J. Inherit. Metab. Dis.

28 (2005) 425^439
# SSIEM and Springer. Printed in the Netherlands

Movement disorders: Classi¢cations

C. Klein
Department of Neurology, University of Lˇbeck, Lˇbeck, Germany
Correspondence: Department of Neurology, University of Lˇbeck, Ratzeburger Allee
160, 23538 Lˇbeck, Germany. E-mail: klein__ch@neuro.mu-luebeck.de

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 the current and evolving classification 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, and
different 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.

425
426 Klein

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 classi¢cation
systems that have been applied to or developed for these di¡erent disorders. Instead,
selected examples will serve to illustrate important concepts of classi¢cation, and a more
detailed description of the dystonias will highlight evolving classi¢cation schemes.
A necessary prelude to this discussion is to consider the plethora of di¡erent classi-
¢cation schemes that have attempted to categorize, classify, group, lump and split
various forms of movement disorders. Not surprisingly, there are inconsistencies
between di¡erent classi¢cations, as a given categorization is not always universally
applicable, and advances in various areas of research sometimes call previous
classi¢cations into question. For example, the identi¢cation 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 identi¢ed, 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 di¡erent 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 di¡erent
denotations when used to discuss di¡erent 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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Movement disorders: classi¢cations 427

to the genetic form of dystonia that clinically manifests as dystonia and possibly
tremor. In e¡orts 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 classi¢cation of the dystonias. The more recent
genetic ‘classi¢cation’ 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 classi¢cation 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 mutational
analysis 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 classi¢cations 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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428 Klein

gene may be unaffected or may present with mild writer’s 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 classi¢cational 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 typical
a-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 classi¢cation 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, di¡use Lewy bodies in the second,
neuro¢brillary tangles without Lewy bodies in the third, and neither neuro¢brillary
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 paralleled
by 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’ de¢nition 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 ‘a¡ected’.

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 shaped
current 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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Movement disorders: classi¢cations 429

Table 1 Di¡erent modes of classi¢cation of movement disorders

Modes of classi¢cation Examples

By aetiology Primary (idiopathic) vs secondary

(symptomatic)
Clinical criteria
Age of onset Early-onset vs late-onset parkinsonism
Distribution of symptoms Focal vs generalized dystonia
Speci¢c clinical phenomenology Resting vs action tremor
Disease onset Rapid vs slow
Disease course Progressive vs stable
Response to treatment Levodopa-responsive vs non-responsive
parkinsonism
Postmortem criteria
Presence of speci¢c hallmarks Lewy bodies in Parkinson disease
Staining with speci¢c antibodies Synucleinopathies, tauopathies, etc.
Genetic/molecular criteria
Mode of inheritance Autosomal dominant vs recessive
Linkage to a chromosomal locus PARK2-linked parkinsonism
Identi¢cation of a mutation Parkin-associated parkinsonism
Defect in molecular mechanism Polyglutamine diseases
Defect in protein function Channelopathies

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 Huntington’s Disease
Collaborative Research Group 1993) and the identification of genes for disorders
such as Alzheimer (Kang et al 1987) and Parkinson diseases (for review see Hardy
et al 2003; Vila and Przedborski 2004).
Clinical criteria: Classi¢cation 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. Speci¢c hallmarks are required to establish
a diagnosis of certain disorders, such as Lewy bodies in PD (Jellinger 2001). Staining
with speci¢c antibodies has led to a further level of pathological di¡erentiation, as illus-
trated by the synucleinopathies or tauopathies (Neumann 2004).
Genetic/molecular criteria: A genetic classi¢cation is based on clinical genetic
pedigree information on mode of inheritance and molecular genetic data, such as
linkage to a known gene locus or identi¢cation of a speci¢c 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.

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430 Klein

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 unidenti¢ed 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 re£ect the
growing number of genetically de¢ned 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? db ¼ OMIM or the Movement Disorder Society at http://www.
movementdisorders.org).
Linking di¡erent forms of classi¢cation: Each of the di¡erent 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 di¡erent classi¢cation
schemes would be desirable. Several attempts have been made to integrate di¡erent
categories and have, in part, resulted in practical approaches of combined
classi¢cations. 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
classi¢cation, 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 identi¢cation 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 de¢ned SCAs (for
review see Albin 2003; Sch˛ls et al 2004).
Taken together, several modes and levels of classi¢cation 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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Movement disorders: classi¢cations 431

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 subclassi¢ed according to speci¢c 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 classi¢cation 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 or
Huntington 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 nonspeci¢c factors, such as stress, fatigue, action or
certain postures. However, more speci¢c 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, ca¡eine, sudden or prolonged movements and exercise may each
precipitate paroxysmal dystonias/dyskinesias. Response to treatment can aid in
the con¢rmation of a diagnosis or in the classi¢cation 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 classi¢cation 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 speci¢c clinical picture
(for example, dystonia with diurnal variation and worsening after exercise suggests
dopa-responsive dystonia), and a speci¢c 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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432 Klein

Reasons for classi¢cation: Establishment of the correct diagnosis is among the most
important reasons for applying classi¢cation schemes. Other reasons for categorization
include prediction of clinical outcome and/or choice of speci¢c treatment options,
and improvement of genetic counselling in hereditary conditions. In a broader sense,
classi¢cations are also used to de¢ne 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 classi¢cations of movement disorders (Table 2).

CLASSIFICATIONS OF DYSTONIA: AN EXAMPLE

The most widely used mode of classification of dystonia is based on clinical grounds and
takes into account age of onset and distribution of symptoms (focal, multifocal,
segmental, hemidystonia, generalized). The simplest aetiological classification of
dystonia distinguishes primary and secondary forms. In the primaryform, 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 not secondary to, other types of movement disorders (Klein and Ozelius 2002).
The concept of classi¢cation according to aetiology was applied by Fahn and Eldridge
in their paper on classi¢cation of dystonia in 1976 (Fahn and Eldridge 1976) and has
undergone various modi¢cations since that time. The initial classi¢cation 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 di¡erentiating dystonias into (I) idiopathic (sporadic or familial)
and (II) symptomatic (Fahn 1988). More recently, Fahn and colleagues revised this
classi¢cation 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
di¡erentiated from other dyskinesia syndromes and pseudodystonia (Fahn et al 1998).
In 2004, Bressman further re¢ned the aetiological classi¢cation 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 ‘classi¢ed’ according to the
genes or gene loci involved. However, the list of ‘DYTs’ cannot be considered a classi-

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Movement disorders: classi¢cations 433

Table 2 Example of evolving classi¢cations based on etiology: dystonias

Fahn and Eldrige (1976)
I. Primary
A. With hereditary pattern
B. Without hereditary pattern
II. Secondary
A. Associated with other hereditary neurological syndromes
B. Due to known environmental cause
III. Psychological
Fahn (1988)
I. Idiopathic
A. Sporadic
B. Familial
II. Symptomatic
Fahn et al (1998)
I. Primary
A. Familial
B. Sporadic
II. Dystonia-plus syndromes
III. Secondary
IV. Heredodegenerative diseases
Bressman (2004)
I. Primary
A. Autosomal dominant
B. Other genetic causes
II. Secondary
A. Inherited
i. Dystonia-plus (nondegenerative)
ii. Degenerative
B. Complex/unknown
C. Acquired
OMIM database
Genetic ‘classi¢cation’ DYT1-15 (see Table 3)

¢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 de¢ned forms. In this review, the dystonias are meant to serve
as an example to illustrate this trend towards ‘genetic classi¢cations’. 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

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 434

Table 3 Example of a genetic ‘classi¢cation’: dystonias

Designation Dystonia type Inheritance Gene locus Gene OMIM no.

DYT1 Early-onset generalized torsion dystonia (TD) Autosomal dominant 9q GAG deletion in DYT1 128100
DYT2 Autosomal recessive TD Autosomal recessiveUnknown Unknown 224500

J. Inherit. Metab. Dis. 28 (2005)

DYT3 X-linked dystonia parkinsonism; ‘lubag’ X-chromosomal Xq Disease-speci¢c change 314250
recessive 3 in DYT3
DYT4 ‘Non-DYT1’ TD; whispering dysphonia Autosomal dominant Unknown Unknown 128101
DYT5 Dopa-responsive dystonia; Segawa syndrome Autosomal dominant 14q GTP-cyclohydrolase (GCH1) 128230
Autosomal recessive11p Tyrosine hydroxylase (TH)
DYT6 Adolescent-onset TD of mixed type Autosomal dominant 8p Unknown 602629
DYT7 Adult-onset focal TD Autosomal dominant 18p Unknown 602124
DYT8 Paroxysmal nonkinesigenic dyskinesia Autosomal dominant 2q Myo¢brillogenesis regulator 118800
(MR-1)
DYT9 Paroxysmal choreoathetosis with episodic Autosomal dominant 1p Unknown 601042
ataxia and spasticity
DYT10 Paroxysmal kinesigenic choreoathetosis Autosomal dominant 16p-q Unknown 128200
DYT11 Myoclonus-dystonia Autosomal dominant 7q Epsilon-sarcoglycan (SGCE) 159900
DYT12 Rapid-onset dystonia-parkinsonism Autosomal dominant 19q Na/K ATPase alpha 3 128235
DYT13 Multifocal/segmental dystonia Autosomal dominant 1p Unknown 607671
DYT14 Dopa-responsive dystonia Autosomal dominant 14q Unknown 607195
DYT15 Myoclonus-dystonia Autosomal dominant 18p Unknown 607488
Klein
Movement disorders: classi¢cations 435

(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 AAAþ superfamily
of ATPases (Neuwald et al 1999). AAAþ proteins are associated with a number of
functions, including protein folding and degradation, cytoskeletal dynamics,
membrane tra⁄cking, vesicle fusion and response to stress (Breake¢eld 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 (Mˇller 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 complete
penetrance by the end of the 5th decade. Speci¢c 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 haploinsu⁄ciency of GCHI activity, thereby leading to dopamine depletion and
explaining the remarkable therapeutic e¡ect 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

J. Inherit. Metab. Dis. 28 (2005)

436 Klein

choreatic dyskinesias that last between two minutes and four hours (Demirkiran and
Jankovic 1995; Mount and Reback 1940). Very recently, mutations in the
myo¢brillogenesis regulator 1 (MR-1) gene have been identi¢ed 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 detoxi¢es methylglyoxal, a compound
in co¡ee and alcoholic beverages, suggesting a mechanism whereby alcohol, co¡ee
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 (Mˇller et al 2002). While there is evidence for genetic heterogeneity
in M-D (Schˇle et al 2004), mutations in the SGCE gene are the only currently ident-
i¢ed cause of M-D (Zimprich et al 2001). The exact function of the
epsilon-sarcoglycan protein is unknown.

DYT12 dystonia (rapid-onset dystonia-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 di¡erent mutations in the Naþ/Kþ-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 classi¢cations have inherent shortcomings owing to the complex nature

of movement disorders and the lack of diagnostic tests for the majority. Modern
classi¢cation schemes are based on clinical, pathological and genetic/molecular
criteria and attempt to integrate all three levels.

J. Inherit. Metab. Dis. 28 (2005)

Movement disorders: classi¢cations 437

2. Genetic ‘classi¢cations’ are now widely used; however, expert clinical diagnosis
remains an important step in correct diagnosis and classi¢cation of movement
disorder.
3. It may not be possible to develop the ‘ultimate’ classi¢cation of movement
disorders. For di¡erent purposes, di¡erent levels of lumping and splitting may
be useful for the clinician, pathologist or geneticist/molecular biologist.
Furthermore, single cases may escape any form of classi¢cation.
4. More research needs to be done by both clinicians and basic scientists to re¢ne and
rede¢ne classi¢cation 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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