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Genealogical studies in LRRK2-associated Parkinson’s disease in central Norway
Parkinsonism and Related Disorders 16 (2010) 527e530
Contents lists available at ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Genealogical studies in LRRK2-associated Parkinson’s disease in central Norwayq Krisztina K. Johansen a, b, *, Kåre Hasselberg a, Linda R. White a, b, Matthew J. Farrer c, Jan O. Aasly a, b a
Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway Department of Neurology, St Olav’s University Hospital, Trondheim, Norway c Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL, USA b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 20 January 2010 Received in revised form 19 May 2010 Accepted 26 May 2010
The most common mutation related to Parkinson’s disease (PD) is the p.G2019S mutation in the LRRK2 gene. Global population frequencies and crude estimates of haplotype conservation suggest most carriers are related. A total of 671 Norwegian PD patients and 215 of their family members were screened for the LRRK2 p.G2019S mutation. Twenty-one PD cases and 44 family members were positive for the mutation and all could be traced back to 10 different families. A genealogical study employed data from the Norwegian National Family Record Centre, local parish registers and population censuses. A common ancestor couple (living between 1580 and 1650) was found in six families, and two other families were associated by intermarriage. The remaining two families could not be traced back to either of these ancestors, though chromosome 12q12 haplotype analysis showed p.G2019S carriers shared alleles for 15 markers in the LRRK2 region. The study provides support for a common ancestor in Norwegian families with LRRK2 p.G2019S parkinsonism. The mutation was probably introduced to Norway through tradesmen from Europe. The extended pedigree that now links modern day carriers may help in mapping penetrance modifiers. Ó 2010 Published by Elsevier Ltd.
Keywords: p.G2019S Common founder Family studies Haplotype analysis
1. Introduction The LRRK2 p.G2019S mutation is the commonest known form of genetically-determined PD [1e3]. The majority of patients with p.G2019S parkinsonism have clinical features indistinguishable from sporadic PD, with asymmetric presentation, predominant resting tremor, bradykinesia, rigidity and a good response to dopaminergic therapy. The non-motor autonomic, psychiatric, and cognitive symptoms are usually reported to be mild [4,5], though not in all cases [6]. The most common neuropathology is Lewy body disease, although pleomorphic pathology has been described [7e9]. The frequency of the p.G2019S substitution varies, being highest in North African Arabs and Ashkenazi Jews [10,11], but is rare in Asia [12]. Across Europe the frequency of p.G2019S parkinsonism has not been rigorously evaluated (estimated 1e4%) [13e17]. Three different haplotypes have been described in various ethnic groups, suggesting common founders with at least three different founding events [6,10,11,18e21]. Haplotype 1, the most common, is a 143 kb segment,
q The review of this paper was entirely handled by an Associate Editor, Vincenzo Bonifati. * Corresponding author. Department of Neuroscience, Norwegian University of Science and Technology, Edvard Griegs gt. 8, 7006 Trondheim, Norway. Tel.: þ47 72575793; fax: þ47 72575657. E-mail address: [email protected] (K.K. Johansen). 1353-8020/$ e see front matter Ó 2010 Published by Elsevier Ltd. doi:10.1016/j.parkreldis.2010.05.005
found in North African Arabs, Ashkenazi Jews and American Europeans [19]. Several groups have tried to identify the common founder in these populations [19,22e24]. Haplotypes 2 and 3 are distinct and rarer. Type 2 has been reported in cases from Western Europe, and type 3 was described in a Japanese population [20]. A considerable number of PD cases with the LRRK2 p.G2019S mutation have been found in central Norway [5]. A high community-based incidence of 3.1% in a relatively small geographical area suggested a common founder effect [5]. In this report we provide genealogic ancestry for these PD patients. 2. Patients and methods A total of 671 consecutive PD patients, all ethnic Norwegians, have been longitudinally followed from 1998 by a movement disorder specialist (JOA) at the outpatient clinic of the Department of Neurology, St Olav’s University Hospital, Trondheim, and two other clinics within 200 miles of Trondheim. The diagnosis of PD was consistent with probable PD according to the Gelb criteria [25]. First degree family members of all PD patients were invited to participate in the study, and up to 2004 when LRRK2-associated PD was discovered, 117 had agreed to take part. Once LRRK2-PD was identified, family members, including children and siblings of LRRK2affected families, were asked to participate (n ¼ 98). All participants signed informed consent for genetic study, approved by the local ethical review board, and the demographic data are presented in Table 1. Peripheral blood was drawn and screened for several pathogenic LRRK2 mutations (p.R1441C, p.R1441G, p.R1441H, p.Y1699C, p.G2019S and p.I2020T) in the first 435 PD patients, as described previously [5]. The remaining 236 PD patients and all family members were tested specifically for p.G2019S. Patients who tested positive
528
K.K. Johansen et al. / Parkinsonism and Related Disorders 16 (2010) 527e530
Table 1 Demographic data of study individuals. N Patients with PD Positive for p.G2019S Healthy family members Positive for p.G2019S
Sex (M/F)
Age
671 414/257 67.2 11.0 21 (16) 10/11 73.1 10.0 116/99 54.8 14.8 215a 44 30/14 52.0 14.4
AAO (years)
Duration
59.4 11.2 7.9 6.8 61.2 10.0 12.4 7.8 e e e e
Five affected PD carriers are deceased, so “age” and “duration of disease” is applicable in 16 cases but “age at disease onset (AAO)” in 21 cases. a 98 of these family members are from G2019S families.
were re-examined, using a standardized case-report form including extended family history and clinical evaluation. Nine patients from seven families and their 12 relatives have been described in an earlier study [5]. Genealogical studies were based on the self-report of family history from patients and family members, as well as additional data from the Norwegian National Registration Office, local parish registers and population censuses. Age-dependent penetrance was calculated by dividing the number of affected mutation carriers within each ten-year age-group by the total number of carriers. Haplotype analysis was performed in seven cases (cases 1, 2, 4, 8, 9, 12, 18) as described earlier [18].
3. Results A total of 65 individuals were heterozygous for LRRK2 p.G2019S, whereof 21 had PD and 44 were asymptomatic carriers. The demographic data are presented in Table 1. The penetrance in this study was 14% at age 40e49 and 50% at age 70e79 years. The 21 symptomatic carriers came from 10 distinct families living in small geographical areas along the coastline of central Norway. The north-south distance was about 500 km. Six of these families (H, D, C, J, F, G, Fig. 1), could be traced back 10 generations to a common Norwegian ancestor couple living between 1580 and 1650. Two families were associated with the same family-tree through intermarriage (E and I, Fig. 1), while two other families (A and B) could not be traced back to these ancestors, probably due to inadequate data. However, seven families including A and B were investigated by haplotype analysis, showing a shared region between markers D12S2514 to D12S1048 (Fig. 2). Five of the
intragenic SNPs identified by Zabetian et al. [19] were not examined for the Norwegian patients. The patients (n ¼ 21) had a wide range of disease onset (mean 61.2 10.0 years, range 43e77 years), but there was no apparent difference between the various family branches. There was no significant difference in age at disease onset between females and males (females: 59.4 10.5, males 63.3 9.7). However, from the data in Table 1 it is clear that of the total 40 male carriers of p.G2019S, only 10 had PD, while 11 of 25 female carriers had PD. Males therefore seemed to have a lower penetrance (25%) than females (44%). The clinical data are presented in Table 2. The phenotype of the patients was heterogeneous with various initial symptoms, though tremor was most frequently reported. One patient had an atypical presentation with bilateral dystonia in both lower extremities. The clinical features were as expected for PD, including both tremordominant and akinetic types, the former being more common in cases under age 60, while patients with later onset had a predominantly akinetic form. Asymmetry and a good levodopa response were seen in all cases. Autonomic dysfunction was not a major problem and cognitive impairment was observed in only one case after 20 years of disease. Development of motor fluctuations with dyskinesias was not distinguishable from sporadic PD. It was not possible to distinguish the genealogical branches based on clinical features. 4. Discussion Twenty-one PD patients from 10 different families living in small geographic areas in central Norway carried the LRRK2 p.G2019S mutation, corresponding to 3.1% of the total PD population in this region. This is probably a greater percentage than in the total Norwegian population. Six families were traced back to a common ancestor, two were associated by intermarriage, and the two remaining families have not yet been linked to the same pedigree. It is not certain (though likely) that the Norwegian haplotype is type 1 as described by Zabetian et al. [19] for Europeans, North African Arabs and Ashkenazi Jews (Fig. 2).
Fig. 1. Pedigree, presenting six kindreds traced back to a common founder couple, as well as two other families associated by intermarriage. (The youngest-affected generation is abridged to maintain confidentiality).
K.K. Johansen et al. / Parkinsonism and Related Disorders 16 (2010) 527e530
D12S2080 D12S2194 D12S2514 rs28903073 D12S2515 rs7966550 D12S2516 rs1427263 rs11176013 rs11564148 rs2404834 G2019S rs10784522 rs10878405 D12S2518 ss52051244 D12S2519 D12S2520 D12S2521 D12S1048
A 188 265 291 ND 224 T 254 A G A/T ND A ND ND 154 ND 132 260 359 214
B 188 265 291 ND 224 T 254 A G A/T ND A ND ND 154 ND 132 260 359 214
C 188 265 291 ND 224 T 254 A G A/T ND A ND ND 154 ND 132 260 327/359 214
D 188 265 291 ND 224 T 254 A G A/T ND A ND ND 154 ND 132 260 359 214
E 188 265 291 ND 224 T 254 A G A/T ND A ND ND 154 ND 132 257/260 359 214
F 188 265 291 ND 224 T 254 A G A/T ND A ND ND 154 ND 132 260 359 211/214
I 188 261 291 ND 224 T 254 A G A/T ND A ND ND 154 ND 132 260 359 214
Type 1. 180/188 257 291 A/G 224 T 254 A G/A A/T C (T) A T (G) A (G) 154 (170) A 132 260 359 214
529
Type 2. 188 249 291 G 216 T 254 A/C G/A A/T T (C) A G G 154 G (A) 138 248 323 211
Fig. 2. The figure presents the haplotype in seven branches from our study compared to haplotypes 1 and 2 reported by Zabetian et al. [19]. Haplotypes 1 and 2 can be differentiated by five intragenic SNPs (bold) and an extragenic microsatellite marker (D12S2519). D12S2515 is an unstable marker. The Norwegian samples were not analysed for the SNPs, though the extragenic microsatellite was the same as for haplotype 1.
Written sources confirm extensive international trade between Norway and European countries in the late Middle Ages [26]. Affected families in the present study originate along the coastline where archaeological studies have found substantial evidence for this [26]. Stockpiles of cranial fish bones dating from the early 15th century indicate the production of stockfish, which was an important Norwegian export product for centuries. Medieval pottery from Germany and the Netherlands, and lead artefacts from English clothes suggest imports from the same era, most probably through trade. We suggest that the p.G2019S mutation was imported to Norway, probably through a tradesman from Europe before the end of the 17th century. This study reported a penetrance of 50% at age 70e79 years which is probably an overestimation since probands have been included in the analysis. Clinical evaluation of separate genealogic branches in the present study indicates no major clinical differences either in disease onset, progression or history. It is not clear whether environmental factors explain the apparent difference in penetrance Table 2 Clinical data of the LRRK2-PD cases; (AAO: age at disease onset, H&Y: Hoehn and Yahr staging; d: died; F: female; M: male; NA: not available). ID Family Age/Sex AAO Initial sign
Tremor H&Y Dementia Surgery
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
0 þþ þþ þ þþ þþ NA þþ þþ þ þ þ þþ NA 0 þ þþ þþ 0 þþ þ
A B B C C C C D E E E F F F F G H I I I J
77/F 57/M d/M 78/M 79/M d/F d/F 90/F 56/F 74/F d/F 91/F 85/F d/F 65/M 69/M 69/M 81/F 71/M 85/F 80/M
53 43 63 58 75 77 43 60 43 57 60 66 60 75 64 64 60 62 61 70 70
Dystonia Tremor Tremor Tremor Tremor Tremor NA Tremor Tremor Tremor Tremor Bradykinesia Tremor NA Rigidity/brady Tremor Tremor Tremor Bradykinesia Bradykinesia Tremor
4 3e4 2 5 2 2 NA 4e5 3 3 2e3 4 3 NA 2 2 2 3e4 3 4 3
no no no yes no no NA no no mild no no no NA no no no no no mild mild
no yes no no no no no yes yes no no no yes no no no yes no no no no
of the mutation between males and females, which is at variance with the prevalence of PD in the general population. It could simply be an artefact caused by the low number of female participants. An extended pedigree such as that presented here, including asymptomatic mutation carriers, reinforces the possibility for mapping environmental and genetic penetrance modifiers in Parkinson’s disease. Acknowledgments This study was supported by grants from the Research Council of Norway (1031400) and Reberg’s Legacy. References [1] Di Fonzo A, Rohe CF, Ferreira J, Chien HF, Vacca L, Stocchi F, et al. A frequent LRRK2 gene mutation associated with autosomal dominant Parkinson’s disease. Lancet 2005;365:412e5. [2] Gilks WP, Abou-Sleiman PM, Gandhi S, Jain S, Singleton A, Lees AJ, et al. A common LRRK2 mutation in idiopathic Parkinson’s disease. Lancet 2005;365:415e6. [3] Nichols WC, Pankratz N, Hernandez D, Paisan-Ruiz C, Jain S, Halter CA, et al. Genetic screening for a single common LRRK2 mutation in familial Parkinson’s disease. Lancet 2005;365:410e2. [4] Healy DG, Falchi M, O’Sullivan SS, Bonifati V, Durr A, Bressman S, et al. Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson’s disease: a case-control study. Lancet Neurol 2008;7:583e90. [5] Aasly JO, Toft M, Fernandez-Mata I, Kachergus J, Hulihan M, White LR, et al. Clinical features of LRRK2-associated Parkinson’s disease in central Norway. Ann Neurol 2005;57:762e5. [6] Goldwurm S, Zini M, Di Fonzo A, De Gaspari D, Siri C, Simons EJ, et al. LRRK2 G2019S mutation and Parkinson’s disease: a clinical, neuropsychological and neuropsychiatric study in a large Italian sample. Parkinsonism Relat Disord 2006;12:410e9. [7] Ross OA, Toft M, Whittle AJ, Johnson JL, Papapetropoulos S, Mash DC, et al. Lrrk2 and Lewy body disease. Ann Neurol 2006;59:388e93. [8] Giasson BI, Covy JP, Bonini NM, Hurtig HI, Farrer MJ, Trojanowski JQ, et al. Biochemical and pathological characterization of Lrrk2. Ann Neurol 2006;59:315e22. [9] Rajput A, Dickson DW, Robinson CA, Ross OA, Dachsel JC, Lincoln SJ, et al. Parkinsonism, Lrrk2 G2019S, and tau neuropathology. Neurology 2006;67:1506e8. [10] Lesage S, Durr A, Tazir M, Lohmann E, Leutenegger AL, Janin S, et al. LRRK2 G2019S as a cause of Parkinson’s disease in north African Arabs. N Engl J Med 2006;354:422e3. [11] Ozelius LJ, Senthil G, Saunders-Pullman R, Ohmann E, Deligtisch A, Tagliati M, et al. LRRK2 G2019S as a cause of Parkinson’s disease in Ashkenazi Jews. N Engl J Med 2006;354:424e5. [12] Tan EK, Shen H, Tan LC, Farrer M, Yew K, Chua E, et al. The G2019S LRRK2 mutation is uncommon in an Asian cohort of Parkinson’s disease patients. Neurosci Lett 2005;384:327e9.
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[13] Funalot B, Nichols WC, Perez-Tur J, Mercier G, Lucotte G. Genetic screening for two LRRK2 mutations in French patients with idiopathic Parkinson’s disease. Genet Test 2006;10:290e3. [14] Gaig C, Ezquerra M, Marti MJ, Munoz E, Valldeoriola F, Tolosa E. LRRK2 mutations in Spanish patients with Parkinson disease: frequency, clinical features, and incomplete penetrance. Arch Neurol 2006;63:377e82. [15] Lesage S, Janin S, Lohmann E, Leutenegger AL, Leclere L, Viallet F, et al. LRRK2 exon 41 mutations in sporadic Parkinson disease in Europeans. Arch Neurol 2007;64:425e30. [16] Marongiu R, Ghezzi D, Ialongo T, Soleti F, Elia A, Cavone S, et al. Frequency and phenotypes of LRRK2 G2019S mutation in Italian patients with Parkinson’s disease. Mov Disord 2006;21:1232e5. [17] Papapetropoulos S, Adi N, Shehadeh L, Bishopric N, Singer C, Argyriou AA, et al. Is the G2019S LRRK2 mutation common in all southern European populations? J Clin Neurosci 2008;15:1027e30. [18] Kachergus J, Mata IF, Hulihan M, Taylor JP, Lincoln S, Aasly J, 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;76:672e80. [19] Zabetian CP, Hutter CM, Yearout D, Lopez AN, Factor SA, Griffith A, et al. LRRK2 G2019S in families with Parkinson disease who originated from Europe and
[20]
[21]
[22]
[23] [24]
[25] [26]
the Middle East: evidence of two distinct founding events beginning two millennia ago. Am J Hum Genet 2006;79:752e8. Zabetian CP, Morino H, Ujike H, Yamamoto M, Oda M, Maruyama H, et al. Identification and haplotype analysis of LRRK2 G2019S in Japanese patients with Parkinson disease. Neurology 2006;67:697e9. Lesage S, Leutenegger AL, Ibanez P, Janin S, Lohmann E, Durr A, 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;77:330e2. Warren L, Gibson R, Ishihara L, Elango R, Xue Z, Akkari A, et al. A founding LRRK2 haplotype shared by Tunisian, US, European and Middle Eastern families with Parkinson’s disease. Parkinsonism Relat Disord 2008;14:77e80. Benamer HT. The ancestry of LRRK2 Gly2019Ser parkinsonism. Lancet Neurol 2008;7:769e70. author reply 770e771. Bar-Shira A, Hutter CM, Giladi N, Zabetian CP, Orr-Urtreger A. Ashkenazi Parkinson’s disease patients with the LRRK2 G2019S mutation share a common founder dating from the second to fifth centuries. Neurogenetics 2009;10:355e8. Gelb DJ, Oliver E, Gilman S. Diagnostic criteria for Parkinson disease. Arch Neurol 1999;56:33e9. Berglund B. Alstahaug på Helgeland 1000-1750. Trondheim: Tapir Academic Press; 2007.
Contents lists available at ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Genealogical studies in LRRK2-associated Parkinson’s disease in central Norwayq Krisztina K. Johansen a, b, *, Kåre Hasselberg a, Linda R. White a, b, Matthew J. Farrer c, Jan O. Aasly a, b a
Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway Department of Neurology, St Olav’s University Hospital, Trondheim, Norway c Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL, USA b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 20 January 2010 Received in revised form 19 May 2010 Accepted 26 May 2010
The most common mutation related to Parkinson’s disease (PD) is the p.G2019S mutation in the LRRK2 gene. Global population frequencies and crude estimates of haplotype conservation suggest most carriers are related. A total of 671 Norwegian PD patients and 215 of their family members were screened for the LRRK2 p.G2019S mutation. Twenty-one PD cases and 44 family members were positive for the mutation and all could be traced back to 10 different families. A genealogical study employed data from the Norwegian National Family Record Centre, local parish registers and population censuses. A common ancestor couple (living between 1580 and 1650) was found in six families, and two other families were associated by intermarriage. The remaining two families could not be traced back to either of these ancestors, though chromosome 12q12 haplotype analysis showed p.G2019S carriers shared alleles for 15 markers in the LRRK2 region. The study provides support for a common ancestor in Norwegian families with LRRK2 p.G2019S parkinsonism. The mutation was probably introduced to Norway through tradesmen from Europe. The extended pedigree that now links modern day carriers may help in mapping penetrance modifiers. Ó 2010 Published by Elsevier Ltd.
Keywords: p.G2019S Common founder Family studies Haplotype analysis
1. Introduction The LRRK2 p.G2019S mutation is the commonest known form of genetically-determined PD [1e3]. The majority of patients with p.G2019S parkinsonism have clinical features indistinguishable from sporadic PD, with asymmetric presentation, predominant resting tremor, bradykinesia, rigidity and a good response to dopaminergic therapy. The non-motor autonomic, psychiatric, and cognitive symptoms are usually reported to be mild [4,5], though not in all cases [6]. The most common neuropathology is Lewy body disease, although pleomorphic pathology has been described [7e9]. The frequency of the p.G2019S substitution varies, being highest in North African Arabs and Ashkenazi Jews [10,11], but is rare in Asia [12]. Across Europe the frequency of p.G2019S parkinsonism has not been rigorously evaluated (estimated 1e4%) [13e17]. Three different haplotypes have been described in various ethnic groups, suggesting common founders with at least three different founding events [6,10,11,18e21]. Haplotype 1, the most common, is a 143 kb segment,
q The review of this paper was entirely handled by an Associate Editor, Vincenzo Bonifati. * Corresponding author. Department of Neuroscience, Norwegian University of Science and Technology, Edvard Griegs gt. 8, 7006 Trondheim, Norway. Tel.: þ47 72575793; fax: þ47 72575657. E-mail address: [email protected] (K.K. Johansen). 1353-8020/$ e see front matter Ó 2010 Published by Elsevier Ltd. doi:10.1016/j.parkreldis.2010.05.005
found in North African Arabs, Ashkenazi Jews and American Europeans [19]. Several groups have tried to identify the common founder in these populations [19,22e24]. Haplotypes 2 and 3 are distinct and rarer. Type 2 has been reported in cases from Western Europe, and type 3 was described in a Japanese population [20]. A considerable number of PD cases with the LRRK2 p.G2019S mutation have been found in central Norway [5]. A high community-based incidence of 3.1% in a relatively small geographical area suggested a common founder effect [5]. In this report we provide genealogic ancestry for these PD patients. 2. Patients and methods A total of 671 consecutive PD patients, all ethnic Norwegians, have been longitudinally followed from 1998 by a movement disorder specialist (JOA) at the outpatient clinic of the Department of Neurology, St Olav’s University Hospital, Trondheim, and two other clinics within 200 miles of Trondheim. The diagnosis of PD was consistent with probable PD according to the Gelb criteria [25]. First degree family members of all PD patients were invited to participate in the study, and up to 2004 when LRRK2-associated PD was discovered, 117 had agreed to take part. Once LRRK2-PD was identified, family members, including children and siblings of LRRK2affected families, were asked to participate (n ¼ 98). All participants signed informed consent for genetic study, approved by the local ethical review board, and the demographic data are presented in Table 1. Peripheral blood was drawn and screened for several pathogenic LRRK2 mutations (p.R1441C, p.R1441G, p.R1441H, p.Y1699C, p.G2019S and p.I2020T) in the first 435 PD patients, as described previously [5]. The remaining 236 PD patients and all family members were tested specifically for p.G2019S. Patients who tested positive
528
K.K. Johansen et al. / Parkinsonism and Related Disorders 16 (2010) 527e530
Table 1 Demographic data of study individuals. N Patients with PD Positive for p.G2019S Healthy family members Positive for p.G2019S
Sex (M/F)
Age
671 414/257 67.2 11.0 21 (16) 10/11 73.1 10.0 116/99 54.8 14.8 215a 44 30/14 52.0 14.4
AAO (years)
Duration
59.4 11.2 7.9 6.8 61.2 10.0 12.4 7.8 e e e e
Five affected PD carriers are deceased, so “age” and “duration of disease” is applicable in 16 cases but “age at disease onset (AAO)” in 21 cases. a 98 of these family members are from G2019S families.
were re-examined, using a standardized case-report form including extended family history and clinical evaluation. Nine patients from seven families and their 12 relatives have been described in an earlier study [5]. Genealogical studies were based on the self-report of family history from patients and family members, as well as additional data from the Norwegian National Registration Office, local parish registers and population censuses. Age-dependent penetrance was calculated by dividing the number of affected mutation carriers within each ten-year age-group by the total number of carriers. Haplotype analysis was performed in seven cases (cases 1, 2, 4, 8, 9, 12, 18) as described earlier [18].
3. Results A total of 65 individuals were heterozygous for LRRK2 p.G2019S, whereof 21 had PD and 44 were asymptomatic carriers. The demographic data are presented in Table 1. The penetrance in this study was 14% at age 40e49 and 50% at age 70e79 years. The 21 symptomatic carriers came from 10 distinct families living in small geographical areas along the coastline of central Norway. The north-south distance was about 500 km. Six of these families (H, D, C, J, F, G, Fig. 1), could be traced back 10 generations to a common Norwegian ancestor couple living between 1580 and 1650. Two families were associated with the same family-tree through intermarriage (E and I, Fig. 1), while two other families (A and B) could not be traced back to these ancestors, probably due to inadequate data. However, seven families including A and B were investigated by haplotype analysis, showing a shared region between markers D12S2514 to D12S1048 (Fig. 2). Five of the
intragenic SNPs identified by Zabetian et al. [19] were not examined for the Norwegian patients. The patients (n ¼ 21) had a wide range of disease onset (mean 61.2 10.0 years, range 43e77 years), but there was no apparent difference between the various family branches. There was no significant difference in age at disease onset between females and males (females: 59.4 10.5, males 63.3 9.7). However, from the data in Table 1 it is clear that of the total 40 male carriers of p.G2019S, only 10 had PD, while 11 of 25 female carriers had PD. Males therefore seemed to have a lower penetrance (25%) than females (44%). The clinical data are presented in Table 2. The phenotype of the patients was heterogeneous with various initial symptoms, though tremor was most frequently reported. One patient had an atypical presentation with bilateral dystonia in both lower extremities. The clinical features were as expected for PD, including both tremordominant and akinetic types, the former being more common in cases under age 60, while patients with later onset had a predominantly akinetic form. Asymmetry and a good levodopa response were seen in all cases. Autonomic dysfunction was not a major problem and cognitive impairment was observed in only one case after 20 years of disease. Development of motor fluctuations with dyskinesias was not distinguishable from sporadic PD. It was not possible to distinguish the genealogical branches based on clinical features. 4. Discussion Twenty-one PD patients from 10 different families living in small geographic areas in central Norway carried the LRRK2 p.G2019S mutation, corresponding to 3.1% of the total PD population in this region. This is probably a greater percentage than in the total Norwegian population. Six families were traced back to a common ancestor, two were associated by intermarriage, and the two remaining families have not yet been linked to the same pedigree. It is not certain (though likely) that the Norwegian haplotype is type 1 as described by Zabetian et al. [19] for Europeans, North African Arabs and Ashkenazi Jews (Fig. 2).
Fig. 1. Pedigree, presenting six kindreds traced back to a common founder couple, as well as two other families associated by intermarriage. (The youngest-affected generation is abridged to maintain confidentiality).
K.K. Johansen et al. / Parkinsonism and Related Disorders 16 (2010) 527e530
D12S2080 D12S2194 D12S2514 rs28903073 D12S2515 rs7966550 D12S2516 rs1427263 rs11176013 rs11564148 rs2404834 G2019S rs10784522 rs10878405 D12S2518 ss52051244 D12S2519 D12S2520 D12S2521 D12S1048
A 188 265 291 ND 224 T 254 A G A/T ND A ND ND 154 ND 132 260 359 214
B 188 265 291 ND 224 T 254 A G A/T ND A ND ND 154 ND 132 260 359 214
C 188 265 291 ND 224 T 254 A G A/T ND A ND ND 154 ND 132 260 327/359 214
D 188 265 291 ND 224 T 254 A G A/T ND A ND ND 154 ND 132 260 359 214
E 188 265 291 ND 224 T 254 A G A/T ND A ND ND 154 ND 132 257/260 359 214
F 188 265 291 ND 224 T 254 A G A/T ND A ND ND 154 ND 132 260 359 211/214
I 188 261 291 ND 224 T 254 A G A/T ND A ND ND 154 ND 132 260 359 214
Type 1. 180/188 257 291 A/G 224 T 254 A G/A A/T C (T) A T (G) A (G) 154 (170) A 132 260 359 214
529
Type 2. 188 249 291 G 216 T 254 A/C G/A A/T T (C) A G G 154 G (A) 138 248 323 211
Fig. 2. The figure presents the haplotype in seven branches from our study compared to haplotypes 1 and 2 reported by Zabetian et al. [19]. Haplotypes 1 and 2 can be differentiated by five intragenic SNPs (bold) and an extragenic microsatellite marker (D12S2519). D12S2515 is an unstable marker. The Norwegian samples were not analysed for the SNPs, though the extragenic microsatellite was the same as for haplotype 1.
Written sources confirm extensive international trade between Norway and European countries in the late Middle Ages [26]. Affected families in the present study originate along the coastline where archaeological studies have found substantial evidence for this [26]. Stockpiles of cranial fish bones dating from the early 15th century indicate the production of stockfish, which was an important Norwegian export product for centuries. Medieval pottery from Germany and the Netherlands, and lead artefacts from English clothes suggest imports from the same era, most probably through trade. We suggest that the p.G2019S mutation was imported to Norway, probably through a tradesman from Europe before the end of the 17th century. This study reported a penetrance of 50% at age 70e79 years which is probably an overestimation since probands have been included in the analysis. Clinical evaluation of separate genealogic branches in the present study indicates no major clinical differences either in disease onset, progression or history. It is not clear whether environmental factors explain the apparent difference in penetrance Table 2 Clinical data of the LRRK2-PD cases; (AAO: age at disease onset, H&Y: Hoehn and Yahr staging; d: died; F: female; M: male; NA: not available). ID Family Age/Sex AAO Initial sign
Tremor H&Y Dementia Surgery
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
0 þþ þþ þ þþ þþ NA þþ þþ þ þ þ þþ NA 0 þ þþ þþ 0 þþ þ
A B B C C C C D E E E F F F F G H I I I J
77/F 57/M d/M 78/M 79/M d/F d/F 90/F 56/F 74/F d/F 91/F 85/F d/F 65/M 69/M 69/M 81/F 71/M 85/F 80/M
53 43 63 58 75 77 43 60 43 57 60 66 60 75 64 64 60 62 61 70 70
Dystonia Tremor Tremor Tremor Tremor Tremor NA Tremor Tremor Tremor Tremor Bradykinesia Tremor NA Rigidity/brady Tremor Tremor Tremor Bradykinesia Bradykinesia Tremor
4 3e4 2 5 2 2 NA 4e5 3 3 2e3 4 3 NA 2 2 2 3e4 3 4 3
no no no yes no no NA no no mild no no no NA no no no no no mild mild
no yes no no no no no yes yes no no no yes no no no yes no no no no
of the mutation between males and females, which is at variance with the prevalence of PD in the general population. It could simply be an artefact caused by the low number of female participants. An extended pedigree such as that presented here, including asymptomatic mutation carriers, reinforces the possibility for mapping environmental and genetic penetrance modifiers in Parkinson’s disease. Acknowledgments This study was supported by grants from the Research Council of Norway (1031400) and Reberg’s Legacy. References [1] Di Fonzo A, Rohe CF, Ferreira J, Chien HF, Vacca L, Stocchi F, et al. A frequent LRRK2 gene mutation associated with autosomal dominant Parkinson’s disease. Lancet 2005;365:412e5. [2] Gilks WP, Abou-Sleiman PM, Gandhi S, Jain S, Singleton A, Lees AJ, et al. A common LRRK2 mutation in idiopathic Parkinson’s disease. Lancet 2005;365:415e6. [3] Nichols WC, Pankratz N, Hernandez D, Paisan-Ruiz C, Jain S, Halter CA, et al. Genetic screening for a single common LRRK2 mutation in familial Parkinson’s disease. Lancet 2005;365:410e2. [4] Healy DG, Falchi M, O’Sullivan SS, Bonifati V, Durr A, Bressman S, et al. Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson’s disease: a case-control study. Lancet Neurol 2008;7:583e90. [5] Aasly JO, Toft M, Fernandez-Mata I, Kachergus J, Hulihan M, White LR, et al. Clinical features of LRRK2-associated Parkinson’s disease in central Norway. Ann Neurol 2005;57:762e5. [6] Goldwurm S, Zini M, Di Fonzo A, De Gaspari D, Siri C, Simons EJ, et al. LRRK2 G2019S mutation and Parkinson’s disease: a clinical, neuropsychological and neuropsychiatric study in a large Italian sample. Parkinsonism Relat Disord 2006;12:410e9. [7] Ross OA, Toft M, Whittle AJ, Johnson JL, Papapetropoulos S, Mash DC, et al. Lrrk2 and Lewy body disease. Ann Neurol 2006;59:388e93. [8] Giasson BI, Covy JP, Bonini NM, Hurtig HI, Farrer MJ, Trojanowski JQ, et al. Biochemical and pathological characterization of Lrrk2. Ann Neurol 2006;59:315e22. [9] Rajput A, Dickson DW, Robinson CA, Ross OA, Dachsel JC, Lincoln SJ, et al. Parkinsonism, Lrrk2 G2019S, and tau neuropathology. Neurology 2006;67:1506e8. [10] Lesage S, Durr A, Tazir M, Lohmann E, Leutenegger AL, Janin S, et al. LRRK2 G2019S as a cause of Parkinson’s disease in north African Arabs. N Engl J Med 2006;354:422e3. [11] Ozelius LJ, Senthil G, Saunders-Pullman R, Ohmann E, Deligtisch A, Tagliati M, et al. LRRK2 G2019S as a cause of Parkinson’s disease in Ashkenazi Jews. N Engl J Med 2006;354:424e5. [12] Tan EK, Shen H, Tan LC, Farrer M, Yew K, Chua E, et al. The G2019S LRRK2 mutation is uncommon in an Asian cohort of Parkinson’s disease patients. Neurosci Lett 2005;384:327e9.
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K.K. Johansen et al. / Parkinsonism and Related Disorders 16 (2010) 527e530
[13] Funalot B, Nichols WC, Perez-Tur J, Mercier G, Lucotte G. Genetic screening for two LRRK2 mutations in French patients with idiopathic Parkinson’s disease. Genet Test 2006;10:290e3. [14] Gaig C, Ezquerra M, Marti MJ, Munoz E, Valldeoriola F, Tolosa E. LRRK2 mutations in Spanish patients with Parkinson disease: frequency, clinical features, and incomplete penetrance. Arch Neurol 2006;63:377e82. [15] Lesage S, Janin S, Lohmann E, Leutenegger AL, Leclere L, Viallet F, et al. LRRK2 exon 41 mutations in sporadic Parkinson disease in Europeans. Arch Neurol 2007;64:425e30. [16] Marongiu R, Ghezzi D, Ialongo T, Soleti F, Elia A, Cavone S, et al. Frequency and phenotypes of LRRK2 G2019S mutation in Italian patients with Parkinson’s disease. Mov Disord 2006;21:1232e5. [17] Papapetropoulos S, Adi N, Shehadeh L, Bishopric N, Singer C, Argyriou AA, et al. Is the G2019S LRRK2 mutation common in all southern European populations? J Clin Neurosci 2008;15:1027e30. [18] Kachergus J, Mata IF, Hulihan M, Taylor JP, Lincoln S, Aasly J, 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;76:672e80. [19] Zabetian CP, Hutter CM, Yearout D, Lopez AN, Factor SA, Griffith A, et al. LRRK2 G2019S in families with Parkinson disease who originated from Europe and
[20]
[21]
[22]
[23] [24]
[25] [26]
the Middle East: evidence of two distinct founding events beginning two millennia ago. Am J Hum Genet 2006;79:752e8. Zabetian CP, Morino H, Ujike H, Yamamoto M, Oda M, Maruyama H, et al. Identification and haplotype analysis of LRRK2 G2019S in Japanese patients with Parkinson disease. Neurology 2006;67:697e9. Lesage S, Leutenegger AL, Ibanez P, Janin S, Lohmann E, Durr A, 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;77:330e2. Warren L, Gibson R, Ishihara L, Elango R, Xue Z, Akkari A, et al. A founding LRRK2 haplotype shared by Tunisian, US, European and Middle Eastern families with Parkinson’s disease. Parkinsonism Relat Disord 2008;14:77e80. Benamer HT. The ancestry of LRRK2 Gly2019Ser parkinsonism. Lancet Neurol 2008;7:769e70. author reply 770e771. Bar-Shira A, Hutter CM, Giladi N, Zabetian CP, Orr-Urtreger A. Ashkenazi Parkinson’s disease patients with the LRRK2 G2019S mutation share a common founder dating from the second to fifth centuries. Neurogenetics 2009;10:355e8. Gelb DJ, Oliver E, Gilman S. Diagnostic criteria for Parkinson disease. Arch Neurol 1999;56:33e9. Berglund B. Alstahaug på Helgeland 1000-1750. Trondheim: Tapir Academic Press; 2007.