Correspondence
LRRK2 G2019S as a Cause of Parkinson's Disease in Ashkenazi Jews
N Engl J Med 2006; 354:424-425January 26, 2006
- Article
To the Editor:
Most cases of Parkinson's disease are considered sporadic and idiopathic, although there is evidence of familial aggregation, and several monogenic forms have been identified.1 Recently, several pathogenic mutations in the highly conserved leucine-rich repeat kinase 2 gene (LRRK2) have been associated with autosomal dominant, late-onset Parkinson's disease.1 Of these, the G2019S substitution is the most frequently reported.2 It occurs in about 1 percent of unselected cases and 3 to 6 percent of familial cases of Parkinson's disease in persons primarily of European ancestry2 but in 7 of 17 cases of familial disease in persons from North Africa (41 percent).3 At most, 5 carriers among 10,000 persons without Parkinson's disease have been reported.2-4
We screened 120 unrelated Ashkenazi Jewish patients with Parkinson's disease in the outpatient setting of the Department of Neurology at the Beth Israel Medical Center in New York City. Specialists in movement disorders performed clinical assessments, and all subjects met stringent diagnostic criteria for Parkinson's disease.5 Ancestry was determined according to the patients' self-descriptions, and all but one patient (who reported being 50 percent Sephardic) reported that both parents were Ashkenazic. The Unified Parkinson's Disease Rating Scale, the Hoehn–Yahr scale, and a diagnostic checklist were completed, and peripheral blood or a cheek swab for DNA analysis was obtained with written informed consent. An Ashkenazi Jewish control group of 317 persons consisted of 113 parents from unrelated families with DYT1 dystonia and 16 from families with dysautonomia, and 188 unrelated Ashkenazi Jewish subjects from the Einstein Aging Study. All were of Ashkenazi Jewish ancestry according to self-report, were examined, and did not have Parkinson's disease at the time blood was drawn. The institutional review boards of both the Beth Israel Medical Center and the Albert Einstein College of Medicine approved these studies.
DNA was extracted from white cells or buccal cells with the use of standard techniques. The G2019S mutation in LRRK2 (G6055A single-nucleotide polymorphism [SNP] in exon 41), two other coding SNPs, rs1427263 and rs11564148, and five microsatellite markers were genotyped (see the table in the Supplementary Appendix, available with the full text of this letter at www.nejm.org).
Among 120 Ashkenazi Jewish patients with Parkinson's disease, the LRRK2 G2019S mutation was detected in 22 (18.3 percent; 95 percent confidence interval, 11.9 to 26.4 percent). Of 317 Ashkenazi Jewish controls, 4 were identified as carrying the mutation (1.3 percent; 95 percent confidence interval, 0.34 to 3.2 percent) (odds ratio among the patients, 17.6; 95 percent confidence interval, 5.9 to 52.2; P<0.001). The mutation was present in 11 of 37 subjects with a familial pattern, defined by having at least one affected first-degree, second-degree, or third-degree relative (29.7 percent), and 11 of 83 subjects with no family history of Parkinson's disease (13.3 percent) (P=0.03). These rates are 15 to 20 times as high as those in most prior reports involving European subjects.2
A common founder mutation has been reported in the European and North African populations.6,7 We evaluated allelic association at individual markers surrounding and within the LRRK2 gene.8 For six of the seven markers, the associated allele was the same as reported for the common European–North African haplotype, indicating a common ancestral origin. The apparently high frequency among North African patients with Parkinson's disease and controls,7 particularly those of Arab ancestry as well as among Ashkenazi Jewish subjects as shown here, suggests a likely Middle Eastern origin for the G2019S mutation. It also establishes once again the Middle Eastern origin of Ashkenazim.
Lifetime penetrance of the G2019S mutation in the Ashkenazi Jewish population was estimated in two ways. First, we used the observed frequency of carriers of the mutation among the patients with Parkinson's disease and the controls. The relative penetrance for carriers as compared with noncarriers could then be calculated as the odds ratio (17.6). If we assume a lifetime risk of Parkinson's disease of 2 percent, the lifetime penetrance for those who carried the mutation would be approximately 2×17.6, or 35.2 percent. An alternative estimate of penetrance is obtained by examining the risk of Parkinson's disease among the parents of the carriers. We found 7 of 44 parents to be so affected. If we assume that half of the parents also carried the mutation, and the 7 cases occurred among these carriers (probably because Parkinson's disease is uncommon in noncarriers), we obtain a lifetime penetrance of 7÷22, or 31.8 percent. These figures are substantially lower than previous estimates that were calculated on the basis of multigenerational pedigrees.6
The G2019S mutation appears to be an important cause of both familial and sporadic Parkinson's disease in this group of Ashkenazi Jewish subjects. There was no evidence in the literature that prevalence or familial aggregation of Parkinson's disease is increased in the Ashkenazi Jewish population as compared with non-Ashkenazi subjects; further epidemiologic study of this population is warranted.
Laurie J. Ozelius, Ph.D.
Geetha Senthil, Ph.D.
Albert Einstein College of Medicine, Bronx, NY 10461
ozelius@aecom.yu. edu Rachel Saunders-Pullman, M.D., M.P.H.
Erin Ohmann, B.S.
Amanda Deligtisch, M.D.
Michele Tagliati, M.D.
Ann L. Hunt, D.O.
Beth Israel Medical Center, New York, NY 10003Christine Klein, M.D.
University of Lübeck, 23538 Lübeck, GermanyBrian Henick
Beth Israel Medical Center, New York, NY 10003Susan M. Hailpern, M.S., M.P.H.
Richard B. Lipton, M.D.
Albert Einstein College of Medicine, Bronx, NY 10461Jeannie Soto-Valencia, B.A.
Beth Israel Medical Center, New York, NY 10003Neil Risch, Ph.D.
University of California at San Francisco, San Francisco, CA 94143Susan B. Bressman, M.D.
Beth Israel Medical Center, New York, NY 10003Dr. Tagliati reports having received consulting fees from Schwarz Pharma, Boehringer Ingelheim, and Novartis and lecture fees from Medtronic Neurological, Novartis, GlaxoSmithKline, and Boehringer Ingelheim; and Dr. Klein, lecture fees from Boehringer Ingelheim.
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