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Dystonia in Ashkenazi Jews Clinical characterization of a founder mutation.

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Dystonia in Ashkenazi Jews: Clinical
Characterization of a Founder Mutation
Susan B. Bressman, MD,* Deborah de Leon, MS," Patricia L. Kramer, PhD,? Laurie J. Ozelius, BS,$§
Mitchell F. Brin, MD," Paul E. Greene, MD," Stanley Fahn, MD," Xandra 0. Breakefield, PhD,$"
and Neil J. Risch, PhD**
A gene (DYT1) for idiopathic torsion dystonia maps to chromosome 9q34 in Ashkenazi Jewish families with early
onset of symptoms. Further, there is linkage disequilibrium between DYTl and a particular haplotype of alleles at
9q34 loci in this population. This implies that a large proportion of early-onset idiopathic torsion dystonia in Ashkenazi
Jews is due to a founder mutation in DYT1. To characterize the phenotypic range of this mutation, we studied 174
Ashkenazi Jewish individuals affected with idiopathic torsion dystonia. We used GT(n) markers on chromosome 9434
(D9S62, D!E63, and ASS) and classified individuals as having (''carriers''), not having ("noncarriers"), or being ambiguous with respect to a DYT1-associated haplotype. We assessed clinical features and found marked clinical differences
between haplotype carriers and noncarriers. There were 90 carriers, 70 noncarriers, and 14 ambiguous individuals.
The mean age at onset of symptoms was significantly lower in carriers than in noncarriers (12.5 2 8.2 vs 36.5 2 16.4
years). In 94% of carriers, symptoms began in a limb (arm or leg equally); rarely the disorder started in the neck
(3.396) or larynx (2.2%). In contrast, the neck, larynx, and other cranial muscles were the sites of onset in 79% of
noncarriers; onset in the arms occurred in 21% and onset in the legs never occurred. Limb onset, leg involvement in
the course of disease, and age at onset distinguished haplotype carriers from noncarriers with 90% accuracy. In
conclusion, there are clinical differences between Ashkenazi Jewish individuals with idiopathic torsion dystonia who
do or do not have a unique DYTl mutation, as determined by a DYT1-associated haplotype of 9q34 alleles. These
differences suggest that early, limb-onset idiopathic torsion dystonia and late, cervical cranial-onset idiopathic torsion
dystonia are genetically distinct entities.
Bressman SB, de Leon D, Kramer PL, Ozelius LJ, Brin MF, Greene PE, Fahn S, Breakefield XO,
Risch NJ. Dystonia in Ashkenazi Jews: clinical characterization of a
founder mutation. Ann Neurol 1994;36:771-17?
Idiopathic torsion dystonia (ITD) is characterized by
involuntary twisting and repetitive movements and
postures that are not attributed to exogenous factors
(e.g., trauma, neuroleptics) or other neurological disorders (e.g., Wilson's disease, Parkinson's disease) 11, 2).
Clinical studies describe a relationship between the age
at onset of symptoms, body region first affected, and
progression of signs 13-61. There is a bimodal distribution in the ages of onset of ITD, with modes at 9 (early
onset) and 45 (late onset) years, and a nadir at 27 years
11, 7). In children and adolescents, ITD usually starts
in a leg or arm and progresses to involve other limbs
within 5 years, regardless of treatment 13, 4, 6). In
adults, the neck, larynx, and other c ra nd muscles are
usually affected first and dystonia remains localized 12,
51. This clinical heterogeneity may be due to etiological
heterogeneity. Ethnic differences in disease frequency
also suggest etiological heterogeneity; Ashkenazi Jews
are reported to have a five-fold increased incidence of
early-onset ITD compared to non-Jews and AfricanAsian Jews [S, 91.
Family studies of ITD in the Ashkenazi Jews (AJ)
population indicate that the disorder is inherited in an
autosomal dominant fashion with reduced penetrance
of 30% 19-12). In these studies, families were ascertained through probands with early-onset or generalized signs 19-12); dystonia in affected relatives ranged
from early-onset generalized to adult-onset focal dystonia 110). However, there are no systematic family studies of late-onset and focal AJ ITD.
Kramer and colleagues 113) mapped a dystonia gene
(DYT1) by linkage analysis in 12 AJ families to chromosome 9q32-34, the same region previously implicated in an early-onset non-Jewish family t141. In each
of the 12 AJ families, at least 1 member was affected
before the age of 12 years and the mean age at onset of
~~
From the *Department of Neurology, Columbia-Presbyterian Medical Center, New York, NY; ?Department of Neurology, Oregon
Health Sciences University, Portland, OR, $Molecular Neurogenetics Unit, Neuroscience Center-Neurology, Massachusetts General
Hospital, East Charlestown, MA; Departments of $Genetics, and
'Neuroscience Program, Harvard Medical School, Boston, MA; and
the ""Departments of Epidemiology and Public Health and Genetics,
Yale University School of Medicine, New Haven, CT.
~
~~
~
~~
~
Received Mar 16, 1994, and in revised form May 6. Accepted for
publication May 10, 1994.
Address correspondence to Dr Bressman, Department of Neurology, Neurological Institute, Columbia-Presbyterian Medical Cenrer,
West 168th Street, New York, NY 1o032,
Copyright 0 1994 by the American Neurological Association
771
all affected members was 13.2 years. Recently, linkage
disequilibrium between DYTl and a particular haplotype of alleles at t h e 9434 loci ABL and ASS was found
[l5} and a single progenitor AJ ITD chromosome was
defined by haplotype analysis [l6J Linkage disequilibrium refers t o the tendency of particular alleles (at two
or more linked loci) t o occur together on t h e same
chromosome more frequently than would be expected
by chance. For markers that are very tightly linked t o
a disease gene, such a n association of an allele or g r o u p
of linked alleles t o a disease gene is expected t o occur
if the disease is largely d u e to a single mutation that
occurred in the recent past and equilibrium has not
yet been achieved. The finding of a DYTl-associated
haplotype of 9q34 alleles implies that a founder mutation in this gene underlies early-onset AJ ITD in most
patients.
The previous reports of linkage disequilibrium did
not describe the clinical features of ITD in the affected
AJ individuals with a DYT1-associated haplotype (“carriers’’) [l5, 163. Also, the number of affected individuals who did not have a DYTl-associated haplotype
(“noncarriers”) was small. if noncarriers represent a different mutation or even a nongenetic disease, there
might be clinical differences between carriers and noncarriers. To delineate t h e clinical characteristics of dystonia in AJ patients w h o harbor the founder DYTl
mutation, as defined by a DYTl-associated haplotype,
and also to investigate whether there are differences
between haplotype carriers and noncarriers, we studied
174 singleton and familial AJ ITD patients with a range
of clinical features.
Materials and Methods
Examination and Families
W e ascertained subjects from a computerized data base file
of 370 AJ ITD patients examined by members of the Movement Disorder Group at the Columbia-Presbyterian Medical
Center between January 1983 and January 1993; 164 affected individuals from 121 families were available and consented to participate in the study. Also, 10 consenting affected AJ individuals from 4 families were ascertained
through the Dystonia Medical Research Foundation. Clinical
descriptions of 29 of these 174 patients were reported previously [l3f. The study was approved by the ColumbiaPresbyterian Medical Center Review Board.
The criteria for the diagnosis of ITD and the methods of
evaluation were the same as described previously [lo, 131.
Briefly, a neurologist trained in the analysis of movement
disorders obtained a hisrory including detailed review of
prior drug exposure, pedigree history, and standardized examination with videotape examination of each affected patient. Computed tomography or magnetic resonance imaging,
measurement of serum ceruloplasmin level, and a trial of
levodopa therapy to exclude dopa-responsive dystonia were
performed on at least 1 affected member from each family.
All individuals included for clinical analysis were considered
to be affected with ITD as determined by video and personal
772 Annals of Neurology
Vol 36 No 5
examination and review of available records; distributions of
dystonia were categorized as focal, segmental, multifocal, or
generalized 12). All clinical evaluations and categorizations
were performed by neurologists “blinded” to the genetic
data. The criteria for designation as Ashkenazi were the same
as described previously {lo).
D N A Methods, Probes, and Polymorphism Analysis
Blood was obtained by venipuncture from consenting affected individuals and family members as necessary for phasing. D N A was extracted from lymphoblastoid lines or whole
blood as described [17, 181. Polymerase chain reaction
(PCR) analysis of the dinucleotide repeat polymorphisms for
the loci D9S62 (1290/1301), D9S63 (28/34), and ASS was
carried out on genomic D N A as described [19-21}.
Statistical Analysis
Based on our previous studies [ 15, 161, the minimum associated haplotype consisted of alleles “8”and “16” at loci D9S62
and D9S63, respectively, or “16” and “12” at loci D9S63
and ASS, respectively. Specifically, in 36 multiplex AJ families with early-onset ITD initially involving the limb or neck,
Risch and colleagues I1 61 found that 3 1 of 36 disease chromosomes had the 8-16, 29 had the 16-12, and 28 had the
entire 8-16-12 haplotype. The frequency of these three haplotypes in a sample of 306 AJ control chromosomes was very
low at 5 (1.6%), 0, and 0, respectively. It is possible that
some individuals were misclassified as to whether they do or
do not carry this specific mutation; however, we expect the
number of such misclassifications to be small. We then classified affected members into four groups:
1. Those with a DYT1-associated haplotype (“carriers”) in
whom the disease-bearing chromosome could be identified by inheritance (“I”). W e identified the inherited disease-bearing chromosome based on the neurological examination and determination of linkage phase in at least
2 affected members in the family who shared only the
associated haplotype, except in 2 families. In each of these
2 families, 1 of 2 affected family members was deceased;
the deceased were considered affected based on medical
records, and haplotypes were deduced from living relatives. Only the living affected member was included in
the clinical analysis.
2. Those with a DYTl-associated haplotype (“carriers”) in
whom the disease-bearing chromosome could not be
identified by inheritance (‘“1”). We determined linkage
phase but could not identify an inherited disease-bearing
chromosome because the affected individual was the only
individual known to be affected in the family, except in
2 families; in these 2 families there were 2 affected sibs,
but the disease-bearing chromosome could not be determined because the sibs shared two chromosomes identical
by descent from both parents.
3. Those without a DYT1-associated haplotype (“noncarriers”). This group included individuals for whom linkage
phase was determined and who did not have a DYT1associated haplotype and also individuals for whom linkage phase was not determined but who could not have a
DYT1-associated haplotype on either chromosome.
November 1994
4 . Ambiguous. These individuals had associated alleles but
the haplotype could not be determined because family
data needed for determining linkage phase were inadequate or unavailable.
Of the 174 affected individuals studied, 14 were ambiguous. Therefore, 160 individuals from 1 1 1 families were available for clinical analysis. Data on clinical features including
age at onset, site of onset (leg, arm, trunk, neck, larynx,
and other cranial regions), duration of disease, body regions
affected at the time of last examination (same regions as sites
of onset), and distribution of dystonia at last examination
(focal, segmental, multifocal, and generalized) were tabulated. We used x2 tests to compare groups for discrete variables. W e used t tests to compare groups for the continuous
variable, age at onset. Square root transformation was performed to adjust for skewness; however, analyses based on
transformed and untransformed data were negligibly different. W e performed stepwise linear discriminant analysis using
the computer program BMDP7M of the Biomedical Computer Program Series [ 2 2 ) to determine which clinical features best distinguish haplotype carriers from noncarriers using all clinical variables listed above simultaneously; this
analysis also included the clinical variable of limb (leg or arm)
onset.
Results
Of 160 affected individuals, 90 definitely carried a
DYT1-associated haplotype: 75 carried the entire 816-12 haplotype, 13 carried the 8-16, and 2 carried
the 16-12. Seventy affected individuals did not carry
an associated haplotype (Table 1). Of the 90 carriers,
68 from 32 families were classified as carriers-I and 22
from 20 families were classified as carriers-NI. The 70
noncarriers represented 59 families.
Clinical Features in Haplotype Carriers
There were no significant differences in clinical features between carriers-I and carriers-NI, including age
Table I . Clinical Features of Definite Haplotype Carriers
and Noncarriers
No. of cases
No. of families
Male-female ratio
Age at onset (yr)”
Mean rfr S D
Median
Range
Duration of disease
to last examination
(ydb
Mean 5 S D
Median
Range
Carriers
Noncarriers
90
52
1.1
70
59
0.84
12.5
9.0
4-44
5
8.2
22.7 2 14.7
20
0.5-66.2
36.5
37.5
6-74
?
16.4
15.3 5 13.3
12
0.8-63
‘Significant difference: carriers vs noncarriers, p < 0.001.
bSignificant difference: carriers vs noncarriers, p < 0.01.
SD = standard deviation.
at onset, site of onset, and distribution of dystonia at
last examination. Therefore, the following description
is based on the combined group (n = 90) of haplotype
carriers.
Dystonia began at a mean ( k standard deviation
[SD]) age of 12.5
8.2 years and started in a limb in
85 (94.4%) of the 90 haplotype carriers; in 42 a leg
was first affected, and in 43 an arm was first affected
(Table 2). In all carriers with onset in a leg, dystonia
progressed to involve other limbs, except in 2 individuals whose dystonia remained focal; however, the follow-up time was short (0.5 and 3.9 years) in both. In
haplotype carriers with onset in the arm, symptoms
began later and progression to other body regions varied widely (see Table 2). Dystonia spread to a leg (and
possibly elsewhere) in about one half; in 21% (9 of
43) there was spread segmentally to the other arm or
rarely the neck or cranial muscles and in 28% (12 of
43) signs remained restricted to the arm despite a long
follow-up time (mean, 20 years).
Age at onset in the 3 haplotype carriers whose symptoms began in the neck was later than in carriers with
onset in a limb (see Table 2), and progression to other
muscles varied. Only 2 haplotype carriers had onset in
the larynx. In one, dystonia began at age 18 and spread
to the limbs; in the other, dystonia began at age 12
and remained locahzed after 13 years of follow-up. No
haplotype carriers had onset of symptoms in other cranial muscles.
At the time of last examination, a leg was involved
in 66 (73%) of 90 haplotype carriers and an arm in 85
(94%); overall, 71% (64 of 90) progressed to involve
at least one leg and one arm as a generalized or multifocal distribution. Although the neck was rarely the
first region affected, it was involved at the time of last
examination in 28 (31%) of the 90 haplotype carriers.
Involvement of the larynx or other cranial muscles at
last examination was uncommon (9% [8 of 901).
*
Clinical Features in Haplotype Noncarriers
In the 70 noncarriers, dystonia began at a mean ( k SD)
age of 36.5
16.4 years and none of the 70 had onset
of symptoms in a leg (Tables 1, 3). Dystonia spread to
the legs in only 2 individuals, one with onset of symptoms in an arm at age 13 and the other with onset in
the neck at age 12. In both of these patients, the disease was familial; affected relatives had later onset in
the same body region but dystonia did not progress to
involve the legs.
Age at onset was similar for those with first symptoms in the arm, neck, or larynx (Table 3), but was
later for those with onset of symptoms in the face, jaw,
and tongue. Progression of dystonia outside the site of
onset was limited; in over one half, the distribution
remained focal after a long follow-up time (mean, 15.2
years).
*
Bressman et al: Dystonia in Ashkenazi Jews
773
Table 2. Clinical Features by Site of Onset in 90 Definite Carriers
Distribution at
Last
Site of Onset
N
Age at Onset (yr)
Leg
42/90 (46.7%)
Arm
43/90 (47.8%)
Mean 5 SD = 9.1
Median = 8.0
Range = 4-23
Mean 2 SD = 14.7
Median = 11
Range = 7-44
Neck
3190 (3.3%)
Ages
2/90 (2.2%)
Ages = 12, 18
* 3.9
=
?
Generalized = 37
Multifocal = 3
Focal = 2
Generalized = 16
Multifocal = 6
Segmental = 9
Focal = 12
Generalized = 1
Segmental = 1
Focal = 1
Multifocal = 1
Focal = 1
9.7
21, 25, 34
"Distribution at last examination for all carriers: generalized = 60%; multifocal = 11.1%; segmental = 11.1%; focal = 17.8%.
bRegions affected at last examination for all carriers: leg = 66/90 (73%);arm = 85/90 (94.496);neck = 28/90 (31.1%); larynx = 3/90 (3.3%);
other cranial muscles = 5/90 (5.5%).
SD
=
standard deviation.
Table 3 . Clinical FeatureJ by Site of Onset in 70" Noncarriers
Site of Onset"
N
Age at Onset (yr)
Arm
15/71 (21%)
Neck
1917 1 (26.8%)
Larynx
2617 1 (36.6%)
Other cranial (jaw = 2,
tongue = 2, upper
face = 7)
11/71 (15.5%)
SD = 32.5
Mean
Median = 31.5
Range = 7-60
Mean & SD = 33.2
Median = 36
Range = 7-53
Mean 5 SD = 34.0
Mean = 35
Range = 6-57
Mean ? SD = 54.9
Median = 55
Range = 28-74
*
Distribution at
Last Examinationb%'
2
17
2
14.6
2
13.6
2
14.6
Generalized = 1
Segmental = 8
Focal = 6
Generalized = 1
Segmental = 5
Focal = 13
Segmental = 9
Focal = 17
Segmental
Focal = 6
=
5
=
27/70
"7 1 sites of onset for 70 patients.
bDisrribution at last examination for all noncarriers: generalized = 2.9%; segmental = 38.6%; focal = 58.6%.
'Regions affected at last examination for all noncarriers: leg = 2/70 (2.996); arm = 20170 (28.6%); neck = 27/70 (38.6%); larynx
(38.6%); other cranial = 20170 (28.6%).
SD
=
standard deviation.
Clinical Differences Between Haplotype Carriers and
Noncarriers
We found a highly significant difference between haplotype carriers and noncarriers in age at onset (t =
12.51, p < 0.001) (Table 1, Fig 1).Of the 58 patients
with onset before the age of 11 years, 54 (93%) were
haplotype carriers, whereas all 3 1 (100%) with onset
after the age of 44 years were noncarriers.
There was a remarkable difference in the sites of
onset, in haplotype carriers and noncarriers (x2 =
111.1, df = 4 , p < 0.001) (Fig 2). All 42 with onset
of symptoms in a leg were haplotype carriers as were
43 (74%) of 58 with onset in an arm. Only 3 (14%)
of 22 with onset in the neck, 2 (7%) of 28 with onset
774 Annals of Neurology
in the larynx, and none with onset in cranial sites were
haplotype carriers.
W e also found a highly significant difference in the
four distributions of dystonia in haplotype carriers and
noncarriers at last examination (x2 = 75.9, df = 3, p
< 0.001) (see Tables 2, 3); 54 of 56 (96.4%) whose
dystonia was generalized and all 10 (100%) with a
multifocal distribution were haplotype carriers. O n the
other hand, 26 (72%') of 36 with segmental and 42
(72%) of 58 with focal distributions were noncarriers.
It is unlikely that the difference in distribution is due
to the differential length of follow-up in carriers and
noncarriers. The mean duration of disease to the last
examination was shorter in noncarriers because of the
Vol 36 N o 5 November 1994
Table 4. Results of Stepwise Discriminant Analysis
w
50
Variable
Step Entered
F Value
to Enter
Coefficient
Limb onset
Leg involved
Age of onset
Constant
1
2
3
200.9
51.9
5 1.0
1.92
1.31
- 0.03
In
8")
2
E 3 0
f
INon-Carriers
20
-
1.06
10
0
0-10
11-20
21-30
31-40
41-50
51-60
61-70
71-80
Age at Onset
Fig 1 . Age at onset of idiopathic torsion dystonia in Ashkenazi
Jewish carriers and noncarriers of the haplotype associated with
the DYTl mutation.
cranial
~
0% carriers
/T* 100% non-carriers (age onset.54.9)
larynx
n=22
7.1% carriers (age onset=15.0)
92.9% non-carriers (age onsel-34.0)
13.6% carriers (age onsek26.7)
86.4% non-carriers (age onset=33.2)
arm
n.58
74% carriers (age onsek14.7)
26% non-carriers(age onsek32.5)
/\)I
100% carriers (age onset=9.l)
0% non-carriers
Fig 2. The proportion of haplotype carriers and noncarriers far
the various sites of onset of idiopathic torsion dystonia.
later age at onset (see Table 1); however, in both
groups, the follow-up time was sufficiently long to observe the natural extent of disease progression C4, 6 ,
23-251.
Only the group with symptom onset in the arm contained substantial numbers of both haplotype carriers
and noncarriers; we further analyzed this group for
differences between haplotype carriers and noncarriers. Age at onset was earlier in haplotype carriers
Canonical Variable
Fig 3. Distribution of canonical ziariable based on the three clinical variables (limb onset, leg ever intiolved, and age at onset)
and their coefficients listed in Table 4.
( p < 0.001). The direction of spread of dystonia also
differed; 22 (96%) of 23 with arm onset that spread
to a leg (and possibly other regions) and 8 (73%) of
11 that spread to the other arm (and other regions,
but not the leg) were haplotype carriers. In contrast, 5
(83%) of 6 with arm onset that spread up to the neck
and cranial muscles, but did not involve the other arm
or a leg, were noncarriers. Twelve (67%) of 18 with a
distribution that remained focal were carriers.
On stepwise linear discriminant analysis we found
that all clinical variables, with the exception of neck
involvement, significantly differentiated haplotype carriers from noncarriers. The three most significant discriminators were limb onset, leg ever involved, and age
at onset, which entered the equation in that order (Table 4). Once these three variables entered, no further
variables were significant.
As described above, this analysis demonstrated that
those with onset of symptoms in a iimb, leg involvement, and early age at onset were likely to be haplotype carriers, whereas those without these characteristics were not. Classification of haplotype carriers and
noncarriers by the discriminant function was excellent:
Only 9 (10.0%) of 90 haplotype carriers were misclassified, while 9 (12.9%) of 70 noncarriers were misclassified (Fig 3).
Lnear discriminant function analysis also provides a
canonical variable defined as that linear combination of
variables that best discriminates between the two
Bressman et al: Dystonia in Ashkenazi Jews
775
groups, carriers and noncarriers. Examination of the
canonical variable in Figure 3 demonstrates a region of
overlap between carriers and noncarriers. Most of
these individuals had adult (age 18-44) arm-onset dystonia that either remained focal or spread up to the
neck and cranial muscles or, less commonly, they had
cervical- or laryngeal-onset dystonia that spread down
to the arm and leg.
Three carriers had especially low canonical variable
values (see Fig 3). One of these had onset in the neck
at age 21 and symptoms spread to an arm, one had
onset in the neck at age 34 and the disease remained
focal, and one had onset in the larynx at age 12 and
symptoms remained focal. These are highly atypical
characteristics for haplotype carriers.
One noncarrier had a very high canonical value. This
individual had early onset (age 13)in an arm and dystonia generalized to involve all four limbs. These are
characteristics strongly suggestive of carriers. It is notable that this individual's father and brother were also
affected and misclassified as carriers; one had onset of
symptoms in an arm at age 18 that spread to the other
arm and one had onset at age 20 and symptoms remained focal. We believe that this family may contain
a similar, although distinct mutation at DYT1, leading
to a carrier-like clinical phenotype. This may also be
true of some of the other misclassified noncarriers.
However, even leaving out these individuals, there is
still likely to be some overlap between haplotype carriers of DYTl mutations and noncarriers. This is particularly true for patients with early adult arm-onset dystonia that remain focal.
Discussion
This study confirms our previous impression that earlyonset ITD in Ashkenazim is a genetically homogeneous disorder { 10, 111 and strongly supports the idea
that the great majority of early limb-onset AJ ITD results from a founder mutation in the DYTl gene. In
our previous studies {lo-12, 15, 161, we included primarily or only families of index patients with earlyonset ITD based on the hypothesis that the clinical
differences between early- and late-onset ITD are due
to genetic or etiological heterogeneity. In support of
that hypothesis, we noted in our AJ family study that
onset of symptoms after age 44 and onset in cranial
muscles were never observed in affected family members of probands with early-onset disease [lo]. The
present findings suggest that clinical differences between early- and late-onset ITD do indeed imply etiological differences between these clinical subgroups.
We found that there is a range of clinical expression
in carriers, but it is limited. Dystonia typically begins
in childhood or adolescence; it starts in a limb (arm
and leg about equally) and spreads to other limbs; however, it may remain localized as writer's cramp. In a
small minority of haplotype carriers, dystonia begins in
the fourth or fifth decade and rarely affects the neck
or larynx first.
In contrast, noncarriers display a wide range of age
at onset and constitute almost all cases beginning after
40 years. Dystonia usually first affects the neck, larynx,
and other cranial muscles and it remains localized. In
some noncarriers, dystonia begins in an arm, and very
rarely noncarriers mimic the carrier phenotype.
On discriminant analysis we found that onset of dystonia in a limb, leg involvement in the course of disease, and early onset distinguished haplotype carriers
from noncarriers with about 90% accuracy. This information will aid the clinician in future application of
DNA testing for the diagnosis of this common form
of AJ ITD and in counseling haplotype carriers and
their families on the range of clinical features associated
with this mutation. Testing will be particularly important in patients with no known family history. In our
previous studies, we found reduced penetrance (0.30)
of early-onset AJ ITD and concluded that in singleton
cases the disease is inherited [lo, 1I}; further, linkage
disequilibrium results indicate that in many singleton
cases with early onset, ITD is due to the same DYTl
mutation found in familial cases {l5]. The present data
are consistent with the earlier findings. Of the 90 haplotype carriers from 52 families, 18 were singleton.
These singleton cases were indistinguishable clinically
from cases with familial cases.
Although this study provides additional evidence
that most early limb-onset dystonia in AJ is due to a
founder mutation in the DYTl gene, the genetic basis
of ITD in noncarriers remains to be clarified. There
have been no systematic family studies of late-onset AJ
ITD. In the present study, affected individuals provided detailed pedigree information. In 23 of the 70
noncarriers, the disease was familial and included brachial, cervical, laryngeal, and facial dystonia. Thus, a
proportion of noncarrier AJ ITD may be inherited.
This is consistent with family studies of non-Jewish
ITD [26, 271, which concluded that there is autosomal
dominant inheritance with reduced penetrance in both
early-onset generalized and late-onset focal clinical subtypes.
We suspect, based on a noncarrier family with early
arm-onset ITD,that at least one other similar mutation
event in the DYTl gene exists in the AJ population.
However, the marked clinical differences between
most haplotype carriers and noncarriers suggest that
the causes of ITD are different in these groups; different mutations of DYT1, other dystonia genes, and
nongenetic factors may be causes of the adult cervicalcranial-onset dystonia in noncarriers. In support of the
hypothesis that a dystonia gene other than DYTl may
be responsible for adult cervical-cranial-onset ITD in
the AJ population is our recent exclusion of the DYTl
776 Annals of Neurology Vol 36 No 5 November 1994
locus in a large non-Jewish family with this clinical subtype of ITD [28]. Additional family and linkage studies
of adult-onset AJ ITD will help in determining the role
of heredity and the underlying genetic mechanism of
ITD in this population.
This work was supported by grants NS26656, NS28384, and
HG00148 from the National Institutes of Health, a Clinical Research Center grant and individual grants from the Dystonia Medical
Research Foundation, and a grant from the Red Fund of the Tides
Foundation.
We thank the patients and family members who participated in this
study and we also wish to thank Drs L. P. Rowland and T. G. Nygaard for their helpful comments.
14.
15.
16.
17.
~
18.
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