Movement disorders- Classi¢cations

8/14/2019 Movement disorders- Classications

1/15

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

# SSIEMand Springer. Printed in the Netherlands

425


2/15

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

426 Klein

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


3/15

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

Movement disorders: classications 427



4/15

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-

428 Klein



5/15

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




6/15

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,

430 Klein



7/15

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.




8/15

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-

432 Klein



9/15

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)




10/15

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

434 Klein



11/15

(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




12/15

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.

436 Klein



13/15

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.

REFERENCES

Albin RL (2003) Dominant ataxias and Friedreich ataxia: an update. Curr Opin Neurol16: 507^514.

Blau N, Bonafe L, Thony B (2001) Tetrahydrobiopterin deciencies withouthyperphenylalaninemia: diagnosis and genetics of dopa-responsive dystonia and sepiapterinreductase deciency. Mol Genet Metab 74: 172^185.

Brashear A, DeLeon D, Bressman SB, Thyagarajan D, Farlow MR, Dobyns WB (1997)Rapid-onset dystonia-parkinsonism in a second family. Neurology 48: 1066^1069.Breakeeld XO, Kamm C, Hanson PI (2001) TorsinA: movement at many levels. Neuron

31: 9^12.Bressman SB (2004) Dystonia genotypes, phenotypes, and classication. Adv Neurol94: 101^107.Bressman SB, Sabatti C, Raymond D, et al (2000) The DYT1 phenotype and guidelines for

diagnostic testing. Neurology 54: 1746^1752.Calne DB, Lang AE (1988) Secondary dystonia. Adv Neurol 50: 9^33.de Carvalho Aguiar P, Sweadner KJ, Penniston JT, et al (2004) Mutations in the

Na/K-ATPase alpha3 gene ATP1A3 are associated with rapid-onset dystoniaparkinsonism. Neuron 43: 169^175.

Demirkiran M, Jankovic J (1995) Paroxysmal dyskinesias: clinical features and classication.Ann Neurol 38: 571^579.

Dobyns WB, Ozelius LJ, Kramer PL, et al (1993) Rapid-onset dystonia-parkinsonism.Neurology 43: 2596^2602.

Fahn S (1988) Concept and classication of dystonia. Adv Neurol 50: 1^8.Fahn (2003) Description of Parkinsons disease as a clinical syndrome. Ann NY Acad Sci 991 :1^14.

Fahn S, Eldridge R (1976) Denition of dystonia and classication of the dystonic states. AdvNeurol 14: 1^5.

Fahn S, Bressman SB, Marsden CD (1998) Classication of dystonia. Adv Neurol 78: 1^10.Gasser T, Bressman S, Drr A, Higgins J, Klockgether T, Myers RH (2003) State of the art

review: molecular diagnosis of inherited movement disorders. Movement Disorders Societytask force on molecular diagnosis. Mov Disord 18: 3^18.

Hagenah JM, Zhlke C, Hellenbroich Y, Heide W, Klein C (2004) Focal dystonia as a pre-senting sign of spinocerebellar ataxia 17. Mov Disord 19: 217^220.




14/15

Harding AE (1983) Classication of the hereditary ataxias and paraplegias. Lancet 1:1151^1155.

Hardy J, Gwinn-Hardy K (1998) Genetic classication of primary neurodegenerative disease.Science 282 : 1075^1079.

Hardy J, Cookson MR, Singleton A (2003) Genes and parkinsonism. LancetNeurol2: 221^228.Hedrich K, Djarmati A, Schafer N, et al (2004) DJ-1 (PARK7) mutations are less frequent than

Parkin (PARK2) mutations in early-onset Parkinson disease. Neurology 63: 389^394.Hicks AA, Petursson H, Jonsson T, et al (2002) A susceptibility gene for late-onset idiopathic

Parkinsons disease. Ann Neurol 52: 549^555.Hilker R, Klein C, Ghaemi M, et al (2001) Positron emission tomographic analysis of the

nigrostriatal dopaminergic system in familial parkinsonism associated with mutations inthe parkin gene. Ann Neurol 49: 367^376.

Hoehn MM, Yahr MD (1967) Parkinsonism: onset, progression and mortality. Neurology 7:427^442.

Hsiao K, Baker HF, Crow TJ, et al (1989) Linkage of a prion protein missense variant toGerstmann^Strussler syndrome. Nature 338 : 342^345.

Jellinger KA (2001) The pathology of Parkinsons disease. Adv Neurol 86: 55^72.Kabakci K, Hedrich K, Leung JC, et al (2004) Mutations in DYT1: extension of the phenotypic

and mutational spectrum. Neurology 62: 395^400.Kang J, Lemaire HG, Unterbeck A, et al (1987) The precursor of Alzheimers disease amyloid

A4 protein resembles a cell-surface receptor. Nature 325 : 733^736.Klein C (2003) Myoclonus and myoclonus-dystonias. In: Pulst SM, ed. Genetics of Movement

Disorders. New York: Academic Press, 451^471.Klein C, Ozelius LJ (2002) Dystonia: clinical features, genetics, and treatment. Curr Opin

Neurol 15: 491^497.Klein C, Kann M, Kis B, et al (2000a) Genetik der Dystonien. Nervenarzt 71: 431^441.Klein C, Pramstaller PP, Kis B, et al (2000b) Parkin deletions in a family with adult-onset,

tremor-dominant parkinsonism: expanding the phenotype. Ann Neurol 48: 65^71.Klein C, Hedrich K, Wellenbrock C, et al (2003) Frequency of parkin mutations in late-onset

Parkinsons disease. Ann Neurol 54: 415^416.Kock N, Kasten M, Schle B, et al (2004) Clinical and genetic features of myoclonus-dystonia in

3 cases: a video presentation. Mov Disord 19: 231^234.La Spada AR, Wilson EM, Lubahn DB, Harding AE, Fischbeck KH (1991) Androgen receptor

gene mutations in X-linked spinal and bulbar muscular atrophy. Nature 352 : 77^79.Lee HY, Xu Y, Huang Y, et al (2004) The gene for paroxysmal non-kinesigenic dyskinesia

encodes an enzyme in a stress response pathway. Hum Mol Genet 13: 3161^3170.Lee LV, Pascasio FM, Fuentes FD, Viterbo GH (1976) Torsion dystonia in Panay, Philippines.

Adv Neurol 14: 137^151.Litvan I, Bhatia KP, Burn DJ, et al (2003) Movement Disorders Society Scientic Issues

Committee report: SIC Task Force appraisal of clinical diagnostic criteria for Parkinsoniandisorders. Mov Disord 18: 467^486.

Mahloudji M, Pikielny RT (1967) Hereditary essential myoclonus. Brain 90: 669^674.Morrison PJ (1999) Adult and paediatric movement disorders. Eur J Paediatr Neurol3: 39^41.

Morrison PJ (2001) Paediatric and adult movement disorders (update). Eur J Paediatr Neurol5: 265^268.Morrison PJ (2003) Paediatric and adult movement disorders. Eur J Paediatr Neurol 7:

235^237.Mount LA, Reback S (1940) Familial paroxysmal choreoathetosis: preliminary report on a

hitherto undescribed clinical syndrome. Arch Neurol Psychiatry 44: 841^847.Mller U, Steinberger D, Nemeth AH (1998) Clinical and molecular genetics of primary

dystonias. Neurogenetics 1: 165^177.M ller B, Hedrich K, Kock N, et al (2002) Evidence that paternal expression of the

epsilon-sarcoglycan gene accounts for reduced penetrance in myoclonus-dystonia. Am JHum Genet 71: 1303^1311.

438 Klein



15/15

Najim al-Din AS, Wriekat A, Mubaidin A, Dasouki M, Hiari M (1994) Pallido-pyramidaldegeneration, supranuclear upgaze paresis and dementia: Kufor Rakeb syndrome. ActaNeurol Scand 89: 347^352.

Neumann M, Muller V, Gorner K, Kretzschmar HA, Haass C, Kahle PJ (2004) Pathologicalproperties of the Parkinsons disease-associated protein DJ-1 in alpha-synucleinopathiesand tauopathies: relevance for multiple system atrophy and Picks disease. Acta Neuropathol(Berl) 107 : 489^496.

Neuwald AF, Aravind L, Spouge JL, Koonin EV (1999) AAA : a class of chaperone-likeATPases associated with the assembly, operation, and disassembly of protein complexes.Genome Res 9: 27^43.

Nolte D, Niemann S, Mller U (2003) Specic sequence changes in multiple transcript systemDYT3 are associated with X-linked dystonia parkinsonism. Proc Natl Acad Sci USA 100 :10347^10352.

Owen F, Poulter M, Lofthouse R, et al (1989) Insertion in prion protein gene in familialCreutzfeldt^Jakob disease. Lancet 1: 51^52.

Ozelius LJ, Hewett JW, Page CE, et al (1997) The early-onset torsion dystonia gene (DYT1)encodes an ATP-binding protein. Nature Genetics 17: 40^48.

Pankratz N, Nichols WC, Uniacke SK, et al (2003) Signicant linkage of Parkinson disease tochromosome 2q36-37. Am J Hum Genet 72: 1053^1057.

Quinn N (1993) Parkinsonism and dystonia, pseudo-parkinsonism and pseudodystonia. AdvNeurol 60: 540^543.

Schls L, Bauer P, Schmidt T, Schulte T, Riess O (2004) Autosomal dominant cerebellarataxias: clinical features, genetics, and pathogenesis. Lancet Neurol 3: 291^304.

Sch le B, Kock N, Svetel M, et al (2004) Genetic heterogeneity in ten families withmyoclonus-dystonia. J Neurol Neurosurg Psychiatry 75: 1181^1185.

Segawa M, Hosaka A, Miyagawa F, Nomura Y, Imai H (1976) Hereditary progressive dystoniawith marked diurnal uctuation. Adv Neurol 14: 215^233.

Singleton AB, Farrer M, Johnson J, et al (2003) alpha-Synuclein locus triplication causesParkinsons disease. Science 302 : 841.

The Huntingtons Disease Collaborative Research Group (1993) A novel gene containing atrinucleotide repeat that is expanded and unstable on Huntingtons disease chromosomes.Cell 72: 971^983.

Valente EM, Salvi S, Ialongo T, et al (2004) PINK1 mutations are associated with sporadicearly-onset parkinsonism. Ann Neurol 56: 336^341.

Vila M, Przedborski S (2004) Genetic clues to the pathogenesis of Parkinsons disease. NatureMedicine 10 (supplement) : S58^62.

Walter U, Klein C, Hilker R, Benecke R, Pramstaller PP, Dressler D (2004) Brain parenchymasonography detects preclinical parkinsonism. Mov Disord 19: 1445^1449.

Waters CH, Faust PL, Powers J, et al (1993) Neuropathology of lubag (x-linked dystoniaparkinsonism). Mov Disord 8: 387^390.

Wszolek ZK, Pfeier RF, Tsuboi Y, et al (2004) Autosomal dominant parkinsonism associatedwith variable synuclein and tau pathology. Neurology 62: 1619^1622.

Zimprich A, Grabowski M, Asmus F, et al (2001) Mutations in the gene encoding

epsilon-sarcoglycan cause myoclonus-dystonia syndrome. Nature Genetics 29: 66^69.



Movement disorders- Classi¢cations

Documents

Transcript of Movement disorders- Classi¢cations