Genetics of essential tremor
Department of Neurology, Medical University of Silesia, Katowice, Poland. Parkinsonism & Related Disorders
(Impact Factor: 3.97).
01/2012; 18 Suppl 1((Suppl 1)):S138-9. DOI: 10.1016/S1353-8020(11)70043-8
Essential tremor (ET) is a prevalent condition manifesting with progressive action tremor. Although ET was traditionally viewed as a sporadic disease, a significant proportion of cases report a positive family history of tremor. Autosomal dominant inheritance can be demonstrated in many families. Previously, genome-wide linkage studies in families mapped three loci for ET, hereditary essential tremor-1 (ETM1), ETM2 and ETM3. However, no causal mutation has been replicated in candidate genes within these loci, including dopamine D3 receptor (DRD3) and HS1-binding protein 3 (HS1BP3). Recently, the first genome-wide association study in ET followed by replication studies conducted in diverse populations identified a significant association between the leucine-rich repeat and Ig domain containing 1 gene (LINGO1) SNP rs9652490 and risk for ET Although further novel variants were indentified in LINGO1 and its paralog LINGO2 that may be associated with risk for ET, the pathogenic mechanisms involved remain elusive. Given the possibility that ET as a complex trait may be influenced by the combined effects of rare variants, novel high-throughput technologies sequencing all exons across the genome (exome sequencing) or the whole genome (genome sequencing) may become crucial in understanding/deciphering the genetic background of ET.
Available from: Peter Hedera
- "A positive family history of ET can be found in 30% to 80% of all affected patients, suggesting a strong genetic contribution to its etiology.64 Linkage analysis using parametric methods have identified several putative genetic loci on chromosomes 3q13, 2p24.1, and 6p23, with additional evidence for further genetic heterogeneity.65–67 "
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ABSTRACT: Essential tremor (ET) is a common movement disorder but its pathogenesis remains poorly understood. This has limited the development of effective pharmacotherapy. The current therapeutic armamentaria for ET represent the product of careful clinical observation rather than targeted molecular modeling. Here we review their pharmacokinetics, metabolism, dosing, and adverse effect profiles and propose a treatment algorithm. We also discuss the concept of medically refractory tremor, as therapeutic trials should be limited unless invasive therapy is contraindicated or not desired by patients.
Available from: PubMed Central
- "ET was originally conceptualized as a phenotypically homogeneous familial entity, caused by common genetic variants. ET is better characterized as a complex trait;14, 121 pathophysiology could therefore involve rare genetic variants in combination, instead of a few common variants.121,140–143 As reflected by the association studies in ET (Table 1), the field is moving from single genetic variant analysis to more detailed, comprehensive sequencing approaches of candidate areas or the genome. "
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ABSTRACT: Genetics research is an avenue towards understanding essential tremor (ET). Advances have been made in genetic linkage and association: there are three reported ET susceptibility loci, and mixed but growing data on risk associations. However, causal mutations have not been forthcoming. This disappointing lack of progress has opened productive discussions on challenges in ET and specifically ET genetics research, including fundamental assumptions in the field.
This article reviews the ET genetics literature, results to date, the open questions in ET genetics and the current challenges in addressing them.
SEVERAL INHERENT ET FEATURES COMPLICATE GENETIC LINKAGE AND ASSOCIATION STUDIES: high potential phenocopy rates, inaccurate tremor self-reporting, and ET misdiagnoses are examples. Increasing use of direct examination data for subjects, family members, and controls is one current response. Smaller moves towards expanding ET phenotype research concepts into non-tremor features, clinically disputed ET subsets, and testing phenotype features instead of clinical diagnosis against genetic data are gradually occurring. The field has already moved to considering complex trait mechanisms requiring detection of combinations of rare genetic variants. Hypotheses may move further to consider novel mechanisms of inheritance, such as epigenetics.
It is an exciting time in ET genetics as investigators start moving past assumptions underlying both phenotype and genetics experimental contributions, overcoming challenges to collaboration, and engaging the ET community. Multicenter collaborative efforts comprising rich longitudinal prospective phenotype data and neuropathologic analysis combined with the latest in genetics experimental design and technology will be the next wave in the field.
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ABSTRACT: We will review the recent advances in the genetics of Parkinson disease and other movement disorders such as dystonia, essential tremor and restless legs syndrome (RLS).
Mutations in VPS35 were identified as a novel cause of autosomal dominant Parkinson disease using exome sequencing. Next generation sequencing (NGS) was also used to identify PRRT2 mutations as a cause of paroxysmal kinesigenic dyskinesia (DYT10). Using a different technique, that is linkage analysis, mutations in EIF4G1 were implicated as a cause of Parkinson disease and mutations in SLC20A2 as a cause of familial idiopathic basal ganglia calcification. Furthermore, genome-wide association studies (GWAS) and meta-analyses have confirmed known risk genes and identified new risk loci in Parkinson disease, RLS and essential tremor. New models to study genetic forms of Parkinson disease, such as stem cell-derived neurons, have helped to elucidate disease-relevant molecular pathways, such as the molecular link between Gaucher disease and Parkinson disease.
New genes have been implicated in Parkinson disease and other movement disorders through the use of NGS. The identification of risk variants has been facilitated by GWAS and meta-analyses. Furthermore, new models are being developed to study the molecular mechanisms involved in the pathogenesis of these diseases.
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