‘Essential Tremor' or ‘the Essential Tremors': Is This One Disease or a Family of Diseases?

Louis, Elan D.

doi:10.1159/000356351

Cited by 72 publications

(51 citation statements)

References 119 publications

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“…This points to the progressiveness of ET‐related WM changes and further supports the proposed neurodegenerative nature of ET (Louis, 2014b). Also, ET in younger versus elder patients can have a different disease nature supporting the hypothesis of ET being not a single disease but rather a family of diseases with a large heterogeneity (Louis, 2014a). The lower RD values, are often associated with higher myelination (Song et al., 2002), which might lead to increased transmission velocity between brain regions but does not necessarily indicate an increased communication efficiency (Laughlin & Sejnowski, 2003) and may, in fact, represent a compensation for aberrant function elsewhere in the brain (Mandl et al., 2010).…”

Section: Discussionmentioning

confidence: 75%

White matter measures correlate with essential tremor severity—A pilot diffusion tensor imaging study

et al. 2018

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BackgroundAn evolving pathophysiological concept of essential tremor (ET) points to diffuse brain network involvement, which emphasizes the need to investigate white matter (WM) changes associated with motor symptoms of ET.ObjectivesTo investigate ET‐related WM changes and WM correlates of tremor severity using tremor clinical rating scales and accelerometry.MethodsTract‐based spatial statistics (TBSS) approach was utilized to compare 3 Tesla diffusion tensor imaging (DTI) data from 12 ET patients and 10 age‐ and gender‐matched healthy individuals. Clinical scales, tremor frequency and amplitude as measured by accelerometry were correlated with DTI data.Results ET patients demonstrated mean (MD) and radial diffusivity (RD) abnormalities in tracts involved in primary and associative motor functions such as bilateral corticospinal tracts, the superior longitudinal fascicles, and the corpus callosum but also in nonmotor regions including the inferior fronto‐occipital and longitudinal fascicles, cingulum bundles, anterior thalamic radiations, and uncinate fascicles. A combined tremor frequency and amplitude score correlated with RD and MD in extensive WM areas, which partially overlapped the regions that were associated with tremor frequency. No significant relationship was found between DTI measures and clinical rating scales scores.ConclusionsThe results show that ET‐related diffusion WM changes and their correlates with tremor severity are preferentially located in the primary and associative motor areas. In contrast, a relationship between WM was not detected with clinical rating scales. Accelerometry parameters may, therefore, serve as a potentially useful clinical measures that relate to WM deficits in ET.

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Section: Discussionmentioning

confidence: 75%

White matter measures correlate with essential tremor severity—A pilot diffusion tensor imaging study

et al. 2018

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“…Complexities of essential tremor include genetic heterogeneity, age-dependent penetrance, and variable expressivity, leading to difficulties both in differential diagnosis and in genetic analysis (18). Our results suggest that mutation of HTRA2 can be responsible for essential tremor in some families and that parkinsonian features may develop in these patients, after age 70 in heterozygotes and in middle age in homozygotes.…”

Section: Discussionmentioning

confidence: 81%

“…Homozygotes for the mutation expressed a more severe phenotype, including signs of Parkinson disease at middle age, suggesting a dosage effect for this allele. Even among heterozygotes, age at onset of tremor was variable, due to genetic or environmental modifiers or stochastic effects (18).…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial serine protease HTRA2 p.G399S in a kindred with essential tremor and Parkinson disease

Gulsuner

Gülsüner

Mercan

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

120

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Essential tremor is one of the most frequent movement disorders of humans and can be associated with substantial disability. Some but not all persons with essential tremor develop signs of Parkinson disease, and the relationship between the conditions has not been clear. In a six-generation consanguineous Turkish kindred with both essential tremor and Parkinson disease, we carried out whole exome sequencing and pedigree analysis, identifying HTRA2 p.G399S as the allele likely responsible for both conditions. Essential tremor was present in persons either heterozygous or homozygous for this allele. Homozygosity was associated with earlier age at onset of tremor (P < 0.0001), more severe postural tremor (P < 0.0001), and more severe kinetic tremor (P = 0.0019). Homozygotes, but not heterozygotes, developed Parkinson signs in the middle age. Among population controls from the same Anatolian region as the family, frequency of HTRA2 p.G399S was 0.0027, slightly lower than other populations. HTRA2 encodes a mitochondrial serine protease. Loss of function of HtrA2 was previously shown to lead to parkinsonian features in motor neuron degeneration (mnd2) mice. HTRA2 p. G399S was previously shown to lead to mitochondrial dysfunction, altered mitochondrial morphology, and decreased protease activity, but epidemiologic studies of an association between HTRA2 and Parkinson disease yielded conflicting results. Our results suggest that in some families, HTRA2 p.G399S is responsible for hereditary essential tremor and that homozygotes for this allele develop Parkinson disease. This hypothesis has implications for understanding the pathogenesis of essential tremor and its relationship to Parkinson disease.gene identification | neurodegenerative disease | mitochondrial dysfunction | DNA sequencing | mutation

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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%

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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‘Essential Tremor' or ‘the Essential Tremors': Is This One Disease or a Family of Diseases?

Cited by 72 publications

References 119 publications

White matter measures correlate with essential tremor severity—A pilot diffusion tensor imaging study

White matter measures correlate with essential tremor severity—A pilot diffusion tensor imaging study

Mitochondrial serine protease HTRA2 p.G399S in a kindred with essential tremor and Parkinson disease

Identification of candidate genes for familial early-onset essential tremor

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