RESUMO
OBJECTIVE: Estimates of the penetrance of LRRK2 G2019S vary widely (24%-100%), reflective of differences in ascertainment, age, sex, ethnic group, and genetic and environmental modifiers. METHODS: The kin-cohort method was used to predict penetrance in 2,270 relatives of 474 Ashkenazi Jewish (AJ) Parkinson disease (PD) probands in the Michael J. Fox LRRK2 AJ Consortium in New York and Tel Aviv, Israel. Patients with PD were genotyped for the LRRK2 G2019S mutation and at least 7 founder GBA mutations. GBA mutation carriers were excluded. A validated family history interview, including age at onset of PD and current age or age at death for each first-degree relative, was administered. Neurologic examination and LRRK2 genotype of relatives were included when available. RESULTS: Risk of PD in relatives predicted to carry an LRRK2 G2019S mutation was 0.26 (95% confidence interval [CI] 0.18-0.36) to age 80 years, and was almost 3-fold higher than in relatives predicted to be noncarriers (hazard ratio [HR] 2.89, 95% CI 1.73-4.55, p < 0.001). The risk among predicted G2019S carrier male relatives (0.22, 95% CI 0.10-0.37) was similar to predicted carrier female relatives (0.29, 95% CI 0.18-0.40; HR male to female: 0.74, 95% CI 0.27-1.63, p = 0.44). In contrast, predicted noncarrier male relatives had a higher risk (0.15, 95% CI 0.11-0.20) than predicted noncarrier female relatives (0.07, 95% CI 0.04-0.10; HR male to female: 2.40, 95% CI 1.50-4.15, p < 0.001). CONCLUSION: Penetrance of LRRK2 G2019S in AJ is only 26% and lower than reported in other ethnic groups. Further study of the genetic and environmental risk factors that influence G2019S penetrance is warranted.
Assuntos
Judeus/genética , Doença de Parkinson/diagnóstico , Doença de Parkinson/genética , Penetrância , Proteínas Serina-Treonina Quinases/genética , Fatores Etários , Idoso , Estudos de Coortes , Feminino , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: The clinical delineation of dementia with Lewy bodies (DLB) from Alzheimer disease (AD) remains unclear. OBJECTIVES: To compare neuropsychological profiles in DLB and AD among Caribbean Hispanic family members and participants in a population-based epidemiologic sample using extended neuropsychological test batteries and to explore whether these differences were related to heritable factors. DESIGN: Cross-sectional study. SETTING: Clinics in northern Manhattan (New York City), the Dominican Republic, and Puerto Rico. PATIENTS: We compared measures of memory, orientation, language, and executive and visuospatial functioning between patients with DLB vs AD in 2 Caribbean Hispanic cohorts, including a family sample (89 patients with DLB and 118 patients with AD) and an epidemiologic sample (70 patients with DLB and 157 patients with AD). Patients with DLB in the family sample were further categorized as patients having at least 2 family members with DLB or as patients having 1 family member with DLB. MAIN OUTCOME MEASURES: To determine whether observed differences in cognitive profiles were driven by heritable factors, we repeated analyses in the epidemiologic sample after excluding familial cases. We applied general linear models adjusted for age, sex, educational level, disease duration, and apolipoprotein E epsilon4 (OMIM 104310) genotype. RESULTS: Patients with DLB in both samples were more severely impaired in orientation, visuoconstruction, and nonverbal reasoning after controlling for potential confounders. Patients having at least 2 family members with DLB had the most severe impairment in memory, followed by patients having 1 family member with DLB, and then by patients with AD. After excluding familial AD and DLB cases in the epidemiologic sample, the differences between the groups persisted but were attenuated. CONCLUSIONS: Compared with patients having AD, patients having DLB are more severely impaired in various cognitive domains, particularly orientation and visuospatial functioning. The difference seems stronger in familial DLB than in sporadic DLB. Whether this divergence in cognitive functions is caused by gene-gene or gene-environmental interactions remains unclear.