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Essential tremor and the common LRRK2 G2385R variant
Parkinsonism and Related Disorders 14 (2008) 569e571 www.elsevier.com/locate/parkreldis
Short communication
Essential tremor and the common LRRK2 G2385R variant Eng-King Tan a,d,e,*, Jasinda Lee a, Hui-Qin Lim a, Yih Yuen c, Yi Zhao b a Department of Neurology, Singapore General Hospital, Singapore Department of Clinical Research, Singapore General Hospital, Singapore c Department of Health Screening, Singapore General Hospital, Singapore d National Neuroscience Institute, Singapore General Hospital, Singapore e SingHealth Research, Singapore General Hospital, Singapore
b
Received 6 November 2007; received in revised form 17 December 2007; accepted 21 December 2007
Abstract Co-existence of Parkinson’s disease (PD) and essential tremor (ET) suggests a possible overlapping pathophysiology between these two conditions. PD patients with leucine-rich repeat kinase-2 (LRRK2) mutations have been reported to present initially with ET. A common LRRK2 Gly2385Arg variant has been widely shown to be associated with a two fold increased risk of PD in various Asian populations. We analyzed the Gly2385Arg variant in a cohort of ET and controls. A total of 419 subjects comprising of 172 ET and 247 controls were included. The mean age, age at onset of ET, and age of controls were 52.1 19.6, 41.8 21.6, and 62.2 11.6 years, comprising of 53.0% and 54.3% men, respectively. The Gly2385Arg variant was demonstrated in 5/172 (2.9%) ET patients compared to 10/247 (4.0%) of controls (odds ratio ¼ 0.72, 95% CI 0.24, 2.1, p ¼ 0.6). All the Gly2385Arg carriers were heterozygotes. The LRRK2 Gly2385Arg variant is not a significant risk factor for ET in our population. Ó 2008 Elsevier Ltd. All rights reserved. Keywords: Essential tremor; LRRK2; Variant; Polymorphism
Numerous genetic mutations have been associated with Parkinson’s disease (PD) [1]. A common leucine-rich repeat kinase-2 (LRRK2 and PARK8) variant (Gly2385Arg) has recently been found to be a common genetic risk factor amongst ethnic Asians [2e7]. Post-mortem studies have revealed varying pathologies such as dementia with Lewy body, tauopathy, and supranuclear palsy in Parkinson’s disease (PD) patients with LRRK2 mutations [8], suggesting that LRRK2 may be associated with a spectrum of neurodegenerative diseases. An LRRK2 mutation has been described in a PD patient who presented with a typical ET phenotype [9]. Autopsy findings have found that ET patients with focal non-nigral Lewy bodies [10] and genetic polymorphism of alpha synuclein promoter have been associated with an increased risk of ET and PD [11]. * Corresponding author. Department of Neurology, Singapore General Hospital, National Neuroscience Institute, Outram Road, Singapore 169608, Singapore. Tel.: þ65 6326 5003; fax: þ65 6220 3321. E-mail address: [email protected] (E.-K. Tan). 1353-8020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.parkreldis.2007.12.003
Furthermore, numerous clinical and functional imaging studies [12e19] have hypothesized that ET and PD may share common pathophysiology. These observations, together with the co-existence of PD and ET in some patients suggest that the Gly2385Arg variant could be a biologically plausible risk variant in ET among Asians. We performed the first case control study to investigate whether the LRRK2 Gly2385Arg variant is associated with risk of ET in our Asian population. 1. Methods Consecutive subjects diagnosed with classic ET by a movement disorders neurologist based on the Consensus Criteria of the Movement Disorder Society on Tremor (1998) [20] were recruited from a tertiary institution in Singapore. Healthy controls without ET and examined by the authors were included. Some controls had participated in our previous genetic study in PD [2]. Familial ET was defined as ET with at least one affected first degree relative. All study subjects gave written informed consent. The institutional ethics committee approved the study.
E.-K. Tan et al. / Parkinsonism and Related Disorders 14 (2008) 569e571
570
2. Genetic analysis Allelic discrimination using the 50 nuclease activity assay was adapted to detect the Gly2385Arg variant. Primers and probes were designed using the Primer Express 1.5 software. The amplification reactions were carried out in an ABI Prism 7700 Sequence Detection System (Applied Biosystems) with two initial steps (50 C for 2 min, followed by 95 C for 10 min) and 40 cycles of a two step PCR (95 C for 15 s and 60 C for 1 min). After PCR, the allelic specific fluorescence was measured on the ABI Prism 7700 Sequence Detection System (Applied Biosystems) using the Sequence Detection Systems 1.7 software for allelic discrimination. Each run was carried out with Gly2385Arg positive and negative samples. The Gly2385Arg variant was also confirmed on sequence analysis for representative samples. Sequencing in the forward and reverse directions was undertaken according to the manufacturers’ instructions (BigDye, Applied Biosystems, Warrington, UK). Electrophoreses of the products were done using the ABI 3100 automated DNA sequencer (Applied Biosystems). 3. Statistical analysis The demographic and genotype data were collected and tabulated. Categorical and numerical variables were analyzed with the chi-square and student’s t test. Statistical significance was defined at p < 0.05. 4. Results We included a total of 419 subjects comprising of 172 ET and 247 controls. The mean age, age at onset of ET, and age of controls were 52.1 19.6, 41.8 21.6, and 62.2 11.6 years, comprising of 53.0% and 54.3% men, respectively. The Gly2385Arg variant was demonstrated in 5/172 (2.9%) ET patients compared to 10/247 (4.0%) of controls (odds ratio ¼ 0.72, 95% CI 0.24, 2.1, p ¼ 0.6). All the Gly2385Arg carriers were heterozygotes (Table 1). We could not perform a multivariate analysis as the number of the G2385R genotypes was low. Among the carriers, about two thirds of the ET cases reported a positive family history while none of the controls had tremor or reported a positive family history. 5. Discussion The LRRK2 Gly2385Arg variant appears pro-apoptotic, and may lead to a decrease in kinase activity in vitro [2]. The Table 1 Frequency of the LRRK2 G2385R variant in ET and controls Genotype
Controls
ET
Total
Wild-type Heterozygote Homozygote
237 (96.0%) 10 (4.0%) 0
167 (97.1%) 5 (2.9%) 0
404 (96.4%) 15 (3.6%) 0 (0%)
Total
247
172
419
variant is located at the WD40 domain of the LRRK2 protein and it is possible that the arginine substitution could modulate its interaction with other proteins. Even though studies have shown that the variant is a risk factor in several Asian PD populations, our study did not demonstrate an association between the variant and ET (2.9% in ET vs 4.0% in controls). The controls in this study were on average 10 years older than ET, and 20 years older compared to the age of onset of ET. It could be argued that a larger sample size may be needed to detect small differences between cases and controls. However, there was not a trend towards a higher prevalence of the variant in ET in our study, suggesting that this variant is highly unlikely to be a risk factor for ET. Previous studies have demonstrated an 8e10% prevalence of the variant in PD and 4e6% in controls [2e7]. To date the causative ET gene remains to be identified, though linkage analysis studies in Icelandic and North American families have identified three genetic loci where the causative gene could be located; chromosome 3q13 (ETM1); 2p22p25 (ETM2) and 6p23 [21e24]. A variant in the HS1-BP3 gene and the Ser9Gly variant of the dopamine D3 receptor (DRD3) gene have separately been shown to associate with ET in American and/or French populations though these observations could not be consistently replicated [22e28]. The varied phenotypic and genetic heterogeneity of ET adds to the inherent methodological problems of genetic association studies [7,29] in this population. In conclusion, our study suggests that the common Gly2385Arg Asian variant is unlikely to play a major role in our ET population. However, the possible association of other genetic variants of LRRK2 with ET could not be excluded. Acknowledgement We thank the National Medical Research Council and Biomedical Research Council for their support. References [1] Tan EK, Skipper LM. Pathogenic mutations in Parkinson disease. Hum Mutat 2007;28(7):641e53. [2] Di Fonzo A, Wu-Chou YH, Lu CS, van Doeselaar M, Simons EJ, Rohe´ CF, et al. A common missense variant in the LRRK2 gene, Gly2385Arg, associated with Parkinson’s disease risk in Taiwan. Neurogenetics 2006;7(3):133e8. [3] Tan EK, Zhao Y, Skipper L, Tan MG, Di Fonzo A, Sun L, et al. The LRRK2 Gly2385Arg variant is associated with Parkinson’s disease: genetic and functional evidence. Hum Genet 2007;120(6):857e63. [4] Fung HC, Chen CM, Hardy J, Singleton AB, Wu YR. A common genetic factor for Parkinson disease in ethnic Chinese population in Taiwan. BMC Neurol 2006;6(1):47. [5] Farrer MJ, Stone JT, Lin CH, Da¨chsel JC, Hulihan MM, Haugarvoll, et al. Lrrk2 G2385R is an ancestral risk factor for Parkinson’s disease in Asia. Parkinsonism Relat Disord 2007;13(2):89e92. [6] Funayama M, Li Y, Yoshino H, Yoshino H, Imamichi Y, Yamamoto M, et al. A variation in LRRK2 is associated with Parkinson’s disease in Asian population. Neuroreport 2007;18(3):273e5. [7] Tan EK. The role of common genetic risk variants in Parkinson disease. Clin Genet 2007;72(5):387e93.
E.-K. Tan et al. / Parkinsonism and Related Disorders 14 (2008) 569e571 [8] Zimprich A, Biskup S, Leitner P, Lichtner P, Farrer M, Lincoln S, et al. Mutations in LRRK2 cause autosomal-dominant Parkinsonism with pleomorphic pathology. Neuron 2004;44:601e60. [9] Skipper L, Shen H, Chua E, Bonnard C, Kolatkar P, Tan LC, et al. Analysis of LRRK2 functional domains in nondominant Parkinson disease. Neurology 2005;65(8):1319e21. [10] Louis ED, Honig LS, Vonsattel JP, Maraganore DM, Borden S, Moskowitz CB. Essential tremor associated with focal nonnigral Lewy bodies: a clinicopathologic study. Arch Neurol 2005;62(6):1004e7. [11] Tan EK, Matsuura T, Nagamitsu S, Khajavi M, Jankovic J, Ashizawa T. Polymorphism of NACP-Rep1 in Parkinson’s disease: an etiologic link with essential tremor? Neurology 2000;54(5):1195e8. [12] Geraghty JJ, Jankovic J, Zetusky WJ. Association between essential tremor and Parkinson’s disease. Ann Neurol 1985;17:329e33. [13] Rocca WA, Bower JH, Ahlskog JE, Elbaz A, Grossardt BR, McDonnell SK, et al. Increased risk of essential tremor in first-degree relatives of patients with Parkinson’s disease. Mov Disord 2007;22(11): 1607e14. [14] Louis ED, Frucht SJ. Prevalence of essential tremor in patients with Parkinson’s disease vs. Parkinson-plus syndromes. Mov Disord 2007;22(10):1402e7. [15] Jankovic J, Beach J, Schwartz K, Contant C. Tremor and longevity in relatives of patients with Parkinson’s disease, essential tremor, and control subjects. Neurology 1995;45(4):645e8. [16] Louis ED, Levy G, Mejia-Santana H, Cote L, Andrews H, Harris J, et al. Risk of action tremor in relatives of tremor-dominant and postural instability gait disorder PD. Neurology 2003;61(7):931e6. [17] Shahed J, Jankovic J. Exploring the relationship between essential tremor and Parkinson’s disease. Parkinsonism Relat Disord 2007; 13(2):67e76. [18] Lee MS, Kim YD, Im JH, Kim HJ, Rinne JO, Bhatia KP. 123I-IPT brain SPECT study in essential tremor and Parkinson’s disease. Neurology 1999;52:1422e6.
571
[19] Brooks DJ, Playford ED, Ibanez V, Sawle GV, Thompson PD, Findley LJ, et al. Isolated tremor and disruption of the nigrostriatal dopaminergic system: an 18F-dopa PET study. Neurology 1992;42(8):1554e60. [20] Deuschl G, Bain P, Brin M. Consensus statement of the Movement Disorder Society on tremor. Ad Hoc Scientific Committee. Mov Disord 1998;13(Suppl. 3):2e23. [21] Gulcher JR, Jonsson P, Kong A, Kristjansson K, Frigge ML, Karason A, et al. Mapping of a familial essential tremor gene, FET1, to chromosome 3q13. Nat Genet 1997;17(1):84e7. [22] Higgins JJ, Pho LT, Nee LE. A gene (ETM) for essential tremor maps to chromosome 2p22-p25. Mov Disord 1997;12(6):859e64. [23] Shatunov A, Sambuughin N, Jankovic J, Elble R, Lee HS, Singleton AB, et al. Genomewide scans in North American families reveal genetic linkage of essential tremor to a region on chromosome 6p23. Brain 2006; 129(Pt 9):2318e31. [24] Deng H, Le W, Jankovic J. Genetics of essential tremor. Brain 2007 Jun;130(Pt 6):1456e64. [25] Higgins JJ, Lombardi RQ, Pucilowska J, Jankovic J, Tan EK, Rooney JP. A variant in the HS1-BP3 gene is associated with familial essential tremor. Neurology 2005;64(3):417e21. [26] Shatunov A, Jankovic J, Elble R, Sambuughin N, Singleton A, Hallett M, et al. A variant in the HS1-BP3 gene is associated with familial essential tremor. Neurology 2005;65(12):1995. [27] Jeanneteau F, Funalot B, Jankovic J, Deng H, Lagarde JP, Lucotte G, et al. A functional variant of the dopamine D3 receptor is associated with risk and age-at-onset of essential tremor. Proc Natl Acad Sci U S A 2006;103(28):10753e8. [28] Tan EK, Prakash KM, Fook-Chong S, Yih Y, Chua E, Lum SY, et al. DRD3 variant and risk of essential tremor. Neurology 2007;68(10): 790e1. [29] Tan EK, Khajavi M, Thornby JI, Nagamitsu S, Jankovic J, Ashizawa T. Variability and validity of polymorphism association studies in Parkinson’s disease. Neurology 2000;55(4):533e8.
Short communication
Essential tremor and the common LRRK2 G2385R variant Eng-King Tan a,d,e,*, Jasinda Lee a, Hui-Qin Lim a, Yih Yuen c, Yi Zhao b a Department of Neurology, Singapore General Hospital, Singapore Department of Clinical Research, Singapore General Hospital, Singapore c Department of Health Screening, Singapore General Hospital, Singapore d National Neuroscience Institute, Singapore General Hospital, Singapore e SingHealth Research, Singapore General Hospital, Singapore
b
Received 6 November 2007; received in revised form 17 December 2007; accepted 21 December 2007
Abstract Co-existence of Parkinson’s disease (PD) and essential tremor (ET) suggests a possible overlapping pathophysiology between these two conditions. PD patients with leucine-rich repeat kinase-2 (LRRK2) mutations have been reported to present initially with ET. A common LRRK2 Gly2385Arg variant has been widely shown to be associated with a two fold increased risk of PD in various Asian populations. We analyzed the Gly2385Arg variant in a cohort of ET and controls. A total of 419 subjects comprising of 172 ET and 247 controls were included. The mean age, age at onset of ET, and age of controls were 52.1 19.6, 41.8 21.6, and 62.2 11.6 years, comprising of 53.0% and 54.3% men, respectively. The Gly2385Arg variant was demonstrated in 5/172 (2.9%) ET patients compared to 10/247 (4.0%) of controls (odds ratio ¼ 0.72, 95% CI 0.24, 2.1, p ¼ 0.6). All the Gly2385Arg carriers were heterozygotes. The LRRK2 Gly2385Arg variant is not a significant risk factor for ET in our population. Ó 2008 Elsevier Ltd. All rights reserved. Keywords: Essential tremor; LRRK2; Variant; Polymorphism
Numerous genetic mutations have been associated with Parkinson’s disease (PD) [1]. A common leucine-rich repeat kinase-2 (LRRK2 and PARK8) variant (Gly2385Arg) has recently been found to be a common genetic risk factor amongst ethnic Asians [2e7]. Post-mortem studies have revealed varying pathologies such as dementia with Lewy body, tauopathy, and supranuclear palsy in Parkinson’s disease (PD) patients with LRRK2 mutations [8], suggesting that LRRK2 may be associated with a spectrum of neurodegenerative diseases. An LRRK2 mutation has been described in a PD patient who presented with a typical ET phenotype [9]. Autopsy findings have found that ET patients with focal non-nigral Lewy bodies [10] and genetic polymorphism of alpha synuclein promoter have been associated with an increased risk of ET and PD [11]. * Corresponding author. Department of Neurology, Singapore General Hospital, National Neuroscience Institute, Outram Road, Singapore 169608, Singapore. Tel.: þ65 6326 5003; fax: þ65 6220 3321. E-mail address: [email protected] (E.-K. Tan). 1353-8020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.parkreldis.2007.12.003
Furthermore, numerous clinical and functional imaging studies [12e19] have hypothesized that ET and PD may share common pathophysiology. These observations, together with the co-existence of PD and ET in some patients suggest that the Gly2385Arg variant could be a biologically plausible risk variant in ET among Asians. We performed the first case control study to investigate whether the LRRK2 Gly2385Arg variant is associated with risk of ET in our Asian population. 1. Methods Consecutive subjects diagnosed with classic ET by a movement disorders neurologist based on the Consensus Criteria of the Movement Disorder Society on Tremor (1998) [20] were recruited from a tertiary institution in Singapore. Healthy controls without ET and examined by the authors were included. Some controls had participated in our previous genetic study in PD [2]. Familial ET was defined as ET with at least one affected first degree relative. All study subjects gave written informed consent. The institutional ethics committee approved the study.
E.-K. Tan et al. / Parkinsonism and Related Disorders 14 (2008) 569e571
570
2. Genetic analysis Allelic discrimination using the 50 nuclease activity assay was adapted to detect the Gly2385Arg variant. Primers and probes were designed using the Primer Express 1.5 software. The amplification reactions were carried out in an ABI Prism 7700 Sequence Detection System (Applied Biosystems) with two initial steps (50 C for 2 min, followed by 95 C for 10 min) and 40 cycles of a two step PCR (95 C for 15 s and 60 C for 1 min). After PCR, the allelic specific fluorescence was measured on the ABI Prism 7700 Sequence Detection System (Applied Biosystems) using the Sequence Detection Systems 1.7 software for allelic discrimination. Each run was carried out with Gly2385Arg positive and negative samples. The Gly2385Arg variant was also confirmed on sequence analysis for representative samples. Sequencing in the forward and reverse directions was undertaken according to the manufacturers’ instructions (BigDye, Applied Biosystems, Warrington, UK). Electrophoreses of the products were done using the ABI 3100 automated DNA sequencer (Applied Biosystems). 3. Statistical analysis The demographic and genotype data were collected and tabulated. Categorical and numerical variables were analyzed with the chi-square and student’s t test. Statistical significance was defined at p < 0.05. 4. Results We included a total of 419 subjects comprising of 172 ET and 247 controls. The mean age, age at onset of ET, and age of controls were 52.1 19.6, 41.8 21.6, and 62.2 11.6 years, comprising of 53.0% and 54.3% men, respectively. The Gly2385Arg variant was demonstrated in 5/172 (2.9%) ET patients compared to 10/247 (4.0%) of controls (odds ratio ¼ 0.72, 95% CI 0.24, 2.1, p ¼ 0.6). All the Gly2385Arg carriers were heterozygotes (Table 1). We could not perform a multivariate analysis as the number of the G2385R genotypes was low. Among the carriers, about two thirds of the ET cases reported a positive family history while none of the controls had tremor or reported a positive family history. 5. Discussion The LRRK2 Gly2385Arg variant appears pro-apoptotic, and may lead to a decrease in kinase activity in vitro [2]. The Table 1 Frequency of the LRRK2 G2385R variant in ET and controls Genotype
Controls
ET
Total
Wild-type Heterozygote Homozygote
237 (96.0%) 10 (4.0%) 0
167 (97.1%) 5 (2.9%) 0
404 (96.4%) 15 (3.6%) 0 (0%)
Total
247
172
419
variant is located at the WD40 domain of the LRRK2 protein and it is possible that the arginine substitution could modulate its interaction with other proteins. Even though studies have shown that the variant is a risk factor in several Asian PD populations, our study did not demonstrate an association between the variant and ET (2.9% in ET vs 4.0% in controls). The controls in this study were on average 10 years older than ET, and 20 years older compared to the age of onset of ET. It could be argued that a larger sample size may be needed to detect small differences between cases and controls. However, there was not a trend towards a higher prevalence of the variant in ET in our study, suggesting that this variant is highly unlikely to be a risk factor for ET. Previous studies have demonstrated an 8e10% prevalence of the variant in PD and 4e6% in controls [2e7]. To date the causative ET gene remains to be identified, though linkage analysis studies in Icelandic and North American families have identified three genetic loci where the causative gene could be located; chromosome 3q13 (ETM1); 2p22p25 (ETM2) and 6p23 [21e24]. A variant in the HS1-BP3 gene and the Ser9Gly variant of the dopamine D3 receptor (DRD3) gene have separately been shown to associate with ET in American and/or French populations though these observations could not be consistently replicated [22e28]. The varied phenotypic and genetic heterogeneity of ET adds to the inherent methodological problems of genetic association studies [7,29] in this population. In conclusion, our study suggests that the common Gly2385Arg Asian variant is unlikely to play a major role in our ET population. However, the possible association of other genetic variants of LRRK2 with ET could not be excluded. Acknowledgement We thank the National Medical Research Council and Biomedical Research Council for their support. References [1] Tan EK, Skipper LM. Pathogenic mutations in Parkinson disease. Hum Mutat 2007;28(7):641e53. [2] Di Fonzo A, Wu-Chou YH, Lu CS, van Doeselaar M, Simons EJ, Rohe´ CF, et al. A common missense variant in the LRRK2 gene, Gly2385Arg, associated with Parkinson’s disease risk in Taiwan. Neurogenetics 2006;7(3):133e8. [3] Tan EK, Zhao Y, Skipper L, Tan MG, Di Fonzo A, Sun L, et al. The LRRK2 Gly2385Arg variant is associated with Parkinson’s disease: genetic and functional evidence. Hum Genet 2007;120(6):857e63. [4] Fung HC, Chen CM, Hardy J, Singleton AB, Wu YR. A common genetic factor for Parkinson disease in ethnic Chinese population in Taiwan. BMC Neurol 2006;6(1):47. [5] Farrer MJ, Stone JT, Lin CH, Da¨chsel JC, Hulihan MM, Haugarvoll, et al. Lrrk2 G2385R is an ancestral risk factor for Parkinson’s disease in Asia. Parkinsonism Relat Disord 2007;13(2):89e92. [6] Funayama M, Li Y, Yoshino H, Yoshino H, Imamichi Y, Yamamoto M, et al. A variation in LRRK2 is associated with Parkinson’s disease in Asian population. Neuroreport 2007;18(3):273e5. [7] Tan EK. The role of common genetic risk variants in Parkinson disease. Clin Genet 2007;72(5):387e93.
E.-K. Tan et al. / Parkinsonism and Related Disorders 14 (2008) 569e571 [8] Zimprich A, Biskup S, Leitner P, Lichtner P, Farrer M, Lincoln S, et al. Mutations in LRRK2 cause autosomal-dominant Parkinsonism with pleomorphic pathology. Neuron 2004;44:601e60. [9] Skipper L, Shen H, Chua E, Bonnard C, Kolatkar P, Tan LC, et al. Analysis of LRRK2 functional domains in nondominant Parkinson disease. Neurology 2005;65(8):1319e21. [10] Louis ED, Honig LS, Vonsattel JP, Maraganore DM, Borden S, Moskowitz CB. Essential tremor associated with focal nonnigral Lewy bodies: a clinicopathologic study. Arch Neurol 2005;62(6):1004e7. [11] Tan EK, Matsuura T, Nagamitsu S, Khajavi M, Jankovic J, Ashizawa T. Polymorphism of NACP-Rep1 in Parkinson’s disease: an etiologic link with essential tremor? Neurology 2000;54(5):1195e8. [12] Geraghty JJ, Jankovic J, Zetusky WJ. Association between essential tremor and Parkinson’s disease. Ann Neurol 1985;17:329e33. [13] Rocca WA, Bower JH, Ahlskog JE, Elbaz A, Grossardt BR, McDonnell SK, et al. Increased risk of essential tremor in first-degree relatives of patients with Parkinson’s disease. Mov Disord 2007;22(11): 1607e14. [14] Louis ED, Frucht SJ. Prevalence of essential tremor in patients with Parkinson’s disease vs. Parkinson-plus syndromes. Mov Disord 2007;22(10):1402e7. [15] Jankovic J, Beach J, Schwartz K, Contant C. Tremor and longevity in relatives of patients with Parkinson’s disease, essential tremor, and control subjects. Neurology 1995;45(4):645e8. [16] Louis ED, Levy G, Mejia-Santana H, Cote L, Andrews H, Harris J, et al. Risk of action tremor in relatives of tremor-dominant and postural instability gait disorder PD. Neurology 2003;61(7):931e6. [17] Shahed J, Jankovic J. Exploring the relationship between essential tremor and Parkinson’s disease. Parkinsonism Relat Disord 2007; 13(2):67e76. [18] Lee MS, Kim YD, Im JH, Kim HJ, Rinne JO, Bhatia KP. 123I-IPT brain SPECT study in essential tremor and Parkinson’s disease. Neurology 1999;52:1422e6.
571
[19] Brooks DJ, Playford ED, Ibanez V, Sawle GV, Thompson PD, Findley LJ, et al. Isolated tremor and disruption of the nigrostriatal dopaminergic system: an 18F-dopa PET study. Neurology 1992;42(8):1554e60. [20] Deuschl G, Bain P, Brin M. Consensus statement of the Movement Disorder Society on tremor. Ad Hoc Scientific Committee. Mov Disord 1998;13(Suppl. 3):2e23. [21] Gulcher JR, Jonsson P, Kong A, Kristjansson K, Frigge ML, Karason A, et al. Mapping of a familial essential tremor gene, FET1, to chromosome 3q13. Nat Genet 1997;17(1):84e7. [22] Higgins JJ, Pho LT, Nee LE. A gene (ETM) for essential tremor maps to chromosome 2p22-p25. Mov Disord 1997;12(6):859e64. [23] Shatunov A, Sambuughin N, Jankovic J, Elble R, Lee HS, Singleton AB, et al. Genomewide scans in North American families reveal genetic linkage of essential tremor to a region on chromosome 6p23. Brain 2006; 129(Pt 9):2318e31. [24] Deng H, Le W, Jankovic J. Genetics of essential tremor. Brain 2007 Jun;130(Pt 6):1456e64. [25] Higgins JJ, Lombardi RQ, Pucilowska J, Jankovic J, Tan EK, Rooney JP. A variant in the HS1-BP3 gene is associated with familial essential tremor. Neurology 2005;64(3):417e21. [26] Shatunov A, Jankovic J, Elble R, Sambuughin N, Singleton A, Hallett M, et al. A variant in the HS1-BP3 gene is associated with familial essential tremor. Neurology 2005;65(12):1995. [27] Jeanneteau F, Funalot B, Jankovic J, Deng H, Lagarde JP, Lucotte G, et al. A functional variant of the dopamine D3 receptor is associated with risk and age-at-onset of essential tremor. Proc Natl Acad Sci U S A 2006;103(28):10753e8. [28] Tan EK, Prakash KM, Fook-Chong S, Yih Y, Chua E, Lum SY, et al. DRD3 variant and risk of essential tremor. Neurology 2007;68(10): 790e1. [29] Tan EK, Khajavi M, Thornby JI, Nagamitsu S, Jankovic J, Ashizawa T. Variability and validity of polymorphism association studies in Parkinson’s disease. Neurology 2000;55(4):533e8.