LINGO1 variants in essential tremor and Parkinson's disease

The leucine-rich repeat and Ig domain containing 1 gene (LINGO1), recently considered to be conferred increased risk of essential tremor (ET), has been also implicated in Parkinson disease (PD). As the two common movement disorders have overlapping clinical and pathological features, it has been postulated that the LINGO1 gene may play a role in the pathogenesis of the two diseases. Here, we review published reports of the LINGO1 variants in ET and PD in an attempt to better understand the molecular and pathogenic relationship of LINGO1 to the two disorders.     

Lack of association of LINGO1 rs9652490 and rs11856808 SNPs with familial essential tremor

Background: Essential tremor (ET) is a frequent movement disorder with a substantial family aggregation. A genome‐wide association study has recently shown that LINGO1 gene variants are associated with increased risk of ET. Methods: We intended to replicate these findings by genotyping rs9652490 and rs11856808 in a series of 226 familial ET subjects and 1117 healthy controls from referral movement disorder clinics in Spain. Results: We were unable to replicate the association between LINGO1 variants and familial ET. Conclusions: Our results indicate that the LINGO1 variants analyzed are not a major risk factor for developing familial ET in our population, which suggests the existence of other unknown genetic risk factors responsible for familial ET in the Spanish population.     

LINGO1 polymorphisms are associated with essential tremor in Europeans

Essential tremor (ET) is one of the most common movement disorders. Former association studies focussing on candidate genes in ET found a number of risk variants but most of them were not replicated. Recently, a genome‐wide association study revealed two intronic sequence variants in the LINGO1 gene associated with ET. Here, we have confirmed association between sequence variants in the LINGO1 gene and the ET phenotype in independent German and French ET samples. The odds ratios for the identified intronic markers rs8030859 (P = 1.0×10^?4), rs9652490 (P = 9.1×10^?4), and rs11856808 (P = 3.6×10^?2) were 1.72 (CI 1.31‐2.26), 1.61 (CI 1.21‐2.14), and 1.30 (CI 1.02‐1.66), respectively, in our German sample. LINGO1 is an interesting candidate gene because it plays a key role in central nervous system biology, is selectively expressed in the nervous system, and is an inhibitor of oligodendrocyte differentiation and neuronal myelination. Our study gives further evidence that LINGO1 acts as a susceptibility gene for ET. © 2010 Movement Disorder Society     

Increased risk of essential tremor in first-degree relatives of patients with Parkinson's disease.

We conducted a historical cohort study of 981 first-degree relatives of 162 patients with Parkinson's disease (PD) and of 838 first-degree relatives of 147 controls representative of the population of Olmsted County, Minnesota. In addition, we studied 2,684 first-degree relatives of 411 patients with PD referred to the Mayo Clinic. Relatives were interviewed and screened for tremor either directly or through a proxy, and those who screened positive were examined or copies of their medical records were obtained to confirm the diagnosis of essential tremor (ET). We also obtained ET information from a medical records-linkage system (family study method). In the population-based sample, the risk of ET was significantly increased for relatives of patients with onset of PD相似文献   

Genetic analysis of the fused in sarcoma gene in Chinese Han patients with Parkinson's disease

Background and purposeExome sequencing in a large essential tremor (ET) family identified a novel nonsense mutation (p.Q290X) in the fused in sarcoma gene (FUS) as the cause of this family. Because of the clinical overlap between ET and Parkinson's disease (PD), the role of FUS in an independent cohort of PD patients from China mainland was evaluated.MethodsThe entire coding region of FUS in 508 Chinese Han patients with PD and the identified variants in 633 normal controls were evaluated. A variant was further screened in an additional 382 controls for the frequency in our population.ResultsA novel variant c.696C > T (p.Y232Y) in 2 sporadic patients with PD and six variants (c.52C > A, p.P18T; c.52C > T, p.P18S; c.147C > A, p.G49G; c.291C > T, p.Y97Y; c.684C > T, p.G228G; c.1176G > A, p.M392I) without significant difference in genotypic and allelic distributions in our PD cohort were identified.ConclusionThe FUS gene is not a genetic risk factor for PD in the population of Chinese Han ethnicity.     

Prevalence of essential tremor in patients with Parkinson's disease vs. Parkinson-plus syndromes.

Clinical literature suggests an association between essential tremor (ET) and Parkinson's disease (PD), and recent pathological studies describe Lewy bodies in some ET patients. If some ET were an expression of Lewy body disease, one could hypothesize that ET patients who develop parkinsonism would more likely develop PD (a Lewy body disease) than non-Lewy body forms of parkinsonism. The objective was to compare the proportions of patients with PD vs. Parkinson-plus syndromes who had diagnoses of ET. Retrospective chart review at the Neurological Institute (NI) of New York. A larger proportion of the 210 PD than 210 Parkinson-plus syndrome patients had kinetic tremor on examination (119 [56.7%] vs. 70 [33.3%], P < 0.001). Patients with PD were more likely to have a prior diagnosis of ET than were patients with Parkinson-plus syndromes (7.1% vs. 2.4%, OR 3.16, 95% CI 1.13-8.85, P = 0.02) and more likely to have a diagnosis of ET assigned by an NI neurologist (5.3% vs. 0.0%, OR 12.85, 95% CI 1.66-99.8, P = 0.001). Patients with PD were three to thirteen times more likely to have diagnoses of ET than were patients with Parkinson-plus syndromes. These data further confirm the link between ET and PD, and possibly, between ET and Lewy body disease.     

Resetting of essential tremor and postural tremor in Parkinson's disease with transcranial magnetic stimulation

We studied the effects of transcranial motor cortex stimulation on the electromyographic characteristics of tremor in 9 patients with familial essential tremor and in 12 patients with postural tremor associated with Parkinson's disease. Transcranial magnetic stimulation reset both types of tremor equally. The resetting depended on the stimulus intensity, but was most closely correlated with the duration of the electromyographic silent period that followed the stimulus-induced motor evoked potential. Tremor resetting was present bilaterally even after focal, unilateral stimulation. Transcranial electrical stimulation failed to reset the tremor in either patient group. These results emphasize the role of central, intracortical structures in the generation of essential tremor and postural tremor in Parkinson's disease. © 1994 John Wiley & Sons, Inc.     

Head tremor in Parkinson's disease.

Head tremor is a typical feature of essential tremor. Patients with sporadic Parkinson's disease can have tremor of the tongue, lip, or chin, but classically do not have head tremor. We describe five patients with Parkinson's disease and head tremor in whom clinical and neurophysiological findings suggested that head tremor was a manifestation of Parkinson's disease.     

Association study between the LINGO1 gene and Parkinson's disease in the Italian population

Some studies have suggested an overlap of clinical and genetic findings between essential tremor (ET) and Parkinson’s disease (PD). The first genome-wide association study in ET showed a significant association with the rs9652490 SNP of the leucine-rich repeat and Ig domain containing 1 (LINGO1) gene. Since patients with PD have higher LINGO1 expression levels compared to healthy controls, and animal models of PD show elevated LINGO1 protein levels after experimentally induced damage in the striatum, it can be inferred that LINGO1 is probably involved in PD pathophysiology.In this study, we performed a genetic association analysis of the rs9652490 and rs11856808 SNPs in Italian PD patients and controls to assess the role of these variants in our population. A total of 567 patients with PD and 468 control subjects were enrolled in five Movement Disorder centers located in Central-Southern Italy. Both variants were significantly associated with PD under a recessive model of inheritance before applying the Bonferroni correction. The GG genotype of rs9652490 and the TT genotype of rs11856808 were less frequent in patients than in controls, suggesting a protective effect against the disease. However, after stringent correction, only the P-values obtained from allele and genotype comparisons of the rs11856808 SNP remained significant. Our findings suggest that LINGO1 plays a certain role in the development of PD in the Italian population and represents an interesting candidate gene responsible for PD, due to its involvement in neurological processes.     

Translated mutation in the Nurr1 gene as a cause for Parkinson's disease.

Multiple genes have been now identified as causing Parkinson's disease (PD). In 2003, two mutations were identified in exon 1 of the Nurr1 gene in 10 of 107 individuals with familial PD. To date, investigators have only focused on screening for these known mutations of the Nurr1 gene. All individuals were recruited from two Parkinson's disease clinics in Canada. Following PCR amplification of each exon of the Nurr1 gene, samples underwent denaturing high-performance liquid chromatography (DHPLC) analysis. Ten individuals also underwent direct sequencing as well as any samples where variants were identified. The Nurr1 gene was evaluated for 202 PD individuals, 37% of whom had at least one relative with PD and 100 control non-PD individuals. Using DHPLC and direct sequencing, we did not detect any sequence variants in exon 1. Variants in amplicon 6 were seen and direct sequencing confirmed a known NI6P polymorphism in intron 6. Novel polymorphisms were also identified in exon 3 and intron 5. A novel mutation was identified in exon 3 in one nonfamilial PD individual. This heterozygous C-to-G transversion resulted in a serine-to-cysteine substitution and was not identified in any of the other 602 chromosomes screened. Mutations in the Nurr1 gene in our large cohort of familial and sporadic PD individuals are rare. The novel mutation in exon 3 is predicted to affect phosphorylation and functional studies to assess this are underway. This is the first coding mutation identified in the Nurr1 gene for Parkinson's disease.     

Nonlinear dynamic analysis of oscillatory repetitive movements in Parkinson's disease and essential tremor

Uncertainty exists on whether Parkinson's disease (PD) and essential tremor (ET) patients have similar degree of impairment during motor tasks. We investigated this problem by analyzing nonlinear dynamics of repetitive movements in 21 control subjects, 33 mild‐moderate PD patients, and 18 ET patients. Accelerometer signals were recorded during finger tapping and unbounded forearm movements between two points, and processed with moving average filtering to generate a new signal consisting of the temporal distance between consecutive cycles. We calculated: mean interpeak interval (slowness), interpeak interval variability (irregularity), and beat decay (BD) of the auto mutual information (AMI) value, which estimates signal predictability by measuring the loss of signal information over a timescale. Both PD and ET had longer interpeak interval (except for finger tapping), higher interpeak interval variability, and higher BD‐AMI values than controls (P ≤ 0.007, all comparisons). ET patients had higher BD‐AMI values than PD (P = 0.003). BD‐AMI was the parameter that discriminated better between subjects (diagnosis accuracies about 80%). No differences existed between PD patients with and without tremor or between PD or ET patients with different disease stages, for any parameter. Evaluation of nonlinear dynamics of oscillatory repetitive movements is a feasible and promising tool for studying movement physiology. Movement performance is more predictable in PD and ET than in controls, even in early disease stages. Slowness and irregularity of movement in PD and ET cannot be fully explained by tremor. Some common pathogenic mechanisms leading to bradykinesia may contribute to this impairment. © 2010 Movement Disorder Society