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Movement disorders: Classications
C. Klein
Department of Neurology, University of Lbeck, Lbeck, Germany
Correspondence: Department of Neurology, University of Lbeck, Ratzeburger Allee
160, 23538 Lbeck, Germany. E-mail: [email protected]
Summary: Movement disorders (ataxia, dystonic disorders, gait disorders,
Huntington disease, myoclonus, parkinsonism, spasticity, tardive dyskinesia, tics
and tremor) are clinically, pathologically and genetically heterogeneous and
are characterized by impairment of the planning, control or execution of
movement. Current classifications of these disorders have inherent shortcomings
due to the complex nature of movement disorders and the lack of diagnostic tests
for the majority. Undiscriminating terminology, as well as the clinical, pathologi-
cal and genetic heterogeneity, further complicate the development of comprehen-
sive categorizations. Modern classification schemes tend to focus on clinical,
pathological or genetic/molecular criteria, but more recent attempts have been
made to integrate across these levels. From a historical perspective, two golden
ages have shaped thecurrent andevolvingclassification schemes: (1) the definition
of clinical pathological entities in the early twentieth century and (2) the appli-cation of molecular neurogenetics in the past 10^15 years. However, the classi-
fication of movement disorders on clinical grounds (according to age at onset,
distribution of symptoms, disease course, provoking factors and therapeutic
response) remains one of the most useful modes of categorization. Postmortem
criteria have been employed to distinguish between degenerative and
nondegenerative disorders, and specific hallmarks may be required to establish
or confirm a diagnosis. Genetic features used for classification purposes include
mode of inheritance and molecular genetic data, such as linkage to a known gene
locus or identification of a specific genetic defect. A final classification scheme
is based on alterations in molecular mechanisms (e.g. trinucleotide expansions)
or protein function (e.g. channelopathies). Despite recent advances, it may not
be possible to develop the ultimate classification of movement disorders, anddifferent patterns of lumping and splitting may be useful for the clinician, the
pathologist or the geneticist/molecular biologist. Furthermore, certain individual
cases with unique features may not fit into any particular category. Continued
research by both clinicians and basic scientists is necessary in order to refine
and redefine classification schemes of movement disorders.
J. Inherit.Metab.Dis. 28 (2005) 425^439
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CLASSIFICATION OF MOVEMENT DISORDERS
Movement disorders are a clinically, pathologically and genetically heterogeneous
group of neurological conditions. Despite this variability, there is considerable overlap
between different forms of movement disorders, as they all share the common features
of impaired planning, control or execution of movement.
The clinical spectrum of movement disorders includes, but is not limited to, ataxia,
blepharospasm, dysphonia, dystonic disorders, gait disorders, Huntington disease,
myoclonus, Parkinson disease, spasticity, tardive dyskinesia, tics and Tourette
syndrome, and tremor (The Movement Disorder Society; http://www.movement
disorders.org). It is beyond the scope of this article to review all of the classication
systems that have been applied to or developed for these dierent disorders. Instead,
selected examples will serve to illustrate important concepts of classication, and a moredetailed description of the dystonias will highlight evolving classication schemes.
A necessary prelude to this discussion is to consider the plethora of dierent classi-
cation schemes that have attempted to categorize, classify, group, lump and split
various forms of movement disorders. Not surprisingly, there are inconsistencies
between dierent classications, as a given categorization is not always universally
applicable, and advances in various areas of research sometimes call previous
classications into question. For example, the identication of hereditary forms of
movement disorders, such as monogenic parkinsonism or dystonia, has revealed
an unexpectedly large amount of clinical and genetic heterogeneity for many con-
ditions. This issue is further complicated by the likelihood that a large number of
movement disorder genes have yet to be identied, and by the fact that comprehensive
genetic data are available for only a small percentage of movement disorder patients.The ultimate solution to the general problem of classifying movement disorders will be
the integration of dierent clinical, pathological and genetic schemes. However, this is
a daunting, if not impossible, task.
The problem of terminology
Terminology is an invaluable prerequisite to and inherent part of any type of classi-
fication and is directly connected with the diagnosis of the respective movement dis-
order. However, consensus statements regarding terminology and diagnostic criteria
have only recently been developed for several movement disorders (Litvan et al 2003).
Despite these efforts, several definitions of terms still lack discrimination. Dystonia,
for example, may imply three different meanings: (1) a physical sign; (2) a syndrome
of sustained muscle contractions, causing twisting and repetitive movements and abnor-mal postures; (3) the disease idiopathic (or primary) dystonia (Quinn 1993).
In addition, mostly for historical reasons, identical terms may have dierent
denotations when used to discuss dierent disorders. For example, when evaluating
parkinsonism, the term idiopathic classically refers to clinically typical, non-genetic
Parkinson disease (PD) with Lewy bodies (Fahn 2003). Thus, idiopathic PD is
considered clinically distinct from other parkinsonian syndromes with atypical fea-
tures and is probably genetically distinct from the monogenic forms of PD. On
the other hand, when discussing dystonia, the term idiopathic dystonia usually refers
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to the genetic form of dystonia that clinically manifests as dystonia and possibly
tremor. In eorts to clarify this terminology, it has been suggested the term
idiopathic be replaced with the term primary (Bressman 2004), though such a
change has been proposed only in the classication of the dystonias. The more recent
genetic classication of the dystonias considers several of the monogenic forms of
dystonia as primary (DYT1, 6, 7 and 13). By contrast, in parkinsonism, the term
primary is not used, whereas the term secondary has been reserved for cases with
a known cause, with the exception of the known monogenic forms. Surprisingly,
the latter are not considered primary. Unlike in the dystonias, an umbrella term
parkinsonism has been coined to broadly categorize this set of disorders, with
PD being the most frequent cause of parkinsonism.
The problem of genetics
While the identification of several movement disorder genes has improved our under-
standing of the pathophysiology of many of these conditions, these discoveries have
complicated certain aspects of disease classification. First, the growing lists of
PARKs (monogenic forms of parkinsonism), DYTs (monogenic forms of dystonia)
or SCAs (dominantly inherited forms of spinocerebellar ataxias) are mixed bags of
clinically heterogeneous conditions. For example, the clinical phenotype associated
with mutations in the PARK9 gene (Kufor^Rakeb syndrome) differs markedly from
idiopathic PD (Najim al-Din et al 1994). Conversely, some cases of autosomal
recessive parkinsonism (PARK2, 6 and 7), may be clinically indistinguishable from
idiopathic PD (Klein et al 2000b; Hedrich et al 2004; Valente et al 2004). The DYTs
represent an equally heterogeneous group of disorders, including primary forms of
dystonia, secondary forms of dystonia, and the dystonia-plus syndromes (Klein
and Ozelius 2002). There is ongoing debate whether the latter category should be
classified as a primary or secondary dystonia. Postmortem findings have demon-
strated 14 of the 15 types to be nondegenerative disorders; however, DYT3 (X-linked
dystonia-parkinsonism) is the exception to this rule.
Modes of inheritance are also variable and sometimes even uncertain, thereby adding
a further level of complexity to the classication of these disorders. For example, PARK1
^ PARK9 all follow a typical Mendelian pattern of inheritance (autosomal dominant or
autosomal recessive), whereas PARK10 (Hicks et al 2002) and PARK11 (Pankratz et al
2003) represent susceptibility loci with an unknown pattern of transmission.
Importantly, genetic data should be interpreted with caution, as errors have been found.
For example, based on incorrect genotyping, PARK4 recently turned out to be identical
with PARK1 (Singleton et al 2003). Moreover, in cases of a known gene, the mutationalanalysis may be complicated by false-positive or false-negative results (Klein et al 2003).
Finally, the genetic status of most patients is simply unknown, thus limiting the
generalization of genetic classications in the clinical setting.
The problem of heterogeneity
The heterogeneity of movement disorders complicates the development and use of
classification schemes. First, phenotypic heterogeneity may lead to clinical
misclassification. For example, carriers of an identical GAG deletion in the DYT1
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gene may be unaffected or may present with mild writers cramp, severe generalized
dystonia or a jerky type of dystonic tremor reminiscent of myoclonus-dystonia
(Kabakci et al 2004). Second, there is genetic heterogeneity: two cases with a virtually
identical movement disorder (e.g. myoclonus-dystonia) may have different underlying
genetic defects (Kock et al 2004). Third, phenotypically different manifestations may
appear in the same patient. For example, three patients with genetically proven
SCA17 have recently presented with a purely dystonic syndrome that was later
followed by ataxia and other signs suggestive of a spinocerebellar ataxia (Hagenah
et al 2004).
Current classicational concepts are often challenged by new clinical, postmortem
or genetic ndings: For example, a recent case that clinically appeared to have a
late-onset parkinsonian syndrome was found not only to have typicala-synuclein-positive Lewy bodies (unpublished data), consistent with a diagnosis
of idiopathic PD, but also to carry compound heterozygous deletions in the Parkin
gene, suggesting a diagnosis of Parkin-associated parkinsonism (Klein et al 2000b).
Thus, the current clinical, pathological, and genetic criteria for the diagnosis of these
disorders may be less distinct than previously thought. A similar demonstration
of the limitations of our current classication schemes comes from the evaluation
of four individuals with PARK8-linked parkinsonism and cardinal clinical signs
of PD. Postmortem analysis revealed a surprisingly broad spectrum of ndings, with
Lewy bodies limited to brainstem nuclei in one case, diuse Lewy bodies in the second,
neurobrillary tangles without Lewy bodies in the third, and neither neurobrillary
tangles nor Lewy bodies in the fourth (Wszolek et al 2004).
Advances in molecular genetics provide a powerful tool to identify at-risk
individuals on the basis of their mutational status. These advances are paralleledby the development of novel neuroimaging and other techniques used to identify
preclinical changes, such as abnormalities on positron emission tomography (Hilker
et al 2001) or transcranial ultrasonography (Walter et al 2004). Consequently, the
classic denition of the phenotype may have to be revised and expanded beyond
the ndings evident upon clinical examination. These recent developments highlight
the issue of where exactly to draw the line to call an individual aected.
MODES OF CLASSIFICATION: A LOT TO CHOOSE FROM
When it comes to modes of classification of movement disorders, there are numerous
options (Table 1). From a historical perspective, two golden ages of advances in our
understanding of movement disorders have had a major impact on and have shapedcurrent and evolving classificational schemes (Hardy and Gwinn-Hardy 1998). In
the early twentieth century, microscopy and histological procedures had become avail-
able and led to the definition of clinical pathological entities. Many diseases now carry
the names of these pioneering neuropathologists, such as Alzheimer, Pick or Lewy,
just to name a few. The second major set of developments, molecular neurogenetics
and neurobiology, dates back about 10^15 years and continues to influence our
thinking about how different conditions should be grouped and classified. The number
of contributions to this field is enormous and ever increasing, including such import-
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ant discoveries as the concept of prion diseases (Hsiao et al 1989; Owen et al 1989),
trinucleotide repeat disorders (La Spada et al. 1991; The Huntingtons Disease
Collaborative Research Group 1993) and the identification of genes for disorderssuch as Alzheimer (Kang et al 1987) and Parkinson diseases (for review see Hardy
et al 2003; Vila and Przedborski 2004).
Clinical criteria: Classication of movement disorders on clinical grounds remains
one of the most useful and widely used modes of categorization. For example, move-
ment disorders can be grouped according to age of onset or with respect to distribution
of symptoms. Involvement of body sites is also used to rate the severity of movement
disorders, as illustrated by the Hoehn and Yahr Scale, which distinguishes between
hemilateral and bilateral parkinsonism, parkinsonism with and without axial
involvement, and so on (Hoehn and Yahr 1967).
Postmortem criteria: Postmortem criteria have been employed to distinguish between
degenerative and nondegenerative disorders. Specic hallmarks are required to establish
a diagnosis of certain disorders, such as Lewy bodies in PD (Jellinger 2001). Staining
with specic antibodies has led to a further level of pathological dierentiation, as illus-
trated by the synucleinopathies or tauopathies (Neumann 2004).
Genetic/molecular criteria: A genetic classication is based on clinical genetic
pedigree information on mode of inheritance and molecular genetic data, such as
linkage to a known gene locus or identication of a specic genetic defect in a can-
didate gene (for review see Gasser et al 2003). Additionally, defects in particular mol-
ecular mechanisms (e.g. polyglutamine diseases) or protein function (e.g.
Table1 Dierent modes of classication of movement disorders
Modes of classication Examples
By aetiology Primary (idiopathic) vs secondary(symptomatic)
Clinical criteriaAge of onset Early-onset vs late-onset parkinsonismDistribution of symptoms Focal vs generalized dystoniaSpecic clinical phenomenology Resting vs action tremorDisease onset Rapid vs slowDisease course Progressive vs stableResponse to treatment Levodopa-responsive vs non-responsive
parkinsonism
Postmortem criteriaPresence of specic hallmarks Lewy bodies in Parkinson diseaseStaining with specic antibodies Synucleinopathies, tauopathies, etc.
Genetic/molecular criteriaMode of inheritance Autosomal dominant vs recessiveLinkage to a chromosomal locus PARK2-linked parkinsonismIdentication of a mutation Parkin-associated parkinsonismDefect in molecular mechanism Polyglutamine diseasesDefect in protein function Channelopathies
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channelopathies) serve to classify movement disorders. This genetic/molecular classi-
cation has been successfully applied to the inherited ataxias, taking into account
mode of inheritance and mechanism of mutations. Dominantly inherited ataxias
(SCAs) are one major group of ataxias; this set of disorders can be subdivided into
expanded exonic CAG repeat (polyglutamine; polyQ) disorders, dominantly inherited
ataxias with mutations in noncoding regions, and dominantly inherited ataxias with
chromosomal localizations but unidentied loci. Another group of dominantly
inherited ataxias is the episodic ataxias with ion channel mutations. Recessive ataxias,
on the other hand, are more heterogeneous and are due to loss-of-function changes in
various genes/loci (Albin 2003). Gene tables summarizing paediatric and adult
movement disorders are published and updated on a regular basis and reect the
growing number of genetically dened movement disorders (Morrison 1999, 2001,2003). Additional useful sources of information include several public databases (e.g.
Online Mendelian Inheritance in Man at http://www.ncbi.nlm.nih.gov/entrez/
query.fcgi? dbOMIM or the Movement Disorder Society at http://www.
movementdisorders.org).
Linking dierent forms of classication: Each of the dierent modes of classi-
cation described above is useful in a given context of a clinical, pathological, or genetic
study. Each, however, is limited by the fact that it focuses on certain features of a given
movement disorder. Thus, as outlined above, the integration of dierent classication
schemes would be desirable. Several attempts have been made to integrate dierent
categories and have, in part, resulted in practical approaches of combined
classications. For example, as a rule of thumb, early-onset dystonia frequently starts
in a limb, often generalizes, and tends to have a (mono)genic background. Conversely,late-onset dystonia often starts in the neck or face, remains focal, and appears spor-
adic in the majority of cases. A similar correlation between clinical and genetic fea-
tures has been observed in the dominantly inherited SCAs. The original Harding
classication, which distinguishes autosomal dominant cerebellar ataxias (ADCA)
I^III (Harding 1983), is based on clinical grounds: ADCAI is characterized by
progressive ataxia, a cerebellar syndrome, pyramidal and extrapyramidal features,
and neuropathy; ADCAII by visual loss due to retinal degeneration; and ADCAIII
by pure cerebellar ataxia. The identication of genetic forms of SCAs has linked sev-
eral genotypes to certain phenotypes: SCA7 is identical to ADCAII, whereas both
ADCAI and ADCAIII can be caused by a variety of genetically dened SCAs (for
review see Albin 2003; Schls et al 2004).
Taken together, several modes and levels of classication are important and ideally
should be linked at the molecular and the phenotypic levels, including preclinical changes,
postmortem ndings, and results of modern neuroimaging.
WHAT MOVEMENT DISORDER IS THIS? REASONS
FOR CLASSIFICATION
An accurate description of the phenomenology of a movement disorder is the first
step when trying to diagnose and classify a certain condition. Importantly, however,
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one will correctly diagnose a given movement disorder only when one knows of the
disorder and considers it when evaluating the patient.
Clinical considerations: It would go beyond the scope of this article to review the
phenomenology of movement disorders. It should, however, be noted that movement
disorders can be further subclassied according to specic clinical ndings. For
example, tremor may occur as rest tremor (Parkinson disease), as action or postural
tremor (essential tremor), as dystonic tremor (accompanying dystonia), or as
intention tremor (cerebellar syndrome). Important diagnostic and classication hints
can also be derived from the disease course: a sudden onset of a movement disorder
is compatible with a vascular aetiology or an acute dystonic reaction. Conversely,
a slow onset is characteristic of neurodegenerative disorders such as Parkinson orHuntington diseases. The latter conditions are also characterized by a progressive
course, whereas other disorders, such as tardive dyskinesias, may fully remit
after discontinuation of the inducing drug. Most movement disorders can be
triggered or exacerbated by nonspecic factors, such as stress, fatigue, action or
certain postures. However, more specic triggers may point towards the correct diag-
nosis associated with the involuntary movements: intake of neuroleptics may cause an
acute dystonic reaction, tardive dyskinesias, parkinsonism or akathisia. Moreover,
alcohol, caeine, sudden or prolonged movements and exercise may each
precipitate paroxysmal dystonias/dyskinesias. Response to treatment can aid in
the conrmation of a diagnosis or in the classication of a movement disorder. A
response to alcohol is almost pathognomonic of essential tremor and
myoclonus-dystonia, and improvement with levodopa supports a diagnosis of PD
or dopa-responsive dystonia.
Genetic considerations: The role of genetic factors, and particularly of monogenic
forms, is variable among movement disorders. Nearly all cases of Huntington disease
and a considerable number of patients with restless legs syndrome will have an under-
lying monogenic cause. In PD and the dystonias, however, such an aetiology has not
been demonstrated for the majority. Thus, as described above, additional information
beyond genetics needs to be incorporated into any diagnostic or classication scheme.
For example, an early age of onset of parkinsonism points towards a monogenic form
with mutations in one of the three genes implicated in early-onset parkinsonism
(Parkin at PARK2, PINK1 at PARK6, and DJ-1 at PARK7). In addition to an
early age of onset, several other lines of evidence may indicate a genetic aetiology
of a movement disorder, including a positive family history, a specic clinical picture(for example, dystonia with diurnal variation and worsening after exercise suggests
dopa-responsive dystonia), and a specic ethnic background (for example, SCA3
is most frequent in patients of Portuguese background; DYT1 dystonia is more
common among Ashkenazi Jews).
It has to be stressed, however, that a genetic aetiology should be suspected also in
patients with a negative family history. Nonpaternity, adoption, variable expressivity,
small family size, reduced penetrance, anticipation, and de novo mutations may all
account for a pseudo-negative family history in the presence of a genetic disorder.
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Reasons for classication: Establishment of the correct diagnosis is among the most
important reasons for applying classication schemes. Other reasons for categorization
include prediction of clinical outcome and/or choice of specic treatment options,
and improvement of genetic counselling in hereditary conditions. In a broader sense,
classications are also used to dene the phenotypic and genotypic spectrum of a given
movement disorder and to understand, compare and contrast biological mechanisms.
In the following two sections, the dystonias will be used to illustrate the clinical and
genetic heterogeneity and evolving classications of movement disorders (Table 2).
CLASSIFICATIONS OF DYSTONIA: AN EXAMPLE
The most widely used mode of classification of dystonia is based on clinical grounds andtakes into account age of onset and distribution of symptoms (focal, multifocal,
segmental, hemidystonia, generalized). The simplest aetiological classification of
dystoniadistinguishesprimaryandsecondaryforms.Intheprimaryform,dystonia(with
the exception of tremor) is the only symptom of the disease, and the cause is either
unknown or genetic. In the secondary form, dystonia is usually one of several clinical
features and the cause is identifiable (e.g. lesion, drugs/toxins, metabolic disorders).
As previously mentioned, uncertainties remain about the categorization of the
dystonia-plus group; this set of dystonias is considered a special subcategory associated
with, but notsecondary to,other types of movement disorders (Kleinand Ozelius 2002).
The concept of classication according to aetiology was applied by Fahn and Eldridge
in their paper on classication of dystonia in 1976 (Fahn and Eldridge 1976) and has
undergone various modications since that time. The initial classication distinguished
between (I) primary dystonia (with and without hereditary pattern), (II) secondary
dystonia (with other hereditary neurological syndromes or due to known environmental
cause) and (III) psychological forms of dystonia (Fahn and Eldridge 1976). Twelve years
later, Fahn proposed dierentiating dystonias into (I) idiopathic (sporadic or familial)
and (II) symptomatic (Fahn 1988). More recently, Fahn and colleagues revised this
classication and suggested the following four subgroups: (I) primary dystonia, (II)
dystonia-plus (i.e. dystonia with parkinsonism, dystonia with myoclonic jerks), (III)
secondary, and (IV) heredodegenerative. These four types have to be further
dierentiated from other dyskinesia syndromes and pseudodystonia (Fahn et al 1998).
In 2004, Bressman further rened the aetiological classication of the dystonias and
proposed the following categorization: (I) primary dystonia (autosomal dominant or
other genetic causes); (II) secondary dystonia (inherited including dystonia-plus and
degenerative, complex/unknown, and acquired) (Bressman 2004).The following section will focus on the example of the primary dystonias and
dystonia-plus syndromes. Other dystonias, including metabolic forms, have been
reviewed elsewhere (Calne and Lang 1988; Klein et al 2000a) and is the topic of
another article in this issue.
In the past decade, monogenic defects have been found to underlie many forms of
primary dystonia and dystonia-plus syndromes. As has been discussed previously,
these monogenic forms of dystonia have recently been classied according to the
genes or gene loci involved. However, the list of DYTs cannot be considered a classi-
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cation in the true sense of the word. Rather, it represents a number of clinically and
genetically heterogeneous disorders with dystonia as one, if not the only, feature. This
scheme lists the dystonias in chronological order based on their rst appearance in the
literature (Table 3). Although some of these forms can be recognized clinically by a
characteristic phenotype, considerable phenotypic overlap exists between several
of the genetically dened forms. In this review, the dystonias are meant to serveas an example to illustrate this trend towards genetic classications. Similar lists
of monogenic forms exist for the parkinsonian syndromes, the dominantly inherited
SCAs, and many other movement disorders.
MONOGENIC FORMS OF DYSTONIA: DYT1^15
Currently, at least 15 different types of dystonia can be distinguished genetically,
which are designated DYT1-15 (Table 3). Six of these 15 dystonias are primary forms
Table 2 Example of evolving classications based on etiology: dystonias
Fahn and Eldrige (1976)
I. PrimaryA. With hereditary patternB. Without hereditary pattern
II. SecondaryA. Associated with other hereditary neurological syndromesB. Due to known environmental cause
III. Psychological
Fahn (1988)I. Idiopathic
A. Sporadic
B. FamilialII. Symptomatic
Fahn et al (1998)I. Primary
A. FamilialB. Sporadic
II. Dystonia-plus syndromesIII. SecondaryIV. Heredodegenerative diseases
Bressman (2004)I. Primary
A. Autosomal dominantB. Other genetic causes
II. SecondaryA. Inherited
i. Dystonia-plus (nondegenerative)ii. Degenerative
B. Complex/unknownC. Acquired
OMIM databaseGenetic classication DYT1-15 (see Table 3)
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Table3
Exampleofage
neticclassication:dystonias
Designation
Dystoniatype
Inheritance
Genelocus
Gene
OMIMno.
DYT1
Early-onsetgeneralizedtorsiondystonia(TD)
Au
tosomaldominant9q
GAG
deletioninDYT1
128100
DYT2
Autosomalr
ecessiveTD
Au
tosomalrecessive
Unknown
Unknown
224500
DYT3
X-l
inkeddys
toniaparkinsonism;lubag
X-chromosomal
rec
essive
Xq
Disease-specicchange
3inD
YT3
314250
DYT4
Non-D
YT1TD;whisperingdysphonia
Au
tosomaldominantUnknown
Unknown
128101
DYT5
Dopa-respon
sivedystonia;Segawasyndrome
Au
tosomaldominant14q
GTP-cyclohydrolase(GCH1)128230
Au
tosomalrecessive
11p
Tyrosinehydroxylase(TH)
DYT6
Adolescent-o
nsetTD
ofmixedtype
Au
tosomaldominant8p
Unknown
602629
DYT7
Adult-onsetfocalTD
Au
tosomaldominant18p
Unknown
602124
DYT8
Paroxysmalnonkinesigenicdyskinesia
Au
tosomaldominant2q
Myo
brillogenesisregulator
(MR-1)
118800
DYT9
Paroxysmal
choreoathetosis
with
episodic
ataxiaandspasticity
Au
tosomaldominant1p
Unknown
601042
DYT10
Paroxysmalkinesigenicchoreoathetosis
Au
tosomaldominant16p-q
Unknown
128200
DYT11
Myoclonus-d
ystonia
Au
tosomaldominant7q
Epsilo
n-sarcoglycan(SGCE)
159900
DYT12
Rapid-onset
dystonia-parkinsonism
Au
tosomaldominant19q
Na/K
ATPasealpha3
128235
DYT13
Multifocal/segmentaldystonia
Au
tosomaldominant1p
Unknown
607671
DYT14
Dopa-respon
sivedystonia
Au
tosomaldominant14q
Unknown
607195
DYT15
Myoclonus-d
ystonia
Au
tosomaldominant18p
Unknown
607488
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(DYT1, 2, 4, 6, 7 and 13). With the exception of three rare forms (DYT2, 3 and 5b), all
of them are inherited in an autosomal dominant fashion. Genes have been identified
for six (DYT1, 3, 5, 8, 11 and 12), while the chromosomal location is known for
another seven forms (DYT6, 7, 9, 10, 13, 14 and 15).
DYT1 dystonia (primary torsion dystonia): DYT1 dystonia usually begins in child-
hood, starts in a limb and tends to generalize to other body parts as the disease
progresses (Bressman et al 2000). The mode of inheritance is autosomal dominant
with reduced penetrance of about 30^40%, including both mild and severe cases.
DYT1 dystonia is caused by a GAG deletion in the DYT1 gene (Ozelius et al 1997).
This deletion results in the loss of one of a pair of glutamic acid residues in the
C-terminus of the protein torsinA that shares homology with the AAA superfamily
of ATPases (Neuwald et al 1999). AAA proteins are associated with a number of
functions, including protein folding and degradation, cytoskeletal dynamics,
membrane tracking, vesicle fusion and response to stress (Breakeeld et al 2001).
DYT3 dystonia (X-linked dystonia-parkinsonism; lubag): DYT3 dystonia is clini-
cally characterized by dystonia-parkinsonism and occurs almost exclusively in males
from the Island of Panay in the Philippines (Lee et al 1976). This disorder is often
referred to as lubag which means twist in the local dialect. Dystonic symptoms
usually start in adulthood as focal dystonia. Symptoms progress and generalize, with
parkinsonism being a frequent concurrent feature (Mller et al 1998). In contrast
to other forms of dystonia that lack obvious pathological changes, postmortem analy-
sis revealed neuronal loss and astrocytosis in the caudate nucleus and lateral putamen
(Waters et al 1993). The mode of inheritance is X-linked recessive with completepenetrance by the end of the 5th decade. Specic sequence changes in a multiple
transcript system DYT3 are associated with X-linked dystonia-parkinsonism (Nolte
et al 2003). The pathogenic role and functional consequences of these sequence
changes remain elusive.
DYT5 dystonia (dopa-responsive dystonia; Segawa syndrome): Dopa-responsive
dystonia (DRD) is characterized by childhood onset of dystonia, diurnal uctuation
of symptoms, and a dramatic response to levodopa therapy. Later in the course
of the disease, parkinsonian features may occur (Segawa et al 1976). While the rare
autosomal recessive form of DRD (DYT5b) is associated with mutations in the tyro-
sine hydroxylase (TH) gene, the more frequent dominantly inherited DRD is often
caused by mutations in the GTP cyclohydrolase I (GCHI) gene (DYT5a). There
is haploinsuciency of GCHI activity, thereby leading to dopamine depletion andexplaining the remarkable therapeutic eect of L-dopa substitution (Blau et al 2001).
DYT8 dystonia (paroxysmal nonkinesigenic dyskinesia): Paroxysmal nonkine-
sigenic dyskinesia (PNKD) is a paroxysmal form of dystonia that has also been
referred to as dyskinesia with dystonia present (Fahn 1998). Symptoms normally
begin shortly after birth but may also manifest in childhood or adolescence. Attacks
are precipitated by emotional stress, fatigue, on intake of chocolate or alcohol,
and frequently start with an aura, followed by unilateral or bilateral dystonic or
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choreatic dyskinesias that last between two minutes and four hours (Demirkiran and
Jankovic 1995; Mount and Reback 1940). Very recently, mutations in the
myobrillogenesis regulator 1 (MR-1) gene have been identied as causing PNKD
in 50 individuals from eight families (Lee et al 2004). Bioinformatic analysis has
revealed that the MR-1 gene is homologous to the hydroxyacylglutathione hydrolase
gene. The latter functions in a pathway that detoxies methylglyoxal, a compound
in coee and alcoholic beverages, suggesting a mechanism whereby alcohol, coee
and stress may provoke attacks in PNKD (Lee et al 2004).
DYT11 dystonia (myoclonus-dystonia): In myoclonus-dystonia (M-D), a predomi-
nantly myoclonic syndrome is combined with dystonic features. Rarely, dystonia may
be the only manifestation of the disorder. The symptoms are usually highly responsive
to alcohol, and psychiatric problems are a common nding (Klein 2003). Age of onset
is usually in the rst or second decade of life. The inheritance pattern is autosomal
dominant with variable expressivity and incomplete penetrance (Klein 2003;
Mahloudji and Pikielny 1967) due to maternal imprinting of the epsilon-sarcoglycan
(SGCE) gene (Mller et al 2002). While there is evidence for genetic heterogeneity
in M-D (Schle et al 2004), mutations in the SGCEgene are the only currently ident-
ied cause of M-D (Zimprich et al 2001). The exact function of the
epsilon-sarcoglycan protein is unknown.
DYT12dystonia(rapid-onsetdystonia-parkinsonism): Rapid-onset dystonia-park-
insonism (RDP) is characterized by sudden onset of orofacial dystonia, dysarthria,
dysphagia, and involuntary dystonic spasms, predominantly of the upper limbs, along
with signs of parkinsonism, such as bradykinesia, rigidity and postural instability.Symptoms usually manifest over hours to weeks and may be followed by moderate
or no progression. Onset of symptoms is in adolescence or young adulthood, and
mode of inheritance is autosomal dominant with reduced penetrance (Brashear et al
1997; Dobyns et al 1993). Recently, six dierent mutations in the Na/K-ATPase
alpha 3 gene have been demonstrated (de Carvalho Aguiar et al 2004).
As is evident from these brief descriptions of monogenic forms of dystonia with known
genetic defects, the DYT classification comprises primary and dystonia-plus
syndromes; the mode of inheritance is autosomal dominant or recessive or X-linked;
the majority are nondegenerative, with the exception of DYT3 dystonia; and the pro-
teins involved in these disorders appear to have very different functions. Despite this
heterogeneity, correct assessment and classification of the clinical and genetic features
of each of these dystonias will, in most cases, lead to the correct diagnosis.
CONCLUSIONS
1. Current classications have inherent shortcomings owing to the complex nature
of movement disorders and the lack of diagnostic tests for the majority. Modern
classication schemes are based on clinical, pathological and genetic/molecular
criteria and attempt to integrate all three levels.
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2. Genetic classications are now widely used; however, expert clinical diagnosis
remains an important step in correct diagnosis and classication of movement
disorder.
3. It may not be possible to develop the ultimate classication of movement
disorders. For dierent purposes, dierent levels of lumping and splitting may
be useful for the clinician, pathologist or geneticist/molecular biologist.
Furthermore, single cases may escape any form of classication.
4. More research needs to be done by both clinicians and basic scientists to rene and
redene classication schemes of movement disorders.
ACKNOWLEDGEMENTS
I thank Wendy Galpern, MD PhD and Katja Hedrich, PhD for helpful suggestions
and critical reading of the manuscript. I am grateful to Sylwia Dankert for assistance
in preparing the manuscript. C.K. has been a Heisenberg Fellow of the Deutsche
Forschungsgemeinschaft.
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