Kin‐cohort analysis of <i>LRRK2</i>‐G2019S penetrance in Parkinson's disease

Goldwurm, Stefano; Tùnesi, Sara; Tesei, Silvana; Zini, Michela; Sironi, Francesca; Primignani, Paola; Magnani, Corrado; Pezzoli, Gianni

doi:10.1002/mds.23807

Cited by 49 publications

(60 citation statements)

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“…23 We reported a lifetime penetrance of 24% up to age 80 years (95% CI 13.5%-43.7%) in 2,975 carrier and noncarrier relatives of 459 cases with PD and 2,044 relatives of 310 control probands using the kin-cohort method, 14,24 which was similar in AJ and non-AJ cases. 4 In contrast, 2 a risk of 28% at age 59 years, 51% at 69 years, and 74% at 79 years for the G2019S mutation in 1,045 mutation carriers from 133 families from 24 populations worldwide has been reported.…”

Section: Resultsmentioning

confidence: 86%

Age-specific penetrance ofLRRK2G2019S in the Michael J. Fox Ashkenazi Jewish LRRK2 Consortium

et al. 2015

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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 5 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. Neurology ® 2015;85:89-95 GLOSSARY AJ 5 Ashkenazi Jewish; CI 5 confidence interval; FHI 5 family history interview; GBA 5 glucocerebrosidase; HR 5 hazard ratio; PD 5 Parkinson disease.

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Section: Resultsmentioning

confidence: 86%

Age-specific penetrance ofLRRK2G2019S in the Michael J. Fox Ashkenazi Jewish LRRK2 Consortium

et al. 2015

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“…The most common mutation associated with PD in Caucasian populations is the G2019S mutation in the leucine-rich repeat kinase-2 ( LRRK2 ) gene (Kachergus et al 2005). Penetrance is variable, ranging from 24 to 100 % by age 80 (Goldwurm et al 2011; Trinh et al 2014) depending on ethnic group and methodology employed.…”

Section: Introductionmentioning

confidence: 99%

Interest in Genetic Testing in Ashkenazi Jewish Parkinson's Disease Patients and Their Unaffected Relatives

Gupte

Alcalay

Mejia‐Santana

et al. 2014

Journal of Genetic Counseling

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Our objective was to explore interest in genetic testing among Ashkenazi Jewish (AJ) Parkinson’s Disease (PD) cases and first-degree relatives, as genetic testing for LRRK2 G2019S is widely available. Approximately 18 % of AJ PD cases carry G2019S mutations; penetrance estimations vary between 24 and 100 % by age 80. A Genetic Attitude Questionnaire (GAQ) was administered at two New York sites to PD families unaware of LRRK2 G2019S mutation status. The association of G2019S, age, education, gender and family history of PD with desire for genetic testing (outcome) was modeled using logistic regression. One-hundred eleven PD cases and 77 relatives completed the GAQ. Both PD cases and relatives had excellent PD-specific genetic knowledge. Among PD, 32.6 % “definitely” and 41.1 % “probably” wanted testing, if offered “now.” Among relatives, 23.6 % “definitely” and 36.1 % “probably” wanted testing “now.” Desire for testing in relatives increased incrementally based on hypothetical risk of PD. The most important reasons for testing in probands and relatives were: if it influenced medication response, identifying no mutation, and early prevention and treatment. In logistic regression, older age was associated with less desire for testing in probands OR=0.921 95%CI 0.868–0.977, p=0.009. Both probands and relatives express interest in genetic testing, despite no link to current treatment or prevention.

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“…22 For Ashkenazy Jews carrying the G2019S LRRK2 mutation (i.e., the population tested here), lifetime penetrance until the age of 80 years has been estimated to be 26%. 13 Thus, it is striking that we found altered corticostriatal connectivity in a group of LRRK2 G2O19S mutation carriers with an average age of 650 years.…”

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confidence: 98%

Reorganization of corticostriatal circuits in healthy G2019S LRRK2 carriers

et al. 2015

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Objective: We investigated system-level corticostriatal changes in a human model of premotor Parkinson disease (PD), i.e., healthy carriers of the G2019S LRRK2 mutation that is associated with a markedly increased, age-dependent risk of developing PD.Methods: We compared 37 asymptomatic LRRK2 G2019S mutation carriers (age range 30-78 years) with 32 matched, asymptomatic nonmutation carriers (age range 30-74 years). Using fMRI, we tested the hypothesis that corticostriatal connectivity in premotor PD shifts from severely affected to less affected striatal subregions, as shown previously in symptomatic PD. Specifically, we predicted that in premotor PD, the shift in corticostriatal connectivity would follow the same gradient of striatal dopamine depletion known from overt PD, with the dorsoposterior putamen being more affected than the ventroanterior putamen. Results:The known parallel topology of corticostriatal loops was preserved in each group, but the topography of putamen connectivity shifted. In LRRK2 G2019S mutation carriers, the right inferior parietal cortex had reduced functional connectivity with the dorsoposterior putamen but increased connectivity with the ventroanterior putamen, as compared with noncarriers. This shift in functional connectivity increased with age in LRRK2 G2019S mutation carriers.Conclusions: Asymptomatic LRRK2 G2019S mutation carriers show a reorganization of corticostriatal circuits that mirrors findings in idiopathic PD. These changes may reflect premotor basal ganglia dysfunction or circuit-level compensatory changes. Parkinson disease (PD) is a progressive, neurodegenerative disorder characterized by nigrostriatal dopamine depletion. The motor symptoms of PD appear only when dopaminergic cell death reaches a critical threshold of 50% to 80%.1 This suggests that the nervous system has a marked potential to compensate for these changes.2 However, human studies of cerebral compensation in premotor PD are lacking, given the difficulty of predicting who will develop PD in the future.Previous work has shown that compensatory mechanisms in idiopathic PD depend on brain regions relatively unaffected by dopamine depletion, such as the anterior striatum.3,4 Using fMRI in early-stage PD, we recently showed a shift in corticostriatal connectivity from severely affected striatal regions (posterior putamen) to less affected striatal regions (anterior putamen). 5If these changes reflect compensation, they should also occur in the premotor phase of PD, when functional reorganization of cerebral circuits prevents overt clinical symptoms. 2 *These authors contributed equally to this work.

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Kin‐cohort analysis of LRRK2‐G2019S penetrance in Parkinson's disease

Cited by 49 publications

References 8 publications

Age-specific penetrance ofLRRK2G2019S in the Michael J. Fox Ashkenazi Jewish LRRK2 Consortium

Age-specific penetrance ofLRRK2G2019S in the Michael J. Fox Ashkenazi Jewish LRRK2 Consortium

Interest in Genetic Testing in Ashkenazi Jewish Parkinson's Disease Patients and Their Unaffected Relatives

Reorganization of corticostriatal circuits in healthy G2019S LRRK2 carriers

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