Genetics of essential tremor.
ABSTRACT 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.
- SourceAvailable from: Seok Bum Lee[Show abstract] [Hide abstract]
ABSTRACT: Essential tremor (ET) is one of the most common movement disorders. The prevalence of ET varies substantially among studies. In Korea, there is no well-designed epidemiological study of the prevalence of ET. Thus, we investigated the prevalence of ET in a community in Korea. Standardized interviews and in-person neurological examinations were performed in a random sample of the elderly aged 65 yr or older. Next, movement specialists attempted to diagnose ET clinically. People who showed equivocal parkinsonian features underwent dopamine transporter imaging using [(123)I]-FP-CIT SPECT, to differentiate ET from parkinsonism. A total of 714 subjects participated in this population-based study. Twenty six of these subjects were diagnosed as having ET. The crude prevalence of ET was 3.64 per 100 persons. Age, gender, or education period were not different between the ET patients and the non-ET subjects. The prevalence of ET was slightly lower than those reported in previous studies. Further studies including more subjects are warranted.Journal of Korean Medical Science 12/2014; 29(12):1694-8. · 1.25 Impact Factor
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ABSTRACT: Objective We analyzed the coding region of the Fused in Sarcoma (FUS) gene in familial essential tremor (ET) and reviewed previous studies assessing FUS variants in ET.BackgroundET is often a familial disorder with an autosomal dominant inheritance pattern. A potentially causative variant in FUS has been identified in one ET family. Subsequent studies described further putatively causal variants.Methods We performed DNA sequencing of FUS in 85 unrelated, familial German and French definite ET patients.ResultsWe did not find novel variants affecting the protein sequence. Seven previously published studies and data from the exome variant server (EVS) showed that rare exonic variants in FUS are not more frequent in ET than in the general population.Conclusions Our findings provide no evidence for a role of rare genetic variants in the pathogenesis of ET, apart from the initially published FUS mutation segregating in a large ET family.Movement Disorders 01/2015; · 5.63 Impact Factor
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ABSTRACT: Background: Essential tremor is a common movement disorder with a strong heritable component. Large families with inherited forms of essential tremor have undergone genetic analyses by different approaches. However, our knowledge of genetic variants unequivocally linked to essential tremor is remarkably limited. Several explanations have been put forth to explain this challenge, including the possibility of mutations in non-coding areas of the genome. Methods: We encountered a family with highly penetrant, autosomal dominant tremor. We hypothesized that, if a single coding gene mutation was responsible for the phenotype, novel genetic tools would allow us to identify it. We employed single nucleotide polymorphism (SNP) arrays in 17 members of this family followed by next generation whole-exome sequencing in five affected subjects. Results: We did not identify any copy number variant or mutation that segregated with the disease phenotype. Discussion: This study emphasizes the remarkably challenging field of tremor genetics and indicates that future studies should perhaps shift to analysis of the noncoding genome.Tremor Other Hyperkinet Mov. 10/2014;
Genetics of essential tremor
Hao Deng,Weidong Le and Joseph Jankovic
Department of Neurology, Baylor College of Medicine, Houston,TX,USA
Correspondence to: Joseph Jankovic, MD, Parkinson’s Disease Center and Movement Disorders Clinic, Department of
Neurology, Baylor College of Medicine, 6550 Fannin, Suite1801, Houston,TX 77030,USA
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 con-
tribute 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 D3receptor
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.
Keywords: essential tremor; genetics; dopamine D3receptor gene; variant; autosomal dominant; non-Mendelianinheritance
Abbreviations: ADCA¼autosomal dominant cerebellar ataxia; AIS¼androgen insensitivity syndrome; AR¼androgen
receptor gene; CAP2¼adenylate cyclase-associated protein 2 gene; CMT¼Charcot^Marie^Tooth; CMTX¼X-linked
Charcot^Marie^Tooth; CYP2D6¼cytochrome P450IID6; C6orf79¼chromosome 6 open reading frame 79 gene;
DRD3¼dopamine D3receptor gene; DTNBP1¼dystrobrevin binding protein1gene; ERK1, 2¼extracellular
signal-regulated kinase1, 2; ET¼essential tremor; FMR1¼fragile X mental retardation1gene; FXTAS¼fragile
X-associated tremor/ataxia syndrome; Gabra1¼gamma-aminobutyric acid A receptor a1; GAT1¼GABA transporter
subtype1; GFOD1¼glucose^fructose oxidoreductase domain containing protein1gene; GMPR¼guanosine monophosphate
reductase gene; HMSN¼hereditary motor and sensory neuropathy; HS1BP3¼HS1-binding protein 3 gene; JARID2¼Jumonji
ATrich interactive domain 2 gene; JNK¼c-Jun NH2-terminal kinase; LD¼linkage disequilibrium; LRRK2¼leucine-rich
repeat kinase 2 gene; MAPK¼mitogen-associated protein kinase; MCR¼minimal critical region;
MTHFR¼methylenetetrahydrofolate reductase gene; MYLIP¼myosin regulatory light chain interacting protein gene;
NACP¼alpha-synuclein gene; NHLRC1¼Nhl repeat-containing gene1; NOL7¼nucleolar protein 7 gene;
PHACTR1¼phosphatase and actin regulator1gene; PMP2¼peripheral myelin protein-22 gene; RANBP9¼RAN binding
protein 9 gene; SAPK¼stress-activated protein kinase; SCA1 ,12¼spinocerebellar ataxia gene, type1, type12; SIRT5¼silent
mating-type information regulation-2 homologue 5 gene; SMAX1¼X-linked spinal and bulbar muscular atrophy, type1;
TBCID7¼TBCI domain family, member 7 gene
Received August 8, 2006. Revised January 6, 2007 . Accepted January 8, 2007 . Advance Access publication March12, 2007
Clinical features and epidemiology
Essential tremor (ET), one of the most common neurolo-
gical disorders, is characterized by postural tremor, which
worsens with movement (Jankovic, 2002; Thanvi et al.,
2006). While action tremor is the clinical hallmark of this
illness, it can also be found in a variety of disorders.
For the purposes of this review, we define ET according to
the clinical criteria proposed in the Consensus Statement
on Tremor by the Movement Disorder Society (Deuschl
et al., 1998). A growing body of evidence suggests that this
disorder is not monosymptomatic but heterogeneous, as it
is associated in some cases with parkinsonism, myoclonus,
dystonia, cerebellar dysfunction and other motor and sen-
sory (e.g. hearing impairment) abnormalities (Jankovic,
2002; Ondo et al., 2003). Several studies have demonstrated
that non-motor features (mild cognitive deficits and
personality changes) may occur in patients with ET
(Gasparini et al., 2001; Lombardi et al., 2001; Vermilion
et al., 2001; Lacritz et al., 2002; Troster et al., 2002;
? 2007 The Author(s)
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by guest on May 30, 2013
Chatterjee et al., 2004; Louis, 2005). In two recent case-
control studies, patients performed more poorly on formal
neuropsychological testing than control subjects without
tremor. A complaint of forgetfulness and higher frequency
of dementia was also marginally more common in patients
with late-onset ET (Benito-Leon et al., 2006a, b). The
occasional coexistence of this disorder and other neuro-
logical diseases including Parkinson’s disease, and dystonia
in the same individual or the same family presents a
diagnostic challenge (Geraghty et al., 1985; Jankovic, 2000;
Jankovic et al., 2004; Shahed and Jankovic, 2006). Several
studies have shown that a subset of ET patients may be
predisposed to developing Parkinson’s disease. This associa-
tion is supported by the following evidence: (1) in some
Parkinson’s disease patients, a long-standing postural
tremor in the hands may precede the onset of parkinsonian
features by several years or decades; (2) functional
neuroimaging suggests that some ET patients have dopa-
minergic deficit (Schwartz et al., 2004) and (3) both ET and
Parkinson’s disease phenotypes have been described in
some families and autopsy studies have demonstrated Lewy
body pathology in brains of ET patients (Louis et al.,
2006; Shahed and Jankovic, 2006).
Estimates of the crude prevalence of ET range widely
from 0.008 to 22%, and factors that contribute to the
broad range include differences in study design that
influence validity and differences in characteristics of
study populations that influence comparability of studies.
Louis et al. evaluated that the prevalence of ET worldwide
ranges probably from 0.41 to 3.92% by extraction data
from 5 of 19 studies with the conditions that each
(i) provided diagnostic criteria for ET, (ii) defined ET as
an action tremor and (iii) used community-based rather
than service-based designs (Louis et al., 1998; Benito-Leon
et al., 2005). There are no validated diagnostic tests for
ET, but several clinical criteria have been proposed,
(TRIG), National Institutes of Health Essential Tremor
Consortium and Consensus Statement on Tremor by the
Jankovic, 2002). Lack of consensus on the diagnostic
criteria for ET is an impediment to accessing accurate
Despite these limitations in defining the full spectrum of
ET, typically it is not difficult to diagnose. Its prevalence
increases in the elderly and may be as high as 14% in
people over 65 years (Moghal et al., 1994). Rare cases have
been reported in newborns and infants, but childhood-
onset ET is not unusual (Jankovic et al., 2004), and ?5% of
new ET cases arise during childhood (Louis et al., 2005).
Although prevalence among adults is similar in men and
women (Louis et al., 1998), the odds of developing the
disorder are 3-fold higher in boys than girls. Head tremor is
more prevalent in female than in male adults with ET
(Jankovic et al., 2004; Louis et al., 2005). Mortality rates are
not increased (Rajput et al., 1984, 2004; Jankovic et al.,
(Deuschl et al., 1998;
1995), but the tremor may be quite troublesome and
in some medically refractory cases surgical treatment
(e.g. deep brain stimulation) may be necessary (Pahwa
et al., 2006).
Genetics of ET
Twin and family studies have provided evidence for a
genetic basis for ET in many but not all cases (Busenbark
et al., 1996; Tan et al., 2000; Jankovic and Noebels, 2005).
Linkage mapping efforts have found at least three loci for
familial ET (EMT1, EMT2 and a locus on 6p23) (Shatunov
et al., 2006), and a susceptibility variant (Ser9Gly) in the
dopamine D3 receptor gene (DRD3) has been identified
by association analysis (Jeanneteau et al., 2006; Lucotte
et al., 2006). Here we review the genetic aspects of ET,
focusing on recent discoveries and how these findings
may open a window into a better understanding of disease
There is a wide range of familial history reported in ET
patients, ranging from 17 to 100%, according to various
studies (Busenbark et al., 1996), but most studies indicate
that it is a familial disorder in 50–70% of patients, and the
frequency of family history is inversely proportional to
the age at onset (Sullivan et al., 2004; Louis and Ottman,
reportedly unaffected relatives is of limited use given the
low sensitivity of family history; the neurological examina-
tion remains the only valid means of ascertaining cases of
ET among relatives (Louis et al., 1999, 2001). While familial
cases are less frequent in community-derived populations,
they constitute a majority in those referred for medical
attention (Louis et al., 2001). The occurrence of non-
familial or ‘sporadic’ ET, phenomenologically identical
to the familial version, is well-recognized and possible
‘genetic causes’ of sporadic ET include reduced penetrance
non-Mendelian/multifactorial inheritance and phenocopies.
The genetics of ET is not well understood and twin studies
provide a powerful tool to study it. Pairwise concordance in
monozygotic twins was ?2 times that in dizygotic twins
(0.60 monozygotic, 0.27 dizygotic), indicating that genetic
and non-genetic factors contribute to pathogenesis (Tanner
et al., 2001). In one community-based study the relative
risk in first-degree relatives of subjects with ET was
only 4.7%, much lower than the 50% expected assuming
autosomal dominant inheritance with complete penetrance
(Louis, 2001). This rate is also lower than would be
expected for autosomal recessive inheritance (25%) and
may suggest that ET is an autosomal dominant gene with
very low penetrance, or not inherited as a single gene
disorder but rather behaves as a complex disorder requiring
Alternative explanations include a polygenic or mitochon-
drial origin (Louis, 2001), and even autosomal recessive and
X-linked patterns of inheritance can not be excluded
Genetics of essential tremorBrain (2007),130,1456^1464 1457
by guest on May 30, 2013
(Baughman et al., 1973). Furthermore, recently Ma et al.
(2006) found a non-Mendelian preferential transmission
of the affected allele in several families with multiple
affected membersand apparent
inheritance. Genetic deficiency or non-genetic factors may
exert sole or synthetic roles in the development of ET in
independent patients or families.
Genetic loci of ET
ET-like tremor seems to be common and a clinically
significant component of the male supernumerary X syn-
dromes and supernumerary Y syndromes (Baughman et al.,
1973). A 14-year-old boy with 48, XXYY karyotype was
reported to present with postural tremor and a slight
retardation of psychomotor development. In contrast to
other cases with 48, XXYY syndrome, in this pubertal patient
the testicles were of normal size, he had a small stature, and
showed no behavioural disturbances (Donati et al., 1992).
These findings suggest that dosage alteration of genes on sex
chromosomes may be responsible for an ET phenotype.
At least three disease loci of ET have been identified by
molecular genetic analysis (Table 1).
In 1997, Gulcher et al. (1997) mapped a familial ET gene to
chromosome 3q13 (FET1; ETM1) by a genome-wide scan
in 16 Icelandic families with 75 individuals affected by
definite (pure) tremor using TRIG criteria (Findley and
Koller, 1995), in whom FET1 was apparently inherited as
a dominant trait. The ETM1 locus spans ?10cM region
around the marker D3S1267. More recently, a Ser9Gly
variant in the DRD3 gene, located in the ETM1 locus,
was found associated with risk and age at onset of ET
(Jeanneteau et al., 2006). The DRD3 gene encodes the
dopamine D3 receptor, a member of the D2 family of
dopamine receptors. D3 receptors may be involved in the
regulation of locomotion as DRD3 protein is expressed in
the Purkinje cells of the rat cerebellum, which has been
implicated in the pathogenesis of ET (Jeanneteau et al.,
2006). DRD3 has been also reported to mediate ERK
activation in HEK-293 cells (Beom et al., 2004). In HEK293
transfected cells, the functional Gly9 variant increased
dopamine affinity 4–5 times. Furthermore, the Gly9 variant
was associated with increased dopamine-mediated cyclic
AMP response and the mitogen-associated protein kinase
(MAPK) signal was prolonged, as compared to the Ser9
variant. In mammalian cells, at least three groups of
mitogen-activated protein kinases (MAPKs) have been
identified: the extracellular signal-regulated kinases (ERK1
and 2, which increase the kinase activity of ERK1/2 to
regulate many cellular events such as differentiation,
proliferation, cellular excitability and acute hormonal
responses), the p38 protein kinases and the c-Jun NH2-
terminal kinases (JNKs; also referred to as stress-activated
protein kinases or SAPKs) (McDonald et al., 2000). It is of
interest that the leucine-rich repeat kinase 2 gene (LRRK2)
G2019S and I2020T mutations, which have been associated
with autosomal dominant Parkinson’s disease, have now
been shown to increase the catalytic activity of the
MAPKKK domain, a part of the LRRK2 protein (Deng
et al., 2005b, 2006a, b), and LRRK2 mutations eventually
also lead to the activation of downstream MAPK kinases.
Abnormalities in the JNK signalling pathway may also
account for dopaminergic cell degeneration in patients with
LRRK2 mutation. An increase in MAPK activity (such as
induced by the DRD3 Gly9 variant or by some LRRK2
mutations) may be a common mechanism partly respon-
sible for the pathogenic events leading to ET and
Parkinson’s disease, which may explain the observed over-
lap in phenotype or coexistence of ET and Parkinson’s
disease in some cases (Shahed and Jankovic, 2006). It is not
clear whether the Ser9Gly variant has been shown to
cosegregate with the disease in the original 16 Icelandic
families linked to ETM1 (Gulcher et al., 1997).
ETM2 (2p24.1 ,OMIM 602134)
In 1997, Higgins et al. (1997) mapped the ETM2 gene to
a 15-cM candidate interval on chromosome 2p22–p25 by
linkage analysis in a large American family of Czech descent
with dominantly inherited ‘pure’ ET. The disease gene was
located to a 9.1-cM interval between the D2S224 and
D2S405 loci by analysing three additional, unrelated,
American families with ET; the affected individuals in the
four families shared the same haplotype (Higgins et al.,
1998). They further found an ancestral haplotype on
chromosome 2p24.1 that segregated with the ET disease
phenotype in 29% American familial ET individuals
(N¼45) (Higgins et al., 2003). Kim et al. (2005) reported
an association analysis of three short tandem repeat
(STRs) loci in 30 sporadic ET (23 classic ET and 7 non-
classic ET) patients and 30 controls. Furthermore, eight
specific sequence variants were observed in classic ET,
but not in non-classic ET patients or healthy controls,
supporting the linkage of
An association between ET and an A265G substitution in
the HS1-binding protein 3 gene (HS1BP3, OMIM 609359)
was reported by analysis of two genes and seven transcripts
within a minimal critical region (MCR) of 464 kb (Higgins
et al., 2005, 2006), However, four recombination events
were reported in a region 51cM (D2S2150 to etm1234)
in the large family (Higgins et al., 2005), and the MCR has
been challenged (Deng et al., 2005a). Furthermore, the
association with the HS1BP3 gene was neither confirmed by
our extended study nor by other investigators (Deng et al.,
2005a; Shatunov et al., 2005). Based on our review of
previous studies (Higgins et al., 1997, 1998, 2003, 2004), we
ET to the ETM2 locus.
1458 Brain (2007),130, 1456^1464H. Deng et al.
by guest on May 30, 2013
T able1 Molecular genetic analysis of three candidate loci of ET
Author Sample sizeInheritance
Ethnic or geography
3q13 (ETM1) Gulcher et al. (1997)
Kovach et al. (2001)
Illarioshkin et al. (2002)
Lucotte et al. (2006)
Jeanneteau et al. (2006)
30 unrelated French ET
276 patients,184 controls
AD or polygenic
AD or polygenic
DRD3-Ser9gly variant (risk)
DRD3-Ser9gly variant (risk)
Ma et al. (2006) 4 familiesAD and polygenic?Not relatedDRD3-Ser9gly variant
Not 2p24.1(ETM2) Higgins et al. (1997) 1familyAD American kindred
of Czech ancestry
Higgins et al. (1998)
Higgins et al. (2004)
Kim et al. (2005)
52 ET patients, 49 controls
30 sporadic ET patients
and 30 controls
Higgins et al. (2005)AD AmericaRelated HS1BP3 (A265G variant)
HS1BP3 (A265G variant)
HS1BP3 (A265G variant)
(exclude causative or risk)
HS1BP3 (A265G variant)
(exclude causative or risk)
Higgins et al. (2006)73 familial ET, 304 controls AD America Not reported
Deng et al. (2005a) 222 familial ET,132 controlsNot reported North AmericaNot reported
1family ADNorth America Not related
Shatunov et al. (2005) 7 families Not reportedAmerica Not reported
Kovach et al. (2001)1familyAD Midwestern of
Ma et al. (2006)
Shatunov et al. (2006)
AD and polygenic?
SIRT5; NOL7; RANBP9;
LOC441 130; C6orf79; JARID2;
DTNBP1; MYLIP; GMPR;
SCA1; CAP2; NHLRC1
AD: autosomal dominant.
Genetics of essential tremor
by guest on May 30, 2013http://brain.oxfordjournals.org/Downloaded from
believe that the ETM2 locus may span ?9.1cM region,
between the D2S224 and D2S405 loci, and the MCR should
by studies in several families in which the known loci
have been excluded. Kovach et al. (2001) described a
38-member, 6-generation Midwestern family with ET
that did not map to either the ETM1 or the ETM2 loci.
but in one informative pedigree both ETM1 and ETM2 were
excluded (Illarioshkin et al., 2002). Ma et al. (2006) also
excluded ETM1 and ETM2 loci in four pedigrees. Recently,
genome-widenon-parametric andparametric linkage analysis
were conducted in seven mutigenerational North American
families totalling 65 patients. In two families the third ET
susceptibility locus was revealed on chromosome 6p23 with
maximal non-parametric linkage multipoint score 3.281
(P¼0.0005) and 2.125 (P¼0.0075), respectively. Linkage to
ETM1 and ETM2 was not evident in any of these families.
them was found to bear pathogenic mutations (Shatunov
et al., 2006).
ET has beensuggested
Candidate gene analysis for ET
Many studies have documented an overlap between the
ET phenotype and other neurological diseases including
Parkinson’s disease, dystonia, myoclonus, hereditary periph-
eral neuropathy and other neurological disorders (Jankovic,
2002; Shahed and Jankovic, 2006). Therefore, analyses of gene
abnormalities known to cause the associated neurological
disorders may provide insight into the genetics of ET.
Analysis of Parkinson’s disease-associated
ET has been hypothesized to be a risk factor for the
development of Parkinson’s disease and some patients with
Parkinson’s disease report a long-standing history of bilateral
upper extremity postural tremor long before the onset of
parkinsonian features, such as rest tremor, bradykinesia and
postural tremor, the Parkinson’s disease-related postural
tremor often occurs after a long latency, lasting ?10–20s
(up to a minute or even longer), whereas there is usually no
delay in the onset of postural tremor caused by ET when the
arms assume horizontal position (Jankovic et al., 1999).
Mutations in the parkin gene is the most common cause for
early onset Parkinson disease (EOPD), which is responsible
for 49% of familial EOPD and 18% of sporadic EOPD
(Lucking et al., 2000). No mutation in the parkin gene was
identified in 110 unrelated Italian ET patients (Pigullo et al.,
2004). Several studies observed an association of alpha-
the alpha-synuclein promoter region) with Parkinson’s
disease, but other studies failed to confirm this association
and an inverse association between the alleged risk allele and
Parkinson’s disease was reported in a Japanese population
(Kruger et al., 1999; Farrer et al., 2001; Mizuta et al., 2002;
Holzmann et al., 2003; Spadafora et al., 2003; Pals et al., 2004;
Hadjigeorgiou et al., 2006). Recently, NACP-Rep1 was found
associated with an increased risk of Parkinson’s disease by
analysis of 2692 cases and 2652 controls (Maraganore et al.,
2006). Tan and colleagues (2000) confirmed that the 263bp
variant was significantly more frequent (OR¼6.42) in
American ET patients (46 cases) compared with healthy
controls (100 cases). Pigullo et al. (2003), however, repeated
the association study on 106 Italian patients and 90 controls
and failed to identify all 13 alpha-synuclein-specific haplo-
types as susceptibility factors for ET. The contrasting results
and lack of replication for the association of such variant with
ET could depend on the very small number of patients and
controls in both studies, and therefore these results are not
conclusive and larger studies would be necessary to address
this issue. Of interest was that one female Parkinson’s disease
patient harboring LRRK2 IVS33þ6T!A variant presented
initially with a typical ET phenotype and her symptoms
responded well to propranolol (Skipper et al., 2005).
Investigation of this variant in ET or Parkinson’s disease
with ET patients may provide some insights into the
genetics of ET. We found none of LRRK2 G2019S, I2012T
and I2020T mutations in 272 ET patients, suggesting that
they are rare causes of Caucasian ET (Deng et al., 2006a) and
other mutations in the LRRK2 gene may be investigated in
ET patients. Although an association between cytochrome
P450IID6 (CYP2D6) variant and Parkinson’s disease has been
reported, the study of Agundez et al. (Agundez et al., 1997)
indicates that variants in the CYP2D6 gene do not seem to
be a major factor in determining susceptibility to ET.
Analysis of dystonia-associated gene
Although the frequent coexistence of ET and dystonia has
been reported in individual families (Jankovic et al., 1997),
and autosomal dominant idiopathic torsion dystonia shares
some phenotypic features with ET, such as postural tremor
in body parts not affected by dystonia (Jankovic and Mejia,
2005), tight linkage to the DYT1 locus on chromosome
9q32-34 was excluded in two independent studies by analy-
sis of 13 families with ET (Conway et al., 1993; Durr et al.,
1993). In 2002, Illarioshkin et al. (2002) reported that
mutation analysis of the DYT1 gene did not reveal the
typical GAG deletion in ET patients.
Analysis of other genes
Postural tremor similar to that seen in ET has been
reported in patients with X-linked spinal and bulbar
muscular atrophy, type 1 (SMAX1, OMIM 313200), also
called Kennedy disease, associated with androgen insensi-
tivity syndrome (AIS; OMIM 300068), which is caused by
a mutation characterized by expansion of CAG repeats in
the androgen receptor gene (AR, OMIM 313700) on the
1460Brain (2007),130, 1456^1464H. Deng et al.
by guest on May 30, 2013
X chromosome (La Spada et al., 1991; Jakubiczka et al.,
1997; Sperfeld et al., 2002). A man diagnosed with ET,
but found to have increased CAG repeats in the AR gene
consistent withKennedy disease,
(Kaneko et al., 1993). Although he had postural tremor
of his fingers, the diagnosis of Kennedy syndrome is
supported by the presence of fasciculations in facial muscles
and long-duration, high-amplitude polyphasic motor units,
with decreased recruitment on voluntary contraction in
limb muscles along with evidence of motor neuropathy by
Spinocerebellar ataxia type 12 (SCA-12) is a slowly
progressive autosomal dominant cerebellar ataxia (ADCA)
that differs from other SCAs because it typically begins with
tremor of head and arms, often diagnosed as ET. Nicoletti
et al. (2002) investigated 30 patients with familial ET
from southern Italy and found none with the SCA-12
Fragile X-associated tremor/ataxia syndrome (FXTAS) is
a progressive adult-onset tremor/ataxia syndrome caused by
premutations in the fragile X mental retardation 1 gene
(FMR1). Major features of the syndrome include intention
tremor, gait ataxia and parkinsonism in men over 50 years
of age (Leehey et al., 2003; Jacquemont et al., 2004), and
studies of ours and others showed permutation of FMR1
probably plays little or no role in the pathogenesis of ET in
Cacausian and Asian patients (Deng et al., 2004; Garcia
et al., 2004; Tan et al., 2004).
C677T variant of methylenetetrahydrofolate reductase gene
(MTHFR) has been associated with neurodegenerative dis-
orders including Parkinson’s disease and Alzheimer’s demen-
tia (Chapman et al., 1998; Pollak et al., 2000; Yasui et al.,
2000; Nakaso et al., 2003). Sazci et al. (2004) reported that
the C677C/A1298A compound genotype provided protec-
tion for ET, while the MTHFR 677T, 1298C alleles and
MTHFR T677T genotype and T677T/A1298A, and C677C/
C1298C compound genotypes are genetic risk factors for
ET in Turkey. The correlations must be confirmed in
different ethnic populations and by functional studies.
Potential loci and genes of ET
ET-like tremor was found in patients with hereditary neuro-
pathy including hereditary motor and sensory neuropathy
(HMSN; Charcot–Marie–Tooth, CMT) and the Roussy–Levy
syndrome (RLS, OMIM 180800), etc (Cardoso et al., 1993;
Auer-Grumbach et al., 1998). ET-like tremor was observed
in an X-linked CMT (CMTX) patient who carried 13-bp
mistimed peripheral inputs due to neuropathy may cause
tremor irrespective of an intact central processor (Bain et al.,
1996), some features of ET can be part of the phenotypic
spectrum of some peripheral neuropathies and therefore
genes causative of these neuropathies including connexin-32
and the peripheral myelin protein-22 gene (PMP22) could
be regarded as potential candidates for ET.
Animal models with genetic deficiency
Animal models are important because they provide insights
into the pathophysiology of human disease and may be useful
in the development of novel drugs. Gamma-aminobutyric
acidAreceptor a1 (Gabra1?/?) mice were reported to exhibit
postural and kinetic, alcohol-responsive tremor that is
characteristic of ET disease (Chiu et al., 2005), but no
pathogenic mutations in the GABRA1 gene have been
found by testing 76 patients with familial ET (Deng et al.,
2006c). Mouse GABA transporter subtype 1 (GAT1) knock
out mice exhibit gait abnormality, constant 25–32Hz
tremor, which is aggravated by flunitrazepam, reduced
rotarod performance and reduced locomotor activity in the
home cage. As disturbed GABA-ergic transmission may play
a role in the pathogenesis of ET, suggested by low CSF
GABA concentrations in ET patients compared to controls
(Mally et al., 1996), and the tremor can be suppressed by
medications that work by GABA-ergic mechanisms, includ-
ing alcohol and benzodiazepines, human GAT1 gene may
be a possible candidate gene for ET.
Current problems in ET genetics and
prospects for strategy
Although the preponderance of data supports the view that
ET susceptibility is inherited in an autosomal dominant
pattern, other models should be considered. Further under-
standing of the extent of familial aggregation, extent of
genetic heterogeneity and mode of inheritance is essential
for clinical counselling and for further research aimed at
localizing and identifying susceptibility genes.
The various terms used in the study of genetics of
various disorders, including ET, need to be clearly defined.
Thus, the term ‘sequence variation’ is used to prevent con-
fusion with the terms ‘mutation’ and ‘polymorphism’. The
term ‘mutation’ should be reserved for a sequence variation
that is disease-causing or apparently disease-associated,
although it can also be used to describe any sequence
change. However, a polymorphism largely means a ‘non-
disease-causing change with a frequency of 1% or higher in
the population’ (den Dunnen and Antonarakis, 2001). We
suggest that the term ‘variant’ is used when it is not certain
whether change in nucleotide or the amino acid is a risk or
a cause for disease, or a confirmed risk factor for disease.
This term encompasses ‘polymorphism’ and ‘mutation’.
The DRD3 Ser9Gly variant, a potential risk factor for
schizophrenia, obsessive–compulsive personality disorder,
tardive dyskinesia and other disorders (de Leon et al., 2005;
Keri et al., 2005; Light et al., 2006), was also recently
found associated with increased risk for ET. This common
Gly9 variant is probably a risk allele and may become
pathogenic when internal or external environmental stress
is present. Identification of variants that are associated
with ET, especially if they lead to an abnormal gene
expression or a change of amino acid sequence may exert
Genetics of essential tremorBrain (2007),130,1456^1464 1461
by guest on May 30, 2013
a combined or synergistic effect on susceptibility to disease
(Sivagnanasundaram et al., 2000).
In future genetic studies it may be useful to subdivide
ET into several subtypes based on whether it is present as
a monosymptomatic disorder or whether it coexists with
other neurological diseases, age at onset and other variables
(Benito-Leon et al., 2006). For Mendelian inheritance ET
pedigrees, regular mapping–cloning strategy including para-
metric linkage analysis and candidate gene screening may
be employed, while non-Mendelian inheritance pedigrees or
sporadic patients need to validate a gene–disease relation-
ship through comparative analysis of linkage disequilibrium
(LD) and disease-association patterns (Jonsson et al., 2003;
Farrer, 2006). Although comparison of genotypes between
ET patients and controls among different ethnicities
may lead to the identification of disease-specific and
ethnicity-specific genome variations, most insight might
be gained by studying the functions of genes. Identification
of the defective gene or risk allele will enable a better
understanding and classification of ET, as well as genetic
counselling and therapy of this disorder.
This work was supported by grants from the National
Parkinson Foundation to the Baylor College of Medicine
Center of Excellence, Parkinson’s and Movement Disorder
Foundation (H.D.), Helis Foundation and NS 043567
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