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Educacin Mdica Continua SAVAL
Curso modular de pediatra

Clnica Las Condes 2013
Dr. Felipe Castro

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Leckman J, King R, Cohen D.Tics and Tic disorders en Leckman J, Cohen D eds. Tourette Syndrome: Tics, Obsessions, Compulsions. New York.Wiley & Sons. 1999:23-42.

Tourettes Syndrome. Kenney C. Am Fam Physician.2008;77(5):651-658, 659-660
(un gruo musculur)
vurlos gruos musculures
sonldo
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Tics y sndrome de Tourette: Son psicognicos los tics? Cul es su fisiopatologa y qu opciones teraputicas existen?. Miranda M. Rev Med ClC. Vol 14 n4 Oct 2003

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Tourette Syndrome: Evolving Concepts. Jankovic J. Movement Disorders, Vol. 26,
No. 6, 2011
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Tourettes Syndrome. Kenney C. Am Fam Physician.2008;77(5):651-658, 659-660
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Woods, D.W., and Miltenberger, R.G. "Habit Reversal: A Review of Applications and Variations". Journal of Behavior Therapy and
Experimental Psychiatry1995 26: 123-131
Dr. Felipe Castro

Dr. Felipe Castro

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Dr. Felipe Castro

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Prlmurlus

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Chapter 7 MOTOR STEREOTYPIES 59
as thumb and hand sucking, nail biting, and foot tap-
ping.
49,50
The outcome of stereotypies in this group has
been controversial. Some investigators have suggested
that they increase by 3 years of age and decline after
age 4,
51
whereas others have suggested that the majority
of complex motor behaviors persist.
9,48
Common Stereotypies
Behaviors such as thumb sucking, nail/lip biting, hair
twirling, body rocking, self-biting, and head bang-
ing, sometimes called habits, are relatively common
in childhood and generally most regress.
5054
In some
children stereotypic behaviors evolve with thumb and
hand sucking in the younger child replaced by body
rocking and head banging, and later by nail biting,
finger tapping, and foot tapping.
55
It has been esti-
mated that about 20% of healthy children exhibit
stereotypies.
56
Investigation of stereotypies in col-
lege students has identified a variety of common
movements (touch face; play with hair, pens, or jew-
elry; shake leg, tap fingers, scratch head, etc.), but
most were not time-consuming or disruptive.
57
The
prevalence of body rocking has varied between 3%
and 25% depending on the identifying methodol-
ogy.
58
In the college population, since stereotypies
were often accompanied by general distress, anxiety,
obsessive-compulsive symptoms, and impulsive aggres-
sive traits, some investigators have suggested that com-
mon stereotypies may lie on a spectrum with other
neuropsychiatric disorders, especially obsessive-com-
pulsive phenomena.
25,26,60
Whether body rocking
should be considered as a separate entity, based on a
high frequency in first-degree relatives with similar
movements and without evidence of mental retarda-
tion or autism,
25,26
is controversial.
Head-Nodding Stereotypies
Rhythmic regular head movements (either a side-to-side,
no movement; an up-and-down, yes movement; or
a shoulder-to-shoulder movement) with a frequency of
1 to 2 per second, that can be stopped voluntarily, have
been reported in normal children as a form of stereo-
typy.
9,61
Up-gaze eye deviations or movements of the
hands or feet occasionally accompany the head shaking.
Several different etiologies may be involved, since many
of the children in the Hottinger-Blanc group had hypo-
tonia, delayed motor and language development, and
ataxia. In a study following eight children with typical
development and head nodding, three stopped entirely,
suggesting that outcome may differ in this category as
compared to children with complex motor stereotypies.
9

Pathophysiologic etiologies for head movements have
ranged from a congenital-brainstem-cerebellar abnor-
mality to perpetuation of a normal motor program.
The differential diagnosis in this group of patients
includes such entities as Sandifers syndrome, spasmus
nutans, bobble-head doll syndrome, congenital nystag-
mus, oculomotor apraxia, and jactatio capitis nocturna
(rhythmic movement disorder/nocturnal head banging).
The Bobble head doll syndrome is characterized by
stereotypic antero- posterior (rarely side to side) head
movements at a frequency of 2-3 Hz.
18,22
The move-
ments tend to increase with activity and excitement
and decrease with concentration.
18,22
This phenomenon
is usually associated with lesions of the third ventricle
but has been reported in association with aqueductal
stenosis, Dandy-Walker Syndrome,
117
and large supra-
sellar arachnoid cysts.
118
The precise pathophysiologi-
cal mechanism is unknown. Surgical treatment of the
underlying lesion typically results in complete resolu-
tion of the abnormal head movement.
Complex Hand and Arm Movement Stereotypies
Movements in this group include hand shaking, pos-
turing, flapping or waving, opening and closing of the
hands, finger writhing, arm flapping, and flexion and
extension of the wrists. Additional movement pat-
terns may occur in conjunction (e.g., body rocking, leg
TABLE 7-2 Classification of Stereotypies
Based on Etiology
I. Primary
Common type
Head nodding
Complex motor
II. Secondary (in the Presence of Other Pathology)
Autism: Infantile autism, Aspergers syndrome,
pervasive developmental disability, Rett syndrome
Mental retardation
Sensory deprivation: congenital blindness/deafness,
caging, constraints
Inborn errors of metabolism: Lesch-Nyhan
syndrome
Genetic: Neuroacanthocytosis
Drug-induced: psychostimulants, tardive dyskinesia
Infection: encephalitis
Tumor: bobble-headed doll syndrome
Trauma
Psychiatric: OCD, schizophrenia, catatonia, functional
ChuLer : MoLor SLereoLyles. SecLlon HyerklneLlc und HyoklneLlc MoveMenL dlsorders . Ln:
1)2#3#,4 5.&)*0#*& ., -"./0"))0. Slnger H. 1unkovlc. zoo
Dr. Felipe Castro
6
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Secundurlus
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1rusLornos sensorlules
Sindrome de ReLL
as thumb and hand sucking, nail biting, and foot tap-
ping.
49,50
The outcome of stereotypies in this group has
been controversial. Some investigators have suggested
that they increase by 3 years of age and decline after
age 4,
51
whereas others have suggested that the majority
of complex motor behaviors persist.
9,48
Common Stereotypies
Behaviors such as thumb sucking, nail/lip biting, hair
twirling, body rocking, self-biting, and head bang-
ing, sometimes called habits, are relatively common
in childhood and generally most regress.
5054
In some
children stereotypic behaviors evolve with thumb and
hand sucking in the younger child replaced by body
rocking and head banging, and later by nail biting,
finger tapping, and foot tapping.
55
It has been esti-
mated that about 20% of healthy children exhibit
stereotypies.
56
Investigation of stereotypies in col-
lege students has identified a variety of common
movements (touch face; play with hair, pens, or jew-
elry; shake leg, tap fingers, scratch head, etc.), but
most were not time-consuming or disruptive.
57
The
prevalence of body rocking has varied between 3%
and 25% depending on the identifying methodol-
ogy.
58
In the college population, since stereotypies
were often accompanied by general distress, anxiety,
obsessive-compulsive symptoms, and impulsive aggres-
sive traits, some investigators have suggested that com-
mon stereotypies may lie on a spectrum with other
neuropsychiatric disorders, especially obsessive-com-
pulsive phenomena.
25,26,60
Whether body rocking
should be considered as a separate entity, based on a
high frequency in first-degree relatives with similar
movements and without evidence of mental retarda-
tion or autism,
25,26
is controversial.
Head-Nodding Stereotypies
Rhythmic regular head movements (either a side-to-side,
no movement; an up-and-down, yes movement; or
a shoulder-to-shoulder movement) with a frequency of
1 to 2 per second, that can be stopped voluntarily, have
been reported in normal children as a form of stereo-
typy.
9,61
Up-gaze eye deviations or movements of the
hands or feet occasionally accompany the head shaking.
Several different etiologies may be involved, since many
of the children in the Hottinger-Blanc group had hypo-
tonia, delayed motor and language development, and
ataxia. In a study following eight children with typical
development and head nodding, three stopped entirely,
suggesting that outcome may differ in this category as
compared to children with complex motor stereotypies.
9

Pathophysiologic etiologies for head movements have
ranged from a congenital-brainstem-cerebellar abnor-
mality to perpetuation of a normal motor program.
The differential diagnosis in this group of patients
includes such entities as Sandifers syndrome, spasmus
nutans, bobble-head doll syndrome, congenital nystag-
mus, oculomotor apraxia, and jactatio capitis nocturna
(rhythmic movement disorder/nocturnal head banging).
The Bobble head doll syndrome is characterized by
stereotypic antero- posterior (rarely side to side) head
movements at a frequency of 2-3 Hz.
18,22
The move-
ments tend to increase with activity and excitement
and decrease with concentration.
18,22
This phenomenon
is usually associated with lesions of the third ventricle
but has been reported in association with aqueductal
stenosis, Dandy-Walker Syndrome,
117
and large supra-
sellar arachnoid cysts.
118
The precise pathophysiologi-
cal mechanism is unknown. Surgical treatment of the
underlying lesion typically results in complete resolu-
tion of the abnormal head movement.
Complex Hand and Arm Movement Stereotypies
Movements in this group include hand shaking, pos-
turing, flapping or waving, opening and closing of the
hands, finger writhing, arm flapping, and flexion and
extension of the wrists. Additional movement pat-
terns may occur in conjunction (e.g., body rocking, leg
TABLE 7-2 Classification of Stereotypies
Based on Etiology
I. Primary
Common type
Head nodding
Complex motor
II. Secondary (in the Presence of Other Pathology)
Autism: Infantile autism, Aspergers syndrome,
pervasive developmental disability, Rett syndrome
Mental retardation
Sensory deprivation: congenital blindness/deafness,
caging, constraints
Inborn errors of metabolism: Lesch-Nyhan
syndrome
Genetic: Neuroacanthocytosis
Drug-induced: psychostimulants, tardive dyskinesia
Infection: encephalitis
Tumor: bobble-headed doll syndrome
Trauma
Psychiatric: OCD, schizophrenia, catatonia, functional
Motor Stereotypies. En: Movement Disorders in Childhood. Singer H. Jankovic. 2010
LsLereoLllus:
Dr. Felipe Castro
,
LsLereoLllus
Sindrome de ReLL
LsLereoLllus
O
Motor Stereotypies
3. Compulsions are repetitive behaviors or men-
tal acts that are performed to prevent or reduce
distress or some dreaded event or situation, and
are driven by an obsessive thought or by intrinsic
rules that must be applied rigidly. The compul-
sion is either (a) unrealistically connected to dis-
tress reduction or contingency prevention or (b)
clearly excessive.
11
Compulsions are often asso-
ciated with obsessive thoughts that intrude into
consciousness and are typically experienced as
senseless or alien.
4. Paroxysmal dyskinesias are generally shorter in dura-
tion and usually occur as dystonic or choreoathe-
toid movements that are precipitated by voluntary
movement (paroxysmal kinesigenic dyskinesias),
exertion of exercise (paroxysmal exertional dyski-
nesia), or are less predictable, arising from normal
background activity (paroxysmal nonkinesigenic
dyskinesias) (see Chapter 8).
5. Masturbation, or self-stimulation of the genitalia, is
a normal part of human sexual behavior that occurs
in both males and females. In some infants and
young children such self-gratifying behavior can
manifest as patterned, coordinated, repetitive move-
ments, usually consisting of crossing and extending
of legs or repetitive pelvic movements that may be
classified as a stereotypy.
12,13
Observation of move-
ments on a video can often clarify the diagnosis
and eliminate the need for unnecessary diagnostic
tests.
14
The most challenging aspect of this form
of stereotypy is to help the parents understand the
benign and self-remitting nature of this behavior.
Pathophysiology
The underlying pathophysiologic mechanism for stereo-
typies is unknown, with hypotheses ranging from psy-
chologic concerns to neurobiologic abnormalities.
1522

TABLE 7-1 Factors Distinguishing Stereotypies from Tics
Tics Stereotypies
Age at onset 67 years <3 years
Pattern Variable, wax and wane Fixed, identical, patterned,
predictable
Movements Blink, grimace, twist, shrug Arms/hands (flap, wave), body
rock/head nod
Vocalizations Sniffing, throat clearing Moan, humming with movement
Rhythm Rapid, sudden, random Rhythmic
Duration Intermittent, brief, abrupt Intermittent, continuous,
prolonged
Premonitory urge Yes No
Precipitant Excitement, stress Excitement, stress, also when
engrossed
Suppression Brief, voluntary (but have
increased inner tension)
With distraction, rare conscious
effort
Distraction Reduction of tics Stops
Family history Frequently positive May be positive
Force sensitive
Platform analysis
116
Brief, less rhythmic Longer duration: more rhythmic
qualities
Treatment Clonidine, antidopaminergic
drugs
No established therapy
Adapted from Mahone EM, Bridges D, Prahme C, Singer HS: Repetitive arm and hand movements (complex motor stereotypies)
in children, J Pediatr 145(3):391395, 2004.

Dr. Felipe Castro
8
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Edad
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<20 aos
Inicio tarda
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Focal
Segmentaria
Multifocal
Generalizada
Hemidistonia
Etiologa
Primaria
Secundaria
Camella, Classification and Evaluation of dystonia ,Feb 2010 Review Uptodate
B Bressman,The Diagnosis of Dystonia, Lancet Neurol 2006; 5: 78090
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Un rea
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contiguas
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contiguas
-B Bressman,The Diagnosis of Dystonia, Lancet Neurol 2006; 5: 78090
-Camella, Classification and Evaluation of dystonia ,Feb 2010 Review Uptodate

Dr. Felipe Castro
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LlsLoniu
Edad
Inicio temprano
<20 aos
Inicio tarda
>20 aos
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anatmica
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Segmentaria
Multifocal
Generalizada
Hemidistonia
Etiologa
Primaria
Secundaria
Distribucin anatmica
Focal
Un rea
Multifocal
!2 reas no
contiguas
Generalizada
Hemidistonia
Segmentaria
!2 reas
contiguas
-B Bressman,The Diagnosis of Dystonia, Lancet Neurol 2006; 5: 78090
-Camella, Classification and Evaluation of dystonia ,Feb 2010 Review Uptodate
Carvalho Aguiar, Classification and genetics of Dystonia , Lancet Neurology 2002;
1: 31625

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metabolic activity in the lentiform nuclei, cerebellum and supple-
mentary motor areas (Eidelberg et al., 1998). In contrast, PET
studies in dystonia 1 patients of a Chinese family did not reveal
hypermetabolism in cerebellum or basal ganglia (Ching et al.,
2007). Brain scans of mutation carriers with H2
15
O PET during
sequence learning showed increased cerebellar activation (Carbon
et al., 2008). Furthermore, D2 receptor binding in caudate and
putamen was decreased in individuals with TOR1A mutations
(Asanuma et al., 2005b).
Prevalence, inheritance and mapping
The disorder is most common in the Ashkenazi Jewish population
with a prevalence estimated at 1/16 0001/20 000. In the non-
Jewish population, prevalence is about 1/200 000 (summarized in
Mu ller and Kupke, 1990).
Dystonia 1 is inherited as an autosomal dominant trait with a
reduced penetrance of 30% (Bressman et al, 1989; Risch et al.,
1990). The disease locus, DYT1, has been assigned to the long
arm of chromosome 9 (9q34) by linkage analysis (Ozelius et al.,
1989).
Molecular genetics
The disease gene, TOR1A was identied in 1997 (Ozelius et al.,
1997). It is composed of ve exons and is widely expressed.
Expression of TOR1A is regulated by transcription factors of the
Ets family. These bind to two Ets binding cores in the upstream
region (within _78 and _69bp) of the gene (Armata et al., 2008).
A three-nucleotide deletion (GAG deletion) of one of two
adjacent GAG trinucleotides in exon 5 (904_906delGAG/
907_909delGAG) is the most common mutation and found in
almost all dystonia 1 patients (summarized in Geyer and
Bressman, 2006). This mutation has arisen independently
in several populations (Klein et al., 1998a). In the Ashkenazi
Jewish population, the GAG deletion originated from a founder
who lived in Byelorussia or Lithuania about 350 years ago
(Risch et al., 1995). Today the frequency in this population is
1/3 0001/9 000 (Risch et al., 1990).
The GAG deletion results in the loss of a glutamic acid within
the gene product torsinA (302/303). In addition to the GAG
deletion, a few other mutations have been described in TOR1A.
A G4A transition was detected in exon 5 (c.863G4A) in a female
patient with generalized dystonia and in her unaffected mother.
The mutation causes the exchange of an arginine for a glutamine
(pArg288Gln) in torsinA (Zirn et al., 2008a). A pathogenic role of
this mutation is likely: (i) an arginine at position 288 has been
evolutionarily highly conserved in all vertebrates including sh
(fugu), thus indicating an important function and (ii) functional
studies in a cell system indicate the same morphological changes
in the nuclear membrane (enlargement of the perinuclear space)
that are also found in the common GAG mutation. Pathogenicity
of two additional mutations remains unclear. One, an 18 bp dele-
tion within exon 5 (966_983del Phe328_Tyr328del) was detected
in patients with myoclonus dystonia (M-D), and a mutation within
the gene SGCE commonly mutated in M-D (dystonia 11) was
observed in the same patients (Leung et al., 2001; Klein et al.,
2002). Another mutation (934_937delAGAG) was detected in a
healthy blood donor with no known neurological manifestations
(Kabakci et al., 2004).
A polymorphism (C/G) within exon 4 of TOR1A results in the
exchange of aspartic acid for histidine at position 216 of torsinA
(D216H). Aspartic acid (D) is encoded by 88% and histidine
(H) by 12% of normal alleles. This polymorphism functions as a
modier of mutant torsinA. In a cellular system, the H216 allele
weakens manifestation of the GAG deletion (Kock et al., 2006);
and in individuals carrying the GAG deletion, the frequency of
H216 alleles is increased in non-manifesting carriers and decreased
in carriers with dystonia (Risch et al., 2007; Kamm et al., 2008).
Table 1 Autosomal dominant primary dystonias
Subgroup Designation OMIM Chromosomal mapping Disease gene
Pure dystonia Dystonia 1 Early-onset dystonia, idiopathic torsion dystonia,
dystonia musculorum deformans
128 100 9q34 TOR1A
Dystonia 4 Hereditary whispering dysphonia 128 101
Dystonia 6 Idiopathic torsion dystonia of mixed type 602 629 8p11.21 THAP1
Dystonia 7 Focal, adult-onset dystonia, idiopathic focal
dystonia
602 124 18p
Dystonia 13 Primary dystonia with mixed phenotype 607 671 1p36.13p36.32
Dystonia plus Dystonia 5a DRD; Segawa syndrome; hereditary progressive
dystonia with marked diurnal uctuation, HPD
128 230 14q22.1q22.2 GCH1
Dystonia 11 M-D; alcohol-responsive dystonia 159 900 7q21 SGCE
Dystonia 12 Rapid-onset dystonia-parkinsonism 128 235 19q12q13.2 ATP1A3
Dystonia 15 M-D 607 488 18p11
Paroxysmal
dystonia
Dystonia 8 PDC; PNKD1; non-kinesigenic choreoathetosis;
Mount-Reback disease
118 800 2q35 PNKD1/MR1
Dystonia 9 PDC with episodic ataxia and spasticity; episodic
choreoathetosis/spasticity (CSE)
601 042 1p21p13.3
Dystonia 10 PKC; paroxysmal familial dystonia; PKD 128 200 16p11.2q12.1
Dystonia 18 Paroxysmal exertion-induced dyskinesia; paroxysmal
exercise-induced dystonia
612 126 1p31.3p35 SLC2A1
(Dystonia 19) PKD2 611 031 16q13q22.1
(Dystonia 20) PNKD2 611 147 2q31
Monogenic primary dystonias Brain 2009: 132; 20052025 | 2007
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Dr. Felipe Castro
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Chapter 10 DYSTONIA 101
acids in the C-terminal region.
35
Other rare mutations
in TOR1A have been reported in individuals with dys-
tonia, but a causal role has not been established.
40,41
The basis for the incomplete penetrance is not
known, but one disease-modifying mutation has been
identified. A single nucleotide polymorphism is pres-
ent in the coding sequence for amino acid residue 216
in torsinA. In 88% of the population, this amino acid
is aspartic acid (D), but in 12% of the population it
is histidine (H). The frequency of the 216H allele is
increased in GAG deletion carriers who do not mani-
fest dystonia and is decreased in GAG deletion carri-
ers who do manifest dystonia compared to controls.
42,43

Interestingly, the protective effect of the D216H poly-
morphism is only seen when present on the allele
without the GAG deletion (trans allele). Although
the protective effect of the D216H polymorphism is
important, it only partially accounts for the incomplete
penetrance of the DYT1 mutation.
There are no consistent neuropathologic abnormal-
ities in DYT1 dystonia. Although perinuclear inclu-
sions and other neurodegenerative changes have been
reported in some cases,
44
this initial observation awaits
confirmation from other postmortem studies. TorsinA
is expressed in several brain regions, including the sub-
stantia nigra, striatum, hippocampus, and cerebellum.
20

It is especially highly expressed in nigral dopamine neu-
rons. TorsinA is expressed in neurons and not in glia.
45

In transgenic mouse models of DYT1 dystonia, there is
evidence for impaired dopamine neurotranmission.
46,47

There is also evidence for decreased inhibitory output
from the basal ganglia in transgenic mice.
48
Decreased
inhibitory basal ganglia output is consistent with models
of human dystonia.
14,49,50
Positron emission tomography (PET) studies of
cerebral glucose metabolismhave shown abnormal pat-
terns in individuals with DYT1 dystonia.
51
Although
the DYT1 dystonia is only 30% to 40% penetrant,
nonexpressing carriers of the deletion have abnormali-
ties on PET imaging that are identical to expressing
individuals.
51
This suggests that the DYT1 mutation
conveys a vulnerability to a second hit that deter-
mines whether dystonia manifests or not. An interest-
ing rodent model of cranial dystonia suggests that mild
striatal dopamine deficiency may be a permissive factor
that allows a relatively modest weakening of the lid-
closing orbicularis muscle to produce bilateral forceful
blinking of the eyelids resembling blepharospasm.
52
Management and Treatment
Management and treatment of DTY1 dystonia are
discussed at the end of this chapter under general
discussion of dystonia treatments.
Other Early-Onset Primary Dystonias
(DYT2; DYT4)
A recessive form of early-onset primary dystonia
(DYT2) has been postulated based on observation of
an apparent recessive inheritance pattern in several
families.
53,54
However, some of the reported individ-
ual cases had atypical features and evidence for this
entity is considered weak.
55
No reports of presumed
recessively inherited early-onset primary dystonia
TABLE 10-3 Genetic Causes of Secondary
Dystonia in Childhood
Autosomal
Recessive
Autosomal
Dominant Mitochondrial
AADC deficiency DRPLA Leber disease
Ataxia
telangiectasia
Gangliosidoses
Glutaric aciduria
Hartnup
disease
Homocystinuria
Juvenile
Parkinsons
disease
Metachromatic
leukodystrophy
Methylmalonic
aciduria
Niemann-Pick
type C
PKAN
(Hallervorden-
Spatz)
TH deficiency
TPI deficiency
Tyrosinemia
Vitamin E
deficiency
Wilsons
disease
Hereditary
spastic
paraparesis
with dystonia
Leigh
syndrome
MERRF
MELAS
Huntingtons
disease
Spinocerebellar
ataxias (SCAs)
X-linked
Dystonia-
deafness
Lesch-Nyhan
Pelizaeus
Merzbacher
Rett syndrome

BOX 10-1 Nongenetic Causes of Secondary
Dystonia
Autoimmune
Cerebral palsy
Drugs
Infection
Kernicterus
Psychogenic
Stroke
Toxins
Trauma
*5V2/0/5;B
Chapter 10 DYSTONIA 101
acids in the C-terminal region.
35
Other rare mutations
in TOR1A have been reported in individuals with dys-
tonia, but a causal role has not been established.
40,41
The basis for the incomplete penetrance is not
known, but one disease-modifying mutation has been
identified. A single nucleotide polymorphism is pres-
ent in the coding sequence for amino acid residue 216
in torsinA. In 88% of the population, this amino acid
is aspartic acid (D), but in 12% of the population it
is histidine (H). The frequency of the 216H allele is
increased in GAG deletion carriers who do not mani-
fest dystonia and is decreased in GAG deletion carri-
ers who do manifest dystonia compared to controls.
42,43

Interestingly, the protective effect of the D216H poly-
morphism is only seen when present on the allele
without the GAG deletion (trans allele). Although
the protective effect of the D216H polymorphism is
important, it only partially accounts for the incomplete
penetrance of the DYT1 mutation.
There are no consistent neuropathologic abnormal-
ities in DYT1 dystonia. Although perinuclear inclu-
sions and other neurodegenerative changes have been
reported in some cases,
44
this initial observation awaits
confirmation from other postmortem studies. TorsinA
is expressed in several brain regions, including the sub-
stantia nigra, striatum, hippocampus, and cerebellum.
20

It is especially highly expressed in nigral dopamine neu-
rons. TorsinA is expressed in neurons and not in glia.
45

In transgenic mouse models of DYT1 dystonia, there is
evidence for impaired dopamine neurotranmission.
46,47

There is also evidence for decreased inhibitory output
from the basal ganglia in transgenic mice.
48
Decreased
inhibitory basal ganglia output is consistent with models
of human dystonia.
14,49,50
Positron emission tomography (PET) studies of
cerebral glucose metabolism have shown abnormal pat-
terns in individuals with DYT1 dystonia.
51
Although
the DYT1 dystonia is only 30% to 40% penetrant,
nonexpressing carriers of the deletion have abnormali-
ties on PET imaging that are identical to expressing
individuals.
51
This suggests that the DYT1 mutation
conveys a vulnerability to a second hit that deter-
mines whether dystonia manifests or not. An interest-
ing rodent model of cranial dystonia suggests that mild
striatal dopamine deficiency may be a permissive factor
that allows a relatively modest weakening of the lid-
closing orbicularis muscle to produce bilateral forceful
blinking of the eyelids resembling blepharospasm.
52
Management and Treatment
Management and treatment of DTY1 dystonia are
discussed at the end of this chapter under general
discussion of dystonia treatments.
Other Early-Onset Primary Dystonias
(DYT2; DYT4)
A recessive form of early-onset primary dystonia
(DYT2) has been postulated based on observation of
an apparent recessive inheritance pattern in several
families.
53,54
However, some of the reported individ-
ual cases had atypical features and evidence for this
entity is considered weak.
55
No reports of presumed
recessively inherited early-onset primary dystonia
TABLE 10-3 Genetic Causes of Secondary
Dystonia in Childhood
Autosomal
Recessive
Autosomal
Dominant Mitochondrial
AADC deficiency DRPLA Leber disease
Ataxia
telangiectasia
Gangliosidoses
Glutaric aciduria
Hartnup
disease
Homocystinuria
Juvenile
Parkinsons
disease
Metachromatic
leukodystrophy
Methylmalonic
aciduria
Niemann-Pick
type C
PKAN
(Hallervorden-
Spatz)
TH deficiency
TPI deficiency
Tyrosinemia
Vitamin E
deficiency
Wilsons
disease
Hereditary
spastic
paraparesis
with dystonia
Leigh
syndrome
MERRF
MELAS
Huntingtons
disease
Spinocerebellar
ataxias (SCAs)
X-linked
Dystonia-
deafness
Lesch-Nyhan
Pelizaeus
Merzbacher
Rett syndrome

BOX 10-1 Nongenetic Causes of Secondary
Dystonia
Autoimmune
Cerebral palsy
Drugs
Infection
Kernicterus
Psychogenic
Stroke
Toxins
Trauma
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in which case we recommend that the movement be
described in terms of the features noted above with all
possible classications given. For example, a particular
child might have non-rhythmic hyperkinetic move-
ments with repeated postures and movement fragments
that share elements of dystonia and chorea and might
represent a combination of both.
CONCLUSIONS
We have provided a set of denitions for common
hyperkinetic movements that occur in childhood. To-
gether with previous consensus denitions of hyper-
tonic disorders and negative signs, this provides addi-
tional taxonomy of childhood motor disorders. We
hope that these denitions will be useful for communi-
cation between clinicians, for performing clinical
research, and for relating the results of the research to
measurable elements of the clinical examination. In the
future, it will be important to establish valid and reli-
able clinical rating scales and quantitative measure-
ment tools based on these denitions. Use of such tools
may provide new insights and data that we hope will
lead to continued renement of the denitions. The
ultimate goal is to facilitate research and clinical treat-
ment to optimize motor function and thereby improve
the lives of children with disorders of movement.
Acknowledgments: We are grateful for the support of the
National Institute for Neurological Disorders and Stroke,
the National Institute for Child Health and Development, the
Ofce of Rare Disorders, the Don and Linda Carter Founda-
tion, the Crowley Carter Foundation, and an unrestricted edu-
cational grant from Allergan Inc.
Financial Disclosures: Dr. Chen received research grants
from the Canadian Institutes of Health Research, Michael J.
Fox Foundation for Parkinsons Research, Dystonia Medical
Research Foundation and Medtronic Inc, honoraria from
Allergan, Medtronic, Merz, Novartis, Teva, and from expert
testimony.
REFERENCES
1. Sanger TD. Pediatric movement disorders. Curr Opin Neurol
2003;16:529535.
2. Sanger TD, Delgado MR, Gaebler-Spira D, Hallett M, Mink JW.
Classication and denition of disorders causing hypertonia in
childhood. Pediatrics 2003;111:e89e97.
3. Sanger TD, Chen D, Delgado MR, Gaebler-Spira D, Hallett M,
Mink JW. Denition and classication of negative motor signs in
childhood. Pediatrics 2006;118:21592167.
4. Campbell SK. Quantifying the effects of interventions for move-
ment disorders resulting from cerebral palsy. J Child Neurol
1996;11 Suppl. 1:S61S70.
5. World Health Organization. Towards a common language for
functioning, disability, and health: the International Classication
of Functioning, Disability, and Health (ICF), 2002.
6. Sanger TD, Mink JW. Movement Disorders. In: Swaiman KF,
Ashwal S, Ferriero DM, editors. Pediatric neurology: principles and
practice, Fourth ed. Philadelphia, PA: Mosby; 2006. p 12711311.
7. Meierkord H, Fish DR, Smith SJ, Scott CA, Shorvon SD, Mars-
den CD. Is nocturnal paroxysmal dystonia a form of frontal lobe
epilepsy? Mov Disord 1992;7:3842.
8. Fish DR, Sawyers D, Smith SJ, Allen PJ, Murray NM, Marsden
CD. Motor inhibition from the brainstem is normal in torsion
dystonia during REM sleep. J Neurol Neurosurg Psychiatry
1991;54:140144.
9. Mink JW. The basal ganglia: focused selection and inhibition of
competing motor programs. Prog Neurobiol 1996;50:381425.
10. Sanger TD. Childhood onset generalised dystonia can be mod-
elled by increased gain in the indirect basal ganglia pathway.
J Neurol Neurosurg Psychiatry 2003;74:15091515.
11. Sanger TD, Kaiser J, Placek B. Reaching movements in child-
hood dystonia contain signal-dependent noise. J Child Neurol
2005;20:489496.
12. Sitburana O, Jankovic J. Focal hand dystonia, mirror dystonia
and motor overow. J Neurol Sci 2008;266:3133.
13. Liu X, Tailor J, Wang S, et al. Reversal of hypertonic co-con-
traction after bilateral pallidal stimulation in generalised dysto-
nia: a clinical and electromyogram case study. Mov Disord 2004;
19:336340.
14. Malfait N, Sanger TD. Does dystonia always include co-contrac-
tion? A study of unconstrained reaching in children with primary
and secondary dystonia. Exp Brain Res 2007;176:206216.
15. Le Ber I, Clot F, Vercueil L, et al. Predominant dystonia with
marked cerebellar atrophy: a rare phenotype in familial dystonia.
Neurology 2006;67:17691773.
16. Jinnah HA, Hess EJ. A new twist on the anatomy of dystonia:
the basal ganglia and the cerebellum? Neurology 2006;67:1740
1741.
17. Pizoli CE, Jinnah HA, Billingsley ML, Hess EJ. Abnormal cere-
bellar signaling induces dystonia in mice. J Neurosci 2002;22:
78257833.
18. LeDoux MS, Lorden JF. Abnormal spontaneous and harmaline-
stimulated Purkinje cell activity in the awake genetically dys-
tonic rat. Exp Brain Res 2002;145:457467.
19. Loher TJ, Krauss JK. Dystonia Associated with pontomesence-
phalic lesions. Mov Disord 2008;24:157167.
20. Blake DT, Byl NN, Cheung S, et al. Sensory representation
abnormalities that parallel focal hand dystonia in a primate
model. Somatosens Mot Res 2002;19:347357.
FIG. 1. Schematic illustration of the overlap between several types
of hyperkinetic movements. It is important to realize that the relative
areas of the regions are not to scale, and the combination of chorea,
athetosis, and dystonia may be more common than either of the three
alone.
1548 T.D. SANGER ET AL.
Movement Disorders, Vol. 25, No. 11, 2010
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