Large-scale assessment of polyglutamine repeat expansions in Parkinson disease.

OBJECTIVES: We aim to clarify the pathogenic role of intermediate size repeat expansions of SCA2, SCA3, SCA6, and SCA17 as risk factors for idiopathic Parkinson disease (PD). METHODS: We invited researchers from the Genetic Epidemiology of Parkinson's Disease Consortium to participate in the study. There were 12,346 cases and 8,164 controls genotyped, for a total of 4 repeats within the SCA2, SCA3, SCA6, and SCA17 genes. Fixed- and random-effects models were used to estimate the summary risk estimates for the genes. We investigated between-study heterogeneity and heterogeneity between different ethnic populations. RESULTS: We did not observe any definite pathogenic repeat expansions for SCA2, SCA3, SCA6, and SCA17 genes in patients with idiopathic PD from Caucasian and Asian populations. Furthermore, overall analysis did not reveal any significant association between intermediate repeats and PD. The effect estimates (odds ratio) ranged from 0.93 to 1.01 in the overall cohort for the SCA2, SCA3, SCA6, and SCA17 loci. CONCLUSIONS: Our study did not support a major role for definite pathogenic repeat expansions in SCA2, SCA3, SCA6, and SCA17 genes for idiopathic PD. Thus, results of this large study do not support diagnostic screening of SCA2, SCA3, SCA6, and SCA17 gene repeats in the common idiopathic form of PD. Likewise, this largest multicentered study performed to date excludes the role of intermediate repeats of these genes as a risk factor for PD.

TREM2 R47H variant and risk of essential tremor: a cross-sectional international multicenter study.

INTRODUCTION: Essential tremor (ET) is the most frequent movement disorder in adults. Its pathophysiology is not clearly understood, however there is growing evidence showing common etiologic factors with other neurodegenerative disorders such as Alzheimer's and Parkinson's diseases (AD, PD). Recently, a rare p.R47H substitution (rs75932628) in the TREM2 protein (triggering receptor expressed on myeloid cells 2; OMIM: *605086) has been proposed as a risk factor for AD, PD and amyotrophic lateral sclerosis (ALS). The objective of the study was to determine whether TREM2 p.R47H allele is also a risk factor for developing ET. METHODS: This was a cross-sectional multicenter international study. An initial case-control cohort from Spain (n = 456 ET, n = 2715 controls) was genotyped. In a replication phase, a case-control series (n = 897 ET, n = 1449 controls) from different populations (Italy, Germany, North-America and Taiwan) was studied. Owed to the rarity of the variant, published results on p.R47H allele frequency from 14777 healthy controls from European, North American or Chinese descent were additionally considered. The main outcome measure was p.R47H (rs75932628) allelic frequency. RESULTS: There was a significant association between TREM2 p.R47H variant and ET in the Spanish cohort (odds ratio [OR], 5.97; 95% CI, 1.203-29.626; p = 0.042), but it was not replicated in other populations. CONCLUSIONS: These results argue in favor of population-specific differences in the allelic distribution and suggest that p.R47H (rs75932628) variant may contribute to the susceptibility of ET in Spanish population. However, taking into account the very low frequency of p.R47H, further confirmatory analyses of larger ET series are needed.

Familial paroxysmal nonkinesigenic dyskinesia: clinical and genetic analysis of a Taiwanese family.

Paroxysmal nonkinesigenic dyskinesia (PNKD) is a rare disorder in autosomal dominant inheritance. The clinical features and genetic findings of PNKD, rarely described in the Asians, were mostly delineated from European families. The present study characterized the clinical and genetic findings of a Taiwanese PNKD family. The clinical features of our five patients in successive three generations included onset age less than 10 years, attack duration between 3 min and 4h, and a variety of aura symptoms. The attacks were provoked not by sudden action but by emotional stress, caffeine, fatigue, heavy exercise and sleep deprivation. Sleep could abolish or diminish the attack and the attacks responded well to clonazepam. Sequencing the whole coding region of PNKD/MR-1 gene identified a heterozygous c.20 C>T (p.Ala7Val) mutation which was clearly segregated in the five affected patients. Comparing our patients with previously reported 18 families with PNKD/MR-1 mutations, the majority of the patients exhibited quite similar manifestations in attack patterns and precipitating factors. The recurrent conservative mutations in different ethnicities indicate importance in the pathogenesis of PNKD.

Large-scale replication and heterogeneity in Parkinson disease genetic loci.

OBJECTIVE: Eleven genetic loci have reached genome-wide significance in a recent meta-analysis of genome-wide association studies in Parkinson disease (PD) based on populations of Caucasian descent. The extent to which these genetic effects are consistent across different populations is unknown. METHODS: Investigators from the Genetic Epidemiology of Parkinson's Disease Consortium were invited to participate in the study. A total of 11 SNPs were genotyped in 8,750 cases and 8,955 controls. Fixed as well as random effects models were used to provide the summary risk estimates for these variants. We evaluated between-study heterogeneity and heterogeneity between populations of different ancestry. RESULTS: In the overall analysis, single nucleotide polymorphisms (SNPs) in 9 loci showed significant associations with protective per-allele odds ratios of 0.78-0.87 (LAMP3, BST1, and MAPT) and susceptibility per-allele odds ratios of 1.14-1.43 (STK39, GAK, SNCA, LRRK2, SYT11, and HIP1R). For 5 of the 9 replicated SNPs there was nominally significant between-site heterogeneity in the effect sizes (I(2) estimates ranged from 39% to 48%). Subgroup analysis by ethnicity showed significantly stronger effects for the BST1 (rs11724635) in Asian vs Caucasian populations and similar effects for SNCA, LRRK2, LAMP3, HIP1R, and STK39 in Asian and Caucasian populations, while MAPT rs2942168 and SYT11 rs34372695 were monomorphic in the Asian population, highlighting the role of population-specific heterogeneity in PD. CONCLUSION: Our study allows insight to understand the distribution of newly identified genetic factors contributing to PD and shows that large-scale evaluation in diverse populations is important to understand the role of population-specific heterogeneity.

5,10-methylenetetrahydrofolate reductase C677T gene polymorphism can influence age at onset of Parkinson's disease.

A case-control study was designed to investigate a possible genetic susceptibility of the MTHFR C677T polymorphism and assess whether the genetic polymorphism could be a predictor of levodopa-induced adverse effects in patients with Parkinson's disease (PD) of Chinese descent living in Taiwan. There were 94 sporadic PD patients with levodopa therapy at least for five years and 146 control subjects, matched by sex and gender, in this study. Results revealed that there were no differences of the allelic and genotypic frequencies of the MTHFR C677T polymorphism between PD patients and the controls. Analysis of age at onset stratified by MTHFR C677T polymorphism showed a trend of early age at onset in the PD patients carrying with T allele. The genetic influence was particularly significant in late-onset PD (onset age at or older than 60 years) with an early age at onset for 3.4 years. However, the MTHFR C677T polymorphism was not associated with the risk to develop dyskinesia, motor fluctuation and psychosis induced by levodopa in PD patients. In conclusion, results of the study revealed that the MTHFR C677T polymorphism could significantly influence age at onset of PD in Chinese population, but neither as a genetic susceptibility nor as a predictor of levodopa-induced adverse effects in PD.

Genetic polymorphism of the angiotensin converting enzyme and L-dopa-induced adverse effects in Parkinson's disease.

There was increasing evidence suggesting that angiotensin I-converting enzyme may play an important role in the pathogenesis of PD. Our former study has shown that angiotensin I-converting enzyme gene (ACE) may confer a susceptibility for the risk of Parkinson's disease (PD). Meanwhile, recent studies have emphasized that genetic factors may involve in the occurrence of the adverse effects of chronic L-dopa therapy in PD patients. This study was designed to assess whether genetic polymorphism of the ACE could be a predictor of L-dopa-induced adverse effects in PD. There were 251 patients included in this study and their mean age at onset of disease was 63.3+/-11.4 years. The duration of disease and the treatment with L-dopa was 6.3+/-5.1 and 5.0+/-4.3 years, respectively. The frequency of the homozygote ACE-II genotype of the ACE in PD patients with L-dopa-induced psychosis was significantly higher than that in PD patients without the adverse effect (63.3% vs 43.0%; chi(2)=6.347, OR=1.435, 95%CI=1.105-1.864, p=0.012). However, the ACE polymorphism was not associated with the risk to develop dyskinesia or motor fluctuation induced by L-dopa. Furthermore, a logistic regression analysis confirmed that the ACE-II genotype was an independent risk factor for L-dopa-induced psychosis in PD patients (OR=2.542, p=0.012). In conclusion, results of the study showed that ACE-II genotype might confer a primary predictor for the occurrence of psychosis in L-dopa-treated PD.

Homozygous deletion genotype of angiotensin converting enzyme confers protection against migraine in man.

Studies have shown that migraine may have a major genetic component. Meanwhile, angiotensin converting enzyme (ACE) gene has been implicated as a genetic factor associated with migraine. We designed a case-control study to investigate the association between ACE and migraine in 240 migraine patients and 200 healthy controls, matched by age and sex. There was no significant difference in allelic frequency (I and D) and genotype polymorphism (DD, DI and II) of the ACE gene in migraine patients and controls. Analysis of the difference in ACE polymorphism stratified by gender revealed that male migraine patients with the homozygote DD genotype (ACE-DD) were significantly fewer than that of male controls (OR = 0.331, p = 0.045). There was no existence of a difference among the frequency and duration of headache in each subgroup of migraine patients stratified by ACE genotype. Our findings indicate that ACE-DD may have a slight protective effect against migraine in male patients.

Lumbar zygapophyseal joint injections in patients with chronic lower back pain.

BACKGROUND: This study was designed to assess the diagnostic value and clinical benefits of lumbar zygapophyseal joint injections in patients with chronic lower back pain. METHODS: Two hundred and seventy-seven patients (136 males and 141 females, aged 15-82 years) with chronic lower back pain were enrolled in the trial and met the following criteria: pain for more than 1 year; no root signs; and no history of back surgery. Under fluoroscope, a 0.8-1.5 mL mixture of lidocaine, betamethasone dipropionate and iopamidol (1:1:0.5) was injected into each joint after intra-articular localization of the needle tip was confirmed. A questionnaire with a pain scale was administered immediately or the day after injection, and then after 1, 3, 6 and 12 weeks. Partial arthrograms were reviewed by a radiologist. RESULTS: Four hundred and forty-nine joint injections were performed in 277 patients (L3-4, n = 76; L4-5, n = 272; L5-S1, n = 101). Bilateral injections were performed in 117 patients (42.2%). The study group comprised 204 patients (73.6%) with an excellent or good response, whereas the control group comprised the remaining 73 patients (26.4%). The rates of good response in the study group were 72.1% (147/204) after 3 weeks, 40.7% (83/204) after 6 weeks, and 31.4% (64/204) after 12 weeks. Partial arthrograms revealed 25 patients (9.0%) with synovial cysts (L3-4, n = 3; L4-5, n = 14; L5-S1, n = 8); 23 of these patients (92.0%) had a good response to the injections. Five of the 6 patients with spondylolysis (83.3%), having abnormal communication between the injected and contiguous joint, had a good response to the injections. The abovementioned, abnormal partial-arthrogram findings correlated significantly with the rate of good response to the injections. Although 3 patients had contrast medium extravasated into the epidural space during injection, none of the 277 patients had deteriorating lower back pain after the injections. CONCLUSION: Lumbar zygapophyseal joint injections, as a useful diagnostic tool for facet joint syndrome, could also have useful palliative effects in the management of chronic lower back pain.

The homozygote 10-copy genotype of variable number tandem repeat dopamine transporter gene may confer protection against Parkinson's disease for male, but not to female patients.

We investigated the role of variable number tandem repeat (VNTR) polymorphism of the dopamine transporter gene (DAT) in the pathogenesis of Parkinson's disease (PD) in Taiwanese. A case-control study was carried out to examine the association of the VNTR polymorphism within the DAT between 193 sporadic PD patients and 254 controls, matched by age and sex. Six alleles of VNTR polymorphism in the DAT, consisting of 6, 7, 8, 9, 10 and 11 copies of the 40-base-pair (bp) repeat sequence, were detected in the study. There were no differences of allele frequency (chi(2)=5.239, p=0.387) and genotype polymorphism of the DAT VNTR (chi(2)=11.873, p=0.157) in PD patients from the controls. Further analysis stratified by sex and age at onset did not show associations. However, PD patients carrying homozygote 10-copy genotype of the DAT VNTR polymorphism were 0.67 times fewer than controls (chi(2)=4.569, odds radio (OR)=0.67, 95% confidence interval (CI)=0.45-0.97, p=0.033). The reduced risk of the homozygosity with PD genotype was only in male PD patients (chi(2)=2.923, OR=0.48, 95% CI=0.25-0.93, p=0.026), but not in female PD patients (chi(2)=0.002, OR=1.02, 95% CI=0.49-2.11, p=0.966). In conclusion, the results of our study show that homozygote 10-copy genotype of the VNTR polymorphism within the DAT may confer a protective factor for male PD patients, but not for female PD patients.

Association between genetic polymorphism of angiotensin-converting enzyme gene and Parkinson's disease.

This study was designed to investigate the hypothesis that deletion/insertion (D/I) polymorphism of the angiotensin-converting enzyme (ACE) gene may contribute to increased risk of Parkinson's disease (PD). A case-control study was carried out to examine the association between the ACE genotype and the allele frequency in 127 sporadic PD patients compared with 198 healthy controls. The frequency of the homozygote DD genotype of the ACE gene was significantly increased in patients with PD than in the controls (chi(2)=6.09, p=0.048), despite that there was no significant difference in D/I allele frequency (chi(2)=2.25, p=0.133). Moreover, PD patients carrying the homozygote DD genotype were 1.13 times more frequent than subjects without the DD genotype (chi(2)=5.67, 95% CI=1.01-1.25, p=0.017). A stepwise logistic regression analysis of the presence of the DD genotype and data on risk factors for PD confirmed that the homozygote DD genotype was a modest independent risk factor for PD (OR=1.32, 95% CI=1.12-2.16). In addition, there was a trend of increasing number of DD genotype in older PD patients and the modest risk factor of DD genotype in PD was due to the significant difference of the DD homozygosity in old patients with onset age at or after 60 years. In conclusion, results of our study support the hypothesis that the ACE gene may indicate genetic susceptibility to PD, particularly in older individuals.