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Background: Large-scale Parkinson's disease (PD) genome-wide association studies (GWAS) have, until recently, only been conducted on subjects with European-ancestry. Consequently, polygenic risk scores (PRS) constructed using PD GWAS data are likely to be less predictive when applied to non-European cohorts.Methods: Using GWAS data from the largest study to date, we constructed a PD PRS for a Latino PD cohort (1497 subjects from LARGE-PD) and tested it for association with PD status and age at onset. We validated the PRS performance by testing it in an independent Latino cohort (448 subjects) and by repeating the analysis in LARGE-PD with the addition of 440 external Peruvian controls. We also tested SNCA haplotypes for association with PD risk in LARGE-PD and a European-ancestry PD cohort.Results: The GWAS-significant PD PRS had an area under the receiver-operator curve (AUC) of 0.668 (95% CI: 0.640-0.695) in LARGE-PD. The inclusion of external Peruvian controls mitigated this result, dropping the AUC 0.632 (95% CI: 0.607-0.657). At the SNCA locus, haplotypes differ by ancestry. Ancestry-specific SNCA haplotypes were associated with PD status in both LARGE-PD and the European-ancestry cohort (p-value < 0.05). These haplotypes both include the rs356182 G-allele, but only share 14% of their variants overall.Conclusion: The PD PRS has potential for PD risk prediction in Latinos, but variability caused by admixture patterns and bias in a European-ancestry PD PRS data limits its utility. The inclusion of diverse subjects can help elucidate PD risk loci and improve risk prediction in non-European cohorts. [ABSTRACT FROM AUTHOR]

Background: Mutations in the glucocerebrosidase (GBA) gene are an important risk factor for Parkinson's disease (PD). However, most GBA genetic studies in PD have been performed in patients of European origin and very few data are available in other populations.Methods: We sequenced the entire GBA coding region in 602 PD patients and 319 controls from Colombia and Peru enrolled as part of the Latin American Research Consortium on the Genetics of Parkinson's disease (LARGE-PD).Results: We observed a significantly higher proportion of GBA mutation carriers in patients compared to healthy controls (5.5% vs 1.6%; OR = 4.3, p = 0.004). Interestingly, the frequency of mutations in Colombian patients (9.9%) was more than two-fold greater than in Peruvian patients (4.2%) and other European-derived populations reported in the literature (4-5%). This was primarily due to the presence of a population-specific mutation (p.K198E) found only in the Colombian cohort. We also observed that the age at onset was significantly earlier in GBA carriers when compared to non-carriers (47.1 ± 14.2 y vs. 55.9 ± 14.2 y; p = 0.0004).Conclusion: These findings suggest that GBA mutations are strongly associated with PD risk and earlier age at onset in Peru and Colombia. The high frequency of GBA carriers among Colombian PD patients (∼10%) makes this population especially well-suited for novel therapeutic approaches that target GBA-related PD. [ABSTRACT FROM AUTHOR]

Diseases with a choreic phenotype can be due to a variety of genetic etiologies. As testing for Huntington's disease (HD) becomes more available in previously resource-limited regions, it is becoming apparent that there are patients in these areas with other rare genetic conditions which cause an HD-like phenotype. Documentation of the presence of these conditions is important in order to provide appropriate diagnostic and clinical care for these populations. Information for this article was gathered in two ways; the literature was surveyed for publications reporting a variety of genetic choreic disorders, and movement disorders specialists from countries in Latin America and the Caribbean were contacted regarding their experiences with chorea of genetic etiology. Here we discuss the availability of molecular diagnostics for HD and for other choreic disorders, along with a summary of the published reports of affected subjects, and authors' personal experiences from the regions. While rare, patients affected by non-HD genetic choreas are evidently present in Latin America and the Caribbean. HD-like 2 is particularly prevalent in countries where the population has African ancestry. The incidence of other conditions is likely determined by other variations in ethnic background and settlement patterns. As genetic resources and awareness of these disorders improve, more patients are likely to be identified, and have the potential to benefit from education, support, and ultimately molecular therapies. [ABSTRACT FROM AUTHOR]

Background Mutations in PARK2 result in autosomal recessive young onset Parkinson's disease (YOPD). Although there have been a number of reports on the clinical characteristics of PARK2 -related PD, there is limited information available on the associated neuropathologic changes. Design We describe the clinical and pathological characteristics of a Peruvian family with YOPD. The proband and one unaffected sibling were screened for PARK2 dosage and point mutations. One affected sibling had detailed neuropathologic examination. Setting Instituto Nacional de Ciencias Neurologicas (INCN) in Lima, Peru. Results The proband and two of her four siblings developed YOPD and both parents were unaffected. The clinical course has been characterized by akinetic-rigid parkinsonism predominantly affecting the lower limbs and dyskinesias. Analysis of PARK2 showed that the proband is compound heterozygous for a novel acceptor splice site mutation in intron 5 (IVS5-1G>A) and an exon 7 deletion. Neuropathologic assessment of an affected sibling revealed severe neuronal loss in the substantia nigra (SN) and loss of tyrosine hydroxylase immunopositive fibers in the striatum. No Lewy body pathology was observed using standard histology or immunohistochemistry for α-synuclein. Conclusions Consistent with most neuropathologic reports of patients with PARK2 mutations, we did not observe Lewy body inclusions, despite marked SN degeneration and severe dopaminergic denervation of the striatum. These data describe a novel splice site mutation and further extend the clinicopathological characterization of PARK2 -associated PD. [ABSTRACT FROM AUTHOR]

Abstract: Variation in the leucine-rich repeat kinase 2 (LRRK2) gene represents the most common genetic determinant of Parkinson''s disease (PD) identified to date. While the frequency and distribution of LRRK2 mutations have been well-studied in Europe and North America, few data are available from South America. To address this gap in knowledge, we screened two cohorts of patients with PD from Peru (n =240) and Uruguay (n =125) for the three most common LRRK2 mutations (R1441C, R1441G, G2019S). We identified at total of seven patients with mutations, one with R1441G, and six with G2019S. The carrier frequency was significantly greater in the Uruguayan cohort (4.8%) than in the Peruvian cohort (0.4%; p =0.007). This likely resulted from a greater admixture proportion in the Peruvian sample. Haplotype analyses suggested that G2019S was probably brought to Peru and Uruguay by European settlers. In contrast, the origin of R1441G in our cohort was not clear, as the patient with this mutation had a background haplotype that was clearly distinct from that reported in carriers from Europe and North America. Our data add to a growing body of evidence indicating that LRRK2 mutations are widely distributed across South America but might differ by region in prevalence. [Copyright &y& Elsevier]

Abstract: Mutations in the LRRK2 gene are the most common genetic cause of Parkinson’s disease, with frequencies displaying a high degree of population-specificity. Although more than 100 coding substitutions have been identified, only seven have been proven to be highly penetrant pathogenic mutations. Studies however are lacking in non-white populations. Recently, Lrrk2 p.Q1111H (rs78365431) was identified in two affected Hispanic brothers and absent in 386 non-Hispanic white healthy controls. We therefore screened this variant in 1460 individuals (1150 PD patients and 310 healthy controls) from 4 Latin American countries (Peru, Chile, Uruguay and Argentina). In our case-control series from Peru and Chile we observed an increased frequency of Lrrk2 p.Q1111H in patients (7.9%) compared to controls (5.4%) although the difference did not reach significance (OR 1.38; p = 0.10). In addition, the frequency of Lrrk2 p.Q1111H varied greatly between populations and further screening in a set of pure Amerindian and pure Spanish controls suggested that this variant likely originated in an Amerindian population. Further studies in other Latin American populations are warranted to assess its role as a risk factor for Parkinson’s disease. Screening in Parkinson’s disease patients from under-represented populations will increase our understanding of the role of LRRK2 variants in disease risk worldwide. [Copyright &y& Elsevier]