Alternative titles; symbols
DO: 0111428;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 3q13.31 | {Essential tremor, hereditary, 1} | 190300 | Autosomal dominant | 3 | DRD3 | 126451 |
A number sign (#) is used with this entry because of evidence that susceptibility to hereditary essential tremor-1 (ETM1) is conferred by variation in the DRD3 gene (126451) on chromosome 3q13.
Essential tremor may be the most common human movement disorder. The main feature of essential tremor is postural tremor of the arms, but the head, legs, trunk, voice, jaw, and facial muscles also may be involved. Aggravated by emotions, hunger, fatigue, and temperature extremes, the condition may cause a functional disability or even incapacitation. Autosomal dominant inheritance can be demonstrated in most families (summary by Higgins et al., 1997).
Deng et al. (2007) provided a detailed review of the genetics of essential tremor.
Genetic Heterogeneity of Essential Tremor
Other forms of hereditary essential tremor include ETM2 (602134), mapped to chromosome 2p25-p22; ETM3 (611456), mapped to chromosome 6p23; ETM4 (614782), caused by mutation in the FUS gene (137070) on chromosome 16p11; ETM5 (616736), caused by mutation in the TENM4 gene (610084) on chromosome 11q14; and ETM6 (618866), caused by mutation in the NOTCH2NLC gene (618025) on chromosome 1q21.
Louis (2001) reviewed the clinical features of essential tremor and therapeutic options.
Critchley (1949) gave a classic review of this subject. Larsson and Sjogren (1960) did a thorough study of hereditary essential tremor in a parish of Sweden. In all, 210 cases were ascertained. The age of onset, which showed high intrafamilial correlation, was on the average about 50 years and somewhat later in women than in men. 'Anticipation' (progressively earlier age of onset in successive generations) was not observed. Fine rapid tremor of the hands was usually the first symptom. Tremor of the arms, tongue (with dysarthria), head, legs, and trunk developed later, usually in the order listed. Mild extrapyramidal symptoms in the form of rigidity and stiffness of gait occurred frequently, but the clinical picture was easily distinguishable from parkinsonism (see 168600). Mental deterioration was not a feature. With 2 exceptions, all 210 cases could be traced back to 4 ancestral couples. The inheritance was autosomal dominant. From observation of about 15 presumed homozygous individuals, it was concluded that there is no difference from the disease in heterozygotes. It was estimated that more than 9% of the males and 6 to 6.5% of females of the parish carry the gene for essential tremor. The authors could find no reason to suspect selective fertility, selective mortality, or assortative mating as factors in the high gene frequency observed. Rather, chance variations that occurred when the population was small--about 150 persons in the late 1700s--seem to have been responsible. Kehrer (1965) described a family in which members of 3 successive generations had tremor of the hands and face and in 2 patients studied in detail, cerebral atrophy demonstrable by pneumoencephalography. He suggested that this represents a distinct entity.
Busenbark et al. (1991) reported the results of a self-administered questionnaire concerning sickness-related dysfunction in 753 patients with essential tremor and compared the results with those in 87 controls and 145 patients with Parkinson disease. They concluded that although the disability with essential tremor is significant and may cause relatively greater psychosocial dysfunction, it tends to be less severe than in parkinsonism.
Garcia-Albea et al. (1993) reported a 24-year-old man with paroxysmal episodes of tremor lasting from 10 to 60 minutes and occurring once every 3 to 6 weeks without apparent precipitating factors. The episodes were accompanied by a 9- to 10-Hz tremor electromyographically. A similar pattern was present in the patient's mother and in 2 of his 4 brothers. The authors proposed that this was a distinct variant. Bain and Findley (1994) believed that classic familial essential tremor typically begins with intermittent symptoms and that the observation of Garcia-Albea et al. (1993) should not be considered a novel variant.
Bain et al. (1994) studied 93 first-degree relatives and 38 more distant relatives of 20 index patients with hereditary essential tremor. The age of onset was bimodally distributed with a median at 15 years, and penetrance was virtually complete at the age of 65 years. Approximately 50% of the cases were alcohol responsive. In most families, alcohol responsiveness or its absence was a consistent feature, but in 20% there was heterogeneity of alcohol response within the family. Head tremor was invariably mild and in 75% of cases was of a 'no-no' type. There was no association with Parkinson disease or dystonia, although classical migraine (see 157300) occurred in 26% of cases and cosegregated with tremor.
Gulcher et al. (1997) quoted Jankovic et al. (1995) as finding that the average life expectancy of essential tremor patients is greater than that of unaffected members of their families. However, the disorder has a significant effect on the lives of the persons involved. Essential tremor may not appear until after 65 years of age. Current treatments using beta blockers or primidone have only limited efficacy and frequently become ineffective as the disease progresses. The tremor usually begins between adolescence and 40 years of age.
Farrer et al. (1999) studied a family that raised the question of whether postural tremor (essential tremor) can be an alternative phenotype of the same pathogenic mutation that causes Lewy body parkinsonism (168601). They investigated a large family with levodopa-responsive Lewy body parkinsonism in which the disease segregated as an apparent autosomal dominant trait. After performing a genome screen, they identified a chromosome 4p haplotype that segregated with the disorder; however, this haplotype also occurred in individuals in the pedigree who did not have clinical Lewy body parkinsonism but rather suffered from postural tremor, consistent with essential tremor.
In a population-based study of cognitive function among 232 Spanish patients with essential tremor and 696 control individuals, Benito-Leon et al. (2006) found that patients with essential tremor scored lower than controls on most neuropsychologic tests and global cognitive performance tests. In addition, a complaint of forgetfulness was marginally more common among essential tremor patients.
Busenbark et al. (1996) mailed a screening questionnaire to first-degree relatives of patients with essential tremor who denied a positive family history. Even though only 67.7% of patients had previously reported a positive family history, this more direct assessment demonstrated that 96% of essential tremor patients had a positive family history, suggesting that essential tremor is primarily a hereditary disease.
In a study of relatives of patients with essential tremor, in comparison with relatives of control subjects, Louis et al. (2001) found mild tremor in many relatives of the former group. Even among case relatives 60 years of age or older, there was an increased prevalence of higher tremor scores, suggesting that in that age group, subclinical essential tremor may be present and penetrance may still not be complete.
Louis et al. (2001) examined 59 patients with essential tremor, 72 controls, and over 200 relatives of each group and determined that relatives of patients with essential tremor are 5 times more likely to develop the disease than are members of the general population and 10 times more likely if the proband's tremor began before age 50. Severity of tremor in the proband was an important determinant of tremor severity among relatives.
Lorenz et al. (2004) conducted a twin study in Denmark to assess the relative contribution of genetic and environmental factors in essential tremor and to explore the effect of different diagnostic criteria. A total of 2,448 twins aged 70 years or more were screened for essential tremor by an interview and an Archimedes spiral test. All 162 twin pairs with a positive screening test of at least 1 of the twins were recontacted, and 218 individuals (109 pairs) were interviewed and examined by a movement disorder specialist. The probandwise concordance rate for the broadest definition of essential tremor was 77% for monozygotic twins and 59% for dizygotic twins. However, in an analysis restricted to cases of probable and definite essential tremor, the concordance rates were 93% and 29%. The heritability for the liability to essential tremor ranged from 93% to 99% using a general population prevalence of 1.2% for white persons 70 years of age and older.
Rautakorpi et al. (1982) reported a remarkably high frequency of essential tremor in a Finnish population: 55.5% of persons over 40 years of age.
Benito-Leon et al. (2005) estimated an annual incidence of essential tremor of 616 per 100,000 among Spanish individuals aged 65 years and older. Sixty-four (77.1%) of 83 incident cases were diagnosed only during a follow-up, suggesting that many patients may never seek medical attention. The prevalence and incidence of essential tremor did not differ between men and women.
Tanner et al. (2001) performed a study of essential tremor in twins who were members of the National Academy of Sciences and National Research Council World War II Veteran Twins Registry. When patients with Parkinson disease and incidences of incomplete data were excluded, 16 twin pairs were found in which at least 1 twin had essential tremor. Pairwise concordance in monozygotic twins was approximately 2 times that in dizygotic twins (0.60 for monozygotic, 0.27 for dizygotic). The results indicated that environmental factors may play a role in the cause of the disease.
In a review, Louis (2009) presented evidence that essential tremor may represent a family of diseases rather than a single disease entity. He noted that a broad variety of clinical features have been described in patients with essential tremor, including additional motor, cognitive, and psychiatric impairments. These features are heterogeneously distributed across patients with ET. In addition, there is a heterogeneity of response to common treatments, such as propranolol and primidone. Pathologic reports have identified 2 main, yet distinct, types: one with cerebellar degenerative changes and significant Purkinje cell loss, and another with Lewy bodies confined to the locus ceruleus. Finally, essential tremor is age-associated, shows an insidious onset, is progressive, and in some cases has shown cell loss and structural brain changes, suggesting that it may be considered a neurodegenerative disorder.
Higgins et al. (1997) stated that beta-adrenergic blocking agents and primidone, established treatments for essential tremor, are only partially effective and have significant side effects.
Since hereditary essential tremor is often associated with dystonia, a pathologic connection between it and idiopathic torsion dystonia (DYT1; 128100), which maps to chromosome 9, has been suggested. Durr et al. (1993) excluded this possibility by ruling out linkage to 9q32-q34.
Gulcher et al. (1997) reported the results of a genomewide scan in 16 Icelandic families with 75 individuals affected with essential tremor. A locus, which they symbolized FET1 for familial essential tremor 1, was mapped to 3q13 when the data were analyzed either parametrically, assuming an autosomal dominant model (lod score = 3.71), or nonparametrically (lod score = 4.70).
Shortly after the publication of the study of Gulcher et al. (1997) mapping an essential tremor gene to chromosome 3, Higgins et al. (1997, 1998) reported mapping an essential tremor gene to 2p25-p22 (ETM2; 602134).
Kovach et al. (2001) described a 38-member, 6-generation Midwestern family with essential tremor. This family did not map to either the ETM1 or ETM2 loci; a candidate locus for parkinsonism and postural tremor on chromosome 4p was also excluded, showing further heterogeneity of autosomal dominant essential tremor.
In a genomewide association study including 452 Icelandic patients with essential tremor and 14,394 controls, Stefansson et al. (2009) found linkage to 2 SNPs in the LINGO1 gene (609791) on chromosome 15q24.3 (p less than 1.0 x 10(-5)). Replication studies in samples from Austria, Germany, the United States, and Iceland confirmed a significant association with the G allele of 1 of these SNPS (rs9652490), yielding a combined odds ratio of 1.55 and p value of 1.2 x 10(-9). The SNP is located within intron 3 of the LINGO1 gene, which the authors noted is exclusively expressed in the central nervous system.
In a study of 190 Asian patients with essential tremor and 733 controls, Tan et al. (2009) observed an association between essential tremor and the G allele of rs9652490 in the LINGO1 gene. Seventy-five (39.5%) of 190 patients had a positive family history of ET. In the whole cohort, the population attributable risk of the GG genotype was 18.8%. However, the most robust association was with familial ET for the GG genotype (OR, 3.26; p = 0.005). Analysis of sporadic ET did not show any association with this SNP.
By genotyping of 15 SNPs in the LINGO1 gene in 257 ET patients and 265 controls from northern Manhattan, Clark et al. (2010) found a marginally significant association between ET and the G allele of rs9652490 (OR of 1.33, p = 0.0569). The association with this SNP strengthened in a subset of cases with 'definite' or 'probable' ET (OR of 1.41, p = 0.03). Subsequent analysis of early-onset ET (less than 40 years) showed an association between ET and 3 SNPs: rs177008, rs13313467, and rs8028808 (OR of 1.52, p = 0.028; OR of 1.54, p = 0.0238; and OR of 1.55, p = 0.0391, respectively). These 3 SNPs represented a 2.3-kb haplotype. The study independently suggested that variation in the LINGO1 gene may be a risk factor for ET in a Caucasian population in North America, particularly for those with early onset.
In 23 of 30 unrelated French families, Lucotte et al. (2006) found significant association between hereditary essential tremor and a BalI polymorphism in the DRD3 gene (S9G; 126451.0001) on chromosome 3q13. Parametric linkage analysis and transmission disequilibrium testing also showed significant positive association between the polymorphism and essential tremor. Among probands, gly9 homozygotes had significantly younger age at onset and more severe symptoms compared to heterozygotes, suggesting a gene dosage effect. Lucotte et al. (2006) noted that the polymorphism occurs in the extracellular N terminus of the protein, which may increase dopamine affinity and efficacy. The authors hypothesized that essential tremor may result from a gain-of-function mechanism.
Associations Pending Confirmation
For discussion of a possible association between essential tremor and variation in the SCN4A gene, see 603967.0033.
Dominantly inherited essential tremor was recognized by Dana (1887).
Louis (2001) reviewed evidence related to the progressive tremor from which Samuel Adams (1722-1803), the American Revolutionist and brewer, suffered. The tremor affected his hands, head, and voice. Although mild, the tremor was already manifest when Adams was in his early forties. A prolific writer, Adams experienced progressive difficulty with writing in his fifties and early sixties. By age 71, he was forced to dictate all of his correspondence. His tremor was familial, affecting his daughter Hannah and her children. Louis (2001) concluded that he suffered from one of the earliest documented cases of essential tremor.
Kralic et al. (2005) generated alpha-1 gamma-aminobutyric acid receptor (GABRA1; 137160) -/- mice and observed postural and kinetic tremor and motor incoordination characteristic of essential tremor disease. Drugs used to treat essential tremor patients were efficacious in reducing tremor in Gabra1-null mice, as were several candidate drugs. Electrophysiologic studies revealed that cerebellar Purkinje cells in Gabra1-null mice had a profound loss of all responses to synaptic or exogenous GABA, but there were no differences in abundance, gross morphology, or spontaneous synaptic activity.
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