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The recently identified C9orf72 gene accounts for a large proportion of amyotrophic lateral sclerosis and frontotemporal lobar degenerations. As several forms of these disorders are associated with parkinsonism, we hypothesized that some patients with Parkinson's disease or other forms of parkinsonism might carry pathogenic C9orf72 expansions. Therefore, we looked for C9orf72 repeat expansions in 1446 unrelated parkinsonian patients consisting of 1225 patients clinically diagnosed with Parkinson's disease, 123 with progressive supranuclear palsy, 21 with corticobasal degeneration syndrome, 43 with Lewy body dementia and 25 with multiple system atrophy-parkinsonism. Of the 1446 parkinsonian patients, five carried C9orf72 expansions: three patients with typical Parkinson's disease, one with corticobasal degeneration syndrome and another with progressive supranuclear palsy. This study shows that (i) although rare, C9orf72 repeat expansions may be associated with clinically typical Parkinson's disease and also with other parkinsonism; (ii) in several patients, parkinsonism was levodopa-responsive and remained pure, without associated dementia, for >10 years and (iii) interestingly, all C9orf72 repeat expansion carriers had positive family histories of parkinsonism, degenerative dementias or amyotrophic lateral sclerosis. This study also provides the tools for identifying parkinsonian patients with C9orf72 expansions, with important consequences for genetic counselling.

Mutations in the eukaryotic translation initiation factor 4-gamma (EIF4G1) gene, encoding a component of the eIF4F translation initiation complex, were recently reported as a possible cause for the autosomal dominant form of Parkinson's disease (PD). Here, we describe the screening of all 31 EIF4G1 coding exons in a series of 251 index cases with autosomal dominant PD, mostly of French origin and in 236 European control subjects. We identified 12 rare coding variants (either nonsynonymous amino acid substitutions or in frame deletions/insertions), including 6 variants present only in cases and 3 in controls. Segregation was possible only for 1 variant (p.E462delInsGK) that was found in 2 affected siblings. In addition, we found 2 previously reported pathogenic variants in 2 isolated patients (p.G686C) and in a control subject (p.R1197W). These data do not support the pathogenicity of several EIF4G1 variants in PD, at least in the French population., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objective: Glucocerebrosidase (GBA) gene mutations represent a strong risk factor for Parkinson disease (PD). PD penetrance in GBA mutation carriers, which represents a key issue for genetic counseling, especially for relatives of patients with Gaucher disease (GD), is unknown. Our objective was to estimate PD penetrance in a familial study of GBA mutation carriers., Methods: Probands with familial PD were recruited through the French Parkinson Disease Genetic Study Group. All GBA exons were sequenced in probands and their relatives. To estimate the age-specific cumulative PD risk (i.e., penetrance) in GBA mutation carriers, we used the proband's phenotype exclusion likelihood method and corrected for selection of familial cases by considering the status of one affected relative per family as unknown., Results: Of 525 probands with familial PD, 24 (4.6%) were GBA mutation carriers. Of their 256 relatives, 43 (16.8%) had PD and 26 of 32 affected relatives tested for GBA mutations were mutation carriers; 213 relatives did not have PD and 31 of 71 of unaffected relatives tested for GBA mutations were mutation carriers. Under a dominant model, penetrance was estimated as 7.6%, 13.7%, 21.4%, and 29.7% at 50, 60, 70, and 80 years, respectively. There was no significant difference in penetrance at 70 years between N370S carriers, L444P carriers, and carriers of rarer mutations., Conclusion: The relatively high penetrance estimate in GBA carriers obtained in this study should lead to consideration of GBA as a dominant causal gene with reduced penetrance and should be taken into account for genetic counseling in relatives of patients with GD and patients with GBA-associated PD.

Pathogenic variants in the glucocerebrosidase gene (GBA) encoding the enzyme deficient in Gaucher's disease (GD) are associated with Parkinson's disease (PD). To investigate the sequence variants, their association with PD and the related phenotypes in a large cohort of European, mostly French, patients and controls, we sequenced all exons of GBA in 786 PD patients from 525 unrelated multiplex families, 605 patients with apparently sporadic PD and 391 ethnically matched controls. GBA mutations were significantly more frequent (odds ratio=6.98, 95% confidence interval 2.54-19.21; P=0.00002) in the PD patients (76/1130=6.7%) than in controls (4/391=1.0%) and in patients with family histories of PD (8.4%) than in isolated cases (5.3%). Twenty-eight different mutations were identified in patient and control groups, including seven novel variants. N370S and L444P accounted for 70% of all mutant alleles in the patient group. PD patients with GBA mutations more frequently had bradykinesia as the presenting symptom and levodopa-induced dyskinesias. The phenotype was similar in patients with one, two or complex GBA mutations, although the two patients with c.1263del+RecTL and N370S/RecΔ55 mutations had signs of GD. Segregation analyses in 21 multiplex families showed that 17% of the affected relatives did not carry GBA mutations found in the given family, indicating heterogeneity of the aetiology, but 46% of the unaffected relatives were GBA mutation carriers. These genotype and clinical analyses on the largest homogeneous sample of European patients studied to date confirmed that GBA mutations are the most common genetic risk factor for PD, particularly in familial forms.

Meeus et al. (2009) reported no pathogenic mutations in a comprehensive genetic analysis of the entire GRB10-interacting GYF protein-2 gene (GIGYF2) in a Belgian series of both familial and sporadic patients with Parkinson's disease (PD). Although we initially proposed that GIGYF2 corresponds to the PARK11 locus, in familial PD, we found no causative variations in a follow-up study in which GIGYF2 was screened in an independent series of 185 patients with autosomal dominant PD, mostly of French origin. Together, these results do not support a major role of GIGYF2 in PD., (Copyright 2009 Elsevier Inc. All rights reserved.)

Mutations in the leucine-rich-repeat kinase 2 (LRRK2) gene have been identified in families with autosomal dominant Parkinson's disease (PD) and in sporadic cases; the G2019S mutation is the single most frequent. Intriguingly, the frequency of this mutation in PD patients varies greatly among ethnic groups and geographic origins: it is present at <0.1% in East Asia, approximately 2% in European-descent patients and can reach frequencies of up to 15-40% in PD Ashkenazi Jews and North African Arabs. To ascertain the evolutionary dynamics of the G2019S mutation in different populations, we genotyped 74 markers spanning a 16 Mb genomic region around G2019S, in 191 individuals carrying the mutation from 126 families of different origins. Sixty-seven families were of North-African Arab origin, 18 were of North/Western European descent, 37 were of Jewish origin, mostly from Eastern Europe, one was from Japan, one from Turkey and two were of mixed origins. We found the G2019S mutation on three different haplotypes. Network analyses of the three carrier haplotypes showed that G2019S arose independently at least twice in humans. In addition, the population distribution of the intra-allelic diversity of the most widespread carrier haplotype, together with estimations of the age of G2019S determined by two different methods, suggests that one of the founding G2019S mutational events occurred in the Near East at least 4000 years ago.

Background: Recent studies indicate an increased frequency of mutations in the gene encoding glucocerebrosidase (GBA), a deficiency of which causes Gaucher's disease, among patients with Parkinson's disease. We aimed to ascertain the frequency of GBA mutations in an ethnically diverse group of patients with Parkinson's disease., Methods: Sixteen centers participated in our international, collaborative study: five from the Americas, six from Europe, two from Israel, and three from Asia. Each center genotyped a standard DNA panel to permit comparison of the genotyping results across centers. Genotypes and phenotypic data from a total of 5691 patients with Parkinson's disease (780 Ashkenazi Jews) and 4898 controls (387 Ashkenazi Jews) were analyzed, with multivariate logistic-regression models and the Mantel-Haenszel procedure used to estimate odds ratios across centers., Results: All 16 centers could detect two GBA mutations, L444P and N370S. Among Ashkenazi Jewish subjects, either mutation was found in 15% of patients and 3% of controls, and among non-Ashkenazi Jewish subjects, either mutation was found in 3% of patients and less than 1% of controls. GBA was fully sequenced for 1883 non-Ashkenazi Jewish patients, and mutations were identified in 7%, showing that limited mutation screening can miss half the mutant alleles. The odds ratio for any GBA mutation in patients versus controls was 5.43 across centers. As compared with patients who did not carry a GBA mutation, those with a GBA mutation presented earlier with the disease, were more likely to have affected relatives, and were more likely to have atypical clinical manifestations., Conclusions: Data collected from 16 centers demonstrate that there is a strong association between GBA mutations and Parkinson's disease., (2009 Massachusetts Medical Society)