Essential tremor in twins

Tanner, Caroline M.; Goldman, Samuel; Lyons, Kelly E.; Aston, Diana A.; Tetrud, James W.; Welsh, Mickie; Langston, J. William; Koller, William C.

doi:10.1212/wnl.57.8.1389

Cited by 158 publications

(89 citation statements)

References 13 publications

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“…Many kindreds with autosomal dominant inheritance of ET have been described, and linkage has been demonstrated to regions on chromosomes 2p, 3q, and 6p, although at present the genes that are responsible for ET genes have not been identified (Deng et al, 2007;Gulcher et al, 1997;Higgins et al, 1997;Shatunov et al, 2006). In twin studies, concordance in monozygotic twins was 60 -63%; these and other data indicate that non-genetic (environmental) factors also play an important role in disease etiology (Lorenz et al, 2004;Louis, 2001;Tanner et al, 2001). Environmental factors are similarly thought to play a significant role in several other late life neurological diseases, including PD and Alzheimer's disease (Baldereschi et al, 2007;Dick, 2006;Gorell et al, 1997;Gorell et al, 1999;Gorell et al, 1998;Perl, 1985;Racette et al, 2001;Ritz and Yu, 2000;Rybicki et al, 1993;Semchuk et al, 1992;Shcherbatykh and Carpenter, 2007).…”

Section: Discussionmentioning

confidence: 99%

Elevated blood harmane (1-methyl-9H-pyrido[3,4-b]indole) concentrations in essential tremor

Louis

2008

NeuroToxicology

127

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Essential tremor (ET) is a widespread late-life neurological disease. Genetic and environmental factors likely play an etiological role. Harmane (1-methyl-9H-pyrido[3,4-b]indole) is a potent tremor-producing neurotoxin. In 2002, we demonstrated elevated blood harmane concentrations in an initial sample of 100 ET cases compared to 100 controls. Between 2002 and 2007, we assembled a new and larger sample of ET cases and controls. We now attempt to replicate our previous findings. Cases and controls were frequency-matched on age, gender, and race. Blood harmane concentrations were quantified by high performance liquid chromatography. Subjects comprised 150 ET cases and 135 controls (mean age 65.3 ± 15.5 vs. 65.5 ± 14.2 years, p = 0.94). Mean log blood harmane concentration was ∼50% higher in cases than controls (0.50 ± 0.54 g -10 /ml vs. 0.35 ± 0.62 g -10 /ml, p = 0.038). In a logistic regression analysis, log blood harmane concentration was associated with ET (OR adjusted 1.56, 95% CI 1.01 -2.42, p = 0.04), and odds of ET was 1.90 (95% CI 1.07 -3.39, p = 0.029) in the highest vs. lowest log blood harmane tertile. Log blood harmane was highest in ET cases with familial ET (0.53 ± 0.57 g -10 /ml), intermediate in cases with sporadic ET (0.43 ± 0.45 g -10 /ml) and lowest in controls (0.35 ± 0.62 g -10 /ml) (test for trend, p = 0.026). Blood harmane appears to be elevated in ET. The higher concentrations in familial ET suggests that the mechanism may involve genetic factors.

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Section: Discussionmentioning

confidence: 99%

Elevated blood harmane (1-methyl-9H-pyrido[3,4-b]indole) concentrations in essential tremor

Louis

2008

NeuroToxicology

127

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“…2 Given the presence of etiological, clinical, pharmacological response and pathological heterogeneity, there is growing support for the idea that ET may be a family of diseases whose central defining feature is kinetic tremor of the arms, and therefore it might more appropriately be called 'the essential tremors'. 3 Family studies 4,5 and twin studies 6,7 provide strong evidence for a genetic contribution to ET, with heritability estimates ranging from 45 to 90% in twin studies. 6,7 Despite this high heritability, the field of ET genetics has made only limited advances.…”

Section: Introductionmentioning

confidence: 99%

“…3 Family studies 4,5 and twin studies 6,7 provide strong evidence for a genetic contribution to ET, with heritability estimates ranging from 45 to 90% in twin studies. 6,7 Despite this high heritability, the field of ET genetics has made only limited advances. Previously, we and others reported that ET aggregates in families, with many families containing multiple members with ET.…”

Section: Introductionmentioning

confidence: 99%

Identification of candidate genes for familial early-onset essential tremor

et al. 2015

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Essential tremor (ET) is one of the most common causes of tremor in humans. Despite its high heritability and prevalence, few susceptibility genes for ET have been identified. To identify ET genes, whole-exome sequencing was performed in 37 early-onset ET families with an autosomal-dominant inheritance pattern. We identified candidate genes for follow-up functional studies in five ET families. In two independent families, we identified variants predicted to affect function in the nitric oxide (NO) synthase 3 gene (NOS3) that cosegregated with disease. NOS3 is highly expressed in the central nervous system (including cerebellum), neurons and endothelial cells, and is one of three enzymes that converts L-arginine to the neurotransmitter NO. In one family, a heterozygous variant, c.46G4A (p. (Gly16Ser)), in NOS3, was identified in three affected ET cases and was absent in an unaffected family member; and in a second family, a heterozygous variant, c.164C4T (p.(Pro55Leu)), was identified in three affected ET cases (dizygotic twins and their mother). Both variants result in amino-acid substitutions of highly conserved aminoacid residues that are predicted to be deleterious and damaging by in silico analysis. In three independent families, variants predicted to affect function were also identified in other genes, including KCNS2 (KV9.2), HAPLN4 (BRAL2) and USP46. These genes are highly expressed in the cerebellum and Purkinje cells, and influence function of the gamma-amino butyric acid (GABA)-ergic system. This is in concordance with recent evidence that the pathophysiological process in ET involves cerebellar dysfunction and possibly cerebellar degeneration with a reduction in Purkinje cells, and a decrease in GABA-ergic tone.

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“…Although genetic susceptibility is an important determinant of disease etiology (Louis et al 2001b;Tanner et al 2001), it has been hypothesized that nongenetic factors (i.e., environmental factors such as toxicants) could contribute to disease etiology in many cases (Louis 2001;Louis et al 2002b;Tanner et al 2001). The identification of these factors is a critical step in disease prevention, yet they have received little attention (Louis 2001).…”

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confidence: 99%

Association between essential tremor and blood lead concentration.

Louis

Jurewicz

Applegate

et al. 2003

Environ Health Perspect

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Lead is a ubiquitous toxicant that causes tremor and cerebellar damage. Essential tremor (ET) is a highly prevalent neurologic disease associated with cerebellar involvement. Although environmental toxicants may play a role in ET etiology and their identification is a critical step in disease prevention, these toxicants have received little attention. Our objective was to test the hypothesis that ET is associated with lead exposure. Therefore, blood lead (BPb) concentrations were measured and a lifetime occupational history was assessed in ET patients and in controls. We frequency matched 100 ET patients and 143 controls on age, sex, and ethnicity. BPb concentrations were analyzed using graphite furnace atomic absorption spectrophotometry. A lifetime occupational history was reviewed by an industrial hygienist. BPb concentrations were higher in ET patients than in controls (mean +/- SD, 3.3 +/- 2.4 and 2.6 +/- 1.6 microg/dL, respectively; median, 2.7 and 2.3 microg/dL; p = 0.038). In a logistic regression model, BPb concentration was associated with diagnosis [control vs. ET patient, odds ratio (OR) per unit increase = 1.21; 95% confidence interval (CI), 1.05-1.39; p = 0.007]. BPb concentration was associated with diagnosis (OR per unit increase = 1.19; 95% CI, 1.03-1.37; p = 0.02) after adjusting for potential confounders. Prevalence of lifetime occupational lead exposure was similar in ET patients and controls. We report an association between BPb concentration and ET. Determining whether this association is due to increased exposure to lead or a difference in lead kinetics in ET patients requires further investigation.

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Essential tremor in twins

Abstract: This pattern is consistent with a genetic cause of essential tremor. Because monozygotic concordance is not 100%, environmental factors may also play a role in the cause of the disease.

Cited by 158 publications

References 13 publications

Elevated blood harmane (1-methyl-9H-pyrido[3,4-b]indole) concentrations in essential tremor

Elevated blood harmane (1-methyl-9H-pyrido[3,4-b]indole) concentrations in essential tremor

Identification of candidate genes for familial early-onset essential tremor

Association between essential tremor and blood lead concentration.

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