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
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
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