Increased risk for recurrent depression in DYT1 dystonia mutation carriers

Department of Epidemiology, Columbia University, New York, New York, United States
Neurology (Impact Factor: 8.29). 09/2004; 63(4):631-7. DOI: 10.1212/WNL.64.10.1821-a
Source: PubMed


Prior studies suggest that dystonia is comorbid with affective disorders. This comorbidity could be a reaction to a chronic debilitating disorder or expression of a predisposing gene. The authors took advantage of the identification of a gene for dystonia, DYT1, to test these alternative explanations.
The authors administered a standardized psychiatric interview to members of families with an identified DYT1 mutation. The authors classified family members into three groups: mutation carriers with dystonia (manifesting carriers; n = 96), mutation carriers without dystonia (non-manifesting carriers; n = 60), and noncarriers (n = 65).
The risk for recurrent major depressive disorder was increased in both non-manifesting carriers (RR = 4.95, CI = 1.72 to 14.29) and manifesting carriers (RR = 3.62, CI = 1.00 to 10.53) compared with noncarriers. Mutation carriers also had earlier age at onset of recurrent major depressive disorder than noncarriers. The severity of motor signs was not associated with the likelihood of recurrent depression. Mutation carriers did not have an increased risk for other affective disorders, such as single major depression or bipolar disorder.
Early-onset recurrent major depression is associated with the DYT1 GAG mutation and this association is independent of motor manifestations of dystonia. These findings suggest that early-onset recurrent depression is a clinical expression of the DYT1 gene mutation.


Available from: Rachel Saunders-Pullman, MD, MPH, Nov 13, 2014
Increased risk for recurrent major
depression in DYT1 dystonia
mutation carriers
G.A. Heiman, PhD; R. Ottman, PhD; R.J. Saunders-Pullman, MD, MPH; L.J. Ozelius, PhD;
N.J. Risch, PhD; and S.B. Bressman, MD
Abstract—Background: Prior studies suggest that dystonia is comorbid with affective disorders. This comorbidity could
be a reaction to a chronic debilitating disorder or expression of a predisposing gene. The authors took advantage of the
identification of a gene for dystonia, DYT1, to test these alternative explanations. Methods: The authors administered a
standardized psychiatric interview to members of families with an identified DYT1 mutation. The authors classified
family members into three groups: mutation carriers with dystonia (manifesting carriers; n 96), mutation carriers
without dystonia (non-manifesting carriers; n 60), and noncarriers (n 65). Results: The risk for recurrent major
depressive disorder was increased in both non-manifesting carriers (RR 4.95, CI 1.72 to 14.29) and manifesting
carriers (RR 3.62, CI 1.00 to 10.53) compared with noncarriers. Mutation carriers also had earlier age at onset of
recurrent major depressive disorder than noncarriers. The severity of motor signs was not associated with the likelihood of
recurrent depression. Mutation carriers did not have an increased risk for other affective disorders, such as single major
depression or bipolar disorder. Conclusions: Early-onset recurrent major depression is associated with the DYT1 GAG
mutation and this association is independent of motor manifestations of dystonia. These findings suggest that early-onset
recurrent depression is a clinical expression of the DYT1 gene mutation.
NEUROLOGY 2004;63:631–637
The DYT1 gene on chromosome 9q34 is a major
cause of childhood and adolescent onset primary dys-
A single mutation, a GAG deletion resulting
in the loss of a glutamic acid residue in the encoded
protein, TorsinA,
accounts for all reported DYT1 as-
sociated primary dystonia.
The clinical manifesta-
tions of this mutation range from mild focal dystonia
usually affecting an arm to generalized dystonia in-
volving limbs, axial, and even cranial muscles.
etrance is estimated at only 30%; thus most
mutation carriers are clinically normal, or at least
unaffected with overt signs of dystonia.
studies in individuals with dystonia have reported
an increase of psychiatric symptoms, particularly af-
fective disorders.
The cause of this association is
unknown; it could be a reaction to a chronic debili-
tating disorder or an expression of a predisposing
gene. We took advantage of the identification of the
DYT1 gene to determine if affective disorders are
another manifestation of the mutation. We assessed
whether affective disorders occurred more commonly
in carriers, including carriers not manifesting dysto-
nia, compared to noncarriers by examining these dis-
orders in members of DYT1 families.
Subjects and methods. Participants. Subjects were recruited
from families participating in previous genetic studies of dystonia
and found to harbor the DYT1 GAG deletion.
The study was
approved by institutional review boards; all subjects gave in-
formed consent to participate. The methods for recruitment have
been described previously.
Each subject was classified as having
definite dystonia, probable dystonia, possible dystonia, no dysto-
nia, or unrateable. These classifications were made blinded to
Subjects were classified as manifesting dystonia if
they had definite or probable dystonia. We included probable be-
cause this category includes signs consistent with mild dystonia
that could be symptomatic. Non-manifesting dystonia included
possible and no dystonia. We classified individuals with possible
dystonia as unaffected (noncarriers or non-manifesting) because
muscle contractions were only remotely suggestive of dystonia and
not producing symptoms, e.g., unusual hand grip with mild excess
hand tension but normal flowing handwriting, increased blinking
with no flurries or sustained contractions.
For the present study, we excluded subjects younger than 18
years and those categorized as unrateable. Only at risk family
members were included (i.e., none were married-in and all were
mutation carriers or first-degree noncarrier relatives of mutation
carriers). We divided the sample into manifesting carriers (MC),
See also page 610
From the Department of Epidemiology of Joseph L. Mailman School of Public Health (Drs. Heiman and Ottman) and the Gertrude H. Sergievsky Center (Dr.
Ottman), Columbia University, New York; Department of Neurology (Drs. Saunders-Pullman and Bressman), Beth Israel Medical Center and Albert
Einstein College of Medicine, Bronx; Department of Genetics (Dr. Ozelius), Albert Einstein College of Medicine, Bronx, NY; Epidemiology of Brain Disorders
Research Department, New York State Psychiatric Institute (Dr. Ottman), New York; and the Department of Genetics (Dr. Risch), Stanford University, CA.
Supported by the Dystonia Medical Research Foundation (R.S.P., S.B.B., L.J.O.), the Singer Foundation (R.S.P.), and NIH grant R01-NS26656 (S.B.B.,
L.J.O., R.S.P., N.R.).
Received January 7, 2004. Accepted in final form April 26, 2004.
Address correspondence and reprint requests to Dr. Gary A Heiman, MSPH-Columbia University, 722 West 168th Street, 5th floor, Room R502, New York,
NY 10032; e-mail:
Copyright © 2004 by AAN Enterprises, Inc. 631
Page 1
non-manifesting carriers (NMC), and noncarriers (NC) of the
DYT1 mutation. Among MC, we rated dystonia as severe if it was
generalized or multifocal in distribution and mild if it was seg-
mental or focal.
All NC were non-manifesting as none of them
had probable or definite dystonia.
A total of 415 individuals met criteria for inclusion in this
study (187 MC, 125 NMC, and 103 NC). These individuals were
re-contacted by telephone and asked to participate. Individuals
who consented to participate were asked if they had undergone
genetic testing and whether they knew their carrier status, and
were then scheduled for a telephone interview. We attempted to
reach each individual at least seven times, at different times of
the day and weekends, and if we could not locate them, searched
telephone and internet databases for new addresses and phone
numbers. The interviewers were blind to genetic status and to
study hypotheses.
Measures. Independent variable. To determine DYT1 muta-
tion carrier status, DNA was extracted from whole blood following
standard protocols. We used published primers, 6418 and 6419,
for PCR amplification across the critical region of the DYT1 muta-
tion. PCR products were resolved in a denaturing 6% polyacryl-
amide gel and visualized by silver staining.
Dependent variables. Trained interviewers, blind to the indi-
viduals position in the pedigree and carrier status, administered
the computerized version of the Composite International Diagnos-
tic Interview (CIDI)WHO version (
cidi/computerizedcidi.htm) via telephone. The CIDI is a
comprehensive, fully standardized diagnostic interview used to
assess psychiatric symptomatology in epidemiologic studies
and versions have been administered over the telephone.
Affective disorders. We used the lifetime version of the CIDI
to assess whether an individuals symptoms ever met Diagnostic
and Statistical Manual of Mental DisordersIV criteria for various
affective disorders. Five categories of lifetime prevalence of affec-
tive disorders were included: any affective disorder (defined as
any major depressive disorder, dysthymia, or bipolar disorder),
any major depressive disorder (any MDD) (defined as single epi-
sode or recurrent MDD), single episode MDD, recurrent MDD
(defined as having more than one episode of depression), and
bipolar disorder. We analyzed recurrent MDD separately because
evidence suggests it is more familial.
Analysis. We first compared carriers (both MC and NMC)
with NC. Next, to exclude a difference related to symptoms of
dystonia, we separately analyzed NMC with NC, restricting the
comparison to individuals without dystonic symptoms. Last, we
analyzed MC with NC including an examination of potential con-
founding by severity. Analyses were conducted using a clustered
Cox proportional hazards model using STATA statistical soft-
We used the cluster option because of potential clustering
of the data by family membership, because more than one member
of a family was included.
Results. Study group. A total of 221 of 415 (53.3%) in-
dividuals meeting criteria participated (96 MC, 60 NMC,
and 65 NC). The nonparticipants included 56 (13%) who
refused to participate, and 138 (33%) who could not be
contacted (see figure 1 for recruitment rates by comparison
group). The 138 individuals who could not be contacted
included several subgroups: unreachable (48.6%), death
since previous participation, physical limitation, denial of
permission to contact from physician, residence overseas
(geography), previous refusal to participate, unconfirmed
The three comparison groups did not differ significantly
in refusal rates or in the proportion unreachable after nu-
merous attempts, although a somewhat higher proportion
of MC was unreachable and a lower proportion refused.
Compared to participants, subjects who refused were less
likely to be female (47.2% nonparticipants vs 54.3% partic-
ipants) or Jewish (56.6% nonparticipants vs 63.3% partici-
pants), and were older (mean age nonparticipants 53 years
vs participants 48 years), but none of these differences was
Table 1 shows the demographic characteristics of the
participating groups. Compared with NC, the NMC were
older, more likely to be Jewish, less likely to have a college
education, and had smaller families with fewer affected
family members. The MC also had smaller families and
fewer family members with dystonia than the NC. Carrier
status was not related either to sex or to genetic distance
from an affected relative.
Tests of hypotheses. All carriers and NC. Our first
analysis compared all carriers (n 156) with NC (n 65).
Only two subjects, one NMC and one NC, met criteria for
bipolar disorder. Therefore, bipolar disorder was not in-
cluded as a separate diagnostic category, but was included
as part of any affective disorder. In the univariate analysis
(table 2), the risks were not increased in carriers compared
with NC for any affective disorder, any MDD, or single
MDD. The risk for recurrent MDD was three times higher
in carriers compared to NC, although this increased risk
did not reach significance. In the multivariate analysis,
adjusting for potential confounders including ethnicity,
age, number of affected family members, and family size,
singly or in combination, did not appreciably affect the
risks for any affective disorder, any MDD, or single MDD.
However, for recurrent MDD (table 3), adjustment for the
number of affected family members led to increased risk.
Additional adjustment for ethnicity, age, education, and
family size did not appreciably alter the relative risks.
Adding a variable to the model indicating whether a sub-
ject manifested dystonia (manifesting vs non-manifesting)
Figure 1. Breakdown of recruitment
categories by the three carrier groups.
MC manifesting carriers; NMC
non-manifesting carriers; NC
632 NEUROLOGY 63 August (2 of 2) 2004
Page 2
showed that the increase in recurrent MDD was due to the
DYT1 mutation (adjusted RR 3.23, CI 1.21 to 8.62)
rather than the presence of dystonic symptoms (adjusted
RR 1.07, CI 0.43 to 2.68).
NMC and NC. Our second analysis compared NMC
(n 60) with NC (n 65). In the univariate analysis (see
table 2), the risk was not increased in NMC compared with
NC for any affective disorder, any MDD, or single MDD.
As in the analyses comparing all carriers to NC, the risk
for recurrent MDD was increased in NMC. In the multi-
variate analysis the risk for recurrent MDD (see table 3),
but not other diagnoses, increased after adjusting for the
number of family members with dystonia. Additional ad-
justment for ethnicity, age, education, and family size did
not appreciably alter the relative risks.
MC and NC. Our third analysis compared MC (n
96) with NC (n 65). The pattern of association between
the DYT1 mutation and various affective disorders in MC
was comparable in magnitude to those in the above analy-
ses. In the univariate analysis, the risk was not increased
in MC compared with NC for any affective disorder, any
MDD, or single MDD but was increased for recurrent
Table 1 Comparison of demographic variables among manifesting carriers, non-manifesting carriers, and noncarriers
Manifesting carriers,
n 96
carriers, n 60
n 65
Male 49 (51.0) 24 (40.0) 28 (43.1)
Female 47 (49.0) 36 (60.0) 37 (56.9)
Jewish 59 (61.5) 44 (73.3)* 37 (56.9)
Non-Jewish 37 (38.5) 16 (26.7) 28 (43.1)
College graduate 47 (49.0) 35 (58.3)* 31 (47.7)
College graduate 49 (51.0) 25 (47.7) 34 (52.3)
Genetic distance from
affected relative
1st degree relative 11 (18.3) 9 (13.8)
1st degree relative 49 (81.7) 56 (86.2)
Age at interview, y
49 52 (54.2) 22 (36.7)* 38 (58.5)
49 44 (45.8) 38 (63.3) 27 (41.5)
Number affected in family
5 affected members 67 (69.8)* 39 (65.0)* 33 (50.8)
5 affected members 29 (30.2) 21 (35.0) 32 (49.2)
Family size*
7 members 62 (64.6)* 34 (56.7)* 25 (38.5)
7 members 34 (35.4) 26 (43.3) 40 (61.5)
Values are n (%).
* Significantly different from noncarrier group (p 0.05, from logistic regression).
Variables categorized as bivariate for table clarity but are included as continuous in analyses.
Table 2 Comparison of unadjusted lifetime prevalence of DSM-IV affective disorders in carriers and noncarriers
n 96
n 60
n 65
All carriers vs
carriers vs
carriers vs
Any affective
26 (27.1) 18 (30.0) 14 (21.5) 1.04 (0.691.57) 1.07 (0.641.79) 0.90 (0.481.67)
Any major
26 (27.1) 17 (28.3) 11 (16.9) 1.30 (0.812.09) 1.38 (0.782.47) 1.08 (0.562.08)
Single major
13 (13.5) 9 (15.0) 8 (12.3) 0.68 (0.341.36) 0.74 (0.301.82) 0.58 (0.251.32)
Recurrent major
13 (13.5) 8 (13.3) 3 (4.6) 3.04 (0.979.50) 3.18 (0.8911.40) 2.64 (0.848.29)
Values are n (%) or relative risk (95% CI), computed by Cox proportional hazards model adjusted for clustering by family.
DSM-IV Diagnostic and Statistical Manual of Mental Disorders, 4th ed.
August (2 of 2) 2004 NEUROLOGY 63 633
Page 3
MDD (see table 2). This effect for recurrent MDD in-
creased after adjusting for the number of family members
with dystonia and ethnicity (see table 3). Also, there was
no difference between MC and NMC in the risk for recur-
rent MDD (RR 1.10, CI 0.48 to 2.50).
Because recurrent MDD may be confounded by the se-
verity of dystonia symptoms and signs, we assessed
whether the risk of recurrent MDD differed among three
groups with severe, mild, and probable dystonia. Severity
was not related to risk for recurrent MDD (RR 0.86,
CI 0.73 to 1.01 for each unit increase in severity).
Age at onset of MDD. The age at onset of recurrent
MDD exhibited a bimodal distribution (early-onset 30
and late-onset 45 years). The prevalence of early-onset
recurrent MDD was 11.5% (18/156) in carriers (12.5% in
MC, 10.0% in NMC) and 1.5% (1/65) in NC. The prevalence
of late-onset recurrent MDD was 1.9% (3/156) in carriers
(1.0% in MC, 3.3% in NMC) and 3.1% (2/65) in NC. This
bimodality is illustrated in figure 2.
Additional confirmatory analyses. Adjustment for the
number of family members with dystonia increased the RR
for recurrent MDD. We conducted further analyses to ex-
plore the reasons for this confounding. Initially we in-
cluded this variable in the model because we hypothesized
that families with more affected members might have
greater psychological burden, resulting in increased risk of
depression. This hypothesis proved to be incorrect. Table 4
shows the distribution of families by the total number of
affected members they contained. Confounding by number
of affected family members results from inclusion of a sin-
gle family (Family Z), which contained a greater propor-
tion of individuals who are NC and a greater proportion of
individuals with recurrent MDD than do the other fami-
lies. In Family Z, 15 individuals had dystonia. Among par-
ticipating members, 3 were NMC and 11 NC. Four of the
14 participating family members (2 NMC/2 NC) had recur-
rent MDD (29%), while in all other families 6% of partici-
pating family members had recurrent MDD. Inclusion of
this family reduces the association with recurrent MDD
because the proportion of NC with recurrent MDD is
higher in this family (2/11, 18%) than in the other non-
carriers in the sample (n 1/54, 2%). When Family Z is
removed from the analysis, the univariate RR for recurrent
MDD in the comparison of NMC with NC increases to 5.6
(95% CI 0.65 to 47.13).
We classified subjects with possible dystonia (n 29, 19
NMC, 10 NC) as non-manifesting in the present study.
However, we questioned whether even these nonspecific
asymptomatic features could influence the risk of recur-
rent MDD. Including this classification as a variable in the
model (i.e., possible/unaffected) did not change the RR for
recurrent MDD in the comparison of NMC to NC (4.63,
95% CI 1.39 to 15.44).
Because 30% of the total sample is derived from three
large families, we assessed whether the effect of the DYT1
mutation on recurrent MDD was restricted to the larger
families (see table 4). In the comparison of NMC to NC, the
magnitude of the association of the DYT1 mutation with
recurrent MDD was elevated both in the three large fami-
lies (univariate RR 2.68, CI 1.47 to 4.88; adjusted
RR 8.34, CI 7.29 to 9.54) and the remaining 37
smaller families (univariate RR 4.14, CI 0.48 to 36.04;
adjusted RR 4.19, CI 0.48 to 36.63). Next, to minimize
the effect of the large families, we separated all of the
Figure 2. Kaplan Meier cumulative incidence estimates.
Solid line noncarrier; dotted line manifesting carrier;
dashed line non-manifesting carrier.
Table 3 Comparison of lifetime prevalence of recurrent major affective disorder in carriers and noncarriers
Adjusted for
All carriers vs
Manifesting carriers
vs noncarriers
Non-manifesting carriers
vs noncarriers
Sex 3.04 (0.979.53) 3.17 (0.8911.32) 2.65 (0.848.36)
Ethnicity 3.15 (1.089.14) 3.17 (0.8911.32) 3.56 (1.379.25)
Education 3.00 (0.989.15) 3.20 (0.9410.89) 2.50 (0.788.05)
Number affected 3.37 (1.288.82) 3.22 (0.9810.55) 4.95 (1.7214.29)
Family size 3.05 (1.128.30) 3.10 (0.9510.17) 3.12 (1.188.24)
Number affected and ethnicity 3.38 (1.308.78) 3.29 (1.0110.72) 5.11 (1.7914.59)
Number affected and education 3.28 (1.228.81) 3.04 (0.939.96) 5.11 (1.5916.40)
Number affected and family size 3.21 (1.268.15) 3.08 (0.959.96) 4.84 (1.6913.84)
Sex, ethnicity, education, number affected, family size 3.12 (1.208.10) 2.97 (0.959.29) 5.13 (1.6515.93)
Values are relative risk (95% CI), computed by Cox proportional hazards model adjusted for clustering by family.
634 NEUROLOGY 63 August (2 of 2) 2004
Page 4
families into sibships and analyzed the subset of sibships
containing at least one NMC and at least one NC. This
subset included 19 sibships that comprised 47 individuals
from 10 families. In this analysis, the clustering was by
sibship rather than family membership. In the comparison
of NMC to NC, the association with recurrent MDD was not
diminished either in univariate analysis (RR 3.95, CI
0.83 to 18.70) or after adjustment for the number of family
members with dystonia (RR 5.82, CI 1.46 to 23.22).
One possible explanation for the increased risk of recur-
rent MDD in NMC than NC is that individuals knew their
carrier status, and that this knowledge caused depression
in NMC more than NC. However, in the comparison of
NMC with NC, the effect of the DYT1 mutation on recur-
rent MDD was not reduced when we included as a variable
whether the subject had undergone genetic testing (RR
6.27, CI 1.23 to 31.81) or by additionally including a
variable indicating whether the subject was an obligate
carrier (i.e., having both a parent or sibling and a child
with dystonia) (RR 6.69, CI 1.31 to 34.17). Moreover,
removing subjects who had undergone testing did not di-
minish the association with recurrent MDD either in uni-
variate analysis (RR 5.90, CI 0.56 to 62.14) or after
adjustment for the number of family members with dysto-
nia (RR 10.63, CI 0.49 to 231.96).
Discussion. The findings of this study support the
hypothesis that recurrent MDD is an independent
expression of the DYT1 dystonia mutation and is not
a result of having a chronic and stigmatizing illness.
In an analysis in which no one exhibited symptoms
of dystonia (i.e., comparing NMC and NC), NMC
were over four times more likely than noncarriers to
exhibit recurrent MDD. This association remained
after adjustment for multiple factors that might in-
fluence risk for depression, including knowledge of
genetic status. We also found that MC had the same
increased risk of recurrent MDD as NMC and recur-
rent MDD was not more frequent in those with se-
vere disease than in those with milder signs of
dystonia. The finding of similar risks for recurrent
MDD regardless of motor signs suggests that gene
expression for psychiatric and motor symptomatol-
ogy is independent and that depression is not a har-
binger or consequence of motor manifestations.
A different gene predisposing to early-onset recur-
rent MDD is unlikely to explain the results of this
study. This would occur only if DYT1 were closely
linked to the other locus, and if the high-risk alleles
at the two loci were associated in the population (i.e.,
in linkage disequilibrium). We found an increased
risk of recurrent MDD in DYT1 carriers vs noncarri-
ers in both Jewish (RR 4.62, CI 0.70 to 30.64)
and non-Jewish (RR 2.90, CI 1.10 to 7.60) fami-
lies. If the increased risk of recurrent MDD were due
to a different gene, the risk-raising allele of this gene
would be in linkage disequilibrium with the DYT1
mutation in both Jewish and non-Jewish families. In
Jewish families, almost all DYT1 mutation carriers
share a common haplotype around DYT1 on chromo-
some 9, so in that group, the haplotype could include
a depression-causing allele at another locus. How-
ever, in non-Jews (and in the non-Jewish families
included in this study) no common haplotype is
; hence we would not expect to see linkage
disequilibrium between a depression-causing allele
and the DYT1 mutation.
Psychiatric expression of DYT1 appears to be lim-
ited to recurrent early-onset MDD. Carriers were not
at increased risk for other affective disorders includ-
ing bipolar disorder, single MDD, or a combination of
any MDD, dysthymia, and bipolar disorder. An addi-
tional and unexpected finding was the early age at
onset of recurrent MDD in mutation carriers. The
early onset of MDD is entirely consistent with DYT1
expression where motor signs of dystonia also over-
whelmingly begin by age 30 years.
It is also consis-
tent with studies showing that the most familial
(genetic) form of unipolar depression is early-onset
recurrent MDD.
The design of this study has a number of
strengths. First it permitted us to distinguish be-
tween gene expression and reactive effects because
we were able to compare psychiatric features in
NMC and NC. In these groups no one exhibited signs
of dystonia and all individuals were related to people
with dystonia. Thus we could examine the effect of
the mutation in two groups similarly exposed to the
various factors that may lead to depression in DYT1
family members, e.g., survivor guilt, stress related to
caring for affected family members, and embarrass-
ment from public perception of the illness in their
family. To exclude additional reactive effects result-
ing from knowledge of carrier status, we also re-
peated the analysis adjusting for knowledge of
carrier status and excluding individuals who were
aware of their carrier status. Second, this design,
examining NMC and NC, eliminated the need to de-
termine whether affective symptoms began before or
after the onset of dystoniaan alternative, but diffi-
cult, approach to evaluating whether affective disor-
Table 4 Distribution of families by total number of family
members with dystonia by carrier status irrespective of whether
the affected individual participated in the present study
No. affected
in family
No. of
families MC NMC NC
9 2 14 10 13
15 1 9 3 11
Total 61 96 60 65
MC manifesting carriers; NMC non-manifesting carriers;
NC noncarriers.
August (2 of 2) 2004 NEUROLOGY 63 635
Page 5
ders occur in response to having dystonia. Third,
unlike the previous studies investigating the rela-
tionship between dystonia and psychopathology, this
design only included individuals with one etiologic
type of dystonia, the DYT1 mutation.
Our study also has limitations. Although our sam-
ple of DYT1 family members (221 total, 96 MC, 60
NMC, and 65 NC) is one of the largest described
it is only moderate in size. The comparison between
NMC and NC included only 11 subjects (8 NMC/3
NC) with recurrent MDD. While statistically signifi-
cant, these findings could be altered by misclassifica-
tion of only a few people. However, the consistent
finding of recurrent MDD in MC, the lack of relation-
ship between dystonia severity and recurrent MDD,
and differing age at onset of recurrent MDD in carri-
ers vs noncarriers all strongly support the conclusion
that this is an independent gene expression. We also
had a relatively high nonparticipation rate. Roughly
a third of the subjects meeting criteria for inclusion
could not be contacted for various reasons including
death, physical limitations, and residence overseas.
Subjects who could not be reached after numerous
attempts comprised the largest proportion, 49%, of
this noncontacted group. However, the proportion in
this group was similar with respect to gene status
(21% MC; 13% NMC; 12% NC) suggesting that any
potential bias would be toward the null hypothesis.
Finally, because we restricted this study to families
with DYT1 dystonia, the findings cannot be general-
ized to other dystonia subtypes.
The pathophysiologic mechanism by which the
DYT1 mutation causes dystonia or recurrent MDD is
unclear. TorsinA, the DYT1 protein product, shares
sequence similarity with the functionally diverse
AAA family of proteins that includes heat shock
proteins, Clp proteases, and molecular chaperones.
Recent studies using models of alpha-synuclein
polyglutamine aggregation
demonstrate that
torsinA (or the C elegans related TOR-2) has sup-
pressive effects on aggregation that are lost with
mutated protein. TorsinA might work as a molecular
chaperone in the management of protein misfolding,
and the GAG deletion may alter neuronal response
to stress induced changes in protein structure.
However, there is no evidence for degenerative brain
changes in DYT1 and pathology, although limited,
has detected only minor changes in striatal dopa-
and an increase in dopamine turnover.
Studies of functional brain networks in DYT1 car-
riers are relevant to the current findings in support-
ing a broader view of DYT1 expression.
studies found that DYT1 carriers, regardless of mo-
tor signs, have abnormal brain networks as detected
by FDG PET with hypermetabolism of the lenticular
nuclei, cerebellum, and SMA. This suggests a meta-
bolic substrate that is associated with genotype re-
gardless of clinical expression. Further, because
neither dystonia, MDD, nor the combination is ex-
pressed in all mutation carriers, modifiers of DYT1
are implicated. Other genes or environmental effects
may be interacting with DYT1 and its associated
metabolic substrate to produce neurologic or psychi-
atric expression. Future studies may help identify
the factors that contribute to DYT1 expression.
The authors thank the families who participated in this study.
They also thank Patricia Kramer, Deborah Raymond, Stanley
Fahn, and the Movement Disorders Group at Columbia Univer-
sity, Mitchell Brin, and Xandra Breakefield for their efforts in
prior dystonia genetic studies that form the basis for this work.
They also thank Cora DeLeon, Ricardo Rieppi, and Sandy Espi-
nosa for clinical interviews, Deborah DeLeon for assistance in
recruitment, and Sharon Schwartz and Ezra Susser for comments
and advice.
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This issue has two videos posted online:
Upbeat about downbeat nystagmus
G.M. Halmagyi and J. Leigh
Neurology 2004;63:606 607
Progression of dystonia in complex regional pain syndrome
A.L. Oaklander
Neurology 2004;63:751
Access and search for the article. Click on Video to view.
August (2 of 2) 2004 NEUROLOGY 63 637
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  • Source
    • "Psychiatric symptoms in 96 motor affected mutation (GAG deletion) carriers (MC) were compared to 125 controls (60 NMC and 65 non-carriers (NC)) [2] [3]. The relative risk of recurrent major depressive disorder (MDD) was found to be increased in mutation carriers (MC 3.62, NMC 4.95) compared to NC. Mutation carriers also had an earlier age at onset of these symptoms, which were also independent of motor symptom severity. "
    [Show abstract] [Hide abstract] ABSTRACT: Dystonia is a movement disorder involving sustained or intermittent muscle contractions resulting in abnormal movements and postures. Identification of disease causing genes has allowed examination of genetically homogenous groups. Unlike the motor symptoms, non-motor characteristics are less clearly defined, despite their impact on a patient's quality of life. This review aims to examine the evidence for non-motor symptoms, addressing cohort size and methods of assessment in each study. A systematic and standardised search strategy was used to identify the published literature relating to psychiatric symptoms, cognition, sleep disorders, sensory abnormalities and pain in each of the genetically determined dystonias. Studies were divided according to cohort size, method of assessment and whether comparison was made to an appropriate control group. Ninety-five articles were identified including reported clinical histories (n = 42), case reports and smaller case series (n = 12), larger case series (n = 23) and case-control cohorts (n = 18). Psychiatric symptoms were the most frequently investigated with anxiety, depression and Obsessive-Compulsive disorder being most common. Cognitive impairment involved either global deficits or isolated difficulties in specific domains. Disturbances to sleep were most common in the dopa-responsive dystonias. Sensory testing in DYT1 cases identified an intermediate subclinical phenotype. Non-motor symptoms form an integral component of the dystonia phenotype. However, future studies should involve a complete assessment of all symptom subtypes in order to understand the frequency and gene-specificity of these symptoms. This will enable early symptom identification, appropriate clinical management, and provide additional outcome measures in future clinical trials. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Full-text · Article · Jul 2015 · Parkinsonism & Related Disorders
  • Source
    • "In addition , disease-associated DE-TorsinA accumulates abnormally in the nuclear envelope, suggesting that abnormal interaction between DE-TorsinA and a nuclear envelope binding partner may contribute to disease pathogenesis [55] . A previous epidemiologic study suggested an association of DYT1 GAG mutation with early-onset recurrent major depression [56]. However, another study reported no significant association with depression, but instead showed an association with anxiety and dystonia [57]. "
    [Show abstract] [Hide abstract] ABSTRACT: Early life stress is one of the major susceptible factors for stress-related pathologies like Posttraumatic Stress Disorder (PTSD). Recent studies in rats suggest that rather than being overall unfavorable, early life stress may prepare the organism to perform optimally to stressful environments later in life. In this study, severely adverse early life stress was conducted by six consecutive hours of maternal separation (MS), from PND1 to PND21, and contextual fear conditioning model was used from PND90 to mimic the second stress in adulthood and the re-experiencing symptom of PTSD. It was observed that in this investigation pups experienced MS showed decreased sensibility to contextual fear conditioning in adulthood, and there sex plays an important role. For example, female rats suffered MS had much lower freezing than males and controls. Meanwhile, Morris water maze test indicated that MS didn't impair rat's performance of spatial learning and memory. Furthermore, suppression subtractive hybridization (SSH) was used to screen the related genes of fear memory, by examining the changes of mRNA expression in CA1 area between female MS and control rats after contextual fear conditioning. Finally, 9 up-regulated and 1 down-regulated genes, including β2-MG, MAF, Nd1-L, TorsinA and MACF1 gene were found in this study. It is assumed that the Torsin A, MACF1 and Nd1-L gene may contribute to the decreased sensitivity of PTSD induced by MS.
    Full-text · Article · Mar 2014 · Behavioural brain research
  • Source
    • "le , in electrophysiological responses ( Edwards et al . , 2003b ) , temporal processing of sensory stimuli ( Fiorio et al . , 2007 ) , motor sequence learning ( Carbon et al . , 2011 ; Ghilardi et al . , 2003 ) , and sensorimotor cortical activity ( Carbon et al . , 2010 ) , as well as an increase in susceptibility to recurrent major depression ( Heiman et al . , 2004 ) . Second , our results demonstrate that strong neuro - nal activity can alter the synaptic phenotype , and therefore may serve as a ' ' second hit ' ' in DE - torsinA neurons . The low penetrance and phenotypic variabil - ity of DYT1 dystonia imply that genetic polymor - phisms ( Kock et al . , 2006 ; Risch et al . , 2007 ) or envi - "
    [Show abstract] [Hide abstract] ABSTRACT: Early-onset generalized dystonia, DYT1, is caused by a mutation in the gene encoding the evolutionarily conserved AAA+ ATPase torsinA. Synaptic abnormalities have been implicated in DYT1 dystonia, but the details of the synaptic pathophysiology are only partially understood. Here, we demonstrate a novel role for torsinA in synaptic vesicle recycling, using cultured hippocampal neurons from a knock-in mouse model of DYT1 dystonia (ΔE-torsinA) and live-cell imaging with styryl FM dyes. Neurons from heterozygous ΔE-torsinA mice released a larger fraction of the total recycling pool (TRP) during a single round of electrical stimulation than did wild-type neurons. Moreover, when the neurons were subjected to prior high activity, the time course of release was shortened. In neurons from homozygous mice, these enhanced exocytosis phenotypes were similar, but in addition the size of the TRP was reduced. Notably, when release was triggered by applying a calcium ionophore rather than electrical stimuli, neither a single nor two ΔE-torsinA alleles affected the time course of release. Thus, the site of action of ΔE-torsinA is at or upstream of the rise in calcium concentration in nerve terminals. Our results suggest that torsinA regulates synaptic vesicle recycling in central neurons. They also indicate that this regulation is influenced by neuronal activity, further supporting the idea that synaptic abnormalities contribute to the pathophysiology of DYT1 dystonia.
    Full-text · Article · May 2012 · Synapse
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