A comparative study of Parkinson's disease and leucine-rich repeat kinase 2 p.G2019S parkinsonism

Trinh, Joanne; Amouri, Rim; Duda, John E.; Morley, James F.; Read, Matthew; Donald, Alan; Vilariño‐Güell, Carles; Thompson, Christina; Szu-Tu, Chelsea; Gustavsson, Emil K.; Sassi, Samia Ben; Hentati, Emna; Zouari, M.; Farhat, E.; Nabli, Fatma; Hentati, F.; Farrer, Matthew J.

doi:10.1016/j.neurobiolaging.2013.11.015

Cited by 81 publications

(75 citation statements)

References 34 publications

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“…We did not find gender differences at age at onset of PD in either group, contrary to previous report by Haaxma et al32 and a recent Tunisian study where LRRK2 women were affected a median 5 years before men 33. Of interest, men with LRRK2 mutations were slightly younger than IPD men and had younger age at onset, and although this was not seen in women, supports a LRRK2 ‐related effect on age of onset noted in some, but not all studies.…”

Section: Discussioncontrasting

confidence: 99%

Sex differences in LRRK2 G2019S and idiopathic Parkinson's Disease

Luciano

Wang

Ortega

et al. 2017

Ann Clin Transl Neurol

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ObjectiveTo evaluate sex differences and the relative effect of G2019S LRRK2 mutations in Parkinson's disease (PD).Methods530 LRRK2 PD carriers and 759 noncarrier PD (idiopathic, IPD) evaluated as part of the Fox Foundation (MJFF) Consortium were included. All participants completed a study visit including information on clinical features, treatment, examination, and motor and nonmotor questionnaires. Clinical features were compared between men and women separately for IPD and LRRK2 PD; and features were compared between IPD and LRRK2 PD separately for men and women.Results Among IPD: men had higher levodopa equivalency dose (LED), worse activities of daily living and motoric severity but lower complications of therapy (UPDRS‐IV). IPD women had higher olfaction and thermoregulatory scores and were more likely to report family history of PD. Among LRRK2 PD: Male predominance was not observed among G2019S LRRK2 cases. Women had worse UPDRS‐IV but better olfaction. Among same sex:LRRK2 men and women had better olfaction than IPD counterparts. LRRK2 men demonstrated lower motor and higher cognitive, RBD and thermoregulation scores than IPD men and LRRK2 women had greater UDPRS‐IV and rates of dyskinesia.InterpretationThere were clinical differences between sexes with a more severe phenotype in IPD men and more complications of therapy in women. The more severe male phenotype was moderated by LRRK2, with LRRK2 men and women showing less diversity of phenotype. Our study supports that both genetics and sex drive phenotype, and thus trials in LRRK2 and IPD should consider gender stratification in design or analysis.

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Section: Discussioncontrasting

confidence: 99%

Sex differences in LRRK2 G2019S and idiopathic Parkinson's Disease

Luciano

Wang

Ortega

et al. 2017

Ann Clin Transl Neurol

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“…Penetrance was estimated at 80% by age 70 years and women were affected a median of 5 years earlier than men. 25 Age at diagnosis did not predict progression in this cohort. The methodology used in this very large cohort included primarily PD cases (350 cases with idiopathic PD, 220 affected LRRK2 carriers, and 12 unaffected LRRK2 carriers).…”

Section: Resultsmentioning

confidence: 60%

“…In Tunisia, age at onset of LRRK2 PD was 5 years earlier in women compared with men, 25 but this has not been demonstrated in other studies. 21 Crosssectional studies do not demonstrate any phenotypic differences between male and female carriers to explain a difference in disease progression.…”

Section: Resultsmentioning

confidence: 63%

“…Sampling mainly PD-affected individuals may have led to an overestimation of LRRK2 penetrance since essentially almost all individuals in the Tunisian sample developed PD at a certain age before recruitment by their study ascertainment scheme. 25 The authors further compared the Tunisian with a Norwegian cohort and found lower penetrance in Norway despite similar incidence of disease. 26 Systematic assessment of penetrance estimates in the LRRK2 consortium using a common assessment battery and inclusion of both proband and relative characteristics may provide further refinement to these estimates.…”

Section: Resultsmentioning

confidence: 99%

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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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“…However, in Tunisia a sex difference is observed in LRRK2 carriers, women having earlieronset parkinsonism. 6 The same trend appears in Norway but, perhaps due to a smaller sample size, is not significant.…”

Section: Lrrk2 Parkinsonism In Tunisia and Norway: A Comparative Analmentioning

confidence: 89%

LRRK2 parkinsonism in Tunisia and Norway: A comparative analysis of disease penetrance

et al. 2014

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In recent years, the molecular etiology of parkinsonism has yielded to genetic analysis.1 Mutations in the gene leucine-rich repeat kinase 2 (LRRK2) have the highest genotypic and population attributable risk. Disparate penetrance estimates have been reported using a variety of statistical analyses, ethnic populations, and sample sizes.2 We compared the age-associated cumulative incidence (penetrance) of LRRK2 p.G2019S patients from Tunisia and Norway.Methods. Clinic-based population series. The Tunisian Arab-Berber series includes 350 patients with idiopathic Parkinson disease (iPD) (mean onset 55.3 6 14.3 years, range 12-83). An additional 220 are affected LRRK2 p.G2019S carriers (mean onset 57.1 6 11.6 years, range 22-82); 12 unaffected LRRK2 carriers were also identified (mean age 56.7 6 10.9 years). A total of 411 control subjects (spouses or unrelated individuals) were recruited through the Clinic and genotyped. Neither blood relatives of cases nor control subjects were included. The ethnic Norwegian series includes 443 with iPD (mean onset 58.8 6 11.2 years, range 25-88). A total of 520 control subjects (mostly spouses or unrelated individuals) were recruited through the Clinic and genotyped. In Norway, an additional 27 are affected LRRK2 p.G2019S carriers (mean onset 63 6 11.6 years, range 40-82) and 57 unaffected carriers were identified (mean age of 54.2 6 15.2 years) as first-to third-degree relatives through field studies. 3All individuals, clinical data, and blood samples were obtained with local ethical approvals, independently reviewed by the University of British Columbia Research Ethics Board. Written informed consent was provided. Neurologists specializing in movement disorders (F.H. and J.O.A.) diagnosed patients using UK Brain Bank criteria 4 for both the Tunisian and Norwegian populations. Age at onset was obtained from patient medical records or by selfreport. DNA was extracted from blood; LRRK2 genotyping was verified by Sanger sequencing. 5Statistical analysis. The penetrance was estimated for iPD and LRRK2 carriers using a Kaplan-Meier method (JMP software, SAS Institute Inc., Cary, NC) with age at onset as the time variable; asymptomatic carriers were right-censored at the age at last contact or age at death, using log-rank tests to assess significance.

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A comparative study of Parkinson's disease and leucine-rich repeat kinase 2 p.G2019S parkinsonism

Cited by 81 publications

References 34 publications

Sex differences in LRRK2 G2019S and idiopathic Parkinson's Disease

Sex differences in LRRK2 G2019S and idiopathic Parkinson's Disease

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

LRRK2 parkinsonism in Tunisia and Norway: A comparative analysis of disease penetrance

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