LRRK2 G2019S as a Cause of Parkinson's Disease in North African Arabs
http://www.100md.com
《新英格兰医药杂志》
To the Editor: Parkinson's disease is characterized by resting tremor, rigidity, and bradykinesia caused by the loss of dopaminergic neurons in the substantia nigra, a good response to levodopa, and the presence of Lewy bodies. The recently identified G2019S mutation in exon 41 of the leucine-rich repeat kinase 2 gene (LRRK2) accounts for 2 to 6 percent of familial and 1 to 2 percent of sporadic cases.1 The mutation is less common in Asian populations1 but prevalent in patients from North Africa who have Parkinson's disease, as we describe here.
We obtained blood samples from 104 unrelated index patients with Parkinson's disease (76 Arabs, 18 Europeans born in North Africa, 6 Sephardic Jews, and 4 black Africans) and sequenced exon 41 (see the Supplementary Appendix, available with the full text of this letter at www.nejm.org). Seventeen North African families with Parkinson's disease had been reported2; 87 index cases were new. The data for 151 healthy unrelated Arab controls, who were spouses of patients with neurologic disease, were also analyzed.
In the newly ascertained series of North African Arabs, 23 of 59 patients with Parkinson's disease were carriers of the G2019S mutation (39 percent), as compared with only 2 of 69 controls (3 percent; P<0.001) (Table 1). In the previous study2 and the present study combined, 31 of the 104 probands (30 percent) were heterozygous (28 patients) or homozygous (3 patients) for the G2019S mutation. All but one of the 31 G2019S carriers were Arab (30 of 76; 39 percent); one was a Sephardic Jew. The frequency of the mutation among Arabs was 37 percent (10 of 27; 95 percent confidence interval, 22.4 to 61.2 percent) in familial cases and 41 percent (20 of 49; 95 percent confidence interval, 28.8 to 57.8 percent) in sporadic cases. In four families, the mutation was present in two additional patients and in three of nine unaffected relatives, who were 29, 32, and 43 years of age. It was also present in 2 of 151 North African controls, who were 22 and 58 years of age. All carriers had genotypes consistent with a common haplotype3 spanning 60 kb (see the Supplementary Appendix).
Table 1. Frequency of the G2019S Mutation in North African Arabs with Familial and Sporadic Parkinson's Disease and in Ethnically Matched Controls.
The 33 G2019S carriers (including the 2 additional patients) and the 73 noncarriers had similar ages at the onset of disease and at examination (see the table in the Supplementary Appendix for these details and other clinical details about the patients). The symptoms of two homozygous carriers from Algeria and one from Morocco began at the age of 54, 56, and 62 years, respectively, and were typical of Parkinson's disease. One carrier of the LRRK2 G2019S mutation also had a heterozygous A398T parkin mutation, and another had a homozygous triplication in exon 2 of parkin, suggesting digenic inheritance. The latter had the earliest age at onset (31 years) but also the typical levodopa-responsive parkinsonism expected in patients with parkin mutations.4
Our preliminary2 and present results show that the frequency of the G2019S mutation is strikingly high among North African Arabs with familial Parkinson's disease (37 percent; 95 percent confidence interval, 22.4 to 61.2 percent) and more unexpectedly, in those without a family history of the disease (41 percent; 95 percent confidence interval, 28.8 to 57.8 percent). Although it is present at a low level in Arab controls, the G2019S mutation nevertheless constitutes a significant risk factor for Parkinson's disease in this population (odds ratio, 48.6; 95 percent confidence interval, 11.2 to 211.0, for combined familial and sporadic cases).
The high frequency of a dominant mutation in apparently sporadic cases of Parkinson's disease cannot be explained by recurrent events, since the mutation is associated with the same ancestral haplotype in several populations.3,5 Reduced penetrance (85 percent at 70 years of age among whites,5 but not yet analyzed among Arabs) may account for some apparently sporadic cases. A censor effect may account for others, since in 11 of 17 cases, at least one parent died before 65 years of age.
The phenotype of the G2019S carriers was similar to that of other persons with Parkinson's disease; we could not distinguish one from the other. Our data suggest, however, that more severe progression and more cognitive changes occur in carriers than in noncarriers. Interestingly, homozygous carriers could not be distinguished from heterozygous carriers, and their mean age at onset was even later, indicating the absence of a dose effect, as observed in other studies.1 This result is consistent with an increase in kinase activity caused by the G2019S mutation.6 Possible digenic inheritance in two patients with mutations in both parkin and LRRK2 did not seem to cause a more severe phenotype, either,7 but the earliest onset was observed in the patient with LRRK2 who also carried a homozygous parkin mutation, suggesting an additive effect.
The prevalence of the G2019S mutation is also high in Ashkenazi Jews with Parkinson's disease, reaching 29.7 percent in familial cases and 13.3 percent in sporadic cases.8 Our finding has consequences for genetic diagnosis and counseling, although penetrance must be better evaluated in North African Arabs and Ashkenazi Jews for an optimal evaluation of risk.
Suzanne Lesage, Ph.D.
Alexandra Dürr, M.D., Ph.D.
INSERM Unité 679
75651 Paris CEDEX 13, France
Meriem Tazir, M.D.
Centre Hospitalier Universitaire (CHU) Mustapha
16000 Algiers, Algeria
Ebba Lohmann, M.D.
Anne-Louise Leutenegger, Ph.D.
Sabine Janin, B.S.
INSERM Unité 679
75651 Paris CEDEX 13, France
Pierre Pollak, M.D.
CHU de Grenoble
38000 Grenoble, France
Alexis Brice, M.D.
INSERM Unité 679
75651 Paris CEDEX 13, France
brice@ccr.jussieu.fr
for the French Parkinson's Disease Genetics Study Group
Dr. Pollak reports having received consulting fees from Novartis, GlaxoSmithKline, Boehringer Ingelheim, and Valeant and lecture fees from Medtronic, GlaxoSmithKline, and Boehringer Ingelheim; and Dr. Brice, lecture fees from GlaxoSmithKline.
References
Brice A. Genetics of Parkinson's disease: LRRK2 on the rise. Brain 2005;128:2760-2762.
Lesage S, Ibanez P, Lohmann E, et al. G2019S LRRK2 mutation in French and North African families with Parkinson's disease. Ann Neurol 2005;58:784-787.
Lesage S, Leutenegger AL, Ibanez P, et al. LRRK2 haplotype analyses in European and North African families with Parkinson disease: a common founder for the G2019S mutation dating from the 13th century. Am J Hum Genet 2005;77:330-332.
Lucking CB, Durr A, Bonifati V, et al. Association between early-onset Parkinson's disease and mutations in the parkin gene. N Engl J Med 2000;342:1560-1567.
Kachergus J, Mata IF, Hulihan M, et al. Identification of a novel LRRK2 mutation linked to autosomal dominant Parkinsonism: evidence of a common founder across European populations. Am J Hum Genet 2005;76:672-680.
West AB, Moore DJ, Biskup S. Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. Proc Natl Acad Sci U S A 2005;102:16842-16847.
Paisan-Ruiz C, Lang AE, Kawarai T, et al. LRRK2 gene in Parkinson disease: mutation analysis and case control association study. Neurology 2005;65:696-700.
Ozelius L, Senthil G, Saunders-Pullman R, et al. LRRK2 G2019S as a cause of Parkinson's disease in Ashkenazi Jews. N Engl J Med 2006;354:424-425.
We obtained blood samples from 104 unrelated index patients with Parkinson's disease (76 Arabs, 18 Europeans born in North Africa, 6 Sephardic Jews, and 4 black Africans) and sequenced exon 41 (see the Supplementary Appendix, available with the full text of this letter at www.nejm.org). Seventeen North African families with Parkinson's disease had been reported2; 87 index cases were new. The data for 151 healthy unrelated Arab controls, who were spouses of patients with neurologic disease, were also analyzed.
In the newly ascertained series of North African Arabs, 23 of 59 patients with Parkinson's disease were carriers of the G2019S mutation (39 percent), as compared with only 2 of 69 controls (3 percent; P<0.001) (Table 1). In the previous study2 and the present study combined, 31 of the 104 probands (30 percent) were heterozygous (28 patients) or homozygous (3 patients) for the G2019S mutation. All but one of the 31 G2019S carriers were Arab (30 of 76; 39 percent); one was a Sephardic Jew. The frequency of the mutation among Arabs was 37 percent (10 of 27; 95 percent confidence interval, 22.4 to 61.2 percent) in familial cases and 41 percent (20 of 49; 95 percent confidence interval, 28.8 to 57.8 percent) in sporadic cases. In four families, the mutation was present in two additional patients and in three of nine unaffected relatives, who were 29, 32, and 43 years of age. It was also present in 2 of 151 North African controls, who were 22 and 58 years of age. All carriers had genotypes consistent with a common haplotype3 spanning 60 kb (see the Supplementary Appendix).
Table 1. Frequency of the G2019S Mutation in North African Arabs with Familial and Sporadic Parkinson's Disease and in Ethnically Matched Controls.
The 33 G2019S carriers (including the 2 additional patients) and the 73 noncarriers had similar ages at the onset of disease and at examination (see the table in the Supplementary Appendix for these details and other clinical details about the patients). The symptoms of two homozygous carriers from Algeria and one from Morocco began at the age of 54, 56, and 62 years, respectively, and were typical of Parkinson's disease. One carrier of the LRRK2 G2019S mutation also had a heterozygous A398T parkin mutation, and another had a homozygous triplication in exon 2 of parkin, suggesting digenic inheritance. The latter had the earliest age at onset (31 years) but also the typical levodopa-responsive parkinsonism expected in patients with parkin mutations.4
Our preliminary2 and present results show that the frequency of the G2019S mutation is strikingly high among North African Arabs with familial Parkinson's disease (37 percent; 95 percent confidence interval, 22.4 to 61.2 percent) and more unexpectedly, in those without a family history of the disease (41 percent; 95 percent confidence interval, 28.8 to 57.8 percent). Although it is present at a low level in Arab controls, the G2019S mutation nevertheless constitutes a significant risk factor for Parkinson's disease in this population (odds ratio, 48.6; 95 percent confidence interval, 11.2 to 211.0, for combined familial and sporadic cases).
The high frequency of a dominant mutation in apparently sporadic cases of Parkinson's disease cannot be explained by recurrent events, since the mutation is associated with the same ancestral haplotype in several populations.3,5 Reduced penetrance (85 percent at 70 years of age among whites,5 but not yet analyzed among Arabs) may account for some apparently sporadic cases. A censor effect may account for others, since in 11 of 17 cases, at least one parent died before 65 years of age.
The phenotype of the G2019S carriers was similar to that of other persons with Parkinson's disease; we could not distinguish one from the other. Our data suggest, however, that more severe progression and more cognitive changes occur in carriers than in noncarriers. Interestingly, homozygous carriers could not be distinguished from heterozygous carriers, and their mean age at onset was even later, indicating the absence of a dose effect, as observed in other studies.1 This result is consistent with an increase in kinase activity caused by the G2019S mutation.6 Possible digenic inheritance in two patients with mutations in both parkin and LRRK2 did not seem to cause a more severe phenotype, either,7 but the earliest onset was observed in the patient with LRRK2 who also carried a homozygous parkin mutation, suggesting an additive effect.
The prevalence of the G2019S mutation is also high in Ashkenazi Jews with Parkinson's disease, reaching 29.7 percent in familial cases and 13.3 percent in sporadic cases.8 Our finding has consequences for genetic diagnosis and counseling, although penetrance must be better evaluated in North African Arabs and Ashkenazi Jews for an optimal evaluation of risk.
Suzanne Lesage, Ph.D.
Alexandra Dürr, M.D., Ph.D.
INSERM Unité 679
75651 Paris CEDEX 13, France
Meriem Tazir, M.D.
Centre Hospitalier Universitaire (CHU) Mustapha
16000 Algiers, Algeria
Ebba Lohmann, M.D.
Anne-Louise Leutenegger, Ph.D.
Sabine Janin, B.S.
INSERM Unité 679
75651 Paris CEDEX 13, France
Pierre Pollak, M.D.
CHU de Grenoble
38000 Grenoble, France
Alexis Brice, M.D.
INSERM Unité 679
75651 Paris CEDEX 13, France
brice@ccr.jussieu.fr
for the French Parkinson's Disease Genetics Study Group
Dr. Pollak reports having received consulting fees from Novartis, GlaxoSmithKline, Boehringer Ingelheim, and Valeant and lecture fees from Medtronic, GlaxoSmithKline, and Boehringer Ingelheim; and Dr. Brice, lecture fees from GlaxoSmithKline.
References
Brice A. Genetics of Parkinson's disease: LRRK2 on the rise. Brain 2005;128:2760-2762.
Lesage S, Ibanez P, Lohmann E, et al. G2019S LRRK2 mutation in French and North African families with Parkinson's disease. Ann Neurol 2005;58:784-787.
Lesage S, Leutenegger AL, Ibanez P, et al. LRRK2 haplotype analyses in European and North African families with Parkinson disease: a common founder for the G2019S mutation dating from the 13th century. Am J Hum Genet 2005;77:330-332.
Lucking CB, Durr A, Bonifati V, et al. Association between early-onset Parkinson's disease and mutations in the parkin gene. N Engl J Med 2000;342:1560-1567.
Kachergus J, Mata IF, Hulihan M, et al. Identification of a novel LRRK2 mutation linked to autosomal dominant Parkinsonism: evidence of a common founder across European populations. Am J Hum Genet 2005;76:672-680.
West AB, Moore DJ, Biskup S. Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. Proc Natl Acad Sci U S A 2005;102:16842-16847.
Paisan-Ruiz C, Lang AE, Kawarai T, et al. LRRK2 gene in Parkinson disease: mutation analysis and case control association study. Neurology 2005;65:696-700.
Ozelius L, Senthil G, Saunders-Pullman R, et al. LRRK2 G2019S as a cause of Parkinson's disease in Ashkenazi Jews. N Engl J Med 2006;354:424-425.