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Brain 2009: 132; 2005–2025
| 2005
The monogenic primary dystonias
Ulrich Müller
Institut für Humangenetik, Justus-Liebig-Universität, Schlangenzahl 14, 35392 Giessen, Germany.
Correspondence to: Prof. Dr Ulrich Müller,
Institut für Humangenetik,
Schlangenzahl 14,
35392 Giessen,
E-mail: [email protected]
Presently, 17 distinct monogenic primary dystonias referred to as dystonias 1– 4, 5a,b, 6–8, 10–13 and 15–18 (loci DYT 1–4,
5a,b, 6–8, 10–13, 15–18) have been recognized. Twelve forms are inherited as autosomal dominant, four as autosomal recessive
and one as an X-linked recessive trait. Three additional autosomal dominant forms (DYT9, DYT19 and DYT20) might exist based
on linkage mapping to regions apparently different from, yet in close proximity to or overlapping with the known loci DYT18,
DYT10 and DYT8. Clinically, this group of movement disorders includes pure dystonias and dystonia plus syndromes. In
addition, dyskinesias (paroxysmal dystonias), although phenotypically distinct from classical dystonias, are discussed within
this group. In pure dystonias, dystonia is occasionally accompanied by tremor. In dystonia plus syndromes, dystonia as the
prominent sign concurs with other movement abnormalities such as myoclonus and parkinsonism. In the dyskinesias, dystonia
occurs as a paroxysmal sign in association with other movement anomalies and sometimes seizures. While gross neuropathological changes are absent in most primary dystonias, including the paroxysmal forms, striking morphological alterations are
found in some, such as in the X-linked dystonia–parkinsonism syndrome (DYT3). Neuropathological findings at the microscopic
level have also been reported in several cases of dystonia 1 and 5, both of which were previously thought to be morphologically
normal. One locus, DYT14 had been erroneously assigned, by linkage mapping, in a family with dystonia 5. There are two forms
of dystonia 5, one autosomal dominant and one autosomal recessive. These forms are designated here as dystonia 5a and
dystonia 5b (DYT5a, DYT5b), respectively. The disease gene has been identified in 10 primary dystonias, seven autosomal
dominant (TOR1A/DYT1, GCH1/DYT5a, THAP1/DYT6, PNKD1/MR-1/DYT8, SGCE/DYT11, ATP1A3/DYT12 and SLC2A1/
DYT18), two autosomal recessive (TH/DYT5b and PRKRA/DYT16) and one X-chromosomal recessive (TAF1/DYT3). This article
summarizes all known aspects on each of the monogenic primary dystonias, including phenotype, neuropathology, imaging,
inheritance, mapping, molecular genetics, molecular pathology, animal models and treatment. Suggestions for the diagnostic
procedure in primary dystonias are given. Although much is now known about the molecular basis of primary dystonias,
treatment of patients is still mainly symptomatic. The only exceptions are dystonias 5a and 5b with their excellent long-term
response to L-dopa substitution.
Abbreviations: CT = computed tomography; DA = dopamine; DRD = dopa-responsive dystonia; ER = endoplasmic reticulum;
MRI = magnetic resonance imaging; M-D = myoclonus dystonia; NE = nuclear envelope; PKC = paroxysmal kinesigenic
choreoathetosis; PKD = paroxysmal kinesigenic dyskinesia; PTS = 6-pyruvoyltetrahydropterin synthase; SR = sepiapterine reductase;
THAP = thanatos-associated protein; TH = tyrosine hydroxylase; XDP = X-chromosomal dystonia parkinsonism syndrome.
Received March 16, 2009. Revised and Accepted May 25, 2009
ß The Author (2009). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.
For Permissions, please email: [email protected]
| Brain 2009: 132; 2005–2025
Dystonias are characterized by involuntary muscle contractions
which result in twisting and repetitive movements and abnormal
postures (Fahn et al., 1987). Primary dystonias can be distinguished from secondary ones (Fahn et al., 1998; Geyer and
Bressman, 2006). Primary forms solely or mainly present with
dystonia. They are frequently inherited as monogenic traits and
usually lack gross neuropathological changes. Dystonia plus
syndromes are monogenic dystonias without detectable neuroanatomical abnormalities but with additional neurological manifestations such as myoclonus and parkinsonism (Albanese et al.,
2006). A third group includes paroxysmal dyskinesias with
episodes of dystonic involvement and no gross neuropathological
anomalies. In contrast, secondary dystonia occurs as one of the
several signs and symptoms within another, frequently neurological, oncological or metabolic disorder, after intoxication or after
trauma. In these forms, neuropathological findings are common
and dystonia is thought to occur ‘secondary’ to another disorder
or an external insult. Heredodegenerative diseases associated with
dystonia including various autosomal dominant (e.g. Huntington’s
disease, some spinocerebellar ataxias) and autosomal recessive
(e.g. juvenile parkinsonism, Wilson’s disease, pantothenate kinase
associated neuro-degeneration) disorders should be considered a
subgroup of secondary dystonias (e.g. Geyer and Bresssman, 2006).
Our knowledge and understanding of monogenic forms of
primary dystonias has grown dramatically during the last two
decades. In 1990, only eight monogenic forms were recognized
and only one disease gene (DYT1) had been mapped by linkage
analysis (Müller and Kupke, 1990). The number of distinct primary
dystonias and dystonia plus syndromes had increased to 13 by
1999 (Müller et al., 1999). The disorders were designated as
dystonias 1–12, the disease loci as DYT1-12 (the autosomal
dominant and recessive forms of dopa-responsive dystonia
(DRD) were both listed under Dystonia 5/DYT5). Although eight
variants had been chromosomally mapped, only three disease
genes had been identified at this time. Gene discovery and recognition of additional variants has further accelerated during the last
10 years (e.g. de Carvalho Aguiar and Ozelius, 2002; Nemeth,
2002; Geyer and Bressman, 2006; Tarsy and Simon, 2006;
Breakefield et al., 2008) and was greatly propelled by the
completion of the human genome project.
This article gives a comprehensive update on the monogenic
primary dystonias. It aims at providing the reader with a fast
overview of this group of disorders. The primary dystonias are
divided into three subgroups, all of which present with dystonia
as a major sign. These subgroups are referred to as ‘pure dystonias’ (classified as ‘primary dystonias’ by some, e.g. Albanese
et al., 2006), ‘dystonias plus’ and ‘paroxysmal dystonias’. This
classification system is in line with the original and widely accepted
proposal by Fahn et al. (1987) to divide the dystonias into two
groups: the primary and the secondary forms. It avoids the
introduction of additional dystonias independent of primary and
secondary forms. The known findings are discussed for each of the
currently recognized forms including phenotype, neuropathology,
imaging, prevalence, molecular genetics, molecular pathology,
animal models and treatment. First, the autosomal dominant
U. Müller
pure dystonias are discussed, followed by dystonia plus syndromes
and the paroxysmal dystonias. The autosomal recessive pure
dystonias and dystonia plus syndromes and the only X-linked
recessive dystonia plus syndrome are reviewed thereafter.
Although there are no specific treatments in most dystonias,
aspects on therapy are discussed for various forms of dystonia
separately if therapeutic approaches have been described that
appear to be particularly beneficial in a given dystonia.
Autosomal Dominant Primary
Dystonias (Table 1)
Pure dystonias
Dystonia 1 (early-onset dystonia, idiopathic torsion
dystonia, dystonia musculorum deformans); DYT1,
TOR1A; OMIM 128 100
Onset of dystonia 1 is most commonly during childhood. Usually
first symptoms occur in the limbs and dystonia generalizes within a
few years of onset. However, clinical presentation can vary
remarkably with respect to age and site of onset and progression.
Onset can be during adolescence and early adulthood, and in
some cases dystonia does not generalize but remains focal or
segmental (e.g. Bressman et al., 2002; Grundmann et al., 2003).
Several studies failed to detect neuropathological changes in
dystonia 1. In particular, immunohistochemistry of the basal
ganglia did not reveal morphological abnormalities (Walker
et al., 2002). More recently however, brainstem abnormalities
were observed in four typical dystonia 1 patients. McNaught
et al. (2004) reported the detection of neuronal perinuclear
inclusion bodies in the mid-brain reticular formation and in the
periaqueductal grey matter. These inclusions were immunoreactive
for ubiquitin, torsinA and nuclear envelope (NE) protein lamin
A/C. In brains from patients with adult-onset dystonia thought
to be dystonia 1, Holton et al. (2008) did not find such inclusions.
These findings suggest that the underlying molecular pathological
mechanisms might differ in early- and adult-onset dystonia 1.
However, the diagnosis of dystonia 1 had not been confirmed
molecularly in three of the cases described by Holton et al.
(2008). In another three cases, no mutation had been detected.
Therefore, it is not clear whether these cases could be classified as
‘dystonia 1’. Another study described enlarged dopaminergic cell
bodies in the substantia nigra (Rostasy et al., 2003).
tomography (CT) scans are normal in early-onset dystonia.
[18F]-fluorodeoxyglucose positron emission tomography (PET)
scans of patients with dystonia 1 revealed increased metabolic
activity in mid-brain, cerebellum and thalamus. Non-manifesting
carriers of a mutation in TOR1A (see below) showed an increased
Monogenic primary dystonias
Brain 2009: 132; 2005–2025
| 2007
Table 1 Autosomal dominant primary dystonias
Pure dystonia
Dystonia 1
Dystonia 4
Dystonia 6
Dystonia 7
Dystonia plus
Dystonia 13
Dystonia 5a
Dystonia 9
Dystonia 10
Dystonia 18
(Dystonia 19)
(Dystonia 20)
Early-onset dystonia, idiopathic torsion dystonia,
dystonia musculorum deformans
Hereditary whispering dysphonia
Idiopathic torsion dystonia of ‘mixed’ type
Focal, adult-onset dystonia, idiopathic focal
Primary dystonia with mixed phenotype
DRD; Segawa syndrome; hereditary progressive
dystonia with marked diurnal fluctuation, HPD
M-D; alcohol-responsive dystonia
Rapid-onset dystonia-parkinsonism
PDC; PNKD1; non-kinesigenic choreoathetosis;
Mount-Reback disease
PDC with episodic ataxia and spasticity; episodic
choreoathetosis/spasticity (CSE)
PKC; paroxysmal familial dystonia; PKD
Paroxysmal exertion-induced dyskinesia; paroxysmal
exercise-induced dystonia
metabolic activity in the lentiform nuclei, cerebellum and supplementary motor areas (Eidelberg et al., 1998). In contrast, PET
studies in dystonia 1 patients of a Chinese family did not reveal
hypermetabolism in cerebellum or basal ganglia (Ching et al.,
2007). Brain scans of mutation carriers with H2 15O PET during
sequence learning showed increased cerebellar activation (Carbon
et al., 2008). Furthermore, D2 receptor binding in caudate and
putamen was decreased in individuals with TOR1A mutations
(Asanuma et al., 2005b).
Prevalence, inheritance and mapping
The disorder is most common in the Ashkenazi Jewish population
with a prevalence estimated at 1/16 000–1/20 000. In the nonJewish population, prevalence is about 1/200 000 (summarized in
Müller and Kupke, 1990).
Dystonia 1 is inherited as an autosomal dominant trait with a
reduced penetrance of 30% (Bressman et al, 1989; Risch et al.,
1990). The disease locus, DYT1, has been assigned to the long
arm of chromosome 9 (9q34) by linkage analysis (Ozelius et al.,
Molecular genetics
The disease gene, TOR1A was identified in 1997 (Ozelius et al.,
1997). It is composed of five exons and is widely expressed.
Expression of TOR1A is regulated by transcription factors of the
Ets family. These bind to two Ets binding cores in the upstream
region (within _78 and _69 bp) of the gene (Armata et al., 2008).
A three-nucleotide deletion (‘GAG deletion’) of one of two
adjacent GAG trinucleotides in exon 5 (904_906delGAG/
907_909delGAG) is the most common mutation and found in
almost all dystonia 1 patients (summarized in Geyer and
Bressman, 2006). This mutation has arisen independently
in several populations (Klein et al., 1998a). In the Ashkenazi
Jewish population, the GAG deletion originated from a founder
Chromosomal mapping
Disease gene
128 100
128 101
602 629
602 124
607 671
128 230
159 900
128 235
607 488
118 800
601 042
128 200
612 126
611 031
611 147
who lived in Byelorussia or Lithuania about 350 years ago
(Risch et al., 1995). Today the frequency in this population is
1/3 000–1/9 000 (Risch et al., 1990).
The GAG deletion results in the loss of a glutamic acid within
the gene product torsinA (302/303). In addition to the GAG
deletion, a few other mutations have been described in TOR1A.
A G4A transition was detected in exon 5 (c.863G4A) in a female
patient with generalized dystonia and in her unaffected mother.
The mutation causes the exchange of an arginine for a glutamine
(pArg288Gln) in torsinA (Zirn et al., 2008a). A pathogenic role of
this mutation is likely: (i) an arginine at position 288 has been
evolutionarily highly conserved in all vertebrates including fish
(fugu), thus indicating an important function and (ii) functional
studies in a cell system indicate the same morphological changes
in the nuclear membrane (enlargement of the perinuclear space)
that are also found in the common GAG mutation. Pathogenicity
of two additional mutations remains unclear. One, an 18 bp deletion within exon 5 (966_983del Phe328_Tyr328del) was detected
in patients with myoclonus dystonia (M-D), and a mutation within
the gene SGCE commonly mutated in M-D (dystonia 11) was
observed in the same patients (Leung et al., 2001; Klein et al.,
2002). Another mutation (934_937delAGAG) was detected in a
healthy blood donor with no known neurological manifestations
(Kabakci et al., 2004).
A polymorphism (C/G) within exon 4 of TOR1A results in the
exchange of aspartic acid for histidine at position 216 of torsinA
(D216H). Aspartic acid (D) is encoded by 88% and histidine
(H) by 12% of normal alleles. This polymorphism functions as a
modifier of mutant torsinA. In a cellular system, the H216 allele
weakens manifestation of the GAG deletion (Kock et al., 2006);
and in individuals carrying the GAG deletion, the frequency of
H216 alleles is increased in non-manifesting carriers and decreased
in carriers with dystonia (Risch et al., 2007; Kamm et al., 2008).
| Brain 2009: 132; 2005–2025
Molecular pathology
TOR1A encoded torsinA is a member of the AAA+ family of
ATPases. AAA+ ATPases (ATPases associated with diverse cellular
activities) function as chaperones and mediate conformational
changes in target proteins. Affinity for target proteins is high in
the ATP-bound but low in the ATP-free state.
TorsinA is mainly located within the NE and the lumen of the
endoplasmic reticulum (ER) (Naismith et al., 2004). The NE is
composed of an inner (INM) and an outer membrane (ONM),
separated by a lumen, the perinuclear space. The ONM is
contiguous with the ER. The location of torsinA within the NE
and ER indicates a role in structure and/or function of these cellular membranes. In fact many observations and experimental
findings support this notion:
(i) ATP-bound torsinA is associated with the NE, the ATP-free
form however, is diffusely distributed throughout the ER.
Therefore, torsinA in its active (ATP-bound) state appears
to specifically target proteins of the NE (Naismith et al.;
2004; Goodchild et al., 2005);
(ii) torsinA interacts with the luminal domain of laminaassociated polypeptide 1 (LAP1), an integral protein
of the inner membrane of the NE (Goodchild and Dauer,
(iii) a function of torsinA in the NE appears to be neuron
specific. While expression of mutated (904_906delGAG/
907_909delGAG) TOR1A results in abnormal NE in neurons,
it does not affect the NE in non-neuronal cells (Goodchild
et al., 2005);
(iv) overexpression of mutant (E-) torsinA in cells results in
accumulation within the NE and in the formation of
ER-derived membrane whorls (Hewett et al., 2000;
Kustedjo et al., 2000). TorsinA also interacts with the
LAP1-related ER protein LULL1/NET9 (Goodchild and
Dauer, 2005);
(v) a potential role of torsinA in processing polypeptides
through the ER is suggested by experiments using Gaussia
luciferase (Gluc) either alone or fused in-frame to a yellow
fluorescent protein (Gluc-YFP). Gluc-YFP co-localizes with
ER proteins including torsinA. Fibroblasts from patients
with the GAG deletion secreted significantly less Gluc
activity than cells from controls (Hewett et al., 2007); and
(vi) torsinA binds to the KASH (klarsicht/ANC-1/syne homology)
domain of nesprins (Nery et al., 2008). Nesprins (nesprin-1,
-2, -3 including multiple isoforms) span the outer membrane
of the NE. They are composed of an N-terminal actin-binding domain, a series of spectrin repeats and a C-terminal
KASH domain, which lies within the perinuclear space
(Zhen et al., 2002; Padmakumar et al., 2004). By binding
to the KASH domains of nesprins -1 and -2, torsinA
connects the perinuclear space with cytoplasmic actin.
In addition, it binds to nesprin-3a, which interacts with
vimentin via plectrin. In fibroblasts from torsinA knock-out
mice, nesprin-3a is distributed in the ER. Similar findings
were obtained with fibroblasts from patients with the
GAG deletion.
U. Müller
Taken together, the above findings support a role of torsinA in the
NE and ER. In both the NE and ER, torsinA might be involved
in maintenance of structural integrity and/or normal function of
protein processing and trafficking. Furthermore, in the ER torsinA
appears to play a role in the secretory pathway.
Several experimental investigations point to additional functions
of torsinA in neurons:
(i) torsinA interacts with kinesin light chain. This interaction is
abolished in cells expressing E-torsinA (Kamm et al.,
2004a). Kinesin might direct torsinA along microtubules
towards the distal end of neuronal processes and become
enriched in growth cones. This anterograde transport might
be associated with the ER and/or vesicles. TorsinA may thus
play a role in neurite outgrowth. In fact, E-torsinA
interferes with neurite extension in human neuroblastoma
cells (Hewett et al., 2006) and
(ii) another function of torsinA appears to be related to synaptic
vesicle recycling (Granata et al., 2008). Experiments in a cell
system suggest that torsinA in concert with snapin regulates
exocytosis and that E-torsinA abolishes uptake of neurotransmitters such as dopamine (DA). This phenomenon
might be one contributing factor to dysregulation of
movement in dystonia 1.
Animal models
Expression of human mutant (E-torsinA) but not of wild-type
torsinA in Drosophila results in locomotor deficiencies. Similar to
humans, E- but not wild-type torsinA precipitates protein
aggregations in synaptic membranes, nuclei and endosomes of
the fly (Koh et al., 2004).
Caldwell et al. (2003) studied the function of torsinA in
Caenorhabditis elegans, utilizing a polyglutamine aggregation
model. Overexpression of either human torsinA or C. elegans
torsin-related protein TOR-2 in these worms caused a dramatic
decrease in polyglutamine-induced protein aggregates. A similar
effect has been observed with yeast chaperone Hsp104 in this
system (Satyal et al., 2000). No such effect was found with
E-torsinA. These findings further indicate an important function
of torsinA as a chaperone.
Numerous mouse models of dystonia 1 have been developed.
Transgenic mice constructed so far express human E-torsinA
(hMT1) under the control of either a cytomegalovirus promoter
(Sharma et al., 2005), a neuron-specific enolase promoter
(Shashidharan et al., 2005) or a murine prion protein
promoter (Grundmann et al., 2007). Knock-in mice were
constructed by gene targeting with the target vector carrying
mouse DNA with only one GAG trinucleotide at the relevant
position of tor1a (GAG mutation). This generates the mouse
orthologue of human E-torsinA (Dang et al., 2005; Goodchild
et al., 2005). In addition, tor1a knock-out (Goodchild et al., 2005)
and knock-down mice were developed (Dang et al., 2006). There
is also a conditional, cerebral cortex-specific knock-out model
(Yokoi et al., 2008).
The transgenic mice showed multiple motor deficits, including
hyperkinesias and rapid bi-directional circling, dystonic features of
the limbs (Shashidharan et al., 2005) and impaired motor learning
Monogenic primary dystonias
(Sharma et al., 2005; Grundmann et al., 2007). A decrease in DA
release was described in the transgenic mice of Sharma et al.
(Balcioglu et al., 2007). Motor deficits and hyperactivity were
observed in the tor1a knock-down mouse (Dang et al., 2006).
Similarly, heterozygous knock-in and knock-out mice (homozygotes are not viable) displayed motor hyperactivity and gait
abnormalities (Dang et al., 2005; Goodchild et al., 2005).
Morphological changes in knock-in mice included neuronal aggregates and some of the abnormalities of NE and ER described
above (Dang et al., 2005; Goodchild et al., 2005). Striatal
dopaminergic D2 receptor activation is altered and N-type calcium
currents are abnormal in transgenic mice (Pisani et al., 2006).
Interestingly, cerebral cortex-specific knock-out mice also exhibit
motor anomalies (Yokoi et al., 2008). Therefore, the motor
abnormalities observed in the transgenic and knock-in/knockdown mice cannot be entirely ascribed to striatal malfunction.
Treatment with oral medications including anti-cholinergics,
L-dopa, and benzodiazepines, either alone or in combination, are
frequently only moderately beneficial if at all. Botulinum toxin injections into dystonic muscles causing disability are an option in many
cases. The most efficient treatment of childhood-onset dystonia is
long-term electrical stimulation of the globus pallidus internus or
thalamus (deep-brain stimulation) (Albanese et al., 2006).
Improvement of patients after deep-brain stimulation is between
40% and 90% (Eltahawy et al., 2004; Kraus et al., 2004).
Dystonia 4 (hereditary whispering dysphonia); DYT4;
OMIM 128 101
This form of dystonia was described in one large Australian family
including at least 20 established cases (Parker, 1985; Ahmad et al.,
1993). In all but three patients dysphonia was the first manifestation and was described as ‘whispering dysphonia’ by the
original investigator (Parker, 1985). Ten affected subjects were
re-examined by Ahmad et al. (1993), nine had generalized and
one had segmental dystonia. Onset in affected family members
ranged from 13 to 37 years. In two affected siblings, the diagnosis
of Wilson’s disease was established.
Dystonia 4 is inherited as autosomal dominant trait with
apparently complete penetrance and variable expressivity.
Linkage analyses ruled out known dystonia loci, in particular
DYT1 and DYT6 (Ahmad et al., 1993; Djarmati et al., 2009).
Furthermore, Wilson’s disease was excluded in all affected family
members but in the two clinically and biochemically diagnosed
cases. The disease locus, DYT4 has not yet been chromosomally
Brain 2009: 132; 2005–2025
| 2009
Dysphonia is common. Both frequent cervical and cranial involvement and dysphonia differentiate dystonia 6 from dystonia 1. Age
at onset is during childhood and adolescence but adult-onset also
occurs. The range of age at onset documented so far is between
9 and 49 years (Bressman et al., 2009; Djarmati et al., 2009;
Fuchs et al., 2009). Dystonia 6 was first discovered in Amish–
Mennonite families and was referred to as dystonia of ‘mixed’
type (Almasy et al., 1997).
Prevalence, inheritance, mapping and molecular genetics
Presently no data are available on the prevalence of dystonia 6.
Recent reports of gene mutations (see below) indicate that
dystonia 6 might turn out to be the second most common pure
primary monogenic dystonia.
Dystonia 6 is inherited as an autosomal dominant trait with
reduced sex-independent penetrance of 60%. The disease
locus, DYT6, was originally assigned to 8p21-q22 by linkage
analysis in Amish–Mennonite families (Almasy et al., 1997).
Based on the identification of the disease gene, DYT6 is now
known to be located in 8p11.21.
Dystonia 6 is caused by mutations in the gene THAP1. THAP1
is composed of three exons and codes for Thanatos-associated
protein domain containing apoptosis-associated protein 1
(THAP1). Missense, nonsense and frameshift mutations, including
a small insertion/deletion, have been described (Bressman et al.,
2009; Djarmati et al., 2009; Fuchs et al., 2009). All three exons
can be affected.
Molecular pathology
THAP1 is composed of an N-terminal THAP (thanatos-associated
protein) domain. This domain is an atypical zinc-finger and binds
to DNA. A proline-rich region, a coiled-coil domain and a nuclear
localization signal are located towards the C-terminus of THAP1.
The mutations described interfere with THAP1 function, specifically its DNA-binding capacity and its nuclear translocation.
Given that deep brain stimulation is a treatment of choice in
patients with complex cervical dystonia (Albanese et al., 2006),
this surgical procedure should be beneficial in dystonia 6.
However, to the best of this author’s knowledge, it has not yet
been tried in any of the molecularly diagnosed dystonia 6 patients.
Dystonia 7 (focal, adult-onset dystonia, idiopathic
focal dystonia); DYT7; OMIM 602 124
Dystonia 6 (idiopathic torsion dystonia of ‘mixed’
type); DYT6, THAP1; OMIM 602 629
Dystonia 7 was identified in one large family with adult-onset
(range 28–70 years) focal dystonia. Definite dystonia was diagnosed in seven family members, of whom six had torticollis and
one spasmodic dysphonia. Possible dystonia (signs of torticollis
such as muscular hypertrophy and minimal rotation of the head
and postural tremor of the hands) was reported in six individuals
(Leube et al., 1996).
Inheritance and mapping
Dystonia 6 is a slowly progressive frequently generalized dystonia.
Onset is usually in brachial, cervical or cranial muscles. Occasional
onset in limbs is followed by cervical and cranial involvement.
In this one family, dystonia 7 was inherited as an autosomal
dominant trait. Linkage analysis assigned DYT7 to the short
arm of chromosome 18. The maximum LOD score obtained
| Brain 2009: 132; 2005–2025
was 2.68 at y = 0 for marker D18S452 (Leube et al., 1996).
Sporadic cases with focal cervical dystonia from Northwestern
Germany were thought to share a common haplotype within
the short arm of chromosome 18 (Leube et al., 1997a, b).
This was not confirmed in a larger patient sample (Klein et al.,
Dystonia 13 (primary dystonia with mixed phenotype);
DYT13; OMIM 607 671
Dystonia 13 has been reported in one large Italian family. Onset
was in the cervical or cranial–cervical region in six (out of eight)
patients and the arms in two. Dystonia progressed slowly and
became segmental in most cases. In two, a mild generalized
dystonia had developed. Average age at onset was 15.6 (SD
12.5) years (Bentivoglio et al., 1997). This form is characterized
by a ‘mixed dystonia phenotype’.
U. Müller
CT and MRI are normal in DRD. Using PET and
[18F]-fluorodeoxyglucose, Asanuma et al. (2005a) found a distinct
pattern of regional cerebral metabolic covariation in DRD.
Specifically, there was increased metabolic activity in dorsal midbrain, cerebellum and supplementary motor area and reduced
activity in basal ganglia and in motor and lateral premotor
cortex. DA transporter scans are normal in DRD (Jeon et al.,
1998). This is at variance with juvenile parkinsonism, an important
differential diagnosis of DRD (see ‘Diagnostic procedure in primary
dystonia’ section).
Prevalence, inheritance and mapping
Dystonia 5a (DRD; Segawa syndrome; hereditary
progressive dystonia with marked diurnal fluctuation,
HPD); DYT5a, GCH1; OMIM 128 230
Prevalence was reported as 0.5/106 but is probably higher owing
to under-diagnosis. Females are more frequently affected than
males (2.5/1) (Nygaard et al., 1988).
DRD is inherited as an autosomal dominant trait with reduced
penetrance. In one large family, penetrance was given as 30%
(Nygaard et al., 1990). Once subtle signs and symptoms were
taken into account, the sex-average penetrance reached almost
60% in this family. A genotype–phenotype investigation in five
DRD families reports a sex-average penetrance of 80%; 55% in
males and complete in females (Steinberger et al., 1998). Another
study reported a penetrance of 87% for females and 38%
for males (Furukawa et al. 1998).
The disease locus, DYT5a, was assigned to the long arm of
chromosome 14 (14q22.1-22.2) by linkage analysis (Nygaard
et al., 1993a, b).
Molecular genetics
Dystonia 5, also known as Segawa syndrome or DRD, is characterized by diurnal fluctuation of symptoms in 75% of cases,
parkinsonism and a dramatic therapeutic response to L-dopa
(Segawa et al., 1976; Nygaard, 1993a, b). I will refer to this
form as dystonia 5a to distinguish it from the recessive form,
referred to as dystonia 5b. The phenotypic spectrum of dystonia 5a
can range from generalized, segmental and focal dystonia via
postural anomalies, parkinsonism, abnormal gait and slight
tremor to subjective complaints and signs only seen upon induction during clinical examination (Nygaard et al., 1990; Furukawa
et al., 1998; Steinberger et al., 1998, 1999; Müller et al., 2002).
Age of onset varies widely. While dystonia 5a usually starts
during childhood, onset can also occur during adolescence or
The disease gene, GCH1 is composed of six exons and codes for
GTP-cyclohydrolase I (Ichinose et al., 1994). Single base changes
including nonsense, missense and splice site mutations are
detected in 50%–60% of clinically well-characterized DRD cases
(Bandmann et al., 1996, 1998; Weber et al., 1997; Steinberger
et al., 2000; Furukawa, 2004). In addition, microdeletions are
relatively common (Furukawa et al., 2000; Klein et al., 2002,
Hagenah et al., 2005, Steinberger et al., 2007; Zirn et al.,
2008a). Taken together, mutations in GCH1, including microdeletions, account for 71%–87% of the cases of DRD (Hagenah et al.,
2005, Zirn et al., 2008b). In addition, a heterozygous mutation in
the 50 untranslated region of the sepiapterine reductase (SR) gene
SPR was detected in one case of autosomal dominant DRD
(Steinberger et al., 2004).
Molecular pathology
There are no gross neuropathological anomalies in dystonia 5.
Only a few case reports describe minor morphological anomalies
and/or depigmentation in substantia nigra and striatum (Rajput
et al., 1994; Furukawa et al., 1999; Grötzsch et al., 2002).
Although the case reported by Grötzsch et al. (2002) was
originally classified as DYT14, subsequent studies demonstrated
that the patient actually suffered from dystonia 5a (Wider et al.,
2008). Biochemical analyses of the brain of two autopsied
cases revealed markedly reduced biopterin levels in the
striatum. Tyrosine hydroxylase (TH) levels were reduced to 53%
in the putamen of these two DRD patients (Furukawa et al.,
Both GCH1 coding for GTP-cyclohydrolase I (GTPCH1) and SPR
coding for SR are essential for synthesis of DA. GTPCH1 is the
enzyme catalysing the first and rate-limiting step in the synthesis
of tetrahydrobiopterin (BH4) (Fig. 1). Similarly, SR is an important
enzyme in the BH4 synthetic pathway. BH4 in turn is an
essential cofactor of tyrosine, phenylalanine and tryptophan
hydroxylases, which catalyse synthesis of L-dopa/DA, tyrosine
and 5-hydroxy-tryptophan/serotonin respectively. The clinical
phenotype of DRD is the direct result of insufficient synthesis of
L-dopa and DA.
GTPCH1 activity can be measured in fibrobasts or lymphoblastoid cells and was found to be reduced by more than 50%
Inheritance and mapping
Dystonia 13 is inherited as an autosomal dominant trait. Linkage
analysis assigned the disease locus to a 22 cM interval in the short
arm of chromosome 1 (1p36.13-p36.32) (Valente et al., 2001).
Dystonia plus syndromes
Monogenic primary dystonias
Brain 2009: 132; 2005–2025
| 2011
decreased in striosomes and the occurrence of motor deficits.
TH loss was greater in striosomes than in the surrounding matrix
and this distribution may be relevant for the development of
dystonic movements.
Figure 1 Pteridine pathway. Role of GTP cyclohydrolase 1
(GTPCH1) and of SR in the synthesis of L-dopa.
GTP = guanosine triphosphate, NH2TP = didydroneopterin
triphosphate, 6-PTS = 6-pyruvoyltetrahydropterin synthase,
6-PTH4P = 6-pyruvoyltetrahydropterin, BH4 = tetrahydrobiopterin, qBH2 = quinoid dihydrobiopterin, Phe = phenylalanine,
Tyr = tyrosine, Trp = tryptophan, PAH = phenylalanine
hydroxylase, TRPH = tryptophan hydroxylase. Arrows indicate
that TH, PAH, and TRPH require BH4 as a cofactor.
in some heterozygous mutation carriers (Ichinose et al., 1995).
This observation indicated that a dominant-negative effect might
be the underlying cause of reduced BH4 synthesis. Accordingly,
mutant and wild-type polypeptides would form dys- or nonfunctional GTPCH1 heterodecamers. Cotransfection experiments
using wild-type and mutated GCH1 cDNA appeared to support
this notion (Hirano and Ueno, 1999). However, formation of
heterodecamers was not found for at least two mutations
(R88W, R184H) (Suzuki et al., 1999). This, together with the
occurrence of GCH1 deletions, argues against a dominantnegative effect of GCH1 mutations and favours haploinsufficiency.
Assuming that both the mechanisms played a role in different
individuals, patients with deletions should be affected less severely
than those with a point mutation that exerts a dominant-negative
effect. This, however, does not appear to be the case. Patients
with deletions and point mutations are not clinically distinct.
Animal models
The hph-1 mouse was selected by screening N-ethyl-N-nitrosureatreated mice for hyperphenylalaninaemia (Bode et al., 1988).
Although this mouse strain has slight hyperphenylalaninaemia at
birth, the animals normalize during the first few weeks of life.
They have reduced BH4 and GTPCH1 levels in the liver. No mutation has been detected in GCH1 but linkage analysis assigned
the mutation to a region within 8 cM of the gene. BH4, catecholamines, serotonin and their metabolites are low in the brains of
these mice and TH is significantly reduced in the striatum. These
biochemical findings are similar to those in humans with DRD.
However, hph-1 mice have no obvious motor phenotype
(Hyland et al., 2003).
Sumi-Ichinose et al. (2001) constructed a 6-pyruvoyltetrahydropterin synthase (PTS) knock-out mouse. PTS/PTS mice,
however, are not viable. By transgenic introduction of human
PTS cDNA these mice could be rescued. They have significantly
reduced (20% of wild-type) striatal levels of BH4 and TH and
display motor deficits similar to human DRD (Sato et al., 2008).
A close correlation was observed between the time TH levels
Treatment with low doses (20–300mg) of L-dopa results in complete remission of symptoms in most cases of DRD (Steinberger
et al., 2000). No side effects such as ‘ON–OFF phenomena’ or
‘freezing episodes’ are observed in patients with DRD, even after
long-term treatment.
Dystonia 11 (M-D; alcohol-responsive dystonia);
DYT11, SGCE; OMIM 159 900
Dystonia 11 is characterized by dystonia and myoclonic jerks.
Onset is most commonly during childhood and adolescence but
can occur as late as during the eighth decade (Foncke et al.,
2006). Myoclonic jerks are frequently the first signs and are
followed by a relatively mild dystonia, often manifesting as cervical
dystonia or writer’s cramp. Myoclonus mainly involves arms and
axial musculature. Lower limbs or face (including vocal apparatus)
are affected in 25% of the cases each (Asmus and Gasser, 2004;
Nardocci et al., 2008; Roze et al., 2008). Myoclonus is responsive
to alcohol in most patients. In addition, psychiatric findings are
common in dystonia 11. These include depression, obsessive–
compulsive behaviour, panic attacks and attention deficit
hyperactivity disorder (e.g. Kinugawa et al., 2008).
No neuropathological abnormalities have been described in
dystonia 11.
CT scans and MRI are normal. In a single patient, single photon
emission CT (SPECT) revealed reduced regional cerebral blood
flow in both temporal lobes, both frontal lobes and in the right
caudate. The authors suggest that these findings might reflect
functional/metabolic involvement of these areas in the pathogenesis of dystonia 11 (Papapetropoulos et al., 2008).
Prevalence, inheritance and mapping
Dystonia 11 is very rare. Prevalence data do not exist. Inheritance
is autosomal dominant with reduced penetrance owing to maternal imprinting. While paternal transmission of the gene defect
always results in disease, maternal origin causes M-D in 10–15%
of the cases only. Maternal uniparental disomy can also cause
dystonia 11 due to imprinting (inactivation) of both maternal
genes (Guettard et al., 2008). DYT11 has been assigned to the
long arm of chromosome 7 (7q21) by linkage analysis (Nygaard
et al., 1999; Klein et al., 2000).
Molecular genetics
The disease gene SGCE is composed of 12 exons and codes for
e-sarcoglycan (Zimprich et al., 2001). It is widely expressed in
both embryonic and adult tissues including muscle and nervous
system (Straub et al., 1999; Imamura et al., 2000). Brain regions
with particularly high expression levels include olfactory mitral
cells, the cerebellar Purkinje cells and mid-brain monoaminergic
neurons (Chan et al., 2005). Maternal and paternal alleles of
| Brain 2009: 132; 2005–2025
SGCE are differentially methylated within the CpG island of the
promoter region and the first exon of SGCE. Consistent with the
imprinting data on DYT11/SGCE, the maternal allele is methylated
and therefore inactivated, but the paternal allele is not (Grabowski
et al., 2003). Mutations detected in patients include nonsense,
missense, splice site, insertions, partial and complete deletions.
They result in the synthesis of either aberrant e-sarcoglycan
molecules or of none at all, and are ‘loss of function mutations’
operating via haploinsufficiency (e.g. Hedrich et al., 2004; Asmus
et al., 2005; Tezenas du Montcel et al., 2006; summarized by
Kinugawa et al., 2009). It was experimentally shown that several
missense mutations result in ubiquitination and rapid degradation
of the encoded abnormal e-sarcoglycan molecules (Esapa et al.,
Molecular pathology
e-sarcoglycan is a transmembrane protein consisting of a signal
sequence, a large extracellular domain containing a putative
glycosylation site, a transmembrane and a short cytoplasmic
domain (McNally et al., 1998). Together with five additional
isoforms (a-, b-, g-, d- and z-sarcoglycans), all transmembrane
glycoproteins as well, it is a component of sarcoglycan complexes
that form part of the dystrophin–glycoprotein complex in muscles
and brain (Lapidos et al., 2004). Except e-sarcoglycan, mutations
in other isoforms such as a-, b-, g-, and d-sarcoglycans result in
limb-girdle muscular dystrophies. Knock-out mice provide insights
into possible pathological mechanisms of loss of e-sarcoglycan in
M-D (see below).
Animal models
Heterozygous paternally inherited SGCE knock-out mice display
many features of dystonia 11 including myoclonus, deficient
motor coordination and balance, impaired motor learning and
psychiatric abnormalities such as anxiety and depression-like
behaviour (Yokoi et al., 2006). There are increased levels of DA,
3,4 dihydroxyphenylacetic acid and homovanillic acid in the
striatum of knock-out mice. Serotonin (5-hydroxytryptamine) and
5-hydroxyindoleacetic acid levels were not significantly altered.
However, increased vertical hyperactivity in individual knock-out
mice was positively correlated with 3,4 dihydroxyphenylacetic
acid and inversely correlated to 5-hydroxyindoleacetic acid levels.
These findings directly implicate the dopaminergic and serotonergic
system in the pathology of dystonia 11. Currently, it is not known
how loss of e-sarcoglycan mediates the observed changes in striatal
DA, serotonin and their metabolites.
There are no causal treatments for M-D. Benzodiazepines and antiepileptic drugs can ameliorate myoclonus. Dystonia may respond to
anti-cholinergic treatment. Botulinum toxin injections are beneficial
in focal dystonia such as cervical involvement. Some patients were
shown to benefit from deep-brain stimulation (Cif et al., 2004).
Dystonia 12 (Rapid-onset dystonia–parkinsonism);
DYT12, ATP1A3; OMIM 128 235
Phenotype, neuropathology and imaging
Dystonia 12 is characterized by abrupt onset of dystonia and
parkinsonism, which develop within minutes to days of onset.
U. Müller
Dystonia typically affects limbs and face (dysarthria, dysphagia).
There is a characteristic rostrocaudal (face4arm4leg) gradient
(Brashear et al., 2007). Parkinsonian features are bradykinesia
and loss of postural reflexes. Occasionally, seizures, paroxysmal
dystonia and psychiatric symptoms are observed. Signs and
symptoms can be precipitated or worsened by stress (fever, childbirth, emotional agitation and excessive exercise) and alcohol. Age
of onset varies widely from childhood (from 4 years onwards) to
adulthood (up to 58 years). Most commonly, first attacks occur in
late adolescence or early adulthood (Dobyns et al., 1993, Brashear
et al., 1997; Pittock et al., 2000).
Neuropathological examination of one rapid-onset dystonia–
parkinsonism brain did not reveal abnormalities (Pittock et al.,
2000). CT scans and MRI are normal. Similarly, PET studies did
not reveal abnormalities of the DA transporter system (Brashear
et al., 1999).
Prevalence, inheritance and mapping
Dystonia 12 is extremely rare. It is inherited as an autosomal
dominant trait with reduced penetrance. The exact percentage
of reduction cannot be given owing to the small number of
families described. The disease locus has been assigned to
19q12-q13.2 by linkage analysis (Kramer et al., 1999; Pittock
et al., 2000; Kamm et al., 2004b).
Molecular genetics
The disease gene ATP1A3 was identified in 2004 (de Carvalho
Agular et al., 2004). It is composed of 23 exons (Ovchinnikov
et al., 1988) and codes for Na+/K+-ATPase subunit a3
(ATP1A3). This subunit is exclusively expressed in neurons. Only
missense mutations have been detected so far (de Cavalho Aguiar
et al., 2004; Brashear et al., 2007). The mutations are at evolutionarily highly conserved positions of the ATP1A3 polypeptide
that are the same in vertebrates, invertebrates and some even in
bacteria (de Carvahlho Aguiar et al., 2004). The mutations seem
to inactivate ATP1A3. The mutated polypeptide is unstable
and the mutational mechanism appears to be haploinsufficiency.
There is no evidence of a dominant-negative effect since the
mutations do not interfere with oligomer formation.
Molecular pathology
Mutations in ATP1A3 render the Na+/K+ - ATPase, encoded by
one allele, inactive. Due to haploinsufficiency the ion-transport
capacity of neurons is reduced and causes disturbed cellular function. This is especially dramatic when a high ion transport capacity
is required, e.g. in situations of stress.
Animal models
Heterozygous Atp1a3 knock-out mice (a3+/mice) are hyperactive, display spatial learning and memory deficits, and show an
increased locomotor response to methamphetamine. Hippocampal
NMDA receptors are reduced by 40%. DA and serotonin levels
are unaltered in the striatum. Spatial learning defects are thought
to be the direct consequence of reduced NMDA receptor expression in the hippocampus. The increased activity after methamphetamine might be mediated by alteration in the DA and serotonin
pathways. DA dysfunction would directly link ATP1A3 deficiency to dystonia. However, such effects have not yet been
demonstrated. Interestingly, no abnormal movements have been
Monogenic primary dystonias
Brain 2009: 132; 2005–2025
| 2013
observed in a3+/ mice (Moseley et al., 2007). As pointed out by
Breakefield et al. (2008), no attempts have yet been made to
induce movement abnormalities, e.g. by stress or alcohol.
not been performed in this patient and it is not clear whether he
suffered from dystonia 8.
Dystonia 8 is extremely rare. It is inherited as an autosomal
dominant trait with a penetrance 490%. The disease locus,
DYT8, was assigned to 2q33–35 (Fink et al., 1996) and 2q36
(Fouad et al., 1996) by linkage analysis. DYT8 is now known to
be located in 2q35 based on the identification of the disease gene.
There is no causative treatment. Specific symptoms such as
anxiety, depression and seizures should be treated with psychiatric
drugs and anti-convulsants, respectively. In some cases, L-dopa/
carbidopa results in slight improvement. Physical therapy and
relaxation practices can also be beneficial (Brashear and Ozelius,
Dystonia 15 (M-D); DYT15; OMIM 607488
Dystonia 15 was observed in one large Canadian family. Affected
members presented with jerky movements primarily in upper limbs
and axial musculature, in two patients myoclonus was generalized.
Four had dystonia of the arms and one of the legs. Symptoms
frequently started in the hands as writer’s cramp. Age at onset
was between 7 and 15 years (average 9.6 years). Myoclonus was
responsive to alcohol (Grimes et al., 2001).
Inheritance and mapping
Dystonia 15 is an autosomal dominant disorder and is transmitted
with reduced penetrance of 85% in the one family reported.
DYT15 was assigned to a 17 cM interval on the short arm of
chromosome 18 (18p11) (Grimes et al., 2002).
Molecular genetics
Dystonia 8 is caused by mutations in the gene PNKD1 (formerly
MR1) (Lee et al., 2004; Rainier et al., 2004). PNKD1/MR1 is
composed of 12 exons and codes for PNKD protein (myofibrillogenesis regulator 1). Alternative splicing of the transcript results
in at least three splice variants (Lee et al., 2004). Splice variant
MR-1L, encoded by exons 3–10 is specifically expressed in the
brain. Investigating 14 families with dyskinesias, Bruno et al.
(2007) found mutations in eight families. Only affected members
from the eight mutation-positive families in fact had PNKD1, once
strict diagnostic criteria such as early-onset and precipitation of
attacks by caffeine and alcohol were applied. These patients
were clinically similar to those originally described by Mount and
Reback (1940). Mutations detected include missense mutations
at amino acid positions conserved during mammalian evolution
(A9V; A7V). These two amino acids appear to be mutation
hotspots since they have occurred de novo in several unrelated
families (Lee et al., 2004; Rainier et al., 2004; Bruno et al., 2007).
Molecular pathology
Paroxysmal dystonias
Dystonia 8 [paroxysmal dystonic choreoathetosis
(PDC); paroxysmal non-kinesigenic dyskinesia
(PNKD1); non-kinesigenic choreoathetosis;
Mount-Reback disease]; DYT8, PNKD1, MR1;
OMIM 118 800
Dystonia 8 is characterized by attacks of dystonia, chorea,
athetosis and ballism occurring at rest. Episodes can last from
seconds to several hours and may occur anywhere between
several times a day and a few times a year. Symptoms can
be precipitated by alcohol or caffeine, and to a lesser extent by
nicotine, excitement, fatigue, hunger and emotional stress
(Fink et al., 1997). Age at onset varies widely and can be
during childhood, adolescence or adulthood. Neurological examination is normal between episodes.
There are usually no neuropathological findings. In
individuals with paroxysmal dyskinesias, lesions of the
ganglia have been reported (Blakeley and Jankovic, 2002).
no mutation analyses were performed in these cases, the
diagnosis remains unknown.
Prevalence, inheritance and mapping
MRI findings in dystonia 8 are usually normal. In one case with
paroxysomal non-kinesigenic dyskinesia, low-intensity signals in
globus pallidus and substantia nigra were detected by T2-weighted
MRI (Kimura and Nezu, 1999). Mutation analyses, however, have
BRP17, the mouse orthologue of human MR-1 is expressed in the
substantia nigra pars reticulata and pars compacta. It is also
expressed in other regions involved in motor control such as the
red nucleus and cerebral cortex, cerebellar Purkinje and granule
cells. These findings support an important role of MR-1 in normal
function (maintenance of excitability?) of these essential areas
of the motor system. The polypeptide encoded by splice variant
MR-1L is localized in the perinuclear region. MR-1 is very similar
to hydroxyacylglutathione hydrolase, as deduced by sequence
comparison (Lee et al., 2004). Hydroxyacylglutathione hydrolase,
a member of the zinc metallohydrolase enzymes with b-lactamase
domains, catalyses conversion of methylglyoxal to D-lactate
thereby detoxifying this substance. Methylglyoxal is present in
coffee, alcoholic beverages and is a by-product of oxidative
stress. Impaired function of MR-1 and an increase in methylglyoxal and other upstream compounds of this pathway might
therefore explain precipitation of attacks by alcohol, caffeine and
stress (Lee et al., 2004).
Animal models
Inbred dtsz hamsters display several features of human idiopathic
paroxysmal dystonia, including dystonic attacks induced by stress,
twisting movements and abnormal postures. Affected animals are
neuropathologically normal but metabolic activity is abnormal in
several regions of the brain including basal ganglia and cerebellum
(Nobrega et al., 1998; Richter und Löscher, 1998; Hamann et al.,
2008). Immunohistochemical investigations revealed a reduced
density of striatal GABAergic interneurons in dtsz hamsters. This
results in a decrease in GABA levels and enhanced activity
| Brain 2009: 132; 2005–2025
U. Müller
of GABAergic projection neurons (Gernert et al., 1999). The
gene(s) mutated in the dtsz mutant, however, are yet not
known. Presently, no transgenic, knock-out, or knock-in mice
have been constructed utilizing BRP17/PNKD1.
Dystonia 18 [paroxysmal exertion-induced dyskinesia;
paroxysmal exercise-induced dystonia]; DYT18,
SLC2A1; OMIM 612 126
Dystonia 18 is characterized by exercise-induced attacks of
dystonic, choreatic and ballistic movements primarily affecting
the upper and lower limbs (Margari et al., 2000; Münchau
et al., 2000; Weber et al., 2008). Attacks can last from a few
minutes to close to an hour. Attacks can affect those limbs that
were excessively exercised exclusively (Plant et al., 1984; Weber
et al., 2008). Accompanying signs and symptoms can include
epileptic seizures, migraine, decreased cognitive function, developmental delay and impulsive/aggressive behaviour. Reduced CNS
glucose levels and haemolytic anaemia with echinocytosis were
described in patients from one family (Weber et al. 2008).
Onset of dystonia 18 is during childhood.
Patients should be encouraged to avoid triggering factors such as
alcohol, caffeine and nicotine. Some cases respond to clonazepam,
haloperidol or anti-cholinergics.
Dystonia 9 [PDC with episodic ataxia and spasticity;
episodic choreoathetosis/spasticity (CSE)]; DYT9;
OMIM 601 042
Phenotype and treatment
Dystonia 9 was described in one large family (Auburger et al.,
1996). Patients presented with paroxysmal choreoathetosis and
dystonia, similar to dystonia 8. In contrast to dystonia 8, however,
several affected members of the dystonia 9 family had episodic
ataxia. Episodes could be precipitated by alcohol, fatigue, emotional stress and—unlike in dystonia 8—by physical exercise.
Furthermore, 5 of 18 patients had spastic paraplegia both during
and between episodes of dyskinesia. Episodes occurred between
twice a day to twice a year and lasted for 20 min. Age of onset
ranged from 2 to 15 years.
Acetazolamide and phenytoin ameliorated the condition in
one, and acetazolamide had a positive effect in a second patient.
Other tested patients did not benefit from these medications.
Inheritance and mapping
Dystonia 9 is an autosomal dominant condition. The disease gene,
DYT9/CSE was assigned to a 12 cM interval on the short arm of
chromosome 1 (1p21-p13.3).
Both phenotype and chromosomal location are quite similar to
dystonia 18 and both disorders might be the same. This can now
be tested by mutation analysis of the disease gene identified in
dystonia 18 (see below).
Dystonia 10 [paroxysmal kinesigenic choreoathetosis
(PKC); paroxysmal familial dystonia; paroxysmal
kinesigenic dyskinesia (PKD)]; DYT10; OMIM 128 200
Phenotype and treatment
Dystonia 10/PKC (Kertesz, 1967; Walker, 1981) is characterized
by short attacks of choreiform or dystonic movements that are
precipitated by sudden unexpected movements. Episodes last for
seconds to minutes and can occur up to 100-times per day. In
addition, seizures are observed in some patients (Tan et al., 1998).
Age of onset is usually during childhood and adolescence. In one
family, signs and symptoms ameliorated or even resolved during
adult life (Bennett et al. 2000). Patients respond to anti-convulsant
drugs such as phenytoin and carbamazepine.
MRI detected hypointense signals in the caudal putamen in two
patients and was normal in two additional patients. PET using [18F]
fluorodeoxy-glucose indicated decreased glucose metabolism in
the right thalamus of three patients investigated (Weber et al.,
Inheritance, mapping and molecular genetics
Inheritance of dystonia 18 is autosomal dominant with slightly
reduced penetrance. DYT18 is located in the short arm of
chromosome 1 (1p31.3–p35).
A candidate gene approach revealed two missense mutations
and one 4 bp deletion in the gene SLC2A1 in affected members
from three families (Weber et al., 2008). SLC2A1 is composed of
10 exons and codes for glucose transporter 1 (GLUT1).
Molecular pathology
Studies in Xenopus oocytes and in human erythrocytes showed
that the 4 bp deletion in SLC2A1 causes decreased glucose
transport and alters intracellular Na+, K+ and Ca++ levels. The
two missense mutations were also shown to affect glucose transport but not the transmembrane transport of cations. These data,
in combination with the PET findings (see above), are compatible
with the notion that dyskinesias are the result of exertion-induced
energy deficit. In addition, some mutations such as the 4 bp
deletion can alter cation transport and give rise to haemolysis
(which was not seen in affected individuals carrying either one
of the missense mutations).
Carboanhydrase inhibitors such as acetazolamide and diclofenamide can have limited positive effects. Seizures can be controlled
by anti-epileptic drugs. L-dopa is not beneficial in dystonia 18. In
one patient, a ketogenic diet abolished attacks (Weber et al.,
Dystonia 19 (PKD 2); DYT19; OMIM 611 031
Inheritance and mapping
Inheritance of PKC is autosomal dominant. A disease locus has
been assigned to the pericentromeric region of chromosome
16 (16p11.2-q12.1) (Tomita et al., 1999; Bennett et al., 2000).
Designation ‘dystonia 19’ was used for a PKD in which the disease
locus was mapped to the long arm of chromosome 16
(16q13-q22.1) (Valente et al., 2000). This region lies in very
close proximity to the critical interval of DYT10 and overlaps
Monogenic primary dystonias
Brain 2009: 132; 2005–2025
with the DYT10 critical region delineated in one Afro-American
family (Bennett et al. 2000; Valente et al., 2000). Designation of a
novel locus based on linkage assignment to an interval in close
proximity to an established locus can be problematic as was shown
by the initial erroneous assignment of a novel locus DYT14 in a
family that turned out to be affected by dystonia 5a (see above).
Dystonia 20 PNKD2; DYT20; OMIM 611147
Designation ‘dystonia 20’ is based on findings in one large
Canadian family with PNKD. Linkage analysis in this family
assigned the disease locus to an interval in 2q31 slightly proximal
to PNKD1 (Spacey et al., 2006). The authors failed to detect
a mutation in PNKD1/MR1 and postulate a novel locus DYT20
on chromosome 2p31. This finding needs to be confirmed in
other families. The existence of a second PNKD needs to be
proven by the detection of mutations in a gene different from
Autosomal recessive and
X-linked primary dystonias
(Table 2)
Pure dystonias
Dystonia 2 (autosomal recessive torsion dystonia);
DYT2; OMIM 224 500
Dystonia 2 is an autosomal recessive dystonia detected in Spanish
Gypsy families. In nine affected offspring from four families (three
of whom were proven consanguineous), average age of onset was
during adolescence (15 years). Affected family members had
either generalized (6) or brachial segmental (3) dystonia. Site
of onset affected the lower extremities in six and the upper extremities in three (Giménez-Roldán et al., 1988). Childhood-onset
dystonia with a phenotype overlapping with that of dystonia 1
was reported in three affected siblings of a large Iranian
Sephardic Jewish pedigree (Khan et al., 2003).
Segregation analysis in the three consanguineous Spanish Gypsy
families suggests autosomal recessive inheritance of the disorder
(Giménez-Roldán et al., 1988). No linkage studies have been
performed and no disease locus has been assigned in these
| 2015
families. An additional pedigree with apparent autosomal recessive
inheritance was reported in three siblings from a large consanguineous Iranian Sephardic Jewish family (Khan et al., 2003).
Mutations at DYT1 and DYT11 were not detected. The authors
speculate that the affected Sephardic (i.e. ‘Spanish’) Jews might
carry the same disease-causing mutation as the Spanish gypsies.
Zlotogora (2004), however, points out that a Spanish origin of
Iranian Jews is highly unlikely and that the mutation could actually
be an autosomal dominant new mutation that has occurred in the
germline of one of the parents of the affected sibs (Zlotogora,
Dystonia 17 (autosomal recessive torsion dystonia);
DYT17; OMIM 612 406
Phenotype and imaging
Dystonia 17 was described in one large consanguineous Lebanese
Shiite family with three affected sisters (Chouery et al., 2008).
Dystonia had started as torticollis at 19, 17 and 14 years of age,
respectively, and spread to other body parts within 3 years of
onset. It became segmental in two, and generalized in one patient.
All three affected individuals had severe dysarthria and dysphonia.
Movement abnormalities other than dystonia were not noted.
There is some phenotypic overlap with dystonia 2 patients that
can also present with oromandibular dystonia and torticollis. MRI
did not reveal specific anomalies.
Inheritance and mapping
Inheritance of dystonia 17 is autosomal recessive. The disease
locus was assigned to chromosome 20 (20p11.22-q13.12) by
autozygosity mapping (Chouery et al., 2008). Since the locus in
dystonia 2 has not yet been mapped, it is currently unclear
whether dystonia 17 is related or identical to dystonia 2.
Dystonia plus syndromes
Dystonia 5b (autosomal recessive DRD; autosomal
recessive Segawa syndrome); DYT5b, TH; OMIM
128 230
Phenotype of autosomal recessive DRD (dystonia 5b) is quite
similar to that of dystonia 5a but often more severe (Lüdecke
et al., 1996; Bartholomé and Lüdecke, 1998). The phenotypic
spectrum is quite wide and some cases can present as earlyonset parkinsonism (Swaans et al., 1980).
Table 2 Autosomal and X-chromosomal recessive primary dystonias
Pure dystonia
Dystonia 2
Dystonia 17
Dystonia 5b
Dystonia plus
Dystonia 16
Dystonia 3
Autosomal recessive torsion dystonia
Autosomal recessive torsion dystonia
Autosomal recessive DRD; Autosomal
recessive Segawa syndrome
Autosomal recessive dystonia–parkinsonism
XDP; ’’lubag‘‘
Chromosomal mapping
Disease gene
224 500
612 406
128 230
612 067
314 250
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U. Müller
Prevalence, inheritance and mapping
It is presently unknown how it changes structure and function
of PKR and ultimately causes abnormal movement.
L-dopa/carbidopa had a positive effect on bradykinesia, and
botulinum toxin injections were moderately beneficial in some
Dystonia 5b is less common than dystonia 5a. Inheritance is
autosomal recessive. The disease locus is on the short arm of
chromosome 11 (11p15.5).
Molecular genetics
Dystonia 5b is caused by mutations in the gene TH that is
composed of 14 exons. It codes for tyrosine hydroxylase TH.
There are at least four alternative transcripts of the TH gene. To
date, homozygous and compound heterozygous missense and
frameshift mutations have been described. In addition a homozygous promoter mutation (-70G-A) was reported in two families
(Verbeek et al., 2007). This mutation lies within the cAMP
response element and results in decreased synthesis of TH.
Molecular pathology and treatment
Pathological effects are caused by lack of TH and the resulting
disturbed conversion from tyrosine to L-dopa (Fig. 1). Long-term
treatment with low doses of L-dopa in combination with a
decarboxylase inhibitor such as carbidopa abolishes signs and
symptoms with no side effects.
Dystonia 16 (autosomal recessive dystonia
parkinsonism); DYT16, PRKRA; OMIM 612 067
Phenotype and imaging
Dystonia 16 was identified in two consanguineous Brazilian
families including six affected members and in one single patient
from Brazil (Camargos et al., 2008). All patients had generalized
dystonia, which was classified as slight in one, moderate in three
and severe in three. Disease onset was during childhood in six
(2–12 years) and during adolescence (18 years) in one patient.
It started in the lower extremities in four, in the upper limbs in
two, and initially presented with dysphonia in one. Site of onset
did not affect severity of disease. Concurrent parkinsonism was
diagnosed in four patients.
Neither CT scans nor MRI revealed abnormalities in the patients
Inheritance, mapping and molecular genetics
Inheritance of dystonia 16 is autosomal recessive. The disease
locus, DYT16 was assigned to 2q31.3 by autozygosity mapping.
The same homozygous missense mutation (c.665C4T/P222L) was
detected in exon 7 of the gene PRKRA in all seven Brazilian
patients. PRKRA is composed of eight exons and codes for protein
kinase, interferon-inducible double-stranded RNA-dependent
activator. In addition, a heterozygous frameshift mutation
(c.266_267delAT; p.H89fsX20) was observed in exon 3 of the
gene in one sporadic German patient with early-onset dystonia
(Seibler et al., 2008).
Molecular pathology and treatment
PRKRA activates the latent protein kinase PKR in response to
stress. PKR plays a role in several cellular processes including
signal transduction, cellular differentiation and proliferation, and
apoptosis. The p.P222L mutation in the Brazilian patients occurred
at a position that is evolutionarily conserved in mammals and
is located between the second and third RNA-binding motifs.
X-linked recessive dystonia plus
Dystonia 3 (X-linked dystonia–parkinsonism; ‘‘lubag’’);
DYT3, TAF1/DYT3; OMIM 314 250
Dystonia 3 is an adult-onset (35 8 years) dystonia, frequently
accompanied by parkinsonism. Disease can start in either axial
musculature, lower or upper extremities, head or neck. In some
cases, tremor is the first symptom. The disorder generalizes within
5 years of onset (4.7 2.6 years). Concurrent parkinsonism was
described in 35% of a cohort of 42 patients examined (Lee et al.,
1991). However, this percentage may be significantly higher
(Evidente et al., 2002b). Interestingly, the first two publications
on X-chromosomal dystonia parkinsonism syndrome (XDP)
described the phenotypic extremes, i.e. only dystonia or mainly
parkinsonism. One publication (Lee et al., 1976) reports on
‘dystonia musculorum deformans’ in Filipino men. Parkinsonism
was not recognized in this patient sample. The second publication,
an abstract only (Johnston and McKusick, 1963), described
X-linked parkinsonism in one Filipino kindred, without mentioning
dystonia. Figure 2 shows phenotype of four patients with XDP.
Although men are primarily affected, XDP has also been detected
in a few women (Evidente et al., 2004). In women, involvement is
much milder with an average age at onset of 52 years, frequently
only minor motor anomalies such as parkinsonism and cervical
dystonia, and a slow or no progression of symptoms.
Astrocytosis and neuronal loss in caudate and lateral putamen was
reported in two patient brains (Waters et al., 1993a; Evidente
et al., 2002a). A detailed analysis of the striatum of several
XDP-brains also demonstrated neuronal loss and astrocytosis
in the caudate and putamen (neostriatum). Furthermore, while
striatosomes are dramatically depleted, the striatal matrix is only
moderately affected (Goto et al., 2005).
CT and MRI appear to be normal in XDP (Evidente, 2009). PET
studies using [18F] fluorodeoxyglucose revealed reduction of glucose metabolism in the striatum of three XDP patients. Striatal
[18F] fluorodopa uptake was normal, indicating that parkinsonism
in XDP has secondary, extranigral causes (Eidelberg et al., 1993).
Yet in an additional patient, PET did reveal reduced striatal uptake
of fluorodopa (Waters et al., 1993b). Decreased DA D2 receptor
expression was shown in the striatum of an XDP patient by
I-iodobenzamide (IBZM)-SPECT (Tackenberg et al., 2007).
Prevalence, inheritance and mapping
XDP originated by founder effect in the Philippine island of Panay.
Therefore, prevalence is highest on this island, in particular in the
Monogenic primary dystonias
Brain 2009: 132; 2005–2025
| 2017
within the complex transcript system TAF1/DYT3 in all XDP
patients tested (Nolte et al., 2003; Makino et al., 2007). TAF1/
DYT3 is composed of at least 43 exons that are alternatively
spliced (Fig. 3). There are alternative transcripts of exons 1–38
that encode isoforms of TATA box binding protein-associated
factor I (TAF1) and five exons, referred to as d1–d5, downstream
to exon 38. Exons d1–d5 can either form separate transcripts,
regulated by separate promoters (Herzfeld et al., 2007) or
transcripts spliced to some of exons 1–37 of TAF1 (Nolte et al.,
Molecular mechanisms
It is currently not clear how the changes within the TAF1/DYT3
transcript system cause disease. It has been argued that the SVA
transposon might specifically reduce expression of one alternative
transcript (34’, Fig. 3) and also affect expression of the DA
receptor D2 gene (Makino et al., 2007). However, some of
these findings are controversial (Müller et al., 2007; Tamiya
et al., 2007). Preliminary data from the author’s own lab indicate
that a sequence change within one of the d exons causes disturbed regulation of various genes expressed in the striatum.
Finally, the differential neuronal death within the striatum
described by Goto et al. (2005) might cause an imbalance in
activity of striosomal and matrix-based pathways thus giving rise
to abnormal movements.
Figure 2 Phenotype of four patients with XDP. (A) Patient
with generalized dystonia including torticollis and pronounced
truncal involvement; (B) Patient with generalized dystonia
including dysphagia and dystonia of the foot (arrow) plus
parkinsonism (facial bradykinesia); (C) Three brothers, one
(left) unaffected and two with generalized dystonia. The
patient on the right also displays facial bradykinesia; and
(D) Drawing of spirals with left (above) and right hand by
a patient with XDP indicating tremor.
province of Capiz (19/100 000 according to Lee et al., 2002;
25/100 000 according to Kupke et al., 1990b). XDP has only
been diagnosed in Filipinos.
XDP is an X-linked recessive disorder (Kupke et al., 1990b).
Consecutive linkage and association studies assigned DYT3
to Xq13.1 (e.g. Kupke et al., 1990a, 1992; Graeber et al., 1992,
Németh et al., 1999). While some authors group XDP as ‘heredodegenerative disease-associated with dystonia’ (de Carrvalho
Aguiar and Ozelius, 2002) and thus as secondary dystonia (Geyer
and Bressman, 2006), I have — in agreement with the original
suggestion of Fahn et al. (1987) — grouped it as a dystonia plus
syndrome for reasons outlined in the ‘Conclusion’ section.
Molecular genetics
Five disease-specific sequence changes, a 48 bp deletion, and a
SVA (composite of SINE, VNTR and Alu) retroposon are found
Most medications including L-dopa, anti-cholinergic agents such as
trihexyphenidyl, benzodiazepines such as lorazepam, diazepam
and clonazepam were initially thought to be ineffective in XDP
(Lee et al., 1991). However, more recent studies suggest some
benefited, in particular if anti-cholinergic drugs and clonazepam
are given in combination (Evidente, 2009). One patient appeared
to benefit from a combination of L-dopa/benserazide with propranolol (Tackenberg et al., 2007). Zolpidem, an imidazopyridine,
was also found to benefit some patients (Evidente et al., 2002).
Botulinum toxin A injections can alleviate dystonia, such as
torticollis in some patients. Finally, positive results in one patient
give hope that deep brain stimulation might become an effective
treatment (Evidente et al., 2007).
Diagnostic procedure in primary
The findings in the various dystonias are summarized in Table 3
and facilitate standardized diagnostic procedure. First, the phenotype needs to be clinically evaluated. Pure dystonias can easily be
distinguished from dystonia plus syndromes and paroxysmal
If a patient presents with pure dystonia, age of onset, site of
first symptoms, dystonic involvement and family history need to
be determined. Although the finding of affected relatives is highly
indicative of a monogenic form, frequently no affected family
members are reported owing to reduced penetrance in many
dystonias. However, an early age of onset can indicate a monogenic form. Of the monogenic pure dystonias, dystonia 1 is
| Brain 2009: 132; 2005–2025
U. Müller
Figure 3 TAF1/DYT3 transcript system. Alternative transcripts encoded by the TAF1/DYT3 transcript system are divided into four
major variants. Variants 1, 2 use TAF1 ‘proper’ exons plus downstream (‘d’) exons. Variants 3, 4 are encoded by d exons exclusively.
Note that neither the exact 30 - nor 50 -ends of variant 2 transcripts are currently known. ‘DSC’ indicates ‘disease-specific single
nucleotide change’. DSCs are identical in all XDP patients. The SVA retrotransposon and DSC10 are within intron 32 of TAF1. DSC3 is
the only disease-specific sequence change located in a transcribed exon. Currently, both the SVA and some of the DSCs, in particular
DSC3, are implicated in the aetiology of XDP (adapted from Nolte et al., 2003 and Herzfeld et al., 2007).
most common. This diagnosis should be considered in early-onset
cases with first involvement in limbs and rapid generalization.
Testing for the GAG-deletion in TOR1A will provide the definite
diagnosis. If preliminary findings turn out to be correct, dystonia 6
is the second most frequent monogenic pure dystonia. Clinical
indication for this form comes from cervical involvement, a
mixed phenotype, and an older age of onset than in dystonia 1.
The definite diagnosis rests on the detection of a mutation in the
THAP1 gene. Here the possibility of deletions should be considered if no base changes can be found upon sequencing of the
three exons of the gene. The remaining pure dystonias, i.e.
dystonias 2, 4, 7, 13 and 17 are much less common with
dystonias 4 (whispering dystonia), 7, 13 and 17 each described
in one family only. If large families are found with findings
consistent with those in these families, linkage analyses can be
attempted. Dysphonia may indicate dystonia 4, juvenile-onset
with first symptoms in cranial–cervical region and slow progression might indicate dystonia 13. Dystonia 17 can be considered
in persons from the Middle East with adolescent-onset segmental or generalized dystonia. Similar to dystonia 2, which is also
autosomal recessive, it is a possible diagnosis especially in
consanguineous families.
DRD (Segawa syndrome) is probably the most common
dystonia plus syndrome. DRD is a potential diagnosis in patients
with early-onset dystonia and a rapid therapeutic response to low
doses of L-dopa. Mutation analyses of the gene GCH1 should
be performed in all patients with dystonia and responsiveness to
L-dopa. DRD is phenotypically very heterogeneous and needs to
be contemplated even in adult-onset focal dystonia (Steinberger
et al., 1999) or in patients presenting with parkinsonism only.
An important differential diagnosis is juvenile parkinsonism, an
autosomal recessive disorder that can present with symptoms
characteristic of DRD such as circadian fluctuation of symptoms
and dystonia. This heredodegenerative dystonia is caused by
mutations in the gene PARK2 on 6q25.2-q27 (e.g. Matsumine
et al., 1997; Lücking et al., 2000). Furthermore, dystonia 5b
with mutations in the gene TH needs to be considered.
If DRD is excluded, the diagnosis autosomal recessive dystonia
parkinsonism (dystonia 16) can be entertained, especially in
consanguineous settings. Here mutation analyses in the PRKRA
gene can result in a definite diagnosis. Abrupt onset of dystonia
and parkinsonism within minutes to days of onset are characteristic of equally rare dystonia 12 (rapid-onset dystonia–
parkinsonism). This dystonia can be diagnosed by mutation
analysis of the gene ATP1A3. Dystonia and Parkinsonism in
people of Filipino extraction are frequently caused by mutations
in the TAF1/DYT3 multiple transcript system.
In patients with M-D responsive to alcohol, dystonia 11 needs
to be considered. A definite diagnosis should be attempted by
mutation analysis of the gene SGCE. A mutation in another
gene, i.e. the gene coding for the D2 DA receptor (DRD2) has
been reported in one family with M-D. The nucleotide change
results in a Val–Ile substitution in a conserved region at the
cytoplasmic end of transmembrane helix 4 of DRD2 (Klein
et al., 1999). However, experiments in a cell system did not
reveal abnormal function of the receptor carrying the amino acid
substitution (Klein et al., 2000). Therefore, rather than being a
pathogenic mutation the nucleotide change may be a rare neutral
polymorphism. Definite diagnosis of other M-Ds such as dystonia
15 awaits the identification of the disease gene.
Monogenic primary dystonias
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Table 3 Characteristic manifestations in the various forms of primary dystonia
Mode of
Age of onset
Clinical findings
Adolescence or adulthood
Childhood or adolescence
Dystonia plus 3
Childhood, adolescence or
Adolescence or early
Childhood or adolescence
Childhood, adolescence or
Childhood or adolescence
Childhood, generalized
Childhood, adolescence
Generalized, onset in limbs
Generalized or segmental
Generalized brachial, craniocervical
Craniocervical or brachial onset,
mainly segmental
Cervical onset; Segmental or
Generalized dystonia, parkinsonism
Generalized dystonia, parkinsonism
Generalized dystonia, parkinsonism
Focal, segmental dystonia,
Sudden onset of dystonia and
Dystonia and myclonus
Dystonia and parkinsonism
9 (identical
to 18?)
Childhood, adolescence
Childhood, adolescence
Pure dystonia 1
19 (identical AD
to 10?)
20 (identical AD
to 8?)
Additional characteristics
Whispering dysphonia
Striatal neurodegeneration
Therapeutic response to L-dopa
Therapeutic response to L-dopa
Responsive to alcohol
Occasionally seizures,
psychiatric symptoms
Responsive to alcohol
Paroxysmal dystonia, chorea, ballsism,
Paroxysmal dystonia, choreoathetosis,
Paroxysmal dystonia, kinesigenic
Paroxysmal dystonia choreatosis,
Seizures, migraine, decreased
ballism, kinesigenic
cognitive function, developmental delay, impulsive/
aggressive behaviour
Paroxysmal dyskinesia, kinesigenic
Childhood, adolescence, or Paroxysmal dyskinesia,
It should be kept in mind that the phenotype of both
pure primary dystonias and dystonia plus syndromes can vary
dramatically. For example, several cases tested for GCH1
mutations based on a clinical diagnosis of DRD turned out to
have been afflicted by dystonia 1 based on findings of the GAG
deletion in TOR1A (author’s own observations). Testing of alternative genes should be considered in various mutation-negative
forms of dystonias as outlined in Fig. 4.
Finally, the paroxysmal dystonias can be distinguished clinically
on the basis of being kinesigenic or non-kinesigenic. Kinesigenic
forms include dystonias 9, 10, 18 and 19. Note that dystonias
9 and 18 might be identical conditions as might dystonias
19 and 10. Dystonias 8 and 20 are non-kinesigenic forms and
probably identical. In kinesigenic paroxysmal dyskinesias, especially
in those associated with epileptic seizures, migraine, decreased
cognitive function, developmental delay and/or impulsive/
aggressive behaviour, mutation analysis of the gene SLC2A1
should be performed to explore the possibility of the diagnosis
dystonia 18/(dystonia 9?). Dystonias 10/(19?) can currently only
be diagnosed by linkage analysis which requires large families. In
non-kinesigenic hereditary paroxysmal dystonias, detection of
mutations in the gene PNKD1/MR1 can identify dystonia
8/(20?). This diagnosis is particularly likely if symptoms can be
precipitated by alcohol and caffeine.
There are now at least 17, possibly 20 primary dystonias, which
are distinguished by genetic criteria. Definitive distinction becomes
possible once the disease gene has been identified. According to
this strict criterion dystonias 1, 3, 5a, 5b, 6, 8, 11, 12, 16, 18
are definitely distinct entities. Furthermore, those forms which
have been genetically mapped to regions clearly removed from
chromosomal intervals carrying known loci or disease genes can
also be considered distinct (dystonias 7, 10, 13, 15, 17). Dystonias
only assigned based on phenotype and apparent mode of
inheritance but without chromosomal mapping, such as dystonias
2 and 4, are less certainly different entities. In three cases,
i.e. dystonias 9, 19 and 20 the disease gene has been assigned
to an interval in close proximity to the known loci DYT18/
SLC2A1, DYT10 and DYT8/PNKD1. Furthermore, the phenotype
of dystonias 18, 10 and 8 is quite similar to that of putative
dystonias 9, 19 and 20, respectively. As long as no disease-causing
| Brain 2009: 132; 2005–2025
Figure 4 Diagnostic procedure in the more common primary
dystonias. Refer to the text for a comprehensive treatment of
the diagnosis of all forms of primary dystonias. Note that it
is currently unclear whether THAP1 mutation analysis is
promising in TOR1A mutation-negative early-onset dystonia
(therefore, the arrow is dashed). Paroxysmal dystonias are not
listed here. The only molecular diagnostic possibilities are
SLC2A1 mutation analysis in kinesigenic forms and PNKD/
MD1 analysis in non-kinesigenic paroxysmal dystonias. This is
outlined in the text.
gene has been identified, designations ‘dystonia 9’, ‘dystonia 19’
and ‘dystonia 20’ should be accepted under reserve. This caveat is
emphasized by the erroneous designation of a ‘novel’ DYT14 locus
based on linkage analysis in one family in close proximity to
the chromosomal interval containing the disease gene GCH1 of
dystonia 5a. In this instance, further studies clearly showed that
the disease locus ‘DYT14’ was in fact DYT5a (Grötzsch et al.,
2002; Wider et al., 2008).
As outlined in the ‘Introduction’ section, I propose to divide
the monogenic primary dystonias into three groups, the pure
dystonias, the dystonia plus syndromes and the paroxysmal
dystonias. Seven (dystonias 1, 2, 4, 6, 7, 13 and 17) of the
monogenic dystonias discussed here are ‘pure’ dystonias. In this
group, dystonia is the only symptom apart from tremor that is
seen in some cases. In the second group, i.e. the dystonia plus
syndromes, dystonia as the most prominent sign and is accompanied by additional movement abnormalities such as parkinsonism
and myoclonus. This group includes dystonias 3, 5a, 5b, 11, 12,
15, and 16. The remaining group comprises the paroxysmal
dystonias (dystonias 8, 9, 10, 18, 19, 20). Although dystonia
is also a major sign, it occurs paroxysmally and not permanently
as the classical dystonias. In addition, other features, including
epilepsy, can be associated with some paroxymal dystonias.
It has been argued that dystonia plus syndromes can be
distinguished from secondary dystonias by absence of neuropathological findings (Bressmann et al., 2002). This does not appear to
be a generally applicable criterion. In some disorders thought to be
U. Müller
morphologically normal, neuropathological changes have been
observed in some cases. Thus perinuclear inclusions were detected
in the brainstem of some patients who had dystonia 1 and minor
morphological anomalies and/or depigmentaion in substantia nigra
and striatum were found in several cases of dystonia 5a. Clearly,
absence/presence of morphological findings does not allow classification of a monogenic dystonia as ‘dystonia plus’ (i.e. primary)
versus ‘secondary dystonia’. A better criterion might be clinical
findings, i.e. the extent of dystonic versus non-dystonic involvement. Given the clinical phenotype of the XDP (dystonia 3), with
dystonia as the most striking feature (Fig. 2), I have grouped this
heredodegenerative disorder among the primary rather than
secondary dystonias despite the detection of clear neurodegenerative changes.
Findings in dystonias 5a and 5b demonstrate that abnormal
function of the DA system can cause dystonia. Mutations in
GCH1 or SPR (dystonia 5a) disturb normal synthesis of tetrahydrobiopterin, which eventually results in decreased synthesis of
L-dopa/DA and reduced levels of this neurotransmitter in the
striatum. Similarly, loss of TH activity in dystonia 5b causes
decreased levels of L-dopa/DA. Both neuroanatomical and imaging
findings in other forms also point to disturbed striatal function as
one underlying cause of dystonia. Pronounced degeneration of
neurons within the caudate and putamen (neostriatum) is found
in dystonia 3 (XDP). Abnormal striatal MRI or SPECT findings were
reported at least in a few cases of dystonia 11 (reduced regional
blood flow in the caudate of one patient), dystonia 8 (lowintensity signals in globus pallidus and substantia nigra in one
patient), dystonia 5 (reduced metabolic activity in basal ganglia)
and dystonia 1 (decreased D2 receptor binding in caudate and
putamen). It needs to be emphasized that neuropathology and
imaging also indicate that, apart from the basal ganglia, additional
cerebral regions are affected in various types of monogenic
The detection of mutations in genes other than those involved
in the biopterin/DA pathway does not permit the delineation of an
obvious common pathway with the end-point dystonia. Thus,
mutations can affect proteins involved in (i) the function of
other proteins such as the putative chaperone protein torsinA
(dystonia 1), THAP1 which is involved in apoptosis (dystonia 6),
ATP1A3, a Na+/K+-ATPase (dystonia 12) or PRKRA acting as a
protein kinase (dystonia 16); (ii) maintenance of cellular structure
such as PNKD1/MR1 (dystonia 8) and e-sarcoglycan (dytonia 11)
and (iii) regulation of cellular function and metabolism such as
TAF1/DYT3 transcript system (dystonia 3), glucose transporter 1
(dystonia 18), and probably torsinA as well. All these mutations
appear to disturb the normal function of striatal (and other?)
neurons. Yet, the gene products involved do not appear to be
part of one interdependent pathway. Obviously, disturbances
affecting very different proteins in neuronal cells can have the
same effect by incapacitating a specific cell type. They need
not necessarily be part of a common pathway as is the case in
dystonias 5a, b. Although this makes development of causative
therapies for most primary dystonias more difficult, it can be
hoped that the ongoing and ever accelerating elucidation of the
genetic basis of these disorders will open up new avenues towards
their effective treatment.
Monogenic primary dystonias
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