Genetic heterogeneity in autosomal dominant essential tremor

Kovach, Margaret J.; Ruiz, Jimmy; Kimonis, Katerina; Mueed, Sajjad; Sinha, Sukanto; Higgins, Connie; Elble, Suzanne; Elble, Rodger J.; Kimonis, Virginia

doi:10.1097/00125817-200105000-00009

Cited by 63 publications

(35 citation statements)

References 11 publications

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“…Higgins and coworkers 20 mapped another ET gene to a region on chromosome 2p25-p22 in other families (ETM2; OMIM number 602134). The study of Kovach and associates 21 suggested the existence of further genetic heterogeneity.…”

Section: Discussionmentioning

confidence: 99%

Screen for expanded FMR1 alleles in patients with essential tremor

et al. 2004

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Fragile X-associated tremor/ataxia syndrome (FXTAS), a neurodegenerative disorder, was described recently among male carriers of expanded alleles (55-200 CGG repeats; premutation range) of the fragile X mental retardation 1 (FMR1) gene. Major features of the syndrome include intention tremor, gait ataxia, and parkinsonism in men over 50 years of age. This disorder is believed to be relatively common, possibly affecting 1 in 3,000 men over the age of 50 years in the general population. This raises the possibility that some patients presenting with essential tremor (ET) may harbor expanded FMR1 alleles. We screened 81 ET patients (40 males, 41 females) for expanded FMR1 alleles to determine whether ET is associated with such alleles. None of the ET cases had the premutation genotype. CGG repeat sizes ranged from 5 to 47 repeats within this study population, suggesting that expanded FMR1 alleles are uncommon among patients with ET. Screening of movement disorder patients with other clinical features of FXTAS (e.g., ataxia and parkinsonism) may be more likely to yield expanded FMR1 alleles.

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Section: Discussionmentioning

confidence: 99%

Screen for expanded FMR1 alleles in patients with essential tremor

et al. 2004

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“…Aggregation studies indicate that on the order of 30–70% of ET patients have a family history, with the vast majority (>80%) of young-onset (≤40 years old) cases reporting ≥1 affected first-degree relative (Louis and Dogu, 2007). While other modes of inheritance, including autosomal-recessive and complex inheritance patterns, are possible, published family and linkage studies suggest an autosomal-dominant mode of inheritance with reduced penetrance (Gulcher et al, 1997; Higgins et al, 1997; Kovach et al, 2001; Shatunov et al, 2006). Echoing this, our own experience with ET pedigrees strongly suggests an autosomal-dominant mode of inheritance with reduced penetrance.…”

Section: Introductionmentioning

confidence: 99%

Essential tremor

Clark

Louis

2018

Handbook of Clinical Neurology

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Essential tremor (ET) is one of the most common neurologic disorders, and genetic factors are thought to contribute significantly to disease etiology. There has been a relative lack of progress in understanding the genetic etiology of ET. This could reflect a number of factors, including the presence of substantial phenotypic and genotypic heterogeneity. Thus, a meticulous approach to phenotyping is important for genetic research. A lack of standardized phenotyping across studies and patient centers likely has contributed to the relative lack of success of genomewide association studies in ET. To dissect the genetic architecture of ET, whole-genome sequencing will likely be of value. This will allow specific hypotheses about the mode of inheritance and genetic architecture to be tested. A number of approaches still remain unexplored in ET genetics, including the contribution of copy number variants, uncommon moderate-effect alleles, rare variant large-effect alleles (including Mendelian and complex/polygenic modes of inheritance), de novo and gonadal mosaicism, epigenetic changes, and noncoding variation.

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“…[12][13][14] These studies provided evidence for genetic loci harboring ET genes on chromosomes 3q13 (ETM1; OMIM: 190300), 12 2p22-p25 (ETM2; OMIM: 602134) 13 and 6p23 (ETM3; OMIM: 611456). 14 Several studies have attempted to replicate linkage to ETM1, [15][16][17] ETM2 15,18,19 and ETM3, without success (no LOD score 42.0), and the genes and causal variants for these loci (ETM1, ETM2 and ETM3) have yet to be identified. Recently, using a linkage and a whole-exome sequencing approach, the fused in sarcoma/translated in liposarcoma (FUS/TLS) gene (Chr16p11.2) was identified as a candidate gene in a large family with ET from Quebec.…”

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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Genetic heterogeneity in autosomal dominant essential tremor

Cited by 63 publications

References 11 publications

Screen for expanded FMR1 alleles in patients with essential tremor

Screen for expanded FMR1 alleles in patients with essential tremor

Essential tremor

Identification of candidate genes for familial early-onset essential tremor

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