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Clinical and genetic evaluation of a family with a mixed dystonia phenotype from south tyrol.

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mediated by activated macrophages and T lymphocytes. 20 Therefore, if HHV-6 is involved in the pathogenesis of MS, perhaps immune activation results in
greater HHV-6 gene expression in the CNS.
This study was supported by grants from the Health Sciences Center
Research Foundation, Winnipeg, Manitoba, Canada. Dr Mayne is the
recipient of a Manitoba Health Research Council Postdoctoral Fellowship. Dr Power is the recipient of an NHRDWMRC scholarship.
We are indebted to Weimin Ni for her excellent technical help. We
also acknowledge the assistance of registered nurses Marlene Dott,
Tracy Olafson, Bev Davis, and Loressa Klassen, who collected the
blood specimens.
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ffrench-Constant C. Pathogenesis of multiple sclerosis. Lancet
Clinical and Genetic
Evaluation of a Family
with a Mixed Dwtonia
Phenotype from ‘South Tyrol
Christine Klein, MD,* Peter P. Pramstaller, MD,t
Claudio C. Castellan, MD,$ Xandra 0. Breakefield, PhD,*
Patricia L. Kramer, PhD,§ and Laurie J. Ozelius, PhD*
The gene causing early-onset torsion dystonia (DYTl)
has recently been identified, and two new dystonia genes,
one for adult-onset focal dystonia (DYT7) and one for a
mixed dystonia phenotype (DYTG), have been mapped.
We evaluated clinically a family from South Tyrol
(Northern Italy) with 6 definitely affected individuals
who display an unusually large phenotypic range of dystonic symptoms. We excluded the GAG deletion in the
DYTl gene and linkage to any of the above-mentioned
dystonia loci, thus suggesting an as yet undefined dystonia gene in our family.
Klein C, Pramstaller PP, Castellan CC,
Breakefield XO, Kramer PL, Ozelius LJ. Clinical
and genetic evaluation of a family with a mixed
dystonia phenotype from South Tyrol.
Ann Neurol 1998;44:394-398
Idiopathic torsion dystonia (ITD) is defined as the sole
manifestation of involuntary twisting or repetitive
movements and abnormal postures without secondary
From the ‘Molecular Neurogenetics Unit, Massachusetts General
Hospital, and Departments of Neurology and Genetics and Neuroscience Program, Harvard Medical School, Boston, MA; Departments of TNeurology and $Genetics, Regional General Hospital,
Bolzano-Bozen, Italy; and SDepartment of Neurogenetics, Oregon
Health Science University, Portland, OR.
Received Feb 20, 1998. Accepted for publication Mar 20, 1998.
Address correspondence to Dr Ozelius, Molecular Neurogenetics
Unit, Massachusetts General Hospital, CNY 149, Room 6221, 13th
Streer, Charlestown, MA 02129.
Copyright 0 1998 by the American Neurological Association
causes. Recent advances in the molecular generics of
autosomal dominantly inherited ITD have led to the
cloning of the gene causing early-onset generalized torsion dystonia (DYT12) a n d to the mapping of two new
dystonia genes, o n e for adult-onset focal dystonia
(DYT73) a n d another for a mixed dystonia phenotype,
in families of Mennonite origin (DYTG4).Here, we describe a family from South Tyrol (Northern Italy) with
an unusually diverse range of phenotypic manifestations
of ITD. Genetic analysis was used to assess the involvement of these three candidate loci i n this family.
Patients and Methods
In Family I, 3 affected and 6 unaffected family members
underwent standardized neurological examination including
videotaping. Clinical information on 3 deceased patients was
taken from the hospital records. The diagnosis of dystonia
was established according to published criteria’; Doparesponsive dystonia was excluded by an L-Dopa challenge test
in the index patient.
Testingfor the GAG Deletion in DYTl and
DNA Analysis
After obtaining informed consent, venous blood samples
were drawn from all 3 living affected and 6 unaffected family
members. W e used published primers 6418 and 6419 for
polymerase chain reaction (PCR) amplification of the critical
for the GAG
region Of the DYT1 gene2 to
PCR products were resolved in a 6% denaturing polyacrylamide gel and visualized by silver staining5 The following
simple sequence repeat markers were used for DNA analysis
(genetic distances according to D8Sll10-3.7 cM-D8S1464-6.9 cM-D8S11134.4 cM-D8S1136-5.3
(chromosome 8); D9S2161-0.0 cM-D9S63-1.8 cM-ASS
(chromosome 9); D18Sj9-2.8 cM-D18S476-0.0
cMD18S1105-2.7 cM-D18S 1098-1.4 cM-Dl8S48 1-1.4 cMcM-D18S452-9.4 cMD18S54-4. j cM-D18S976-5.9
D I 8S843 (chromosome 18), following standard protocols as
specified by Research Genetics ( or
Ozelius and colleagues.‘ PCR products were analyzed on a
LICOR automated sequencer (LICOR) or visualized by silver staining5
Patient Histories
The family originated in South Tyrol and was not of known
Jewish or Mennonite origin. Six patients (3 men and 3
women) from three generations were definitely affected; 1
woman from the first generation was probably affected (by
history; Fig). Mean age of onset of the 6 definitely affected
patients was 20.0 1- 13.1 years (range, 4-40 years). In 3
patients, dystonia started in the lower limbs (age of onset,
13.3 -C 8.1 years; range, 4-18 years); 2 patients had spasmodic torticollis as their first symptom (age of onset, 18 and
30 years), and 1 patient presented with writer’s cramp at age
40. In 4 of the 6 affected subjects, dystonia became generalized (Table 1). Short patient histories are given below for
each affected:
Patient I K 1 (Propositus)
In this 41-year-old man, dystonia started in the left foot at
age 10 years, followed by left upper limb dystonia 3 years
later and right-sided writer’s cramp. At 18 years, oromandibular dystonia and spasmodic dysphonia appeared. Shortly
thereafter, the dystonia became generalized with cervical and
truncal involvement.
Patient III. 1 (Mother of Patient IV 1)
This 62-year-old woman developed writer‘s cramp at age 40
years. The dystonia remained stable for 19 years, when she
developed left upper limb dystonia and oromandibular dystonia.
patient 111.3 (uncle
ofpatient 1~
In this 62-year-old man, dystonia started with right-sided
torticollis at age 18 years. The disorder slowly progressed to
generalized dystonia by the age of 40 years.
Patient III.4 (Aunt o f Patient W l )
At age 4 years, this patient developed dystonia in the lower
limbs, followed by rapid progression toward generalized dystonia. She died of typhoid fever at age 18 years.
Patient III.6 (Aunt of Patient I K l )
Dystonia started in the left foot at 18 years of age. Subsequently, the left upper limb and cervical muscles became involved. After this time, the dystonia was nonprogressive. The
patient died of hepatic cirrhosis at 43 years of age.
Patient 11.1 (Grandfither of Patient I K 1)
Linkage Analysis
We conducted two-point and multipoint linkage analyses by
using the VITESSE program.’ These analyses were based on
linkage maps for chromosomes 8, 9q, and 18p described
above. We assumed autosomal dominant inheritance of a
rare gene (frequency = 0.0001). T o avoid problems arising
from incorrect specification of penetrance, we followed a
conservative approach and coded only definitely affected individuals as “affected, and all others were coded as “unknown” with respect to disease status. Marker allele frequencies were assumed to be equal, unless reliable population
estimates were available. N o interference was assumed in the
multipoint analysis.
This Alpine tour guide and skiing teacher developed a slowly
but steadily deteriorating generalized dystonia starting in the
upper limbs at age 50 years, and he died at 74 years of age.
Looking at old family pictures, mild rorticollis was already
present at 30 years of age.
Patient I. I (Great-Grandmother o f Patient IV. 1)
This patient was affected by history only. She enjoyed good
health until the age of 60 years, when she developed a slowly
progressive “motor problem” in her lower limbs. Seven years
before death (at age 89) her neck was said to be “rigid” and
involuntarily turning forward, and both hands were held in a
rather fixed posture.
Brief Communication: Klein et al: Evaluation in Dystonia
Family members V.l, V.2, IV.2, IV.3, 111.2, and 111.8 did
not show any signs of dystonia or any other neurological
tive across the entire 28.1-cM region, although not always less than -2.0.
This family displays an unusually variable phenotype of
dystonia ranging from typical early-onset generalized
dystonia (Patient 111.4), to cervical dystonia beginning
at age 30 with slow progression toward generalized dystonia (Patient ILI), or to isolated adult-onset writer's
cramp with only minimal involvement of the contralatera1 upper limb and mild cranial dystonia 20 years later
(Patient 111.1). Intrafamilial phenotypic variation of
ITD has been described p r e v i o ~ s l y ,but
~ ~ ~in most
cases occurs to a lesser degree than in our family. For
example, family members with hereditary adult-onset
ITD may have a very variable age of disease onset
(28-70 years,3 15-62 years," or 7-50 years") but
Exclusion of the GAG Deletion and Linkage on
Chromosomes 8, 9, and 18
The GAG deletion was not found in any of the patients tested. Two-point LOD scores for markers in the
candidate regions on chromosomes 8, 9, and 18 are
given in Table 2, and show no positive evidence for
linkage. We included the set of most informative
markers in each region in the multipoint analyses, and
results confirm what is apparent from the two-point
results. Linkage to chromosomes 9q and 18p is excluded with LOD scores below -2.0 across the entire
candidate regions (1.8 cM and 28.1 cM, respectively).
For chromosome 8, LOD scores are consistently nega-
Table 1. Comparison o f the DYTI, DYT6 and DYT7 Phenotypes
ITD Type
Age of Onset (yr)
Site of Onset
12.5 ? 8.2
(range, 4-44)
Very frequent
Bressman et all2
43.0 2 ?
(range, 28-70)
18.3 t 11.3
(range, 6-38)
Leg, 46.7%
Arm, 47.8%
Neck, 3.3%
Larynx, 2.2%
Neck, 85.7%
Larynx, 14.3%
Arm, 33.3%
Neck, 33.3%
Tongue, 33.3%
Leg, 50%
Arm, 30%
Neck, 20%
Leube et al?
Rare ( 1 of 6 patients)
Almasy et ai4
Family I
20.0 2 13.1
(range, 4-40)
396 Annals of Neurology
Vol 44
No 3
September 1998
Frequent (4 of 6 patients)
Table 2. Results of Two-point Linkage Analysis for Candidate Regions on Chromosomes 8 (Om@,
9 (DYrl),
and 18 (DYT7) in an Italian Family
LOD Score at Theta
Chromosome 8
Chromosome 9
Chromosome 18
D8S 166
D9S2 161
D 18S476
D18S 1105
D 18S976
- 1.10
- 1.40
- 1.40
- 1.40
- 1.55
- 1.72
- 1.72
- 1.72
0.0 1
0.0 1
show a similar clinical pi~ture.”.’~,’Although there is
considerable phenotypic overlap in individual cases,
both the DYTl and the DYT7 mutations appear to be
associated with a fairly characteristic phenotype. l 3 In
most of the DYTl GAG deletion carriers, dystonia
starts in childhood, affects the limbs first, and usually
generalizes12; mutations in DYT7 cause adult-onset focal d y ~ t o n i a .In
~ contrast, a mutation in the DYTG
gene is associated with a mixed dystonia phenotype in
two Mennonite families: thus resembling the clinical
picture in our family, although our patients developed
generalized dystonia more often (see Table 1). In accordance with earlier descriptions,’2 a lower age of disease onset in our patients tended to be associated with
the development of generalized dystonia, whereas
adult-onset dystonia was more likely to remain focal at
one or several sites. We could not find any evidence for
anticipation in our family.
Our data effectively exclude the GAG deletion and
the chromosomal region containing D Y T I as well as
the D U 6 and DYT7 dystonia loci, in this Italian family. Previous studies have shown that adult-onset ITD
in two other families’02’’ and a more variable phenotype of familial dystonia’,’ are not linked in the region
of the DYTl gene. In one of the two latter families,
dystonia turned out to be caused by the DYTG mutat i ~ n The
. ~ similarity of the dystonia phenotype between the patients in our family and the Mennonite
patients* rendered the DYTG gene a particularly good
candidate in this family. As shown by the example of
the DYTl gene, the same mutation underlies a founder
effect in the Ashkenazi Jewish population’* but has
also occurred independently in many other ethnic
groups (unpublished data). Dystonia in our family,
however, is not due to mutations in any of the known
dystonia genes.13 The dystonia loci on chromosomes 9,
8, and 18 have been excluded by linkage analysis,
X-chromosomal dystonia by the mode of inheritance,
Dopa-responsive dystonia on chromosomes 11 and 14
by lack of Dopa responsiveness, and paroxysmal dystonic choreoathetosis on chromosome 2 by phenotypic
analysis. Identification of more affected family members and subsequent genome search may lead to detection of a new dystonia gene locus.
This study was supported by the Dystonia Medical Research Foundation (L.O., P.L.K., and X.O.B.) and by N I H grant NS28384
(X.O.B.). C.K. is a fellow of the Deutsche Forschungsgemeinschaft.
We thank the patients and family members who participated in this
1. Fahn S. Concept and classification of dystonia. Adv Neurol
2. Ozelius LJ, Hewett JW, Page CE, et al. The early-onset torsion
dystonia gene (DYTl) encodes an ATP-binding protein. Nar
Genet 1997;17:40-48
3. Leube B, Rudnicki D, Ratzlaff T, et al. Idiopathic torsion
dystonia: assignment of a gene to chromosome 18p in a German family with adult onset, autosomal dominant inheritance
and purely focal distribution. H u m Mol Genet 1796;10:16731677
4. Almasy L,Bressman SB, Raymond D, et al. Idiopathic torsion
Brief Communication: Klein et al: Evaluation in Dystonia
dystonia linked to chromosome 8 in two Mennonite families.
Ann Neurol 1997;42:670-673
5. von Deimling A, Bender B, Louis DN, Wiestler OD. A rapid
and non-radioactive PCR based assay for the detection of allelic
loss in human gliomas. Neuropathol Appl Neurobiol 1993;19:
6. Ozelius LJ, Hewett J, Kramer P, et al. Fine localization of the
torsion dystonia gene (DYTl) on human chromosome 9q34:
YAC map and linkage disequilibrium. Genome Res 1997;7:
7. O’Connell JR, Weeks DE. The VITESSE algorithm for rapid
exact niultilocus linkage analysis via genotype set-recording and
fuzzy inheritance. Nat Genet 1995;11:402-408
8. Holmgren G, Ozelius L, Forsgren L, et al. Adult onset idiopathic torsion dystonia is excluded from the DYTl region
(9q34) in a Swedish family. J Neurol Neurosurg Psychiatry
9. Bressman SB, Hunt AL, Heiman GA, et al. Exclusion of the
DYTl locus in a non-Jewish family with early-onset dystonia.
Mov Disord 1994;9:626-632
10. Bressman SB, Warner TT, Almasy L, et al. Exclusion of the
DYTl locus in familial torticollis. Ann Neurol 1996;40:681684
11. Bressman SB, Heiman GA, Nygaard TG, et al. A study of idiopathic torsion dystonia in a non-Jewish family: evidence for
genetic heterogeneity. Neurology 1994;44:283-287
12. Bressman SB, de Leon D, Kramer PL, et al. Dystonia in Ashkenazi Jews: clinical characterization of a founder mutation.
Ann Neurol 1994;36:771-777
13. Gasser T . Idiopathic, myoclonic and Dopa-responsive dystonia.
Curr Opin Neurol 1997;10:357-362
14. Ozelius LJ, Kramer PL, de Leon D, et al. Strong allelic association between the torsion dystonia gene (DYTl) and loci on
chromosome 9q34 in Ashkenazi Jews. Am J Hum Genet 1992;
Somatotopical Organization
of Striatal Activation During
Finger and Toe Movement:
A 3-T Functional Magnetic
Resonance Imaging Study
Sttphane Lehtricy, MD, PhD,*t
Pierre-FranFois van de Moortele, MD,* Elie Lobel, MD,*
Anne-Lise Paradis, PhD,* Marie Vidailhet, MD,*
Vincent Frouin, PhD,* Pascal Neveu,*
Yves Agid, MD, PhD,$ Claude Marsault, M D , t
and Denis Le Bihan, MD, PhD*
The present study aimed at determining the distribution
and somatotopical organization of striatal activation during performance of simple motor tasks. Ten right-handed
healthy volunteers were studied by using a 3-T wholebody magnetic resonance unit and echo planar imaging.
The tasks consisted of self-paced flexionlextension of the
right fingers or toes. Motor activation was found mainly
in the putamen posterior to the anterior commissure (10
of 10 subjects) and the globus pallidus (6 subjects),
whereas the caudate nucleus was activated in only 3 subjects, and in a smaller area. Thus, performance of a simple motor task activated the sensorimotor territory of the
basal ganglia. Within the putamen, there was a somatotopical organization of the foot and hand areas similar to
that observed in nonhuman primates. These data suggest
that functional magnetic resonance imaging can be used
to study normal function of the basal ganglia and should
therefore also allow investigation of patients with movement disorders.
Lehtricy S, van de Moortele P-F, Lobel E,
Paradis A-L, Vidailhet M, Frouin V, Neveu P,
Agid Y, Marsault C, Le Bihan D. Somarotopical
organization of striatal activation during finger
and toe movement: a 3-T functional
magnetic resonance imaging study.
Ann Neurol 1998;44:398-404
The basal ganglia are involved in adaptive control of
action in the motor sphere, as well as in planning and
cognition, although their role is not fully under~ t o o d . l -In
~ humans, lesions of the basal ganglia lead
From the *Service Hospitalier FrkdCric Joliot, Department of Medical Research, CEA, Orsay, and Departments of tNeuroradiology
and $Neurology, HBpital de la SalpCtrikre, Paris, France.
Received Sep 11, 1997, and in revised form Mar 11, 1998. Accepted for publication Mar 21, 1998.
Address correspondence to Dr LehCricy, Service de Neuroradiologie,
Batiment Babinski, HBpital de la SalpCtritre, 47 Bd de I’HBpital,
75651 Paris Cedex, France.
Copyright 0 1998 by the American Neurological Association
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tyro, clinical, family, phenotypic, evaluation, dystonic, south, mixed, genetics
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