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.

The estimated life expectancy in a community cohort of Parkinson's disease patients with and without dementia, compared with the UK population.

OBJECTIVE: To compare survival, life expectancies (LE), and the anticipated age at the time of death (AAD), in a community-based cohort of Parkinson's disease (PD) patients with and without significant cognitive impairment, with an age sex matched population of England and Wales. METHODS: The age- and sex-specific standardised mortality ratios (SMR) were calculated and stratified by dementia status. The LE and AAD estimations were calculated from the SMRs of the 2003 UK population, using a modified Gompertz function. RESULTS: In total, 166 PD patients participated in the investigation, of which 91 died by the 4-year follow-up. The overall SMR was 2.09 (95% CI 1.68 to 2.57). Demented patients had significantly higher SMRs than non-demented patients (SMR 3.10, 95% CI 2.39 to 3.96 vs SMR 1.15, 95% CI 0.75 to 1.69, p<0.001). In our cohort, the LE in younger-onset demented patients (55-74 years) was much lower than in non-demented patients (7.5; SD 3 vs 12.4; SD 7). Likewise, the estimated AAD in younger onset patients with dementia was also much lower (demented 72.4; SD 4 vs not demented 77.8; SD 7). In older-onset patients with dementia (>75 years), the differences in LE (demented 2.1; SD 1 vs not demented 4.7; SD 4) and AAD were less apparent (demented 89.5; SD 6 vs not demented 92.2; SD 6). CONCLUSION: The survival, LE and AAD in patients with PD are much lower compared with the general population, apart from those patients who do not develop dementia, who appear to have near normal population mortalities. However, dementia and younger onset of PD appear to be important determinants of survival, LE and AAD.

A comparative study of LRRK2, PINK1 and genetically undefined familial Parkinson's disease.

Genetic classification of Parkinson's disease (PD) subtypes may become the preferred diagnostic tool for neurologists. Herein we compare clinical features from a large cohort of patients with familial PD of unknown aetiology or attributable to distinct genetic forms. Comprehensive neurological examinations were performed in 231 familial PD patients from Tunisia. Analysis was previously performed to screen for mutations in leucine rich repeat kinase 2 (LRRK2), PTEN induced kinase 1 (PINK1) and parkin (PRKN). Clinical features were compared between patients with genetically undefined PD (n=107) and those with LRRK2 (n=73) and PINK1 (n=42) mutations using regression analyses adjusted for gender, age of onset and disease duration. PRKN cases (n=9) were too few for meaningful statistical analysis. In comparison with genetically undefined patients, LRRK2 mutation carriers had more severe motor symptoms (median Unified Parkinson's Disease Rating Scale scores approximately 1.6 times higher, p<0.001), a higher rate of dyskinesia (OR 4.21, p=0.002) and use of dopamine agonists (OR 3.64, p<0.001), and less postural tremor (OR 0.21, p<0.001). PINK1 mutation carriers presented an increased rate of drug induced dyskinesia (OR 3.81, p=0.007) and a lower rate of postural tremor (OR 0.16, p<0.001) than genetically undefined patients. As expected, PINK1 patients had younger ages and ages at disease onset, and a longer disease duration compared with LRRK2 mutation carriers and genetically undefined patients. Clinical differences between LRRK2, PINK1 and genetically undefined familial PD appear more pronounced than previously appreciated, and may prove useful in clinical practice. As future therapies are targeted to specific protein abnormalities, identifying the genetic causes and associated clinical and pathological features will determine diagnosis, preventative medicine and drug intervention strategies.

LRRK2 Gly2019Ser penetrance in Arab-Berber patients from Tunisia: a case-control genetic study.

BACKGROUND: Several genes have been implicated in the pathogenesis of Parkinson's disease (PD). The aim of this study was to define the clinical symptoms and age-associated cumulative incidence of the most frequent mutation associated with PD, LRRK2 Gly2019Ser. METHODS: 238 patients with sporadic PD and 371 unrelated control participants from the Arab-Berber population were screened at the Institut National de Neurologie, Tunis. Symptoms of PD were assessed using the Hoehn and Yahr scale, the unified Parkinson's disease rating scale, and the Epworth scale. Genotyping for LRRK2 6055G-->A, which causes the Gly2019Ser mutation, was done in all participants, and the age-specific cumulative incidence of PD was calculated by Kaplan-Meier analysis. FINDINGS: 30% of patients with PD in this case-control sample were carriers of LRRK2 Gly2019Ser. The age of onset of symptoms and the clinical presentation of patients with LRRK2 Gly2019Ser were similar to those of patients with idiopathic PD. Carriers of LRRK2 Gly2019Ser were 22.6 times (95% CI 10.2-50.1) more likely to be affected by PD than non-carriers. Tremor was the predominant symptom in LRRK2 Gly2019Ser carriers (92% [homozygotes] vs 75% [heterozygotes] vs 69% [non-carriers]; Cochran-Armitage trend test p=0.0587). Disease severity, response to treatment, and disease duration were similar among LRRK2 Gly2019Ser homozygotes, heterozygotes, and non-carriers (p=0.85). Disease penetrance in LRRK2 Gly2019Ser carriers ranged from less than 20% in those younger than 50 years to greater than 80% at 70 years. INTERPRETATION: The LRRK2 Gly2019Ser mutation in patients with PD is a useful aid to diagnosis. LRRK2 Gly2019Ser penetrance can vary but in most carriers PD seems an inevitable consequence of ageing. LRRK2 Gly2019Ser considerably increases susceptibility to neuronal degeneration, although the process might be mediated by many triggers. By contrast, idiopathic PD is rare before 50 years and the prevalence only increases to 4% in the oldest members of the population. FUNDING: GlaxoSmithKline; National Institutes of Health; and Mayo Foundation.