Genetics of essential tremor

Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA.
Brain (Impact Factor: 9.2). 07/2007; 130(Pt 6):1456-64. DOI: 10.1093/brain/awm018
Source: PubMed


Essential tremor (ET), the cause of which remains poorly understood, is one of the most common neurological disorders. While environmental agents have been proposed to play a role, genetic factors are believed to contribute to its onset. Thus far, three gene loci (ETM1 on 3q13, ETM2 on 2p24.1 and a locus on 6p23) have been identified in patients and families with the disorder. In addition, a Ser9Gly variant in the dopamine D3 receptor gene on 3q13 has been suggested to be a risk factor. Moreover, genetically deficient animal models express a phenotype that overlaps with some clinical characteristics of the human form of the illness. Further analyses of these genetic abnormalities may lead to the identification of causative mutations and a better understanding of the molecular mechanisms in this common movement disorder.

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Available from: Joseph Jankovic, Oct 13, 2014
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    • "This is especially true in the case of familial (hereditary) ET, but some reports have shown that the relative risk in first-degree siblings of subjects drop down as low as 4.7%; which is far from the 50% or 25% expected assuming either an autosomaldominant or recessive mode of inheritance (Louis, 2001, 2005; Louis et al., 2001). Hence other models are now being considered, especially in sporadic cases of ET, including autosomal-dominant gene mutations with low penetrance, new mutations, non- Mendelian/multifactorial inheritance and phenocopies (environmental factors) (Bain et al., 1994; Deng et al., 2007a; Louis et al., 2001). The current review will focus on the latest findings in human based population studies in light of the knowledge gathered from pathophysiological studies and expression data from mouse brain, in the hope to guide future functional experiments. "
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    ABSTRACT: Essential tremor (ET) is a prevalent neurological disorder of unknown etiology characterized by the presence of an action tremor that occurs during voluntary motion and affects primarily the upper limbs. The worldwide prevalence of the disease in the general population is 0.9%, increasing to 4.6% in individuals ≥ 65 years old. Standard pharmaceutical treatments are only moderately effective, reducing tremor amplitudes in ∼ 50% of patients, a phenomenon partly explained by the fact that the diagnosis of ET is based solely on clinical findings rather than biological markers. Furthermore, the pathophysiological origin of ET remains controversial, leading to heated debates as to whether it should be considered a neurodegenerative disorder or as a dynamic oscillatory disturbances of neurologic origin. Progress has been made in the understanding of its etiology as it is now accepted that genetic components must at least explain the familial cases of ET, and the evidence implicating the olivocerebellar and cerebello-thalamo-cortical pathways is strong. However, a strong disconnection between human genetics, pathophysiological, and mouse genetics studies exists in the field of ET, with little use of all the knowledge gathered from the different research disciplines. This review highlights our current knowledge on ET from both a human population and mouse genetics perspective hoping to reconcile evidence from both fields and leading to novel clues guiding future studies. We argue that better communication between researchers of different fields is warranted to define the biological origin of ET in the hope of leading to the development of better treatments.
    Progress in Neurobiology 05/2014; 119-120. DOI:10.1016/j.pneurobio.2014.05.001 · 9.99 Impact Factor
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    • "The origins of essential tremor are not fully understood but genetic predisposition is thought to contribute significantly (ca. 50% of cases) (Deng et al., 2007). Given the significant prevalence of this disorder (around 3e4%), seeking potential anti-tremor medications is of key priority. "
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    ABSTRACT: Harmaline induces tremor in animals resembling essential tremor which has been suggested to result from activation of the glutamatergic olivo-cerebellar projection. The aim of the present study was to examine the effects of systemic administration of Lu AF21934, a brain-penetrating positive allosteric modulator of the metabotropic glutamate receptor 4 (mGlu4), on the harmaline-induced tremor and other forms of motor activity in rats using fully automated Force Plate Actimeters. The influence of harmaline on the mGlu4 mRNA expression in the cerebellum and inferior olive was analysed by in situ hybridization. Harmaline at a dose of 15 mg/kg (ip) triggered tremor which was manifested by an increase in the power within 9-15 Hz band and in the tremor index (a difference in power between bands 9-15 Hz and 0-8 Hz). Harmaline induced a biphasic effect on mobility, initially inhibiting the exploratory locomotor activity of rats (0-30 min after administration), followed by an increase in their basic activity. Lu AF21934 (0.5-5 mg/kg sc) did not influence tremor but at doses of 0.5 and 2.5 mg/kg reversed harmaline-induced hyperactivity. MGlu4 mRNA expression was high in the cerebellar cortex and low in the inferior olive. Repeated harmaline (15 mg/kg ip once a day for 5 days] decreased mGlu4 mRNA in the cerebellum and inferior olive. The present study indicates that the mGlu4 stimulation counteracts hyperactivity induced by harmaline which suggests the involvement of cerebellar glutamatergic transmission in this process. In contrast, neuronal mechanisms involved in tremor seem to be insensitive to the stimulation of mGlu4.
    Neuropharmacology 04/2014; 83. DOI:10.1016/j.neuropharm.2014.03.018 · 5.11 Impact Factor
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    • "According to the consensus statement of the movement disorder society on tremor, ET is classically defined mainly by postural tremor of the hands and sometimes of the head [3]. A positive family history has been reported in approximately 50-70% of ET patients in a previous study, and a positive family history for ET is usually associated with a younger age of onset [4,5]. A possible autosomal dominant inheritance pattern with high, but not full, penetrance has been noticed [6–8]. "
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    ABSTRACT: Essential tremor (ET), which is one of the most common movement disorders, may lead to severe interference in quality of life. The first genome-wide association study (GWAS) has identified an association of the LINGO1 variant (rs9652490) with ET in Americans and Europeans. Recently, a second GWAS that was performed in a European population has discovered a new variant (rs3794087) of the main glial glutamate transporter (SLC1A2) that increases the risk of ET with an odds ratio of about 1.4. SLC1A2 encodes for the major glial high-affinity glutamate reuptake transporter in the brain and is a potential ET susceptibility gene. Because replication in a different ethnic population is important for validating a finding, we conducted a case-control study to investigate the SLC1A2 variant in an Asian cohort with ET in Taiwan. A total of 542 subjects (273 ET patients and 269 controls) were included. The results showed that rs3794087 was associated with ET among the Taiwanese. The odds ratio was 1.37. Our results were similar to those of the second GWAS of ET in Europeans, and this confirms that SLC1A2 may be a good functional candidate gene for ET. A replication study in another independent population is of importance to validate this association.
    PLoS ONE 08/2013; 8(8):e71919. DOI:10.1371/journal.pone.0071919 · 3.23 Impact Factor
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