Clinical Neurology and Neurosurgery 111 (2009) 880–882

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Clinical Neurology and Neurosurgery
journal homepage: www.elsevier.com/locate/clineuro

Case report

Characteristics of dystonia in the 18p deletion syndrome,
including a new case
Anna G. Postma a,∗ , Corien C. Verschuuren-Bemelmans b , Klaas Kok b , Teus van Laar a,∗
a
b

Department of Neurology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

a r t i c l e

i n f o

Article history:
Received 8 December 2008
Received in revised form 3 June 2009
Accepted 22 July 2009
Available online 20 August 2009
Keywords:
Dystonia
18p Deletion syndrome
DYT7
DYT15

a b s t r a c t
Objective of the present study was to evaluate the possible pathophysiology and clinical characteristics
of dystonia in patients with the 18p deletion syndrome by describing a new case and reviewing the
literature. Dystonia in patients with the 18p deletion syndrome seems to present heterogeneously with
a variable age of onset and distribution of symptoms. It may be accompanied with white matter lesions
on the MRI. Deletion of 2 known dystonia loci on chromosome 18p, DYT7 and DYT15, or the deletion of
another dystonia gene just above the centromere of chromosome 18p may be the cause of dystonia in
patients with the 18p deletion syndrome. However, dystonia may also be secondary to structural brain
changes often seen in patients with the 18p deletion syndrome.
© 2009 Elsevier B.V. All rights reserved.

1. Introduction
Deletion of the short (p) arm of chromosome 18 (MIM number 146390) is one of the most common autosomal chromosomal
abnormalities [1]. More than 150 cases have been reported in the literature [2]. The most prominent manifestations of the 18p deletion
syndrome are mild to moderate mental retardation and dysmorphic features, including ptosis, strabismus, hypertelorism, a broad
ﬂat nose, big and low set ears and micrognathia. Postnatal growth
retardation and malformations of the heart and brain are common
medical problems [2]. However, the phenotype of patients with a
chromosome 18p deletion is very variable [2].
Dystonia has only been described in six patients with the 18p
deletion syndrome [19–23] and we present the history of a seventh
patient with both the 18p deletion syndrome and dystonia. Dystonia is both clinically and genetically a heterogeneous disorder
and is classiﬁed according to etiology, age of onset, inheritance and
anatomical distribution [3,4]. At least 15 loci for dystonia have been
deﬁned (DYT1–DYT15) and some of their corresponding genes have
been cloned [5–9]. Two loci are located on the short arm of chromosome 18: DYT7 (MIM number 602124) and DYT15 (MIM number
607488). This paper describes a new case with 18p− related dystonia, which is followed by a review of the existing cases, with respect

∗ Corresponding authors. Movement Disorder Unit, Department of Neurology,
University Medical Center Groningen, Hanzeplein 1, P.O. Box 30 001, 9700 RB Groningen, The Netherlands. Tel.: +31 50 361 6161; fax: +31 50 361 1707.
E-mail addresses: a.g.postma@neuro.umcg.nl (A.G. Postma),
t.van.laar@neuro.umcg.nl (T. van Laar).
0303-8467/$ – see front matter © 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.clineuro.2009.07.013

to their clinical characteristics and genetic proﬁles in patients with
the 18p deletion syndrome.
2. Case report
The patient was seen at the department of Neurology of the University Medical Center Groningen. She was a 42-year-old woman,
born to healthy, non-consanguineous parents after a normal pregnancy with a delivery lasting more than 24 h. She had one healthy,
younger brother. During the neonatal period she had feeding difﬁculties. Early developmental milestones were delayed and she
visited a specialized school because of learning problems. At the
age of 22, she developed an intentional tremor and ptosis. At the
age of 30, cervical dystonia presented for the ﬁrst time and she
started to develop progressive gait disturbances due to dystonic
contractions of both legs (right > left). Furthermore, ﬁne myoclonic
jerks in both arms and legs were seen. The following dysmorphic features were present: bilateral ptosis, downslanting palpebral
ﬁssures, micrognathia, posterior rotated and protruding ears, a
broad neck, pectus excavatum and clinodactylia of the ﬁfth ﬁngers (Video 1). The torticollis was successfully treated with repeated
injections of botulinum toxin. The gait disturbances improved during treatment with trihexyfenidyl. No response to levodopa was
observed.
2.1. Imaging
T1-weighted and T2-weighted magnetic resonance images (MRI)
of the brain showed extensive bilateral multifocal white matter

A.G. Postma et al. / Clinical Neurology and Neurosurgery 111 (2009) 880–882

881

Fig. 1. White matter changes on MRI. (A) T1-weighted. (B) T2-weighted.

areas of increased signal and slight cortical atrophy. The basal ganglia did not show any abnormality (Fig. 1).
2.2. Cytogenetic analysis
Chromosome analysis revealed an abnormal female karyotype
containing an unbalanced translocation between chromosome 18 and 21 with a monosomy of chromosome 18p:
45,XX,−18,−21,+der(18)t(18;21)(p11;q11). Parental karyotypes
were normal, indicating a de novo origin for the translocation
(18;21) in this patient.
2.3. Array-based comparative genomic hybridization
DNA of the patient was analyzed by array-based CGH, using a
genome wide BAC array with an average density of one clone per
400 kb [10]. A deletion encompassing all clones but one from the
short arm of chromosome 18 was the only copy number aberration detected for this patient. The retention of one clone just above
the centromere was veriﬁed by FISH, localizing the breakpoint at
18p11.21 in a 600-kb genomic segment, ranging from 14.2 Mb until
14.8 Mb (NCBI build 36.1).
3. Discussion
DYT7 is located on the short arm of chromosome 18 and is a gene
locus for adult-onset focal cervical dystonia. It has been localized
in a German family and was reported to inherit in an autosomal
dominant matter with reduced penetrance [11]. A founder mutation was suspected when analysis of other sporadic cases from the
same area and central Europe with focal dystonia showed linkage disequilibrium for the marker D18S1098 (cytogenetic location
18p11.31–18p11.32) [12,13]. However, the authors were not able to
conﬁrm this ﬁnding by reanalysis of the original data [14]. Link-

age disequilibrium for these markers has not been found in other
patients from northern Germany with focal dystonia either [15].
DYT15 is a gene locus of inherited myoclonus dystonia (IMD),
which is a late-onset, autosomal dominant, non-progressive form
of myoclonus, often seen in combination with dystonia [16,17].
DYT15 has been mapped to 18p11 between the markers D18S1132
(18p11.31) and D18S843 (18p11.22) in a large Canadian family with
IMD [9]. Recently this region has been reduced to 3.18Mb [18]. All
known or predicted genes within this region were sequenced. No
mutations in these genes could be identiﬁed, despite the existence
of several candidate genes with potential roles within the CNS [18].
The presence of dystonia in seven patients with the 18p− syndrome, including the patient presented here, can be considered
as additional evidence for the presence of one or more dystonia
gene(s) on chromosome 18p (Table 1) [19–23].
Table 1 shows that the phenotype of dystonia in patients with
the 18p− syndrome is heterogenic. This variability is different from
the well-deﬁned complex of symptoms in patients with a probable
mutation in DYT7 or DYT15. It is therefore possible that the dystonia in 18p− patients results from different causes, like the combined
loss of DYT7 and DYT15, or from the loss of another gene closer to the
centromere, possibly explaining the heterogenic clinical picture.
Genetic evaluation in our patient revealed a breakpoint in 18p11.21
(Fig. 2), just above the centromere, which resembles all other published cases. Fig. 2 also shows an overlap in the mapped regions
of DYT7 and DYT15 on 18p. Theoretically, this overlap region could
contain a common gene related to dystonia, but this is not obligatory, because other regions of DYT7 and DYT15 may be causative as
well.
A remaining question is why not every patient with the 18p−
syndrome has dystonia? Reduced penetrance of the involved
gene(s) may be the main reason, as has been suggested for mutations in DYT7 and in cases of IMD [12,17]. It is not likely that the
presence of dystonia in a patient with the 18p− syndrome is related

Table 1
Characteristics of patients with the 18p− syndrome and dystonia.
Patienta

Author(s)

Karyotype

Onset

Distribution

1
2
3

Kakinuma (1994) [20]
Tezzon (1998) [23]
Awaad (1998) [19]
Klein (1999) [21]

46,X,dic(Y;18)(p11;p11),inv(9)(p11q13)
46,XY,18p−
46,XY,del(18)(p11.1)

?
?

Focal
Generalized

15 yrs

Segmental

Klein (1999) [21]
Klein (1999) [21]
Nasir (2006) [22]
Postma (2009)

45,XX,−18,−21,+der(18q21q)t(18;21)mat.
18p deletion
Complete deletion of 18p; unbalanced translocation between chrom. 14 and 18
45,XX,−18,−21,+der(18)t(18;21)(p11;q11)

12 yrs
17 yrs
Adolescent
30 yrs

Segmental
Segmental
Segmental
Generalized

4
5
6
7
a

In order of publication.

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A.G. Postma et al. / Clinical Neurology and Neurosurgery 111 (2009) 880–882

Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.clineuro.2009.07.013.
References

Fig. 2. Chromosome 18.

to the extent of the deletion, since a breakpoint close to the centromere has also been found in patients without dystonia [2].
Another interesting ﬁnding in our patient was the multiple
unspeciﬁc foci of increased signal in the white matter on MRI. White
matter changes on MRI have been observed in three other patients
with 18p and dystonia as well [19,21]. One could speculate that
the dystonia is related to white matter changes in the 18p deletion
syndrome, however white matter changes are neither commonly
found in the 18p− syndrome without dystonia [24], nor in idiopathic dystonia (ID) [25]. Publications of new patients with the
18p− syndrome and dystonia may provide further insight in this
issue.
Although our patient showed distinct dysmorphic features, the
appearance of an adult patient with a deletion of the short arm of
chromosome 18 can also be nearly normal [26]. Karyotyping for 18p
is therefore recommended in every patient presenting with dystonia, especially if the dystonia is accompanied by mental retardation
and dysmorphic features.
Disclosure
Each author had full access to all of the data in the study and
takes responsibility for the integrity of the data and the accuracy of
the data analysis.
Conﬂict of interest
There are no conﬂicts of interest.
Funding
No funding was obtained for this paper.

[1] Schinzel A. Catalogue of unbalanced chromosome aberrations in man. Berlin,
New York: De Gruyter; 2001.
[2] Wester U, Bondeson ML, Edeby C, Anneren G. Clinical and molecular characterization of individuals with 18p deletion: a genotype–phenotype correlation.
Am J Med Genet A 2006;140:1164–71.
[3] Fahn S, Marsden CD, Calne DB. Classiﬁcation and investigation of dystonia. In:
Marsden CD, Fahn S, editors. Movement disorders 2. London: Butterworths;
1987. p. 332–58.
[4] Fahn S, Bressman SB, Marsden CD. Classiﬁcation of dystonia. Adv Neurol
1998;78:1–10.
[5] Nemeth AH. The genetics of primary dystonias and related disorders. Brain
2002;125:695–721.
[6] de Carvalho Aguiar PM, Ozelius LJ. Classiﬁcation and genetics of dystonia. Lancet
Neurol 2002;1:316–25.
[7] Klein C, Ozelius LJ. Dystonia: clinical features, genetics, and treatment. Curr
Opin Neurol 2002;15:491–7.
[8] Grotzsch H, Pizzolato GP, Ghika J, et al. Neuropathology of a case of
dopa-responsive dystonia associated with a new genetic locus, DYT14. Neurology 2002;58:1839–42.
[9] Grimes DA, Han F, Lang AE, et al. A novel locus for inherited myoclonus-dystonia
on 18p11. Neurology 2002;59:1183–6.
[10] Kok K, Dijkhuizen T, Swart YE, et al. Application of a comprehensive subtelomere array in clinical diagnosis of mental retardation. Eur J Med Genet
2005;48:250–62.
[11] 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. Hum Mol Genet 1996;5:
1673–7.
[12] Leube B, Hendgen T, Kessler KR, et al. Sporadic focal dystonia in northwest Germany: molecular basis on chromosome 18p. Ann Neurol 1997;42:
111–4.
[13] Leube B, Hendgen T, Kessler KR, et al. Evidence for DYT7 being a common
cause of cervical dystonia (torticollis) in Central Europe. Am J Med Genet
1997;74:529–32.
[14] Leube B, Auburger G. Questionable role of adult-onset focal dystonia among
sporadic dystonia patients. Ann Neurol 1998;44:984–5.
[15] Klein C, Ozelius LJ, Hagenah J, et al. Search for a founder mutation in idiopathic
focal dystonia from Northern Germany. Am J Hum Genet 1998;63:1777–82.
[16] Mahloudji M, Pikielny RT. Hereditary essential myoclonus. Brain 1967;90:
669–74.
[17] Gasser T. Inherited myoclonus-dystonia syndrome. Adv Neurol 1998;78:
325–34.
[18] Han F, Racacho L, Lang AE, Bulman DE, Grimes DA. Reﬁnement of the DYT15
locus in myoclonus dystonia. Mov Disord 2007;22:888–92.
[19] Awaad Y, Munoz S, Nigro M. Progressive dystonia in a child with chromosome
18p deletion, treated with intrathecal baclofen. J Child Neurol 1999;14:75–7.
[20] Kakinuma S, Sasabe F, Negoro K, Nogaki H, Morimatsu M. 18p-syndrome with
bilateral pyramidal tract signs, dystonia of the lower extremities and concentric
visual ﬁeld defect. Rinsho Shinkeigaku 1994;34:474–8.
[21] Klein C, Page CE, LeWitt P, et al. Genetic analysis of three patients with an
18p-syndrome and dystonia. Neurology 1999;52:649–51.
[22] Nasir J, Frima N, Pickard B, et al. Unbalanced whole arm translocation resulting
in loss of 18p in dystonia. Mov Disord 2006;21:859–63.
[23] Tezzon F, Zanoni T, Passarin MG, Ferrari G. Dystonia in a patient with deletion
of 18p. Ital J Neurol Sci 1998;19:90–3.
[24] Kacinski M, Jaworek M, Skowronek-Bala B. Caudal regression syndrome associated with the white matter lesions and chromosome 18p11.2 deletion. Brain
Dev 2007;29:164–6.
[25] Draganski B, Thun-Hohenstein C, Bogdahn U, Winkler J, May A. Motor
circuit” gray matter changes in idiopathic cervical dystonia. Neurology
2003;61:1228–31.
[26] Tonk V, Krishna J. Case report: de novo inherited 18p deletion in a mother-fetus
pair with extremely variable expression, conﬁrmed by ﬂuorescence in situ
hybridization (FISH) analysis. Eur J Obstet Gynecol Reprod Biol 1997;73:
193–6.