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Mild Tremor in Relatives of Patients With Essential Tremor
What Does This Tell Us About the Penetrance of the Disease?
Elan D. Louis, MD, MS;
Blair Ford, MD;
Steven Frucht, MD;
Ruth Ottman, PhD
Arch Neurol. 2001;58:1584-1589.
ABSTRACT
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Background Mild tremor may occur in relatives of patients with essential tremor
(ET). However, this phenomenon has not been studied quantitatively or with
a comparison group. Such a study may provide information on the penetrance
of ET.
Objective To obtain data on the magnitude of tremor in case and control relatives
who did not meet diagnostic criteria for ET.
Methods Cases with ET and control subjects from the Washington Heights–Inwood
community in northern Manhattan, NY, were enrolled in a family study. Their
first- and second-degree relatives underwent a videotaped tremor examination.
Two neurologists rated the severity of tremor, assigning a total tremor score
(0-36 [maximum]). Data were analyzed on 201 case relatives and 212 control
relatives who did not meet diagnostic criteria for ET.
Results The mean total tremor score of first-degree case relatives was higher
than that of first-degree control relatives (4.9 vs 3.9; P<.003). Total tremor scores for second-degree relatives did not
differ (4.1 vs 4.2; P = .68). A larger percentage
(55.2% vs 36.6%; P = .01) of first-degree case relatives
had total tremor scores of 4 or more. Among first-degree relatives who were
older than 60 years, 13 case relatives (59.1%) and 18 control relatives (45.0%)
had total tremor scores of 4 or more.
Conclusions A considerable number of seemingly normal case relatives may have a
genetic predisposition for tremor. Even among older case relatives ( 60
years of age), there was an increased prevalence of higher tremor scores,
suggesting that in that age group, subclinical ET may be present and penetrance
still may not be complete.
INTRODUCTION
RELATIVES OF patients with essential tremor (ET) may have a genetic
predisposition for ET, yet express only mild tremor that is not severe enough
to meet diagnostic criteria for ET.1, 2, 3
This group is particularly important because they pose one of the more difficult
diagnostic challenges in genetic linkage studies.1, 2, 3, 4
Previous studies1, 5, 6
have focused on tremor in more severely affected relatives who fulfilled diagnostic
criteria for ET. The degree of tremor in mildly tremulous relatives has not
been the focus of study, nor have these relatives been compared with control
relatives, making it difficult to interpret their physical findings in a meaningful
context. The presence of mild tremor in relatives may be a useful area of
study, because it could provide additional information on the penetrance of
the disease. Penetrance is one of the central variables used in statistical
analyses in genetic linkage studies.2, 4
The penetrance of ET is believed to be complete by age 65 to 70 years,1, 4, 5 although there are few
data.
We examined several hundred relatives of cases with ET and a similar
number of relatives of normal control subjects as part of a community-based
family study. In a related study6 we presented
data primarily on relatives who had received diagnoses of ET. In this study,
we hypothesized that, even among relatives who were not diagnosed as having
ET, mild tremor might be more prevalent among case relatives than among control
relatives.
SUBJECTS AND METHODS
SUBJECTS
As previously described,6, 7
from 1992 to 1994, 98 subjects with ET were ascertained from the Washington
Heights–Inwood community in northern Manhattan, NY. From 1995 to 1999,
these 98 subjects were contacted to enroll them in the Washington Heights–Inwood
Genetic Study of Essential Tremor, a family study of ET.8
Seventy-two (73%) of 98 subjects were enrolled.6
Each case was matched by age (5-year strata), sex, and ethnicity (white non-Hispanic,
African American non-Hispanic, Hispanic) to a healthy control subject from
the same community who had no neurologic symptoms or action tremor on neurologic
examination. Subjects were informed that the aim of the Washington Heights–Inwood
Genetic Study of Essential Tremor was to assess health conditions in northern
Manhattan families.
EVALUATION OF PROBANDS (CASES WITH ET AND CONTROL SUBJECTS)
Cases with ET and control subjects underwent a semistructured interview
and a videotaped tremor examination, conducted in person by a study physician.8, 9, 10 During the 30-minute
interview, clinical information on tremor, medical conditions, and medications
was collected. The 10-minute videotaped tremor examination elicited tremor
during 1 posture (sustained arm extension) and 5 actions (pouring water, drinking,
using a spoon, finger-to-nose movements, and drawing spirals) performed with
the dominant and nondominant arms (12 tests in total). The examination was
videotaped with a manually operated video camera recorder (Sony CCD-TR700;
Sony, Park Ridge, NJ); Hi-8 videotapes were used to increase the resolution
of the recording.10
All videotapes were independently reviewed by 2 of us (E.D.L. and either
B.F. or S.F.), who rated the severity of the tremor.8, 9, 10
Ratings were as follows: 0 (no visible tremor), 1 (low-amplitude or intermittent
tremor), 2 (tremor of moderate amplitude, clearly oscillatory [alternating
between extremes with a definable period], and usually present), and 3 (large-amplitude
tremor). A total tremor score (0-36 [maximum]) was calculated for each subject
by the addition of the 12 scored items.8, 9, 10
The final total tremor score was the average of the 2 raters' scores. Interrater
agreement between E.D.L. and B.F. was substantial (weighted  statistic, w = 0.62-0.78).11 Agreement between E.D.L.
and S.F. was similarly high (w = 0.89).
Each neurologist independently assigned a diagnosis of ET or normal
on the basis of review of the interview and videotaped examination.8, 9, 10 As previously described,8, 9, 10 diagnoses of ET required,
at a minimum, a tremor rated as 2 or greater during at least 3 actions. In
a previous study of 103 normal subjects,10
8.7% had tremor rated as 2 or greater on 2 tasks, but none had tremor rated
as 2 or greater on 3 tasks, suggesting that 3 ratings of 2 or greater is not
within the range of normal.
Because there is no definitive diagnostic test for ET, clinical criteria
are still somewhat arbitrarily defined.8, 9, 10, 12
We used diagnostic criteria that were based on our previous experience evaluating
ET cases and our review of the tremor literature.13
In previous studies, we found that diagnoses based on these criteria could
be reliably assigned by independent raters,11
and in 94.4% of instances, these clinical diagnoses agreed with independent
electrophysiologic diagnoses based on quantitative computerized tremor analysis.14
EVALUATION OF RELATIVES
Each case and control was asked to name all living or dead first- and
second-degree relatives. Relatives who were 18 years of age and older, for
whom contact information (telephone number and address) was available, and
who lived within 2 hours of the medical center were contacted and asked to
participate in a study of health in families. Those who agreed to participate
(234 case relatives [82.7%] and 226 control relatives [79.6%])6
were given the same evaluation as the probands.8, 9, 10
Videotapes were rated by 2 neurologists (E.D.L. and either B.F. or S.F.),
blinded to the subjects' status as case, control, or relative, and diagnoses
were assigned.
REEVALUATION OF CASE PROBANDS
As previously described,6 40 probands
with ET underwent an annual evaluation. Final assignment of a diagnosis of
ET required that both study neurologists had diagnosed ET at baseline and,
when available, at all of the follow-up assessments. Fifty-nine (82%) of 72
cases with ET met these criteria for ET; 13 did not.
FINAL SUBJECT SELECTION
We did not exclude the 13 enrolled control subjects whose matched case
had been excluded, as this would have resulted in loss of valuable data on
their relatives. Despite this, the 59 cases with ET and 72 control subjects
did not differ by age, sex, or ethnicity
(Table 1).
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Characteristics of 544 Study Subjects
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STATISTICAL ANALYSES
Data were analyzed by  2 tests (categorical variables)
and Pearson correlation coefficients. Total tremor score was not normally
distributed; it also correlated with age. When differences were assessed between
total tremor scores, data were logarithmically transformed, and a 1-factor
analysis of covariance (ANCOVA) with age as the covariate was used. In addition,
in multiple linear regression analyses (enter method), the logarithm of the
total tremor score, which was normally distributed, was used as the outcome
variable.
RESULTS
We examined and videotaped 460 relatives (234 relatives of cases and
226 relatives of control subjects). Thirty-three case relatives and 14 control
relatives who were diagnosed as having ET were excluded from these analyses,
leaving 201 case relatives and 212 control relatives (Table 1). There were fewer whites among first-degree case relatives
than among first-degree control relatives, although total tremor score did
not differ by race.
Clinically detectable tremor (defined as a total tremor score >0) was
present in 193 (96.0%) of 201 case relatives and 207 (97.6%) of 212 control
relatives. There was an association between total tremor score and current
age (r = 0.11, P = .03),
but not between the logarithm of the total tremor score and current age (r = 0.07, P = .17). The mean total
tremor score among first-degree case relatives (4.9; median, 4.5; range, 0-13)
was higher than that of first-degree control relatives (3.9; median, 3.0;
range, 0-12; ANCOVA F = 8.80, P = .003), whereas
among second-degree relatives, the mean total tremor scores were similar (mean,
4.1 vs 4.2; ANCOVA F = 0.18, P = .68). It is important
to emphasize that these individuals had very mild tremor that was well within
the range of normal. A given subject could be assigned a total tremor score
of 4 if he or she had a rating of 1 on only 4 items and absolutely no tremor
on the remaining 8 of 12 scored items. To further place these total tremor
scores in perspective, our 59 control subjects had a mean total tremor score
of 6.6 (range, 0-16.5) and our probands with ET (excluding those with isolated
head tremor) had a mean total tremor score that was considerably higher (19.4;
range, 10.5-34.5).
Across age, first-degree relatives of cases had higher total tremor
scores than did first-degree relatives of control subjects (Figure 1), and multiple regression analyses (see below) demonstrated
that this difference was significant. For second-degree relatives, the regression
lines were approximately superimposed (Figure
2).
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Figure 1. Total tremor score by current
age for first-degree relatives of cases vs first-degree relatives of control
subjects. The lines are the result of a regression analysis.
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Figure 2. Total tremor score by current
age for second-degree relatives of cases vs second-degree relatives of control
subjects. The lines are the result of a regression analysis.
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The mean total tremor score was higher in men than in women. This was
observed both in case relatives (4.9 vs 3.5; ANCOVA F = 24.53, P<.001) and control relatives (6.1 vs 3.7; ANCOVA F = 9.83, P = .002). There were no differences between sexes in use
of a medication that could enhance physiologic tremor (including lithium carbonate,
theophylline, levothyroxine sodium, prednisone, valproate sodium, oral hypoglycemic
agents, and asthma inhalers), use of a medication that could diminish tremor
(including ß-blockers and calcium channel blockers), or presence of hyperthyroidism
by history.
There were no differences in total tremor score by history of hyperthyroidism,
use of a medication that could enhance physiologic tremor, and use of a medication
that might diminish tremor.
In a multivariate linear regression analysis restricted to all first-degree
relatives, type of subject (case relative vs control relative, ß = .14, P = .001) and male sex (ß = .24, P<.001) were associated with total tremor score (r2 of model = 0.17; P<.001).
An independent association with age (ß = .002, P
= .14) did not reach statistical significance.
Although there was a great deal of overlap, the distribution of total
tremor scores seemed to differ in first-degree case and control relatives
(Figure 3), with a larger proportion
of case relatives having total tremor scores of 4 or greater (48 [55.2%] of
case relatives vs 37 [36.6%] of control relatives; difference, 18.6%; 2 = 6.1, P = .01). This difference was not
due to a difference between first-degree case and control relatives in mean
age or sex (Table 1).
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Figure 3. Total tremor scores in first-degree
relatives of cases vs first-degree relatives of control subjects.
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There were 22 first-degree case relatives and 40 first-degree control
relatives who were aged 60 years and older (mean age among case relatives,
72.5 years; range, 60-93 years; mean age among control relatives, 71.8 years;
range, 60-88 years; F = 0.09, P = .76). In this age
group, 13 first-degree case relatives (59.1%) and only 18 first-degree control
relatives (45.0%) had total tremor scores of 4 or greater (Figure 4). Although the difference (14.1%) was similar to that observed
for the entire group (18.6%), the sample size was considerably smaller and
statistical significance was not attained (2 = 1.1, P = .29).
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Figure 4. Total tremor scores in first-degree
relatives of cases vs first-degree relatives of control subjects. All subjects
were older than 60 years.
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COMMENT
Relatives with mild tremor represent a difficult diagnostic challenge
in genetic studies of ET.1, 2, 3
To our knowledge, these individuals have not been studied systematically,
nor have they been compared with relatives of normal control subjects.
We plotted the distribution of total tremor scores in the 2 groups of
relatives, excluding individuals who had been diagnosed as having ET, and
found that total tremor scores of 4 or greater were approximately 20% more
prevalent among first-degree relatives of cases than among first-degree relatives
of control subjects. A total tremor score of 4 is well within the range of
normal. In fact, the mean total tremor score of our 59 control subjects (6.6)
was higher than this (because the control subjects were significantly older
[mean age, 79.2 years] and there was a correlation between age and total tremor
score). While the existence of mild, partially expressed forms of ET among
relatives of cases has been reported previously,1, 2, 3
most references to these individuals allude to relatives whose tremor was
considered borderline abnormal rather than clearly within the range of normal.
Our data draw attention to the latter.
There are several possible explanations for the observed difference
in distribution of tremor among case and control relatives. First, there may
be subclinical forms of ET among relatives of ET cases. We demonstrated that
the mean total tremor score was higher among first-degree relatives of cases
than among first-degree relatives of control subjects, but this difference
was not present when we examined more distantly related (second-degree) relatives.
This suggests that a genetic predisposition for tremor, and possibly ET, may
have contributed to the observed difference in tremor scores. While the relatives
may have a predisposition to develop tremor, since they did not have ET, a
disposition for this particular type of tremor cannot be assumed. Longitudinal
follow-up data would be important to see whether the case relatives with more
tremor actually developed ET at a later date. An alternative explanation is
that there may be more enhanced physiologic tremor in relatives of cases.
We realize that we cannot fully exclude this possibility, but we explored
it by examining the proportion of case and control relatives who were taking
tremor-inducing medications or who had medical conditions (eg, hyperthyroidism)
that might result in enhanced physiologic tremor. We did not find a difference.
It is also not apparent to us why relatives of cases would be prone to developing
more enhanced physiologic tremor than relatives of controls, unless one were
to hypothesize an etiologic link between ET and enhanced physiologic tremor.
Loading the limb and measuring a change in tremor frequency may sometimes
allow one to differentiate ET from enhanced physiologic tremor, although the
role of this technique in classifying extremely mild tremors as early ET vs
enhanced physiologic tremor is still unclear. In addition, this method is
not practical in epidemiologic or genetic field studies because the equipment
is not portable. A third possibility is that our diagnostic criteria for ET
were too stringent, and that some of the case relatives who did not meet our
diagnostic criteria for ET actually had ET. This was probably not the case.
The prevalence of ET among relatives of our control subjects (6.2%)6 was actually higher than most published prevalence
estimates for ET (0.4%-3.9%),15 suggesting
that our diagnostic criteria were not overly stringent.
We also demonstrated more tremor among older (mean age, 71.5 years)
first-degree case than among first-degree control relatives. These case and
control relatives had similar ages. These findings have important implications
because they suggest that subclinical ET may still exist in as many as 15%
of relatives who have reached this advanced age. In other words, the penetrance
of ET may not be complete. The penetrance of ET is generally considered to
be complete by age 65 to 70 years,1, 4, 5
although there are very few data. One study in Sweden5
suggested that the penetrance was complete at age 70 years because the highest
registered age at onset in their cohort was 70 years, although it is apparent
from their data that there were many unaffected relatives who were older than
70 years, and it is not known how many of these carried a genetic predisposition
for ET. The most thorough study of penetrance1
suggested that the penetrance was complete by age 65 years because 46% (ie,
nearly half) of the children of cases with familial ET had developed tremor
by that age. Assuming an autosomal dominant model1, 2, 3, 4, 5
and complete penetrance, 50% of first-degree relatives of familial cases should
develop the disease. However, these calculations do not account for nongenetic
causes of ET among relatives. We reported that 11.1% of control subjects'
relatives had developed ET by age 60 years and 22.2% by age 80 years.6 Nongenetic causes of ET should be similar in relatives
of cases and relatives of controls. Therefore, assuming an autosomal dominant
model with complete penetrance and the occurrence of nongenetic forms of ET,
as many as 72.2% (rather than 50%) of first-degree relatives of familial cases
should develop the disease by age 80 years. One additional argument against
complete penetrance by age 70 years is that the incidence of the disease continues
to rise, even after the age of 80 years.16
If penetrance were complete by age 70 years, then one would have to hypothesize
that 100% of the cases that arose after the age of 70 years were sporadic.
We reported that men had higher total tremor scores than women. We are
not certain of the cause. One possibility is that men may have had more exposure
to work-related tremorogenic toxins (eg, mercury, lead, and pesticides),17, 18, 19, 20, 21
or may have engaged in more behaviors (smoking and caffeine consumption) that
were likely to enhance tremor. A hormonal or other biological difference should
be considered as well. Interestingly, the sex difference in total tremor scores
persisted even in older (60 years) subjects (6.4 in men vs 4.2 in women;
ANCOVA F = 4.31, P = .04), suggesting that postmenopausal
women have lower total tremor scores than do men of similar age.
Strengths of our study included the use of a standardized clinical assessment
of tremor severity by 2 independent neurologists with a high level of agreement.11
The total tremor score is a clinical measure of tremor severity that
correlates with physiologic measures of tremor severity, including a modified
Klove Matthews Motor Steadiness Test Battery22
and quantitative computerized tremor analysis results (eg, correlation [r] of 0.46 between total tremor score and tremor amplitude
of dominant arm tremor while writing; P<.001;
n = 60).14
Our study had limitations. We did not systematically assess smoking
or use of caffeine, both behaviors that might increase tremor. While it is
conceivable that relatives of cases might have engaged in these behaviors
to a greater extent than relatives of controls, it is unlikely that these
behaviors would have been more prevalent among first-degree relatives of cases
than among first-degree relatives of controls but not among the respective
second-degree relatives. Also, independent objective measurements of tremor
severity by methods such as electromyography or accelerometry were not routinely
performed; these would have helped to more precisely quantify the observed
difference in tremor severity between case and control relatives. Despite
this, clinical diagnoses and tremor scores were assigned by 2 neurologists
independently and blinded to knowledge of whether they were studying a relative
of a case or of a control, so that any systematic errors in diagnosis or assignment
of tremor scores would not have been differential across relative type (ie,
case vs control relative).
In summary, a considerable number of seemingly normal case relatives
may have a genetic predisposition for tremor and, possibly, ET. Even among
older case relatives (60 years of age), there was an increased prevalence
of higher tremor scores, suggesting that, in that age group, subclinical ET
may be present and penetrance still may not be complete. These data should
be of interest to individuals who are performing genetic linkage studies,
which hold the clues to the pathophysiology of ET and its treatment.
AUTHOR INFORMATION
Accepted for publication May 17, 2001.
This study was supported by grant NS01863 from the National Institutes
of Health, Bethesda, Md, and the Paul Beeson Physician Faculty Scholars in
Aging Research Award from the American Federation for Aging Research, New
York, NY.
This article was corrected 10/25/2001.
From the Gertrude H. Sergievsky Center (Drs Louis and Ottman) and the
Department of Neurology (Drs Louis, Ford, and Frucht), College of Physicians
and Surgeons, and Mailman School of Public Health (Epidemiology Division)
(Dr Ottman), Columbia University, New York, NY; and the Epidemiology of Brain
Disorders Research Department, New York State Psychiatric Institute, New York
(Dr Ottman).
Corresponding author and reprints: Elan D. Louis, MD, MS, Unit 198,
Neurological Institute, 710 W 168th St, New York, NY 10032 (e-mail:
EDL2{at}Columbia.edu).
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