, are both in this gene but to date have been found exclusively in Asian populations. Concomitant with genetic testing for PD is the need for appropriate and informed genetic counseling. Families of patients with LRRK2 mutations and susceptibility alleles need to be informed about the current lack of disease preventative strategies and the implications surrounding incomplete penetrance. In summary, single-handedly LRRK2 has had a major impact on the field of PD research and the findings have been of interest to both clinicians and scientists. We anticipate that other genes of such major impact exist for PD and look forward to their discovery.     

The leucine rich repeat kinase 2 (LRRK2) G2019S substitution mutation

Background   

A single missense mutation (G2019S) in the leucine rich repeat kinase 2 (LRRK2) gene has been reported to be prevalent among Ashkenazi Jewish patients with Parkinson disease (PD). An association between malignant melanoma (MM) and PD was also recently reported. The nature of this association is still elusive.     

The G2019S LRRK2 mutation is rare in Korean patients with Parkinson's disease

BACKGROUND: A number of causative mutations such as alpha-synuclein, parkin, UCHL1, Pink-1, DJ-1 have been identified in Parkinson's disease (PD). They are usually found in the familial cases. One mutation of great interest is the G2019S mutation in the LRRK2 gene, which has been reported in both familial and sporadic PD. Its prevalence has been reported to vary markedly among different races. We examined the prevalence of the G2019S mutation in the Korean PD population for genetic study planning. METHODS: We conducted a genetic analysis of the G2019S mutation by standard PCR and restriction digestion method. 453 PD patients were studied, 34% of whom had an age at onset of < 50 years and 3.8% had a positive family history. RESULTS: None of the 453 study subjects carried the G2019S mutation. CONCLUSIONS: Our result confirms previous reports that the G2019S mutation is rare among PD patients in the Asian population. This result supports the notion that the prevalence of this LRRK2 mutation is population specific, and that there may be a founder effect within western populations.     

G2019S LRRK2 mutation causing Parkinson's disease without Lewy bodies

The G2019S leucine-rich repeat kinase 2 gene (LRRK2) mutation has been identified in a significant proportion of familial and sporadic cases of Parkinson's disease (PD). Until now, information on the neuropathological changes associated with the G2019S LRRK2 mutation has been sparse. We report a 77-year-old patient who presented with a 14 year history of PD but, unexpectedly, histopathological examination disclosed mild neuronal loss in the substantia nigra without alpha-synuclein, tau or ubiquitin cytoplasmic inclusions. A G2019S LRRK2 mutation was eventually detected. The present case confirms that clinical PD caused by G2019S mutations can be associated with non-specific nigral degeneration without Lewy bodies.     

The G2019S LRRK2 mutation is uncommon amongst Greek patients with sporadic Parkinson's disease

Parkinson's disease (PD) is the second most common neurodegenerative disorder affecting approximately 2% of the population >60 years of age. Although, the etiology of PD is still unknown, the genetic background of the disease has been documented. Recently, a mutation in the LRRK2 gene, G2019S, was associated with 3–41% and 1–2% of familial and sporadic PD, respectively suggesting a pivotal role of LRRK2 in PD. In this report, we examine the association of the G2019S mutation with sporadic late-onset PD, in an independent cohort of Greek patients and controls.     

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.     

G2019S LRRK2 mutation in French and North African families with Parkinson's disease

Mutations in LRRK2 were recently identified in autosomal dominant Parkinson's disease (PD), including the G2019S mutation. To evaluate its frequency, we analyzed 198 probands with autosomal dominant PD, mostly from France and North Africa. Surprisingly, the frequency in North African families (7/17, 41%) was greater than those from Europe (5/174, 2.9%). The clinical features in 21 patients, including 1 with a homozygous mutation, were those of typical PD, with lower Mini-Mental State Examination scores. There were also 15 unaffected mutation carriers, aged 32 to 74 years. LRRK2 mutations appear to be a common cause of autosomal dominant PD, particularly in North Africa.     

Worldwide frequency of G2019S LRRK2 mutation in Parkinson's disease: A systematic review

BackgroundThe LRRK2 G2019S mutation is the most frequent known cause of familial and sporadic Parkinson's disease. Knowledge of its worldwide frequency distribution is essential for clinical and molecular research as well as genetic counseling.ObjectivesTo conduct a systematic review of the reported frequency of G2019S in different populations and to assess critically the quality of the clinical studies.MethodsWe conducted a systematic review of all published papers on G2019S frequency in homogeneous ethnic groups or sub-groups of patients. Selected papers were analyzed for methodological quality.Results68 studies from 32 countries were included in the analysis. A heterogeneous distribution was observed with high frequencies in North African Arab countries, the Middle East, southern Europe, North American Ashkenazi Jewish populations and in South American countries with known European ethnic influence. Frequencies ranged from the no cases to 35.7% in sporadic and 42% in familial North-African Arab patients. Only one paper from one sub-Saharan country was found. Methodological pitfalls were identified.ConclusionsEstimated frequencies were found to be variable, which may reflect ethnic differences and methodological discrepancies. We make recommendations on the methods of selection of participants and on the definition of familial Parkinson's disease to improve the quality of frequency studies on LRRK2 mutations.     

Genetic screening for LRRK2 gene G2019S mutation in Parkinson's disease patients from Southern Italy

Leuchine-rich repeat kinase 2 (LRRK2) gene mutations are a common cause of familial and sporadic Parkinson disease (PD). G2019S is the most frequent mutation of the LRRK2 gene and has been reported in about 5-6% of familial and 1-2% of sporadic PD cases. The aim of this study is to investigate the G2019S frequency in a series of 58 familial and 70 sporadic PD patients recruited from Campania, a region in Southern Italy. We identified one heterozygous G2019S mutation in a PD patient who also suffered from obsessive disorder and depression and presented hallucinations and delusional jealousy while he was treated with l-dopa, pramipexole, and amantadine. Brain (18)F-deoxy-glucose PET showed relative decrease of glucose metabolism in the caudate nuclei and to a lesser extent in cortical parietal/frontal regions. The patient's mother also had PD and molecular analysis demonstrated that she carried the same mutation. G2019S mutation frequency is rather low in overall patients (0.8%) and in the familial group (1.7%), suggesting that it may be an uncommon cause of PD in Southern Italy.     

High frequency and reduced penetrance of LRRK2 G2019S mutation among Parkinson's disease patients in Cantabria (Spain)

The frequency and penetrance of the LRRK2 G2019S mutation varies considerably in different Parkinson disease (PD) populations. This information is essential both for clinical purposes and genetic counseling. The objective of this study was to estimate the prevalence and penetrance of the G2019S mutation of the LRRK2 gene in a small region in northern Spain (Cantabria). The G2019S mutation was tested in 367 consecutive patients with PD attended as outpatients in a tertiary Hospital in Northern Spain, and 126 at-risk family members of probands were also investigated for G2019S mutation and disease status. The gene penetrance was estimated in terms of cumulative age-specific incidence of PD by the Kaplan-Meier method. Thirty-two PD patients (8.7%) carried the G2019S mutation. Penetrance estimation of the G2019S mutation was 2% at 50 years, 12% at 60 years, 26% at 70 years, and 47% at 80 years. The frequency of the G2019S mutation of the LRRK2 gene in PD patients from Cantabria is among the highest reported so far after North African Arabs and Ashkenazi Jews. At the age of 80 years only one-half of G2019S mutation carriers manifest motor symptoms of PD.     

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.