Onset and progression of primary torsion dystonia in sporadic and familial cases.

Abstract

Four hundred and sixty records of patients with primary torsion dystonia (296 women and 164 men) were evaluated. The mean age at disease onset was 48.3 +/- 17.7 years; 13 patients carried the DYT1 CAG deletion. The distribution of age at onset was represented by a bi-modal curve, with a nadir at 21 year separating early onset from late onset cases. In 15.9% of cases there was a positive family history of dystonia. Cranial, cervical or lower limb onset was more common amongst women (M:F ratios were 1:2.7, 1:1.9, and 1:3); by contrast, onset in the upper limb was more common in men (M:F ratio 2.2:1). As expected, disease progression was more pronounced in cases with early onset; it was reckoned that onset at or above 32 years was associated with a negligible likelihood to progress to a generalized form. The mean age at onset of familial cases was 44.8 +/- 11.2 years, significantly lower than the mean age at onset of sporadic cases (53.5 +/- 13.4 years). Familial cases were characterized by more sites involved throughout disease course. Familial cases had a higher tendency to progress to a segmental or generalized form than sporadic cases.

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Onset and progression of primary torsion dystonia in sporadic and familial
cases
A. E. Eliaa,b, G. Filippinib, A. R. Bentivoglioa, A. Fasanoa, T. Ialongoaand A. Albaneseb,c
aIstituto di Neurologia, Universita` Cattolica del Sacro Cuore, Rome, Italy;bIstituto Nazionale Neurologico Carlo Besta, Milan, Italy; and
cCattedra di Neurologia, Universita` Cattolica del Sacro Cuore, Milan, Italy
Keywords:
dystonia, DYT1, familial
cases, genetics
Received 8 March 2005
Accepted 7 September 2005
Four hundred and sixty records of patients with primary torsion dystonia (296 women
and 164 men) were evaluated. The mean age at disease onset was 48.3 ± 17.7 years;
13 patients carried the DYT1 CAG deletion. The distribution of age at onset was
represented by a bi-modal curve, with a nadir at 21 year separating early onset from
late onset cases. In 15.9% of cases there was a positive family history of dystonia.
Cranial, cervical or lower limb onset was more common amongst women (M:F ratios
were 1:2.7, 1:1.9, and 1:3); by contrast, onset in the upper limb was more common in
men (M:F ratio 2.2:1). As expected, disease progression was more pronounced in cases
with early onset; it was reckoned that onset at or above 32 years was associated with a
negligible likelihood to progress to a generalized form. The mean age at onset of
familial cases was 44.8 ± 11.2 years, significantly lower than the mean age at onset of
sporadic cases (53.5 ± 13.4 years). Familial cases were characterized by more sites
involved throughout disease course. Familial cases had a higher tendency to progress
to a segmental or generalized form than sporadic cases.
Introduction
Dystonia is a syndrome of sustained muscle contrac-
tions, causing twisting and repetitive movements or
abnormal postures [1]. The etiological classification in-
cludes: primary torsion dystonia (PTD), secondary
dystonia (often symptomatic of a brain injury), dysto-
nia-plus syndromes (such as dopa-responsive dystonia
or myoclonic dystonia), and heredodegenerative dis-
eases, in which dystonia occurs as a prominent feature
[2]. Primary dystonia is a clinically and genetically
heterogeneous condition, age at onset is a relevant
variable for the clinical presentation and the prognosis
[3]. The definition of early onset dystonia is based on
the identification of a threshold age to use for classi-
fying patients. The age of 21 years has been originally
set by a consensus of experts [1], but later observations
have proposed to increase the threshold for this ter-
minology up to 26 years [4]. PTD may occur sporad-
ically or in familial aggregation; one PTD gene (named
DYT1) and three different loci (named DYT6, DYT7,
and DYT13) have been identified [5–7]. The natural
history of PTD is characterized by focal onset and
occasional spread to other body parts with a variable
natural course. In adult-onset cases, dystonia usually
remains restricted to a single body district or has a
limited diffusion to other body regions; in patients with
early onset dystonia the symptoms tend to generalize
[2]. DYT1 PTD is the best characterized form of dys-
tonia; the typical DYT1 phenotype is with early limb
onset, rapidly progressive course towards generaliza-
tion, and no involvement of cranial segments [8]. By
contrast, limited data are available on the clinical fea-
tures and the natural course of non-DYT1 dystonia,
particularly in the European population.
Subjects and methods
A movement disorders registry was started in 1986 at
the Gemelli Hospital in Rome, a secondary and tertiary
referral center. Patients with movement disorders were
followed up at least twice a year by a staff neurologist,
who reviewed the diagnosis and the treatment plan. All
patients provided information on familial and personal
medical history and filled in a detailed questionnaire on
common motor problems observed in movement dis-
orders. All the reportedly affected relatives of index
patients were examined directly in the clinic whenever
available. The patients? records were entered in the
movement disorders registry. For the purpose of this
study we selected from the registry only patients with a
diagnosis of clinically definite or probable PTD, who
were examined from January 1986 to December 2001.
The diagnostic criteria have been already described
[9,10]. The following clinical data were retrieved from
the registry: gender, ethnic origin, age at onset, distri-
bution of dystonia at onset and during the follow-up
Correspondence: Dr Alberto Albanese, Istituto Nazionale Neurolog-
ico Carlo Besta, Via G. Celoria, 11, I-20133 Milan, Italy
(tel.: +39 (02) 2394 2552; fax: +39 (02) 2394 2539; e-mail:
alberto.albanese@unicatt.it).
? 2006 EFNS
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visits, and the occurrence of family history of move-
ment disorders. Dystonia was considered familial when
at least a first-, second- or third-degree family member
was diagnosed as affected by PTD. The adult onset
index cases of non-DYT1 families were compared with
sporadic PTD patients whose records provide accurate
data of spread of dystonia during the clinical follow-up.
Progression of dystonia was defined as a spread of
symptoms from focal to segmental, multifocal or gen-
eralized dystonia.
Genetic analysis
Blood samples were obtained by all patients who pro-
vided a written informed consent. DNA was extracted
from leukocytes using standard techniques. Screening
for the GAG deletion in the DYT1 gene was performed
according to standard procedures [11].
Statistical analysis
Data were analysed with the use of SPSS software for
Windows v. 10.1 (SPSS, Inc., Chicago, IL, USA).
Results are reported as mean ± SD. A histogram of
ages at onset was drawn, then the best-fit curve of the
distribution of age at onset was analysed and repre-
sented in Cartesian axes. Analysis of variance was used
to compare the mean ages amongst patients who had
different sites of onset of dystonia. Categorical data
were compared with the chi-squared test. Repeated-
measures analysis of variance was performed compu-
ting the mean number of body parts progressively
involved by dystonia during the natural disease course.
The onset and progression of adult-onset sporadic or
familial cases, who were non-carriers of DYT1 GAG
deletion, were compared. The sensitivity and specificity
of age at onset to assess generalization of dystonia were
calculated for patients followed-up for 5 or more years.
Receiver operating characteristic (ROC) curves were
plotted considering different levels of age at onset (with
intervals of 1 year from birth). The age level closest to
80% sensitivity and 80% specificity was defined as the
best trade-off threshold for disease progression. The
estimates of sensitivity and specificity were used to
calculate the positive and negative predictive values of
the best trade-off value of age at onset.
Results
The movement disorders registry encompassed 593
cases of dystonia (356 women and 237 men), 460 of
whom were PTD cases and 133 had other forms of
dystonia. All PTD patients were Caucasian, mostly
originating from central and southern Italy. The
frequency distribution of the ages at onset is shown in
Fig. 1. The best fit was obtained with a bimodal curve
with modes at 9 and 57 years and nadir at 21 years.
Based on this evidence, 21 years were considered as the
most appropriate cut-off to distinguish early onset and
late onset PTD in this series. Four hundred and sixteen
(90.4%) PTD patients had clinical onset after age 21,
whereas 44 patients (9.6%) had early onset. Of the 460
PTD patients, 380 (82.6) were sporadic, and 80 (17.4%)
had a family history of dystonia. Eight families had
more than one member included in the registry, thus the
frequency of familial cases was 15.9%. In 49 families, it
was possible to examine all the reportedly affected
members; 39 of them were affected by dystonia (focal
form in 15, segmental in 16, generalized in eight).
Clinical presentation and progression
Primary torsion dystonia was observed more frequently
in women than in men (M:F ¼ 1:1.8). In all patients
onset was focal, most frequently a cranial dystonia
(50.4%), followed by cervical (22.0%), upper limb
(15.4%), laryngeal (8.3%) or lower limb dystonia
(2.6%). Cranial onset was more frequently observed in
women (M:F ¼ 1:2.7), whereas upper limb onset pre-
vailed in men (M:F ¼ 2.2: 1). Patients with cranial onset
had the highest mean age at disease onset (men: 53.8,
women: 57.3); patients with lower limb onset had the
lowest age (men: 13.3, women: 24.3). Overall, age at
disease onset was lower in men than in women (44.1 and
50.6, respectively; P < 0.001). Cranial and laryngeal
onsetoccurredearlier inmen thanin women (P < 0.001
and P < 0.005, respectively), whereas upper limb onset
occurred earlier in women (P < 0.01; Table 1).
At the last follow-up visit, 269 patients (58.4%, mean
disease duration: 12.2 ± 6.9 years) had focal dystonia,
1
0
2
4
6
8
10
12
14
16
18
20
6 1116 2126 3136 41 46
Age
Number of observations
5156 61 66 71 76 81 86
Figure 1 Frequency distribution of age at onset in 460 primary
torsion dystonia cases seen at the Gemelli Hospital in Rome. The
bimodal distribution observed has a nadir at 21 years that iden-
tifies two well-distinguished clusters of patients with early and late
disease onset (modes at 9 and 57 years, respectively).
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159 (34.5%, mean disease duration: 14.6 ± 9.4 years)
had segmental dystonia and 32 (6.9%, mean disease
duration: 25.5 ± 16.7 years) had a multifocal or gen-
eralized form. Progression occurred in a larger number
of patients with early onset (75%) than in those with
late onset (38%; P < 0.0001). As expected, early onset
cases had a significantly longer disease duration
(P < 0.001). Four hundred and forty-three patients,
who had been followed-up for at least 5 years, were
analysed to determine the predictive accuracy of age at
onset towards generalization of dystonia. The best
trade-off threshold was 32 years, yielding a sensitivity
of 83% (20 of 24 patients with generalization were de-
tected) and a specificity of 83% (349 of 419 cases
without generalization were detected). The negative
predictive value was 99%, indicating a negligible
probability that patients with onset ‡32 years would
progress to generalization.
DYT1 and non-DYT1 patients
Two hundred and forty-three patients were tested for
the DYT1 GAG deletion. This mutation was found in
13 cases (5.4%), three of whom were sporadic. The
remaining 10 DYT1-positive patients belonged to three
families. The DYT1 GAG deletion was excluded in 23
index cases from a total of 39 familial index cases. The
DYT1 mutation was found in seven of 17 patients with
generalized dystonia (41%). All the DYT1-positive
patients with generalized dystonia had limb onset: the
upper limb in one case, the lower limb in six cases. The
meanage atonsetin
17.4 ± 13.7 years. The DYT1-positive cases presented
generalizeddystonia within
5.6 ± 5.1 years from onset. DYT1-negative patients
with generalized dystonia were 10: five of them had limb
onset (the upper limb in two and the lower limb in
DYT1patients was
a meantime of
three), three of them had cervical onset, in one onset
was with laryngeal dystonia and in one with blepharo-
spasm. Non-DYT1 patients had a mean age at onset of
23.9 ± 15.8 years (not significantly different from
DYT1-positive cases) and a milder (although not sta-
tistically different) progression than DYT1-positive
patients; generalization
7.5 ± 5.8 years after onset.
The records of 58 sporadic adult-onset patients who
were non-carriers of DYT1 mutation were considered
appropriate for analysis of progression of dystonia;
they were compared with those of 18 adult-onset pro-
bands who were non-carriers of DYT1 GAG deletion
(Table 2).
Familial cases had lower mean age at disease onset
(44.8 ± 11.2 years) than
(53.5 ± 13.4; P < 0.001). The mean follow-up period
was 15.3 ± 7.9 years for sporadic and 13.8 ± 11.2 for
familial cases. Spread of dystonia to at least a second
body site occurred more frequently in familial cases
(77%) than in sporadic (46%; P < 0.05). Spread of
symptoms occurred either in sporadic or in familial
cases during the natural disease course, the number of
sites involved by disease progression was significantly
higher in familial cases (P < 0.05). The spread of
symptoms was directly related to the duration of illness
either in sporadic or in familial cases (P < 0.001)
however, in sporadic cases the most relevant spread
occurred during the first 10 years; in familial patients,
instead, progressivespread
throughout the disease course (P < 0.05).
occurred onaverage
sporadic patients
ofdystoniaoccurred
Discussion
In the present study, prediction of progression to a
generalized dystonia was specifically addressed. The
data show that 32 years is the best threshold to predict
Table 1 Mean age at onset of primary
dystonia according to the site of onset and
to gender
Site of onset
All PTD cases Women Men
nAgen Agen Age
Cranial
Blepharospasm
Low face
Cervical
Laryngeal
Upper limb
Lower limb
Total
238
230
56.3 ± 12.1a
56.4 ± 11.9
54.5 ± 18.0
41.1 ± 17.1
47.7 ± 21.1
36.4 ± 17.3
21.6 ± 16.3c
48.3 ± 17.7
174b
170
57.3 ± 11.2a
57.2 ± 11.3
60.8 ± 9.0
43.3 ± 17.6
52.1 ± 20.3
28.5 ± 15.9
24.3 ± 18.0c
50.6 ± 17.3
64
60
53.8 ± 14.0a
54.2 ± 13.3
48.3 ± 24.0
37.4 ± 16.0
36.7 ± 19.8
39.9 ± 16.9
13.3 ± 6.1c
44.1 ± 17.7
844
101
38
71
12
460
64
27
22
37
11
49b
93
296 164
PTD, primary torsion dystonia.
aBoth men and women with cranial onset had the highest age at onset (P < 0.001).
bCranial onset was significantly more frequent in women and upper limb onset was significantly
more frequent in men (P < 0.001).
cBoth men and women with lower limb onset had the lowest age at onset (P < 0.001).
Onset and progression of primary torsion dystonia
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generalization in a patient with dystonia. Patients aged
32 years or more at disease onset have a negligible
probability to generalize, whereas generalization occurs
in a sizable proportion of patients with onset before
that age.
Hospital series have repeatedly reported that the
frequency distribution of age at onset in dystonia is
bimodal. Age-at-onset ranks stratify around two modes
that are well divided by a single nadir, thus identifying
two seemingly separate clusters of patients. The
threshold separating these two clusters has been set
variably in different series, based on the observed nadir
(ranging from 15 to 35 years; Table 3). However, the
prospective value of such retrospective clustering of
patients, towards the prediction of the likelihood that
dystonia may generalize in a single individual, has not
been ascertained. A bimodal distribution of frequencies
has also been observed in the present series; the modes
are at 9 and 57 years and the nadir separating the two
clusters of retrospective observations is at 21 years.
Therefore, the present observation is in keeping with
most of the previous studies, which have measured age
intervals for the nadir encompassing approximately
21 years of age (Table 3). This confirms that the ter-
minology used to distinguish early onset and late onset
dystonia should use a threshold age of 21 years, as
originally proposed by a consensus committee [1].
The comparison of the natural history in familial and
sporadic cases showed that spread of symptoms oc-
curred in both groups over time. Progression after 5, 10,
15, 20 or 25 years was more pronounced in familial
PTD cases than in sporadic ones. Earlier evidence
showed that most cases of either early onset or late
onset dystonia present ?maximum progression of dis-
ability within the first 5–10 years after the onset of the
illness? [12], or in the first 5 years after onset [3,13]. In
the present series, this observation is confirmed for
sporadic cases, but not for familial cases that show
Table 2 Mean age at disease onset in cases
with sporadic adult onset dystonia and in
cases with adult onset familial dystonia who
were non-carriers of DYT1 GAG deletion.
Only the proband has been analysed in each
dystonia family
Site of onset
Sporadic dystoniaFamilial dystonia
n M/FAgen M/FAge
Cranial
Cervical
Laryngeal
Upper limb
Lower limb
Total
3710/27
6/3
1/2
7/2
–
24/34
58.2 ± 9.5
46.3 ± 13.4
50.7 ± 21.6
42.2 ± 16.2
–
53.5 ± 13.4
8
6
1
3
0
3/5
2/4
0/1
2/1
–
7/11
51.6 ± 9.10
37.0 ± 8.5
53
39.3 ± 12.2
–
44.8 ± 11.2a
9
3
9
0
58 18
aSignificantly different from mean age at onset of sporadic patients (P ¼ 0.0098).
Table 3 Retrospective series reporting the frequency distribution of age at disease onset in dystonia
Recruiting centers Patients
Age at onset
Modes
Onset <21
(% cases) NadirReferenceYears Distribution
National Hospital (London)
St Barnabas Hospital
(New York)
72 1–59
NA
(mostly
juvenile)
NA
Bimodal
Bimodal
0–10 and 41–50
9 and 16–20
66
82
21–30
15
[22]
[34] 226
Columbia University
(New York)
560Bimodal
(for segmental
dystonia)
6–10 for generalized
dystonia and 50–60
for focal and
segmental
9 and 55
27
?25 [23]
Columbia University
(New York)
Institute of Psychiatry,
King’s College Hospital,
National Hospital,
Hospital for sick
children (London)
Columbia University
(New York)
Gemelli Hospital (Rome)
178 NABimodal NA27 [35]
1074–67 Bimodal 5–10 and 45–50 6530–35[17]
160 4–74Bimodal0–10 and 31–40 5821–30[8]
4601–83Bimodal9 and 57 9.621 Present
series
AJ, Ashkenazi Jewish; NJ, non-Jewish; J, Jewish; NA, not available.
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constant progression even after several (up to 30) years
of follow-up. A comparison of the spread of symptoms
between sporadic and familial dystonia has been pre-
viously performed only in a North American study on
early onset PTD, where no differences were found be-
tween the two groups [3]. The present report suggests
that, in the Italian population, a more severe progres-
sion can be appreciated also several years after onset in
familial dystonia cases. This is probably because of a
specific genetic background. In keeping with this, it has
been observed that dystonia can spread to new body
parts even 30 years after onset in an Italian family with
DYT13 dystonia [14].
In the present series, familial cases had earlier age at
onset than sporadic patients, a difference mainly be-
cause of a lower age of patients with cervical onset.
Some earlier studies failed to observe differences in the
age at onset between familial and sporadic focal [15,16]
or non-focal dystonias [17], whereas others are in
keeping with the present observation [18,19]. Our series
does not support, instead, differences in age at onset in
upper limb dystonia; this confirms a previous study
showing no differences in age at onset between familial
and sporadic cases with writer’s cramp [20].
In the present cohort primary cases accounted for
77.6% of the total population of dystonia patients, in
keeping with earlier observations performed in other
centers [21]. The clinical features of PTD patients in this
series confirms that generalized dystonia has early onset
and often starts in a lower limb. In addition, it has been
observed that spread of symptoms occurs in a much
larger number of patients with early onset than with
late onset, confirming that age at disease onset is the
most important prognostic factor [3,22,23]. The highest
age at disease onset in this series was observed in pa-
tients with cranial presentation, whereas patients with
onset in lower limbs had the lowest age. The frequency
of familial cases observed in the present series is also in
keeping with earlier reports [24,25], although it may be
somewhat underestimated because of the low sensitivity
provided by family history taking [26]. Indeed, other
series describing a higher frequencies of familial
occurrences have been reported [15–17].
The present registry revealed gender-related differ-
ences of age at disease onset in PTD subgroups classi-
fied by the site of onset. In PTD cases with cranial or
laryngeal onset men were affected at a younger age than
women; by contrast, in cases with upper limb onset age
at onset was lower in women than in men. In addition,
gender-related differences in the prevalence of PTD
subgroups were observed. Cranial, cervical or laryngeal
onset occurred more frequently in women than in men;
upper limb onset was more frequent in men. These
observations are in keeping with previous reports form
England [27,28] and suggest that these clinical features
are shared by other patients particularly amongst
European population. These gender-related variations
support the possibility that sex hormones play a role in
the pathophysiology of dystonia [29,30].
A remarkable higher incidence of blepharospasm
compared with other focal forms of dystonia has been
reported in Italy, Spain and Japan [25,31–33]. The
present series had no epidemiological objectives and
may have been biased in part by referrals for botulinum
toxin treatment; notwithstanding, it is interesting to
remark that our patients with blepharospasm outnum-
bered those with other focal forms of dystonia.
In summary, the clinical features of sporadic dystonia
cases appear remarkably heterogeneous in different
series, with a number of consistent core features. This
suggests that some still unmapped genes interact with
an assortment of environmental factor to produce the
varied clinical spectrum of sporadic dystonia.
Acknowledgement
This work was supported by Comitato Promotore
Telethon grant E.1165 to AA.
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