Natural History of Oppenheim's Dystonia (DYT1) in Israel

Abstract

The question of whether a fetus carrying the GAG deletion on the DYT1 gene responsible for Oppenheim's dystonia should be aborted is frequently raised. The objective of this study was to characterize the clinical spectrum and natural course of Oppenheim's dystonia in Israel. Thirty-three patients (19 male) with genetically confirmed Oppenheim's dystonia were evaluated. The Dystonia Rating Scale (maximum score 120) and the Disability Scale (maximum score 30) were used to score severity at the last visit. After a mean of 15.5 +/- 13.8 years of symptoms, the mean Dystonia Rating Scale and Disability Scale scores were 22.7 +/- 14.7 and 7.7 +/- 4.3, respectively. Twenty-one patients (63.6%) have progressed into generalized dystonia. Five patients (15%) are wheelchair bound and three (9%) are using walking aids. All patients have normal cognitive function. Baclofen, trihexyphenidyl, and botulinum toxin were the drugs used. Nine patients (one patient had both) underwent neurosurgical intervention: thalamotomy for six (two bilateral) and pallidotomy for four (three bilateral). The bilateral pallidotomy provided only short-term benefit. The modern treatments combining drugs, botulinum toxin, and functional neurosurgery allow most patients with Oppenheim's dystonia to have independence and a relatively good quality of life.

Full text

Oppenheim’s dystonia is the first primary dystonia to have
been genetically mapped.1The mutation was found to be a
single and uniform deletion of GAG (codes for glutamic
acid) in the DYT1 gene located on chromosome 9q34. The
GAG deletion was found in all patients with classic Oppen-
heim’s dystonia, even though based on haplotype markers,
several founders were identified.2The D Y T 1gene codes for
an adenosine triphosphate–binding protein termed “torsion
A,” which is a protein with distant resemblance to the heat
shock protein superfamily.
Torsion A was found to be widely distributed in nor-
mal adult brain,3with intense expression in the substantia
nigra pars compacta dopaminergic neurons, cerebellar
dentate nucleus, Purkinje cells, basis pontis, locus ceruleus,
thalamus, hippocampal formation, oculomotor nuclei, and
frontal cortex. The intense expression in the nigral neurons
suggests that there could be dysfunction in dopamine
n e u r o t r a n s m i s s i o n .4
O p p e n h e i m ’s dystonia is inherited in an autosomal
dominant pattern with incomplete penetrance and has a
higher prevalence among Ashkenazi Jews than in the gen-
eral population.5S p e c i f i c a l l y, the penetrance rate of Oppen-
heim’s dystonia is about 30% among Ashkenazi Jews and
about 40% in non-Jews.6The prevalence of Oppenheim’s dys-
tonia among Israeli Ashkenazi Jews, based on clinical diag-
nosis only, was estimated to be 6.7 per 100,000 population,
eightfold higher than the prevalence among African and
Asian Jews (0.85 per 100,000 population).7Risch et al esti-
mated the frequency of Oppenheim’s dystonia based on
cases genetically diagnosed at the Columbia Presbyterian
Hospital Movement Disorder Center in New York.8They
found a prevalence among Ashkenazi Jews of 20 to 30 per
325
Original Article
Natural History of Oppenheim’s
Dystonia (DYT1) in Israel
Marieta H. Anca, MD; Tcipora Falik Zaccai, MD; Samih Badarna, MD; Andres M. Lozano, MD;
Anthony E. Lang, MD; Nir Giladi, MD
ABSTRACT
The question of whether a fetus carrying the GAG deletion on the D Y T 1 gene responsible for Oppenheim’s dystonia should
be aborted is frequently raised. The objective of this study was to characterize the clinical spectrum and natural course
of Oppenheim’s dystonia in Israel. Thirty-three patients (19 male) with genetically confirmed Oppenheim’s dystonia were
evaluated. The Dystonia Rating Scale (maximum score 120) and the Disability Scale (maximum score 30) were used to
score severity at the last visit. After a mean of 15.5 ± 13.8 years of symptoms, the mean Dystonia Rating Scale and Disability
Scale scores were 22.7 ± 14.7 and 7.7 ± 4.3, respectively. Twenty-one patients (63.6%) have progressed into generalized
dystonia. Five patients (15%) are wheelchair bound and three (9%) are using walking aids. All patients have normal cog-
nitive function. Baclofen, trihexyphenidyl, and botulinum toxin were the drugs used. Nine patients (one patient had both)
underwent neurosurgical intervention: thalamotomy for six (two bilateral) and pallidotomy for four (three bilateral). The
bilateral pallidotomy provided only short-term benefit. The modern treatments combining drugs, botulinum toxin, and
functional neurosurgery allow most patients with Oppenheim’s dystonia to have independence and a relatively good qual-
ity of life. (J Child Neurol 2003;18:325–330).
Received August 8, 2002. Received revised Feb 10, 2003. Accepted for pub-
lication Feb 11, 2003.
From the Movement Disorders Unit (Drs Anca and Giladi), Department of
N e u r o l o g y, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine,
Tel Aviv University, Tel Aviv, Israel; S. Winter Institute of Human Genetics
(Dr Zaccai), Bnei-Zion Medical Center, Haifa, Israel; Department of Neurology
(Dr Badarna), Carmel Medical Center, Haifa, Israel; Divisions of Neurosurgery
(Dr Lozano) and Neurology (Dr Lang), Toronto Western Hospital, Toronto,
ON, Canada.
The first two authors contributed equally to this work.
Marieta H. Anca, MD, is now at Wolfson Medical Center, Chulon, Israel, and
Tcipora Falik Zaccai, MD, is now at the Hospital of Western Galilee, Naharia,
Israel.
Address correspondence to Dr Nir Giladi, Movement Disorders Unit,
Department of Neurology, Tel-Aviv Sourasky Medical Center, 6 Weizmann
Street, Tel Aviv, 64239 Israel. Tel: 972-3-6974912; fax: 972-3-6974911; e-mail:
ngiladi@tasmc.health.gov.il.

100,000, which is about 3 times the frequency they esti-
mated for early-onset dystonia in non-Jews.8The authors cal-
culated that the mutation in the Ashkenazi Jewish population
first occurred in the northern part of the historic Jewish Pale
(Lithuania, Byelorussia) 350 years ago.8
All cases among the Ashkenazi Jews originally evaluated
by Ozelius et al1had the same founder mutation based on sev-
eral markers around the GAG deletion. Since then, how-
e v e r , a few other founders have been recognized as being
responsible for the disease in single families, suggesting
that there had been some recent spontaneous mutations.2
The GAG deletion was estimated to account for about
90% of Ashkenazi Jewish patients who developed dystonia
in the limbs at an early age.1 0 Several studies that have
appeared during the last few years have indicated that the
range of D Y T 1 expression is limited.1 1 The D Y T 1 p h e n o t y p e
is characterized by symptom onset in early age (ie, before
24 years). The limbs are affected in most cases, and the arms
in 95% of cases. One of the limbs is affected first in 90% of
cases, but the dystonia spreads to other parts of the body
over time. There is some evidence that dystonia among
Ashkenazi Jews tends to begin on the dominant side.11 The
cranial muscles are less likely to be involved. The pheno-
type produced by GAG deletion is similar in both the Ash-
kenazi Jewish and non-Jewish populations.9
The clinical course of the disease among the 30 to 40%
symptomatic cases is highly variable, extending from a mild
focal disease to a generalized form with severe motor dis-
ability but without any other neurologic disturbances. Clin-
ical features such as age of onset, site of onset, and d i s -
tribution of symptoms12 have prognostic significance.10,13,14
Few studies describe the course of the disease in large
groups of genetically confirmed patients with Oppenheim’s
dystonia who undergo therapeutic approaches (drugs and
surgery) that have emerged over recent years. The most
extensive investigation on Oppenheim’s dystonia was done
by Bressman et al on a group of patients with a mutation in
the D Y T 1 gene (267 patients, 168 Ashkenazi Jews and 99 non-
Jews).10 This study did not, however, correlate the clinical
course with the different therapeutic modalities that are now
available for Oppenheim’s dystonia. There are two recent
reports on the therapeutic options in dystonia: one described
the clinical course of five patients with Oppenheim’s dys-
tonia,15 and the other is an overview of therapies but with-
Table 1. Clinical Features and Disease Evolution Related to Different Treatment Strategies in 33 Patients With DYT1 Dystonia
Age Site T B
at Onset/ of T Side T B Side B
Patient Gender Current (yr) Onset Dominance Response Effects mg/d Response Effects mg/d
1 M 17/48 RA R + 8 + 50
2 F 17/43 LA L
3 M 11/19 RL R ++ 100
4 M 11/29 RL R + + 15 + 60
5 M 9/49 Generalized R + 40
6 M 8/25 RL L NR + +
7 M 8/23 RL R NR
8 M 21/29 Generalized R + 22 + 100
9 M 7/20 LL R
10 M 6.5/27 RL + LL R
11 F 10/49 RL R NR + +
12 F 12/39 RA R
13 F 10/39 RL R +
14 F 8/11 RL R + 30 + 100
15 F 7/15 LL L +
16 M 13/45 RL + LL R
17 F 9/63 LL R
18 M 8/12 RL R
19 M 10/39 RA + neck R
20 F 8/13 RL R NR + 160
21 M 11/15 RA R
22 M 8/11 LL R + +
23 M 9/13 RA R
24 M 10/15 RA R ++
25 M 11/18 RA R NR
26 F 8/19 LL R +
27 F 8/26 RA R + +
28 F 28/35 RA R
29 F 9/47 RA R
30 F 7/56 LL R + +
31 M 10/12 RA R +
32 F 10/14 RA L
33 M 11/12 RA R ++ 75
Aids = Walking aids; B = baclofen; BTX = botulinum toxin; DRS = Dystonia Rating Scale; DS = Disability Scale; L = left side; LA = left arm; LL = left leg; ND = not done; NR = no
response; R = right side; RA = right arm; RL = right leg; T = trihexyphenidyl. Continued next page

out statistical applications of their effect on the patients’ clin-
ical course.1 6 There are also isolated case reports on the out-
come of surgical intervention, with 8 years of follow-up for
t h a l a m o t o m y1 7 , 1 8 but only 1 to 2 years of follow-up after
pallidotomy with mixed results.1 9 – 2 4 N o t a b l y, very few
patients were evaluated by validated and standardized
scales, which makes it difficult to compare the published
results.
We describe the clinical characteristics of genetically
confirmed patients with Oppenheim’s dystonia in Israel and
the effect of modern therapeutic strategies on their disease
course and quality of life. We believe that this information
is of special importance for application in genetic counsel-
ing for addressing the issue of whether to terminate a preg-
nancy when the fetus has been identified as a carrier of the
mutation.
SUBJECTS AND METHOD
All study participants were of Ashkenazi Jewish origin and all car-
ried the GAG deletion in the D Y T 1 gene. We had confirmed at
least two founders in earlier studies, according to the commonly
used markers around this gene.2A neurologist trained in movement
disorders examined all of the patients on study entry, and their med-
ical history was compiled by detailed interviews with them and their
relatives as well as from data retrieved from their records at the
Movement Disorders Unit and documents from other hospitals as
well as other outpatients clinics. The clinical assessment was
based on an updated Dystonia Rating Scale and the Disability
Scale.25
R E S U LT S
Patients’ Characteristics and Age at Disease Onset
The study cohort was composed of 33 patients with Oppen-
h e i m ’s dystonia (19 male and 14 female, mean ± SD for age
27.8 ± 15.2 years, range 11–63), all residents of Israel.
Twenty-five patients who had a positive family history of
O p p e n h e i m ’s dystonia originated from 10 families: their
mean age at symptom onset was 10.7 ± 4.6 years (range
6.5–28), and their mean disease duration was 15.5 ± 13.8
years (range 3–54). The other 8 cases were sporadic: their
mean age at symptom onset was 8.8 ± 1.6 years (range
6.5–11) (Table 1).
Table 1. (continued) Clinical Features and Disease Evolution Related to Different Treatment Strategies in 33 Patients With DYT1 Dystonia
BTX
BTX Resp- Surgery Disease Distri- Disease Actual
Patient Site onse Surgery Response Duration DS DRS bution Walk Evolution Treatment
1 2 L + RA + 31 17 35 Generalized +Aids Stable Drugs
2 26 5 14 Multifocal + Drugs
3 8 8 23 Multifocal + Drugs
4 RA + 18 11 29 Generalized + Stable Drugs
5 Bilateral
thalamotomy + 40 15 65 Generalized + Stable Drugs
6 17 10 35 Generalized + Stable No drugs
7 LL + Bilateral
thalamotomy +
L pallidotomy + 15 5 18 Gen +Aids Drugs
8 8 7 20 Generalized + Drugs
9 13 ND ND Generalized — No drugs
10 20 6 7 Generalized + Stable Drugs
11 21 + L thalamotomy 39 8 19 Generalized + Stable Drugs
12 27 ND ND Focal + Stable No drugs
13 17 ND ND Focal + Drugs
14 RL + 3 8 26 Generalized + Drugs
15 Bilateral
pallidotomy + 8 3 15 Generalized + Stable No drugs
16 32 ND ND Multifocal + Stable No drugs
17 LL + R thalamotomy + 54 7 23 Generalized Wheelchair Stable No drugs
18 4 11 28 Focal + Drugs
19 29 2 5 Multifocal + Stable No drugs
20 Neck + 5 3 13 Generalized + Stable Drugs
21 4 3 11 Focal + Stable No drugs
22 Bilateral
pallidotomy ++ 3 13 35 Generalized + Drugs
23 Bilateral
pallidotomy ++ 4 14 43 Generalized + Drugs
24 RA + 5 2 8 Multifocal + Drugs
25 7 5 5 Generalized + No drugs
26 R thalamotomy 32 ++ 11 4 11 Generalized + No drugs
27 RA + 18 ND ND Multifocal + Drugs
28 7 ND ND Generalized + Drugs
29 12 6 5 Multifocal + No drugs
30 R thalamotomy + 49 13 45 Generalized Wheelchair Drugs
31 RA + 3 7 26 Generalized + Drugs
32 14 ND ND Focal + Stable No drugs
33 12 ND ND Generalized + Drugs
Aids = Walking aids; B = baclofen; BTX = botulinum toxin; DRS = Dystonia Rating Scale; DS = Disability Scale; L = left side; LA = left arm; LL = left leg; ND = not done; NR = no
response; R = right side; RA = right arm; RL = right leg; T = trihexyphenidyl.

Initial Symptoms
The first symptom of Oppenheim's dystonia was in the
limbs in 32 patients, 28 of them in one limb. Twelve patients
(37.5%) noticed the first dystonic symptom in the right arm,
9 (28%) patients in the right leg, 6 (19%) in the left leg, and
1 (3%) in the left arm. Two patients experienced the first
dystonic spasms in both legs, one patient noticed symptoms
in the right arm and neck simultaneously (segmental), and
another patient had multifocal onset of the disease. One
patient had only axial symptoms at disease onset (see Ta b l e
1). There was a strong tendency to develop initial symptoms
on the dominant side of the body (72%), particularly in the
dominant arm. Only seven patients (21%) developed the
initial symptom on the nondominant side.
Patients who experienced the initial symptom in the
lower limbs had a statistically significant (P< .05) earlier
age at symptom onset (mean 8.7 ± 2.8 years) compared
with those whose first symptom was in the upper limbs
(mean 12.4 ± 3.7 years). There was a tendency for patients
who developed the first symptom in the nondominant side
to be younger (mean 8.1 ± 3.0 years) than those with initial
symptoms on the dominant side (mean 11.1 ± 4.5 years), but
this difference was not statistically significant. We observed
a trend toward a significant association between earlier
age of symptom onset and the appearance of symptoms on
the nondominant leg (P< .10).
Disease Evolution and Duration
Twenty-one patients (63.6%) with a mean disease duration of
17.4 ± 15.7 years evolved to generalized dystonia. The gen-
eralization occurred over a period ranging between 6 months
(7 cases) and 12 years (1 case), whereas 10 patients (48%) pro-
gressed to the generalized form within ~2 years from symp-
tom onset. Five patients (15% of all patients and 25% of the
ones with the generalized form) required a wheelchair 2 to
8 years after the onset of their symptoms (two of them
regained the ability to walk after they successfully underwent
a recent bilateral pallidotomy), and three patients (9%) started
using walking aids 10 to 20 years after symptom onset.
Seven patients (21%) progressed to a multifocal form.
The mean disease duration in this group was 18.6 ± 10.6
years. Five patients (15%) with a mean age of 23.4 ± 12
years remained with a focal dystonia. However, all five had
symptoms for 4 years or less, suggesting that they might
progress in the future. Notably, all but 1 of the 12 patients
with a focal or multifocal form of dystonia (relatively benign
course) developed the first symptom on the dominant side.
For dystonia distribution according to symptoms duration,
see Table 2.
Five patients (15%, 4 male) developed craniocervical
dystonia; in two cases, it was the initial symptom and in three
it began 4 to 15 years after symptom onset. Three of these
five patients also developed spastic dysphonia as a late
symptom, which appeared 4 to 15 years after symptom
onset.
The mean Dystonia Rating Scale score that was obtained
for the study cohort as a whole was 22.7 ± 14.7 (range 5–65).
We observed a trend toward higher Dystonia Rating Scale
scores with longer disease duration and earlier age of symp-
tom onset. The mean group Disability Scale score was 7.7
± 4.2 (range 2–17), and, as expected, it was higher in patients
with generalized disease.
At least 3 years of a stable disease course were recorded
in 14 patients (42%), 7 with generalized dystonia, 3 with the
focal form, and the other 4 with a multifocal form. A stable
course was associated in all cases with a current age of over
25 years (range 25–63 years) and more than 12 years of
symptom duration (in 11 cases).
Cognitive functions were preserved in all patients and
at all stages of the disease.
Treatment Modalities
The study patients were treated with different drug regimens
and neurosurgical approaches. The medication used most
often was baclofen (19 patients, 57.6%) at a maximum dose
of 165 mg/day and a mean dose of 105 mg/day. The second
most commonly used drug was trihexyphenidyl (17 patients,
51.5%) at a maximum dose of 120 mg/day and a mean dose
of 30 mg/day.
At the last follow-up, 15 patients (all with a generalized
form) were being treated with baclofen, 9 as monotherapy
and 6 in combination with trihexyphenidyl, with good tol-
erability and prolonged benefit.
Baclofen therapy improved leg dystonia and gait in 14
patients in dosages over 50 mg/day, and 9 of them enjoyed
stable and prolonged benefit. The use of anticholinergic
drugs, even when they were effective (6 patients), was lim-
ited by the secondary side effects. One child developed
acute urinary retention on a regimen of 100 mg tri-
hexyphenidyl. Drugs were discontinued only if significant
side effects appeared. In general, most of the patients tended
to taper anticholinergic drug intake over time with little or
no worsening of the dystonia.
Twelve patients (36.4%) were treated for focal symptoms
with botulinum toxin. All of them enjoyed periods of
improvement, but only a few patients are on continuous bot-
ulinum toxin treatment, either because of loss of response
or lack of efficacy.
Nine patients underwent neurosurgical stereotactic pro-
cedures: five underwent thalamotomy more than 10 years ago
(two had a bilateral procedure) and four underwent palli-
dotomy in Toronto, Ontario, Canada (three had a bilateral
procedure). Improvement was immediate and significant.
The follow-up period after thalamotomy ranged between
10 and 37 years. Retrospectively, the patients recalled an
Table 2. Dystonia Distribution and Degree of Disability
According to Disease Duration
Duration of
symptoms (yr) ≤ 5 6–10 11–20 ≥ 21
Generalized 5 4 7 5
Multifocal 1 1 2 3
Focal 2 None 2 1
Total 8 5 11 9
DS 7.6±4.7 5.7±2.2 7.0±2.8 9.6±5.5
DRS 23.7±12/3 15.7±7.9 17.5±12.2 29.4±20.5
DRS = Dystonia Rating Scale; DS = Disability Scale.

improvement period lasting from 1 month to 7 years, fol-
lowed by further disease worsening afterward. All oper-
ated patients had the subjective impression that the disease
progressed at a slower rate postoperatively, but this could
not be objectively confirmed.
The follow-up period after bilateral pallidotomy ranged
from 2 to 4 years. The motor improvement was dramatic and
significant during the first 3 to 4 months. However, there was
a significant slowly progressive worsening of the motor
state in most patients after the first year (Table 3), as well
as a late onset (more than 1 year postoperatively) of severe
aphonia in one patient.
Of the nine patients who could not walk at the time of
s u r g e r y, seven (77%) regained ambulation, two with and
five without walking aids. The other two patients remained
confined to a wheelchair.
D I S C U S S I O N
O p p e n h e i m ’s dystonia in Israel has the same classic features
as those described in the literature. There is a slight male
predominance, and the age at symptom onset varies but is
generally around the second decade of life. The first appear-
ance of symptoms in the limbs is almost equal for the upper
and lower ones. The trend for an onset of the disease to occur
in the arm in DYT1 Ashkenazi Jews was noticed first by
Almasy et al1 3 and is cited in the last guidelines for D Y T 1 p h e-
notype diagnostic features.10
Age at Onset and Presenting Symptom
It was our impression that an initial symptom in the domi-
nant limb, mostly the arm, was associated with a milder
course of the disease. An initial symptom in the lower non-
dominant limb tended to be associated with a younger age
at disease onset and a more severe course, possibilities
that have been suggested by others as well.13,26 Based on
these results and on clinical impressions, the onset or sever-
ity of Oppenheim’s dystonia may not be related to overac-
tivity of the limb, as proposed by Byl et al.27
Natural History of Oppenheim’s Dystonia
and Its Relationship to the Treatment
We observed a tendency for stabilization of the clinical
course after the age of 25 years, without any direct rela-
tionship to therapeutic modalities. A similar observation was
also reported among a more heterogeneous group of dys-
tonic patients in Israel by Inzelberg et al,26 who observed a
tendency for disease stabilization after 10 years. Greene
had suggested that earlier treatment could slow down the
disease progression,28 but we could not test that hypothe-
sis in the present study group, and a prospective controlled
trial would be needed to do so.
Similar to the retrospective study by Greene, who
described gait improvement in 30% of children with idio-
pathic dystonia treated with high-dose baclofen,28 we also
had the impression of a positive effect of baclofen on the
lower limb–associated gait difficulties. However, because
this is a retrospective data analysis report, we could not
demonstrate this effect with the necessary objective mea-
sures and prospective data.
Our patients also exhibited the beneficial effect of anti-
cholinergic drugs described in 61% pediatric and 38% adult
patients by Fahn in 1983.2 9 Because of the beneficial effects
of baclofen and the side effects most patients experienced
with trihexyphenidyl (even if the dose was increased
extremely slowly), we did not test the reported effect of tri-
hexyphenidyl in very high dosages. The current therapeu-
tic modalities, baclofen (orally or intrathecally) and
functional neurosurgery, have made very high-dose tri-
hexyphenidyl a less common therapeutic strategy. Based on
our and others’ observations, we propose a practical ther-
apeutic strategy using high-dose baclofen as first-line ther-
apy. Anticholinergic drugs should be added in those cases
when clinical benefit is not satisfied.
The ablative surgical procedures seem to give some tran-
sient benefit, depending on individual features and type of
intervention. We looked for a relationship between the
treatment modality and the dynamic course of the disease
status during the last 4 years: 44% of the patients in the
neurosurgically operated group (thalamotomy or pallidot-
omy, n= 9) have been clinically stable for 2 years and 67%
are walking independently. This group of patients obviously
includes the most disabled patients, and these outcomes are
important as overall prognostic data for patients with severe
Oppenheim’s dystonia.
The long-term outcome after thalamotomy was
described as being modest by Cardoso et al24 when only 6
of 17 patients with severe primary dystonia maintained
their postoperative improvement for a mean period of 32
months. The previous larger series by Cooper17 and Tasker
et al1 8 reported a follow-up of 8 years with 25% good but tran-
sient improvement, but also 20% worsening or complica-
t i o n s .1 8 The follow-up period for our 6 patients who
underwent thalamotomy was 37 years, but the maximum
benefit lasted only 7 years.
The clinical course following bilateral posteroventral
pallidotomy is of greater significance. Lin at al reported a
follow-up of 6 to 12 months after bilateral pallidotomy in 18
patients and observed a partial improvement limited to the
craniocervical region that was maintained for 1 year.1 9 Te i v e
et al reported 4 patients with idiopathic dystonia whose con-
Table 3. Clinical Characteristics of 3 Cases With Generalized DYT1
Dystonia Who Underwent Bilateral Pallidotomy
Characteristic Case 1 Case 2 Case 3
Current age (yr) 15 13 17
GAG deletion + + +
Preoperative DS 28 NA 26
Preoperative DRS 78 NA 68
Mo/yr of pallidotomy 12/1998 1/1997 4/1999
DS at 1 yr postsurgery 14 4 3.5
DRS at 1 yr postsurgery 42 14 15
DS at 2 yr postsurgery 22 4 9
DRS at 2 yr postsurgery 52 14 25
DS at 3 yr postsurgery 6
DRS at 3 yr postsurgery 23
DS at 4 yr postsurgery 9
DRS at 4 yr postsurgery 38
DRS = Dystonia Rating Scale; DS = Disability Scale; NA = not available.

dition clearly improved at a follow-up of 180 days post–bilat-
eral pallidotomy.2 0 Others have also reported single or a
few cases with good short-term outcome, but no study with
long-term follow-up has been published thus far.21–23 Our
experience and that of others is that bilateral pallidotomy
has significant short-term benefit in most cases. However,
we observed a clear tendency for rapid and continuous
worsening after the first postoperative year (a rate of 23 to
67% deterioration on the disability scales from year to year).
Hypophonia has been recognized as a complication of
pallidotomy since the 1998 study of Favre et al.3 0 The appear-
ance of a delay in the onset of severe postoperative hypo-
phonia is worrying because we failed to detect hypophonia
in any of our D Y T 1 patients who were not operated on. The
fact that it developed several months to a year after surgery
might suggest the presence of secondary changes in the
thalamus, which developed slowly over time. Finally, in light
of the recent reports about the benefit of globus pallidum
interna (Gpi) stimulators,3 1 one should hesitate lesion the
globus pallidum interna in dystonic patients.
C O N C L U S I O N
The findings of the current study provide data that can be
used as guidelines for genetic counseling when a pregnancy
involves a fetus that carries the GAG deletion in the DYT1
gene: (1) disease penetration is low (30–40%); (2) 63% of
affected individuals progress to the generalized form and the
rest will have a milder form (which, in most cases, will not
require medical treatment); (3) most (75%) patients with the
generalized form can maintain ambulation and indepen-
dence with medications and/or surgery; and (4) modern
treatment modalities provide even the most severe cases
with a good chance for improvement and ambulation.
Acknowledgment
Mrs Esther Eshkol is thanked for editorial assistance, and Mrs Judith Knaani is
thanked for her excellent secretarial help.
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