Genetics of essential tremor.
ABSTRACT 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.
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ABSTRACT: Exome-sequencing analyses have identified vacuolar protein sorting 35 homolog (VPS35) and DnaJ (Hsp40) homolog, subfamily C, member 13 (DNAJC13) harboring disease-causing variants for Parkinson disease (PD). Owing to the suggested clinical, pathological and genetic overlap between PD and essential tremor (ET) we assessed the presence of two VPS35 and DNAJC13 disease-causing variants in ET patients. TaqMan probes were used to genotype VPS35 c.1858G>A (p.(D620N)) (rs188286943) and DNAJC13 c.2564A>G (p.(N855S)) (rs387907571) in 571 ET patients of European descent, and microsatellite markers were used to define the disease haplotype in variant carriers. Genotyping of DNAJC13 identified two ET patients harboring the c.2564A>G (p.(N855S)) variant previously identified in PD patients. Both patients appear to share the disease haplotype previously reported. ET patients with the VPS35 c.1858G>A (p.(D620N)) variants were not observed. Although a genetic link between PD and ET has been suggested, DNAJC13 c.2564A>G (p.(N855S)) represents the first disease-causing variant identified in both, and suggests the regulation of clathrin dynamics and endosomal trafficking in the pathophysiology of a subset of ET patients.European Journal of Human Genetics advance online publication, 13 August 2014; doi:10.1038/ejhg.2014.164.European journal of human genetics: EJHG 08/2014; DOI:10.1038/ejhg.2014.164 · 3.56 Impact Factor
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ABSTRACT: Background: Essential tremor is a common movement disorder with a strong heritable component. Large families with inherited forms of essential tremor have undergone genetic analyses by different approaches. However, our knowledge of genetic variants unequivocally linked to essential tremor is remarkably limited. Several explanations have been put forth to explain this challenge, including the possibility of mutations in non-coding areas of the genome. Methods: We encountered a family with highly penetrant, autosomal dominant tremor. We hypothesized that, if a single coding gene mutation was responsible for the phenotype, novel genetic tools would allow us to identify it. We employed single nucleotide polymorphism (SNP) arrays in 17 members of this family followed by next generation whole-exome sequencing in five affected subjects. Results: We did not identify any copy number variant or mutation that segregated with the disease phenotype. Discussion: This study emphasizes the remarkably challenging field of tremor genetics and indicates that future studies should perhaps shift to analysis of the noncoding genome.
Article: Pharmacotherapy of Essential Tremor[Show abstract] [Hide abstract]
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.12/2013; 5:43-55. DOI:10.4137/JCNSD.S6561