Journal of Neural Transmission

https://doi.org/10.1007/s00702-020-02238-3

HIGH IMPACT REVIEW IN NEUROSCIENCE, NEUROLOGY OR PSYCHIATRY - REVIEW

ARTICLE

Chorea in children: etiology, diagnostic approach and management

José Fidel Baizabal‑Carvallo1   · Francisco Cardoso2

Received: 30 April 2020 / Accepted: 1 August 2020

© Springer-Verlag GmbH Austria, part of Springer Nature 2020

Abstract
Chorea is defined by the presence of abnormal, involuntary, continuous, random movements that results from a number of
autoimmune, hereditary, vascular, metabolic, drug-induced and functional (psychogenic) causes. Chorea may present at all
stages of life, from newborns to elderly individuals. While Huntington disease is the main suspicion in adults presenting
with chorea, once a drug-induced or parkinsonian dyskinesia have been ruled out; Huntington disease exceptionally presents
with chorea in children. Sydenham chorea is considered the most common cause of acute childhood-onset chorea, but its
prevalence has decreased in Western countries. However, in younger children other etiologies such as dyskinetic cerebral
palsy, anti-NMDAR receptor encephalitis, other autoimmune conditions, or mutations in NKX2-1, ADCY-5, FOXG1,
GNAO1, GPR88, SLC2A1, SQSTM1, ATP8A2, or SYT-1 should be considered. In this manuscript, we review the main
causes, diagnosis and management of chorea in children.

Keywords  Chorea · Children · Infancy · Autoimmune · Sydenham

Introduction we review the etiologies of chorea or choreoathetosis with

Chorea is a movement disorder (MD) defined by continu-
ous flow of unpredictable sequence of one or more discrete
involuntary movements or movement fragments (Sanger
et al. 2010; Cardoso et al. 2006). It is sometimes reported
simultaneously with athetosis characterized by slow, smooth,
sinuous, writhing movements, predominantly involving the
hands, preventing maintenance of a stable posture (Lanska
2013). The term “athetosis” was introduced in 1871 by the
American physician William Hammond (Lanska 2013).
Although it has been dismissed as a form of post-hemiplegic
chorea or a mixture of chorea and dystonia (Lanska 2010),
it is still used frequently in modern literature. A number
of etiologies can manifest with chorea, however, they vary
according to the age at onset (Table 1). In this manuscript,
onset at or before 15 years of age.
Methods
We performed a systematic search in PubMed using the term
“chorea” and combined with the terms “children”, “infant”,
“cerebral palsy”, “autoimmune”, “hereditary”, “paroxysmal
dyskinesia”, “metabolic”, “vascular”, “drug-induced”, “psy-
chogenic” and “functional”. Papers in English and Spanish
language were selected for this review. The final reference
list was generated after selecting the manuscripts with key
information regarding the selected topics.
Dyskinetic cerebral palsy

Cerebral palsy (CP) is a common disorder with about 2–3

* José Fidel Baizabal‑Carvallo
baizabaljf@hotmail.com
children out of 1000 suffering from it. Dyskinetic cerebral
palsy (DCP) is an important consideration when first evaluat-
1
Department of Sciences and Engineering, University ing children with chorea. DCP is the second largest group of
of Guanajuato, Ave León 428, Jardines del Moral, CP, representing about 14% of cases (Bax et al. 2006). There
37320 León, Guanajuato, Mexico
is often a history of birth difficulties. Patients usually show
2
Movement Disorders Unit, Neurology Service, The Federal choreoathetosis and dystonia simultaneously, presenting at rest
University of Minas Gerais, Belo Horizonte, MG, Brazil

13
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 J. F. Baizabal‑Carvallo, F. Cardoso

Table 1  Causes of chorea
Genetic choreas Parainfectious and autoimmune causes Perinatal hypoxic/ischemic encephalopathy
Benign hereditary chorea* Sydenham chorea* Dyskinetic cerebral palsy*
ADCY-5-related dyskinesia* Anti-basal ganglia encephalitis* Vascular chorea
Phosphodiesterase mutations* Anti-NMDA receptor encephalitis* Ischemic stroke
Huntington disease (HD) Anti-GABAB receptor encephalitis Hemorrhagic stroke
HD-like 2, 3 Chorea gravidarum Moyamoya disease*
Spinocerebellar ataxia types 2,3,7 Systemic lupus erythematosus Post-pump chorea*
Spinocerebellar ataxia type 17* Antiphospholipid antibody syndrome Subdural hematomas
Neuroacanthocytosis Paraneoplastic choreas Structural lesions in basal ganglia
Dentatorubropallidoluysian atrophy Infectious chorea Multiple sclerosis plaques
Ataxia telangiectasia* Toxoplasmosis Extrapontine myelinolysis
Ataxia oculomotor apraxia type 1* Cysticercosis Vascular malformations
Ataxia oculomotor apraxia type 2* HIV encephalopathy Neoplasms (primary CNS, metastatic)
Friedreich ataxia* Diphtheria* Drug-induced
Hypomyelination with atrophy of basal ganglia Bacterial endocarditis Dopamine receptor blocking agents:
and cerebellum (H-ABC)* Neurosyphilis Withdrawal re-emergent syndrome*
Forkhead Box G1 mutations* Scarlet fever* L-dopa
GNAO1/GPR88 mutations* Viral encephalitis (Measles, mumps, varicella)* Dopamine agonists
Sequestosome 1 mutations* Metabolic/toxic encephalopathies Digoxin
Flippase ATP8A2 mutations* Hyper- or hyponatremia Anticholinergics
Synaptagmin-1 mutations* Hypocalcemia Antiepileptic drugs
Munc 13–1 mutations* Acute intermittent porphyria Calcium channel blockers
Synaptobrevin-2 mutations* Hyperthyroidism Psychostimulants (amphetamines, cocaine)
SLC2A1 (Glut-1deficiency) encephalopathy* Hypoparathyroidism Lithium
Paroxysmal kinesigenic dyskinesia* Renal/hepatic failure Baclofen
Paroxysmal non-kinesigenic dyskinesia* Carbon monoxide poisoning Tricyclic antidepressants
Paroxysmal exercise-induced dyskinesia* Mercury poisoning Corticosteroids
Alternating hemiplegia of childhood* Manganese poisoning Oral contraceptives
Cryopyrin-associated periodic syndromes* Organophosphate poisoning Functional (psychogenic) disorder
Neuroferritinopathy
Wilson disease
Lesch–Nyhan disease*
Pantothenate kinase associated degeneration
Methylmalonic aciduria*
Propionic acidemia*
*
 Etiologies with onset predominantly or exclusively during childhood

but accentuated with action (Monbaliu et al. 2017). Chorea is
predominantly observed in the arms; whereas dystonia is more
evenly distributed, although with a tendency to be more severe
in the upper half of the body. Dystonia is often more severe
than choreoathetosis, causing a higher impact in the quality
of life (Monbaliu et al. 2016, 2017). Although periventricular
leukomalacia is the most common finding on MRI (Robinson
et al. 2009), thalamic and basal ganglia lesions are related to
the severity of choreoathetosis (Monbaliu et al. 2016). How-
ever, the majority of patients present with normal structural
imaging. In the following sections, we group and discuss the
diverse etiologies implicated in childhood chorea.
Autoimmune disorders
Sydenham chorea and basal ganglia encephalitis
Sydenham chorea (SC) is a delayed neurological manifesta-
tion of infection with group A β-hemolytic streptococcus
(GABHS) and a major component of the diagnostic crite-
ria for rheumatic fever (RF) (Cardoso 2011). It presents in
10–25% of patients with RF. Onset is usually between 8
and 9 years of age. Chorea is mainly generalized, but may
be asymmetrical or unilateral in 20% of cases (Cardoso
et al. 1997). Other motor manifestations include hypotonia,
motor impersistence, hypometric saccades, oculogyric crisis,
and rarely, phonic and motor tics. Behavioral and cogni-
tive findings are also common, such as: obsessive compul-
sive symptoms, attention deficit and hyperactivity disorder,
anxiety, depression, altered verbal fluency and dysexecutive
syndrome (Maia et al. 2005; Harsányi et al. 2015; Moreira
et al. 2014). In 80% of patients there is clinical resolution
within 2 years, but the remaining subjects develop a persis-
tent course. Relapsing episodes are usually associated with
new streptococcal infections, pregnancy and exposure to
hormones (Cardoso 2011).
The diagnosis of SC is based on the presence of acute
chorea and absence of alternative etiology. The demonstra-
tion of a recent infection with a GABHS by a throat culture,

13
Chorea in children: etiology, diagnostic approach and management
positive anti-streptolysin-O or anti-DNAse antibodies, and
the presence of carditis support the diagnosis. Of note,
unlike other manifestations of RF, there is a long latency
between GABHS exposure and SC. This results in many
patients lacking laboratory evidence of streptococcal infec-
tion (Cardoso 2017). Anti-basal ganglia antibodies have
been deemed as potentially pathogenic. However, the target
antigen has not been clarified; moreover, these antibodies are
not commercially available for testing and they may be non-
specific as they have been detected in healthy controls and
patients with Parkinson and Huntington disease (Cardoso
2017; Church et al. 2002).
Basal ganglia encephalitis may also occur following vac-
cination or an infection by GABHS, mycoplasma or entero-
virus (Dale et al. 2012b). The age at onset is usually before
5 years of age with males and females equally affected;
patients present mainly with dystonia or dystonic tremor,
although chorea, parkinsonism and oculogyric crises have
been reported (Dale et al. 2012b). Basal ganglia hyperinten-
sities are observed in roughly half of cases; whereas anti-D2
dopamine antibodies are positive in about one-third of cases;
the course is usually more aggressive than in SC (Dale et al.
2012b).
Anti‑N‑methyl‑d‑aspartate receptor (NMDAR)
an other encephalitis
Anti-NMDAR encephalitis is the most common autoim-
mune encephalitis and represents the third most common
cause of encephalitis following viral encephalitis and acute
demyelinating encephalo-myelitis (ADEM). The estimated
incidence is 1.5 per million people per year (Dalmau et al.
2019). Most patients are young females about 23 years old,
but it may present at all ages including children (Titulaer
et al. 2013). Presentation usually starts with neuropsychiatric
symptoms, followed by dysautonomia, speech dysfunction
and movement disorders. Finally, individuals may develop
altered level of consciousness and coma (Baizabal-Carvallo
and Jankovic 2018; Graus et al. 2016). Stereotypies are prob-
ably the most common hyperkinetic movements, but a pro-
portion of patients also develop chorea, which predominates
in children (Florance et al. 2009; Baizabal-Carvallo et al.
2013b). A combination of other MDs including dystonia,
catatonia, and myoclonus is frequently observed (Baizabal-
Carvallo et al. 2013b). Orofacial movements are typical
and may represent stereotypies, dystonia, or myorhythmia
(Baizabal-Carvallo et al. 2015; Duan et al. 2016). The diag-
nosis is based on the presence of IgG directed against the
NR1-subunit of the NMDA receptor in the serum or CSF
and is supported by an abnormal EEG, pleocytosis and oli-
goclonal bands in the CSF (Graus et al. 2016).
A form of anti-NMDAR encephalitis may present follow-
ing an episode of herpes virus simplex encephalitis (HSE) in
about 20% of patients. Patients have positive anti-NMDAR
antibodies in the serum or CSF, usually of several isotypes
(IgG, IgM, or IgA) that appear within 1–4 weeks following
the viral infection (Prüss et al. 2012; Armangue et al. 2014).
Children most commonly present with choreoathetosis
sometimes accompanied by lingual and orofacial dyskinesia,
whereas adults present with psychiatric symptoms (Prüss
et al. 2012). The presence of MDs is more common in anti-
NMDAR encephalitis induced by HSE and can discriminate
from a relapse of HSE encephalitis (Nosadini et al. 2019).
Other autoimmune encephalitis may present with chorea in
children although they are less common. Example of these is
γ-aminobutyric acid-B (­ GABAB) receptor encephalitis that
may present with chorea, seizures and various MDs (Kruer
et al. 2014).
Systemic lupus erythematosus (SLE)
and the antiphospholipid syndrome (APS)
SLE is a multisystemic autoimmune disorder with an esti-
mated prevalence of 45.2 cases per 100,000 with males
representing between 7 and 20% of cases (Stojan and Petri
2018). APS presents with recurrent thrombotic episodes
and miscarriages; it has a prevalence of 50 per 100,000
(Duarte-García et al. 2019). APS may present isolated “pri-
mary” or associated “secondary” with SLE. Chorea is the
most common MD reported in patients with SLE and APS,
with prevalence between 1 and 3% of all cases (Baizabal-
Carvallo et  al. 2011). Females represent about 90% of
cases, with onset between 15 and 26 years; but cases with
younger onset are reported (Okun et al. 2000). Chorea is
usually generalized, but unilateral presentations are also
reported (Orzechowski et al. 2008). Comorbid psychosis or
marked behavioral disturbances are more common than in
SC, an important differential diagnosis (Baizabal-Carvallo
et al. 2013a). Although a pathogenic antibody has not been
identified, antiphospholipid antibodies are believed to play
a role in the pathogenesis by disruption of the BBB and
direct damage to neurons (Baizabal-Carvallo et al. 2013a).
Chorea usually subsides, but may have a relapsing course
(Reiner et al. 2011). Of note, a recent case series suggests
that parkinsonism and myoclonus are at least as frequent as
chorea in SLE (Maciel et al. 2016).
Hereditary mildly or non‑progressive
disorders causing chorea
Benign hereditary chorea
This is an autosomal dominant disorder, secondary to muta-
tions in the NKX2-1 gene in chromosome 14q, encoding the
NK2 homeobox-1 also known as thyroid transcription factor
13
 J. F. Baizabal‑Carvallo, F. Cardoso

1 (TITF-1) (Breedveld et al. 2002). NKX2-1 is involved in Table 2  Summary of clinical features presenting in patients with
the morphogenesis of thyroid gland, lungs, and basal ganglia NKX2.1 mutations
(Krude et al. 2002). Mutations may include missense/non- Hyperkinetic movements
sense mutations or complete gene deletions leading to hap-  Chorea
loinsufficiency of TITF-1 (Krude et al. 2002). The mutated  Dystonia (usually axial)
protein shows decreased binding to DNA, with failure to  Myoclonus (usually on extremities)
 Tics
activate genes expressing thyroglobulin, thyroperoxidase  Restless legs syndrome
and surfactant—protein B and C promoters (Moya et al. Other neurological manifestations
2006; Nettore et al. 2013). The mutated protein becomes  Hypotonia
predominantly cytoplasmatic with limited translocation into  Slow saccades
the nucleus, further interfering with its function (Proven-  Gait ataxia
 Developmental delay
zano et al. 2008; Ferrara et al. 2008). Gene deletions located  Psychomotor retardation
nearby NKX2-1 may explain comorbid manifestations such  Seizures
as immunodeficiency and may affect genes involved in  Autism spectrum disorder
NKX2-1 expression (Barnett et al. 2012; Invernizzi et al. Thyroid manifestations
2018; Villafuerte et al. 2018). Despite the large number of  Hypothyroidism congenital or acquired
 Subclinical hypothyroidism
mutations detected, no reliable correlations between geno-  Thyroid carcinoma
type and phenotype have been established (Provenzano et al. Lung manifestations
2016). Of note, regardless of the autosomal dominant trans-  Pulmonary infections (recurrent)
mission, many patients lack a family history because of de  Neonatal respiratory distress
novo mutations.  Obstructive airway disorders
 Interstitial lung disease
The onset is usually before 5 years of age with delayed  Lung cancer
motor development, hypotonia, and chorea, which is fre- Other clinical manifestations
quently accompanied by dystonia, myoclonus, or tics  Dysmorphic facial features
(Kleiner-Fisman et al. 2003; Costa et al. 2005; Iodice et al.  Growth hormone deficiency
2019). Chorea may start before 1 year of age (Koht et al.  Hypogonadotropic hypogonadism
 Joint hyperlaxity
2016) and it may be antedated by delay in motor milestones,  Short stature
severe hypotonia, ataxia and drop attacks (Willemsen et al.  Webbed neck
2005; Williamson et al. 2014; Rosati et al. 2015). Chorea  Pes cavus
is usually generalized and may aggravate with stress and  Kyphosis
 Duplex kidney
excitement, improves with alcohol and resolves during sleep
(Asmus et al. 2007). It frequently persists into adulthood
with a milder phenotype (Costa et al. 2005) but a small
proportion of patients have a complete recovery (Gras of cases showing non-specific findings in the brain and
et al. 2012). Although early studies reported no cognitive cystic masses in the pituitary gland or empty sella turcica
impairment (Kleiner-Fisman et al. 2003), more recent evi- (Mahajnah et al. 2007; Veneziano et al. 2014). Functional
dence showed learning difficulties in 20 out of 28 patients neuroimaging with 18F-2-deoxyglucose PET has shown
(Gras et al. 2012). Combination of affected organs results hypometabolism in basal ganglia and cerebral cortex (Sal-
in three main syndromes: approximately 50% of patients vatore et al. 2010). There was normal presynaptic activity
have a “brain–lung–thyroid syndrome”; 30% present with with decreased postsynaptic D2-receptor function assessed
“brain–thyroid syndrome” and 20% of cases present with with 11C-raclopride in two patients (Konishi et al. 2013).
“benign hereditary chorea”. Other manifestations described
in patients with NKX2-1 mutations are shown in Table 2 ADCY5 and phosphodiesterase A mutations
(Glik et al. 2008; Peall et al. 2014; Parnes et al. 2018; Milone
et al. 2019). Thyroid manifestations commonly involve con- Mutations in the enzyme adenylate (adenylyl) cyclase-5
genital hypothyroidism and thyroid agenesis, whereas the (ADCY-5) cause an autosomal dominant disorder with few
most common respiratory findings are repeated infections biallelic (recessive) pathogenic variants identified (Barrett
and asthma. et al. 2017). The enzyme is highly expressed in the nucleus
Although no significant abnormalities have been reported accumbens and striatum, where it is involved in motor func-
in gross anatomical and histological samples in post-mortem tion and cortical arousal, respectively (Chen et al. 2012).
studies, there are reports of a reduced number of striatal Marked increase in intracellular cAMP results from a gain-
interneurons (Kleiner-Fisman et al. 2003, 2005). Structural of-function of the ADCY-5 enzyme (Chen et  al. 2014),
neuroimaging is usually normal with a small proportion affecting the direct and indirect dopaminergic pathways

13
Chorea in children: etiology, diagnostic approach and management
(Doyle et  al. 2019). However, reduced expression of
ADCY-5 messenger RNA has also been identified, suggest-
ing that some mutation variants may result in haplo-insuf-
ficiency rather than gain of function (Carapito et al. 2015).
Although no clear genotype–phenotype associations have
been established, the p. R418W (most commonly identified)
and p. R418Q mutations have been associated with more
severe phenotype (Chang et al. 2016; Douglas et al. 2017).
The disorder was initially described in 2001, labeled as
“familial dyskinesia with facial myokymia” (FDFM) (Chen
et  al. 2012; Fernandez 2001). Affected patients usually
present with chorea starting between 6 months and 7 years
of age (Carecchio et al. 2017). Delayed motor and/or lan-
guage milestones, axial hypotonia, pyramidal syndrome,
myoclonus, generalized dystonia, and paroxysmal dystonic
episodes may precede or accompany chorea (Carecchio
et al. 2017; Dean et al. 2019). Although common, facial
“myokymia” is not universally present (Mencacci et  al.
2015). Moreover, electromyography (EMG) recordings in
the orbicularis oris and trapezius muscles have shown burst
activity of 100 ms and between 100 and 300 ms, consist-
ent with myoclonus and chorea respectively, rather than
myokymia (Tunc et al. 2017). Chorea is characteristically
exacerbated by drowsiness, preventing sleep or may present
upon awakening and has also been reported as nocturnal
paroxysmal episodes (Chang et al. 2016; Dy et al. 2016).
Chorea is initially episodic, lasting from seconds to hours,
triggered by action, anxiety, mental activity or infections. It
becomes more continuous with ageing, but still showing epi-
sodic exacerbations lasting from minutes to weeks (Chang
et al. 2016). The long-term clinical course of hyperkinesia
may be variable with periods of stability or spontaneous
amelioration with residual axial hypotonia (Carecchio et al.
2017). Phenotypes with prominent myoclonus-dystonia or
alternating hemiplegia have also been recognized (Westen-
berger et al. 2017; Zech et al. 2017). Neuroimaging studies
are unremarkable (Chang et al. 2016). ADCY-5 mutations
may be more common than previously thought: they were
detected in 11% of cases among 44 patients with pediatric
onset hyperkinesia (Carecchio et al. 2017).
The balance between synthesis and degradation of cAMP
in medium spiny neuron is controlled by ADCY-5 and phos-
phodiesterase 10A (PDE10A), respectively (Niccolini et al.
2018). Biallelic mutations of PDE10A cause an infancy
onset (about 3 months of age) syndrome, characterized by
axial hypotonia, chorea, ballismus and intermixing jerky
movements affecting facial, limb and trunk muscles. Some
patients may also have cognitive delay (Mencacci et al.
2016; Diggle et al. 2016). A 70% reduction of PDE10A in
the basal ganglia has been identified with a specific PET
ligand (Mencacci et al. 2016). More recently, mutations in
the enzyme PDE2A have also been identified in a 9-year-
old patient with chorea preceded by fluctuating attacks of
sudden falls, dystonia, cognitive impairment and language
difficulties (Salpietro et al. 2018). Patients with ADCY-5
and PDE10A mutations show decreased dopamine trans-
porter expression, loss of neuromelanin-containing neurons
in the SN, and microstructural changes in cortical/subcorti-
cal white and gray matters (Niccolini et al. 2018). MRI does
not show abnormalities in the basal ganglia (Mencacci et al.
2016).
Syndromes with paroxysmal dyskinesia
Paroxysmal dyskinesia is subdivided into three main syn-
dromes: paroxysmal kinesigenic dyskinesia (PKD), par-
oxysmal exercise-induced dyskinesia (PED) and paroxys-
mal non-kinesigenic dyskinesia (PNKD). Each syndrome
is predominantly associated with a set of gene mutations
(Table 3).
Mutations in the gene SLC2A1, encoding the glucose
transporter 1 (Glut-1) in chromosome 1p are associated
with a variety of phenotypes with dystonia and chorea (Suls
et al. 2008). This transporter carries glucose through the
blood–brain barrier and into astrocytes and neurons, pro-
viding the basal ganglia and other motor-related structures
with glucose (Weber et al. 2008). The classical phenotype
is dominated by epileptic encephalopathy usually present
before 2 years of age (Mullen et al. 2010). It is characterized
by acquired psychomotor retardation with microcephaly and
paroxysmal events such as intractable seizures and a mix
of dystonia, chorea and ataxia (Pérez-Dueñas et al. 2009).
As the patient grows older, seizures become less prominent
and may disappear, whereas new paroxysmal MDs, particu-
larly PED, either appear or worsen (Leen et al. 2014; Kraoua
et al. 2015). Non-classical phenotypes represent about 10%
of cases dominated by PED with chorea and dystonia with
or without epilepsy (Weber et al. 2011; Leen et al. 2010;
Urbizu et al. 2010). In a study of 57 patients with Glut-1
deficiency, mild chorea was the third most common MD,
after ataxia and dystonia (Pons et al. 2010). The diagnosis
is based on low CSF glucose (< 60 mg/dl); and can be con-
firmed by 3-O-methyl-d-glucose uptake in erythrocytes or
identification of heterozygous pathogenic SLC2A1 variants.
There are rare subjects with biallelic mutations (Suls et al.
2008).
Mutations of the proline-rich transmembrane protein 2
(PRRT2) in chromosome 16p is the main cause of PKD
(Erro et al. 2014). PRRT2 is a protein highly expressed in
the basal ganglia, which interacts with the synaptosomal
associated protein 25 (SNAP25) involved in neurotransmit-
ter release from synaptic vesicles (Dressler and Benecke
2005; Groffen et al. 2013; Gardiner et al. 2015). Patients
with PKD and negative for PRRT2 mutations may have a
heterozygous mutation in SCN8A gene encoding a voltage-
gated sodium channel (Gardella et al. 2016). Subjects with
13


13
Table 3  Summary of clinical feature of paroxysmal dyskinesia
PRRT2 mut PNKD (MR-1 mut.) SLC2A1 mut KCNMA1 mut ATP1A3 mut NLRP3 mut
(Glut-1) (CAPS)

Age at onset 9.9 years (1–40 years) 5 years (6 month to 35 8.6 years (1–49 years) 4.6 years (6 month to 15  < 18 months of age Infancy
Mean (range) years ) years)
Phenotypes PKD (main) PNKD Epileptic encephalopathy, Epilepsy AHC Periodic fever, skin lesions,
PHD PED ± epilepsy PNKD ± epilepsy RDP bone/joint symptoms and
ICCA​ CAPOS neurological manifesta-
BFIS tions
Movement disorders Dystonia (17.6%), chorea Dystonia (27.4%), chorea Chorea and dystonia Dystonia (+ common) and Choreoathetosis Chorea
(15.2%), both (67.1%), (2.7%), both (65.1%) (95.2%) chorea Dystonia and ataxia
other: athetosis, bal-
lismus
Precipitants Voluntary, rapid move- Alcohol, tea and caffeine Prolonged exercise usually Alcohol, fatigue, stress, Physical activity, specific Spontaneously, cold, stress,
ments, startle reactions, (most frequent); or walking or running. excitement foods, light sensitiv- exercise
or hyperventilation stress. Less often: fever, Also fasting, stress and ity, water exposure and
menstruation, tiredness, anxiety certain medications
exercise, fatigue, or cold
Attacks duration  < 1 min From 1 min to 12 h Between 15 and 40 min Similar to PNKD MR-1 From minutes to days or Usually days
weeks
Attack frequency From 1 to 2 per year, From 1 in a lifetime to From several per day to 1 Similar to PNKD MR-1 Multiple times per day to Variable
up-to hundreds per day several per day per month one per week
Management Carbamazepine Clonazepam Diazepam Ketogenic diet Dyskinesia: Prophylaxis: Anti-interleukin-1 therapy
Phenytoin Clonazepam Flunarizine (anakinra, canakinumab,
Levetiracetam Seizures: Topiramate rilonacept)
Topiramate Valproate Acute Attacks:
Acetazolamide Lamotrigine Benzodiazepines
Levetiracetam Chloral hydrate
Phenobarbital

AHC alternating hemiplegia of childhood, BFIS benign familial infantile seizures, CAPOS cerebellar ataxia, areflexia, pes cavus, optic atrophy, sensorineural hearing loss, ICCA​infantile convul-
sion and paroxysmal choreoathetosis, PKD paroxysmal kinesigenic dyskinesia, PNKD paroxysmal non-kinesigenic dyskinesia, PHD paroxysmal hypnogenic dyskinesia, RDP rapid-onset dysto-
nia Parkinsonism
J. F. Baizabal‑Carvallo, F. Cardoso
Chorea in children: etiology, diagnostic approach and management
PNKD may have mutations in the myofibrillogenesis regula-
tor 1 gene (MR-1), or KCNMA1 (Table 2) (Yeh et al. 2012;
Liang et al. 2015). Finally, cryopyrin-associated periodic
syndromes have an immune hereditary basis with some
patients presenting with episodic chorea responding to anti-
interleukin-1 therapy (Table 3) (Miyame 2012; Gómez-
Camello and Ortego-Centeno 2014; Schwarzbach et  al.
2016: Landmann and Walker 2017).
Hereditary disorders with severe
or progressive phenotypes causing chorea
Huntington disease
HD is a progressive autosomal dominant neurodegenerative
disorder characterized by the presence of cognitive decline,
behavioral abnormalities and chorea. HD is due to trinu-
cleotide (CAG) repeat expansion in the HTT gene encoding
the protein huntingtin in chromosome 4p with repeat expan-
sion of 39 or above causing full penetrance (Cardoso 2009).
The length of CAG expansion explains about 60–70% of
the variability regarding the age at onset (Cardoso 2009).
Juvenile-onset HD (JOHD) is diagnosed when the age at
onset is before 20 years. It is commonly related to long CAG
repeats (> 60 CAG repeats) and paternal inheritance in upto
90% of cases, representing between 3 and 10% of individuals
with HD (Lehman and Nance 2013; Nicolas et al. 2011; Cui
et al. 2017; Ribaï et al. 2007). These patients usually have
faster progression with shorter survival (Fusilli et al. 2018).
Although chorea is universally present in adult-onset HD, it
is exceptionally seen in JOHD. Instead these patients present
with akinetic-rigid parkinsonism, although dystonia, tics,
excessive blinking, cerebellar ataxia, spasticity, myoclonus,
sleep disturbances, pain and itching may also be observed
(Jankovic and Ashizawa 1995; Xing et  al. 2008; Rossi
Sebastiano 2012; Moser et al. 2017). Seizures are present in
about 40% of cases (Cloud et al. 2012). Although cerebellar
atrophy has been reported in some studies of JOHD (Latimer
et al. 2017; Hedjoudje et al. 2018), this finding has been
recently challenged (Tereschenko et al. 2019).
Huntington disease‑like disorders
Spinocerebellar ataxia type 17 (SCA17) is an autosomal
dominant disorder caused by repeat CAG/CAA expansion
in the TATA box-binding protein (TBP) gene (Yang et al.
2016). Age at onset varies from 3 to 55 years, patients pre-
sent with psychiatric symptoms followed by chorea, ataxia,
pyramidal signs and dementia, resembling HD (Toyoshima
and Takahashi 2018). SCA17 has been reported almost
exclusively among individuals of Asian background.
Hypomyelination with atrophy of basal ganglia and cer-
ebellum (H-ABC) is a progressive disease due to a domi-
nant de novo mutation of TUBB4A, which encodes tubulin
beta-4A. Patients present at about 6 months of age with
ataxia, spasticity, occasional seizures; prominent dystonia
and rigidity; and a small proportion present with choreo-
athetosis (Hamilton et  al. 2014). MRI shows prominent
cerebellar atrophy, hypomyelination and extremely small or
invisible putamen with normal-sized thalamus and globus
pallidus internus (GPi) (Hamilton et al. 2014). Mutations in
the same gene are associated with the disorder previously
known as DYT4, causing hereditary whispering dysphonia
for which phenotypic overlap exists with H-ABC (Erro et al.
2015; Lohmann et al. 2013). Other degenerative disorders
resembling HD usually present after 15 years of age and are
discussed elsewhere.
Epileptic–dyskinetic encephalopathies
Some genetic disorders may present with early encepha-
lopathy, prominent seizures and choreoathetosis and are
discussed in this section.
Forkhead Box G1 (FOXG1) is a transcriptional repressor
important for the development of the telencephalon. Patients
with FOXG1 gene mutations have postnatal microcephaly
resulting in severe developmental delay with no language
skills, seizures, and agenesis of the corpus callosum with
cortical thickening of the frontal lobe (Kortüm et al. 2011).
Chorea is frequently observed involving the upper limbs and
orolingual muscles with little or no fluctuations overtime.
It is often accompanied by dystonia, athetosis and hand-
mouthing stereotypies described as a “congenital variant of
Rett syndrome” (Bertossi et al. 2015).
The GNAO1 gene encodes the alpha subunit of the gua-
nine nucleotide-binding protein G(o), the most abundant
protein in the mammalian central nervous system (Feng et al.
2018). Mutations leading to reduced expression or loss of
function are associated with a severe form of early infan-
tile epileptic encephalopathy (Feng et al. 2017). In contrast,
mutations with gain-of-function are associated with devel-
opmental delay, hypotonia, prominent chorea and dystonia
in about half of cases with a typical age at onset of 4 years.
When the onset is around 14 years of age (Ananth et al.
2016; Menke et al. 2016), patients may present with comor-
bid ataxia, parkinsonism and seizures (Dhamija et al. 2016;
Arya et al. 2017). These dyskinesias are usually progres-
sive with severe exacerbations leading to status dystonicus,
requiring admissions to intensive care units (Schirinzi et al.
2019). Homozygous mutations in the G protein GPR88 are
related to learning disabilities, speech delay and chorea with
onset around 8–9 years of age (Alkufri et al. 2016).
Patients with αII-subunit mutations of the voltage-gated
sodium channel (SCN2A) may present chorea along with
13

intractable seizures, intellectual disability, autism, optic atro-
phy, hypersomnia, hypotonia and diverse brain abnormalities
(Baasch et al. 2014; Hackenberg et al. 2014; Liang et al.
2017). There is a mild phenotype with benign familial neo-
natal–infantile seizures. Missense mutations occurring de
novo explain the majority of cases (Kobayashi et al. 2016).
Hereditary disorders with prominent ataxia
and chorea
Chorea is a common manifestation in patients with heredi-
tary recessive ataxias (Pearson 2016). Ataxia telangiectasia
is secondary to mutations in the ATM gene that encodes a
serine–threonine kinase important for DNA repair (Nissen-
korn and Ben-Zeev 2015). It is characterized by immunode-
ficiency, malignancy predisposition and neurological impair-
ment manifested by progressive ataxia appearing between 1
and 4 years of age, usually with oculomotor apraxia (OMA),
whereas the typical oculocutaneous telangiectasia develops
several years later (Nissenkorn and Ben-Zeev 2015). A
milder phenotype with prominent chorea, dystonia, myo-
clonus and parkinsonism is well-recognized (Lohmann et al.
2015; Teive et al. 2018). Chorea may precede ataxia and
OMA (Klein et al. 1996) and is the initial manifestation in
10% of patients with a prevalence upto 89% over the course
of the disease (Levy and Lang 2018). Choreoathetosis seems
to be more common than dystonia in childhood, although the
latter takes over with ageing (Pearson 2016).
Ataxia with oculomotor apraxia (AOA) type 1 is caused
by mutations in the APTX gene, encoding aprataxin. Onset
is in the first decade of life with ataxia and OMA, followed
by cognitive impairment, progressive axonal sensorimotor
neuropathy, hypoalbuminemia, hypercholesterolaemia and
slight elevations of α-fetoprotein (AFP) (Shahwan et al.
2006; Renaud et al. 2018). Chorea is identified in about 40%
of cases, whereas dystonia and myoclonus are less frequent
(Renaud et al. 2018; Yokoseki et al. 2011). Chorea was pre-
sent in 79% of cases at onset in a study of 14 patients; but
eventually disappeared in most instances (Le Ber 2003).
Hyperkinesia seems to be more common in patients with
rapid disease progression (Le Ber 2003). Mutations in the
SEXT gene encoding senataxin causes AOA type 2. Patients
present in the second decade of life with cerebellar ataxia,
OMA, convergent strabismus, axonal neuropathy and ele-
vated AFP levels (Tazir et al. 2009). Chorea is reported in
9.5% of patients, whereas dystonia and head tremor occurred
in 14% of cases (Anheim et al. 2009).
Friedreich ataxia (FA) is caused by repeat expansion of
the GAA triplet in the X25 gene on chromosome 9, encoding
frataxin (Bürk 2017). The typical syndrome is observed in
patients with homozygous mutations, consisting with ataxia,
dysarthria, limb weakness, areflexia, abnormal propriocep-
tion and vibration sense and extensor plantar reflexes. At
13
J. F. Baizabal‑Carvallo, F. Cardoso
least 30% of patients develop cardiomyopathy and diabetes
(McDaniel et al. 2001). Atypical presentations with chorea
are more commonly observed in compound heterozygous
(GAA expansion on 1 allele and a point mutation in the
other allele), which represent 2–4% of cases with FA (Zhu
et al. 2002; Spacey et al. 2004). This has also been reported
in patients with typical homozygous mutations (Hanna et al.
1998). Chorea may precede ataxia for years although dysto-
nia is more commonly seen in FA (Hou and Jankovic 2003).
Mutations in SQSTM1 (sequestosome 1, also known as
p62) cause childhood-onset (6–15 years) cerebellar ataxia,
gaze palsy, cognitive decline, dysautonomia, tremor, dysto-
nia and choreoathetosis (Haack et al. 2016; Muto et al. 2018;
Zúñiga-Ramírez et al. 2019). Severe ataxia with mild or no
cerebellar atrophy on MRI is considered a major distinctive
feature (Muto et al. 2018). Patients usually have biallelic
mutations (Muto et al. 2018) although compound heterozy-
gous have also been described (Zúñiga-Ramírez et al. 2019).
SQSTM1 is a multidomain protein, which serves in multiple
autophagic processes. Loss of SQSTM1 function causes a
slowdown of autophagic flux and impaired production of
ubiquitin-positive protein aggregates following misfolded
protein stress (Haack et al. 2016).
ATP8A2 belongs to a group of P4-ATPases proteins that
actively translocate phosphatidylserine to the inner surface
of the membrane phospholipid bilayer, a process known as
“flipping”, maintaining lipid asymmetry. This is an essen-
tial property for neuronal cell survival and exosome release,
among other functions (Vestergaard et al. 2014; Andersen
et al. 2016; Naik et al. 2019). Mutations in the ATP8A2
gene causes an autosomal recessive disorder with several
genetic variants identified (McMillan et al. 2018). The usual
clinical phenotype is mental retardation, cerebellar ataxia
and disequilibrium (Onat et al. 2013; Cacciagli et al. 2010).
More recently described phenotype is characterized by early
onset (within 6 months of birth) microcephaly, optic atrophy,
severe cognitive impairment and hypotonia with prominent
chorea and athetosis (Martín-Hernández et al. 2016). Over-
all, less than 50% of patients have ophthalmoplegia, ptosis
and seizures. Neuroimaging may include delayed myelina-
tion, atrophy of cortical ribbon, corpus callosum and optic
nerves (McMillan et al. 2018).
Disorders with increased synaptic transmission
Mutations in the SYT1 gene encoding synaptotagmin-1 are
associated with mental and motor retardation, delayed visual
maturation, infantile hypotonia, sleep disturbances, dystonia,
stereotypies and choreoathetosis (Baker et al. 2015). Unpre-
dictable changes in behavioral pattern activity from calm to
agitate are reported in most cases (Baker et al. 2018). Lack
of epileptic seizures with abnormal EEG showing low-fre-
quency, intermittent, high-amplitude oscillations plus isolated
Chorea in children: etiology, diagnostic approach and management
epileptiform activity is characteristic (Baker et al. 2018). Syn-
aptotagmin-1 is implicated in several processes involving syn-
aptic transmission. Mutation of other proteins implicated in
synaptic transmission such as Munc13-1 and VAMP2 (syn-
aptobrevin-2) show a similar phenotype with developmental
delay, hypotonia, and complex dyskinesia including chorea
(Lipstein et al. 2017; Salpietro et al. 2019). A Munc13-1
mutation causes a gain of function leading to enhanced fusion
propensity of synaptic vesicles increasing the probability of
synaptic release and abnormal plasticity resulting in hyperki-
nesia (Lipstein et al. 2017).
Vascular chorea
Chorea in children may also have a vascular etiology. Chorea
precipitated by hyperventilation or emotional stress is seen
in patients with Moyamoya disease, a chronic cerebral vas-
culopathy with uni- or bilateral progressive occlusion of the
proximal carotid arteries with formation of an abnormal vas-
cular network at the brain base (Baik and Lee 2010). MDs
are rare in Moyamoya disease, they often have a paroxysmal
nature and present mainly in children (Pandey et al. 2010).
Hypoperfusion of subcortical areas is likely the pathogenic
mechanism for chorea which may improve dramatically fol-
lowing bypass surgery (Zheng et al. 2005; Kamijo and Matsui
2008). “Postpump chorea” presents within 2 weeks in about
1.2% of patients undergoing cardiopulmonary bypass surgery
(Medlock et al. 1993; Kupsky et al. 1995). It is commonly
accompanied by some degree of encephalopathy and predomi-
nates in children. Long extracorporeal circulation time, deep
hypothermia (core body temperature < 20 °C), variability in
blood pH and PaCOs have been suggested as predisposing
factors (Bisciglia et al. 2017; Przekop et al. 2011).
Metabolic disorders and miscellaneous
causes
Chorea may present in 20–40% of children with hereditary
metabolic disorders such as Lesch–Nyhan disease (HPRT
gene), methylmalonic aciduria and propionic acidemia
(Jankovic et al. 1988; Jinnah et al. 2010; Baumgartner et al.
2014). However, MDs phenomenology in patients with
hereditary metabolic disorders is frequently dominated by
dystonia, as it occurs with the majority of disorders within
this category such as Wilson disease (Jinnah et al. 2018).
Drug‑induced and functional (psychogenic)
chorea
Many drugs causing chorea in adults may also cause chorea
in children (Table 1) (Cardoso 2009). A subtype of tardive
dyskinesia known as withdrawal re-emergent syndrome,
presents in children usually with choreic movements after
discontinuing a dopamine receptor antagonist (Mejía and
Jankovic 2010). Patients with functional (previously known
as “psychogenic”) movement disorders (FMDs) can present
with any phenomenology including generalized dyskinesia
(Baizabal-Carvallo and Fekete 2015). In a meta-analysis of
reported FMDs in children, tremor followed by dystonia rep-
resented the most common phenomena, whereas true chorea
was uncommon at any age (Harris 2019; Baizabal-Carvallo
and Jankovic 2019).
Pathophysiology
According to the loop model that explains function and
connection between the cortex and basal ganglia, inhibitory
GABAergic projections from the GPi to the thalamus are
decreased in individuals with chorea allowing an increased
excitatory glutamatergic thalamic output to the motor, pre-
motor and supplementary motor cortices (Fig. 1a) (Cardoso
et al. 2006). Such thalamic disinhibition may result from
either: (1) increased activity of the GABAergic projec-
tions or (2) decreased subthalamic nucleus (STN) activity
in the “indirect” pathway, although this one usually leads
to hemiballismus. Pre- and postsynaptic molecular abnor-
malities (Fig. 1b) seem to create an imbalance between the
“direct” and “indirect” pathways resulting in chorea (Abela
and Kurian 2018).
Diagnostic approach
As the number of causes of childhood-onset chorea is large,
the diagnostic approach is not simple. Age at onset is impor-
tant when considering differential diagnosis. For example,
autoimmune disorders and SC rarely presents before 5 years
of age with the youngest reported case at the age of 3 years
(Cardoso 2017; Tani et al. 2003); whereas the majority of
hereditary causes of childhood chorea present before 5 years
of age and even in newborns. A complete clinical and family
history is of paramount importance, as well as the recog-
nition of accompanying manifestations; except for patients
with paroxysmal dyskinesia or ADCY-5 mutations, chorea
itself rarely provides a specific diagnostic. Table 4 provides
clinical, laboratory and neuroimaging findings guiding into
a specific diagnosis in children with chorea. Neuroimag-
ing sometimes provides diagnostic clues. Laboratory find-
ings may occasionally aid the diagnosis such as increased
α-fetoprotein or abnormal X-ray DNA breakage analysis in
subjects with hereditary ataxias (Rudolph et al. 1989). If
an autoimmune cause is suspected, testing for anti-nuclear,
antiphospholipid or anti-NMDAR antibodies is widely avail-
able and should be ordered. Other autoantibodies such as
13

Fig. 1  a Basal ganglia projections to the thalamus and cortex; the
direct pathway mediated by D1 dopaminergic receptors is composed
by GABAergic striatal projections to the GPi; whereas the “indirect
pathway” mediated by D2 receptors projects to the GPe, STN and
ultimately the GPi; a bilateral imbalance between both pathways
likely explains choreic movements; b molecular abnormalities at
the synaptic level caused either by the influence of antibodies, and
anti-basal ganglia are unspecific to diagnose SC and are only
available in research laboratories (Cardoso 2017).
Next-generation sequencing technologies have grown in
popularity as they permit identification of novel variants and
cost has exponentially declined (Seaby et al. 2016; Petersen
et al. 2017). Whole-exome sequencing (WES) has proven
useful to characterize genetic disorders, such as PRRT2 or
ATP1A3 (Seaby et al. 2016; Petersen et al. 2017). However,
WES is not suitable for intronic mutations, polynucleotide
repeats, gene deletions and duplications. Directed genetic
panels are a cost-effective option, guided by specific pheno-
types (Peall et al. 2014). A syndromatic-oriented approach
is provided in Fig. 2. Other techniques such as chromosomal
microarray (CMA) is used to estimate the copy number for
any genome segment and is able to identify microduplica-
tions or microdeletions beyond the resolution of G-banded
karyotype as in PRRT2 or NKX2-1 mutations (Miller et al.
2010; Dale et al. 2012a). Alternatively, Multiplex Ligation-
dependent Probe Amplification (MLPA) can be used for
13
J. F. Baizabal‑Carvallo, F. Cardoso
hereditary or de novo mutations underlie the imbalance between basal
ganglia pathways. At the presynaptic level a number of mechanisms
implicated in vesicular release are implicated in choreic syndromes.
At postsynaptic neurons cAMP modulates PKA activity, which phos-
phorylates important downstream effectors such as DARP-23 and
CREB. Increased intracellular levels of cAMP have been implicated
in chorea
example to detect NKX2-1 mutations when direct sequenc-
ing fails (Teissier et al. 2012).
Management
There are few randomized trials evaluating therapy for chil-
dren chorea. Current evidence is of poor quality, relying on
single case reports and case series. For patients with DCP,
trihexyphenidyl has been traditionally used, but a small ran-
domized trial did not show significant motor benefit (Masson
et al. 2017; Rice and Waugh 2009; Harvey et al. 2018). Lev-
odopa, neuroleptics and levetiracetam have been reported to
improve dyskinesia and fine motor skills in these patients
(Kamate et al. 2018; Vles et al. 2009).
Aggressive immunosuppression is warranted for most
patients with autoimmune disorders, including both types of
anti-NMDAR encephalitis, isolated and post-HSE (Table 5)
(Sutcu 2016; Mohammad et al. 2014). The exception to this
Chorea in children: etiology, diagnostic approach and management

Table 4  Clinical, laboratory and neuroimaging features suggesting a diagnostic in children with chorea
Disorder Red flags

Dyskinetic cerebral palsy Early life insult, stable chronic course

Sydenham chorea Recent GABHS infection
Cardiac involvement or other Jones criteria
Basal ganglia encephalitis Recent infection or vaccination
MRI: BG hyperintensities
Anti-NMDAR encephalitis Rapidly progressive psychosis, behavioral changes, movement disorders, dysautonomia and altered level
of consciousness
Systemic lupus erythematosus Malar rash, oral ulcers, arthritis, photosensitivity, kidney and hematological damage
Antiphospholipid syndrome Thrombotic episodes, miscarriages
Benign hereditary chorea Thyroid and lung abnormalities. Multiple movement disorders may persist into adulthood
ADCY mutation Chorea is exacerbated by drowsiness, may present upon awakening or as nocturnal paroxysmal episodes
Syndromes of paroxysmal dyskinesia Paroxysmal onset of chorea or dystonia with various triggers
Huntington disease Cognitive and behavioral problems. Positive family history
SCA17 Similar to HD, Asian population
H-ABC MRI: severe cerebellar atrophy, hypomyelination and extremely small putamen
Epileptic–dyskinetic encephalopathies Hand-mouthing stereotypies (FOXG1); status dystonicus (GNAO1)
Ataxia telangiectasia Immunodeficiency, predisposition for malignancy, telangiectasia (late onset)
AOA-1, AOA-2 Axonal neuropathy, elevated α-fetoprotein
Friedreich ataxia Cardiomyopathy, diabetes, abnormal proprioception and vibration sense
SQSTM1 mutation Severe ataxia with MRI showing mild or no cerebellar atrophy
ATP8A2 mutation MRI: delayed myelination, atrophy of cortical ribbon, corpus callosum and optic nerves
SYT1 mutation Unpredictable and severe changes in behavioral pattern activity. Lack of epileptic seizures with abnor-
mal EEG
Vascular chorea Chorea precipitated by hyperventilation, recent history of cardiac surgery. MRI: vessels with signal
voids in BG
Lesch–Nyhan disease Self-injurious behavior, hyperuricemia
Methylmalonic aciduria (MMA) and Chronic kidney disease (MMA), cardiomyopathy (PA)
propionic academia (PA) (late onset)
Wilson disease Kayser–Fleischer rings, liver damage, low ceruloplasmin
Drug induced Exposure or withdrawal from certain drugs
Functional “Psychogenic” disorders Distractibility, suggestibility, incongruous clinical finding

AOA ataxia with oculomotor apraxia types 1 and 2, BG basal ganglia, GABHS group A β-hemolytic streptococcus

rule is SC where patients usually do not require immuno-
therapy and respond to valproate, carbamazepine or dopa-
mine receptor blockers; whereas corticosteroids are usually
reserved for patients who fail to respond to these drugs (Car-
doso et al. 2003; Dean and Singer 2017).
Tetrabenazine is a VMAT-2 inhibitor, which depletes
dopamine from the basal ganglia. This medication is highly
useful for HD chorea, and can be used for some etiologies
of children chorea. Deutetrabenazine and valbenazine are
newer agents sharing the same mechanism of action of tetra-
benazine. However, there is little, if any, evidence in support
of their use in children. Tetrabenazine provided benefit in
about two-thirds of patients with NKX2-1-related chorea
(Gras et al. 2012), whereas low-dose dopamine receptor
antagonists (DRA) are poorly tolerated and may exacer-
bate chorea in some instances (Konishi et al. 2013; Ferrara
et al. 2012). These agents may be useful in patients with
comorbid psychosis. Interestingly, levodopa, a medication
with the opposite mechanism of action, may also provide
benefit for NKX2-1 related chorea and drop attacks (Iodice
et al. 2019; Rosati et al. 2015; Asmus et al. 2005; Shiohama
et al. 2018). It has also proved useful in some patients with
SQSTM1 dyskinesia (Muto et al. 2018). ADCY-5-related
dyskinesias do not seem to respond to antidopaminergic
therapy. Improvement has been reported in selected patients
with clobazam, clonazepam, propranolol, acetazolamide and
methylphenidate (Chang et al. 2016; Douglas et al. 2017;
Tübing et al. 2018).
The PKD responds to a variety of antiepileptic drugs
(AED) (Tables 2 and 3) (van Rootselaar et al. 2009; Strzelc-
zyk et al. 2011; Chatterjee et al. 2002; Huang et al. 2005) but
may resolve spontaneously over time (Lotze and Jankovic
2003). In contrast, patients with SYT1 mutations are usually
resistant to AED (Baker et al. 2018). Treatment of Glut1

13


13
Fig. 2  Algorithm suggesting possible etiologies for diverse presentations in children with chorea. Mut mutation
J. F. Baizabal‑Carvallo, F. Cardoso
Chorea in children: etiology, diagnostic approach and management

Table 5  Summary of drugs used to treat chorea in children and adolescents

Medication class Doses Suggested indications Common or severe side effects

Immunomodulators
 Corticosteroids 1–1.5 mg/kg/day Autoimmune encephalitis Hyperglycemia, hypertension, weight gain, acne
 Immunoglobulin IV 2 g/kg in 2–5 days Autoimmune encephalitis Anaphylaxis, thrombosis, meningitis, renal
failure
 Rituximab 375 mg/m2 weekly Autoimmune encephalitis Allergic reactions, neutropenia, infections
 Anakinra SC 1–8 mg/kg/day CAPS Site-injection reactions, neutropenia, infections
VMAT2 inhibitors
 Tetrabenazine (TBZ) 12.5 qd–50 mg tid HD, NKX2.1-associated disease, Parkinsonism, depression, akathisia, insomnia,
Anti-NMDAR encephalitis sedation (check CYP2D6 status)
 Deutetrabenazine 6–48 mg/day HD, TD Similar to TBZ
 Valvenazine 40–80 mg/qd TD Somnolence, anticholinergic effects, falls,
headache, akathisia
Dopaminergic medications
 Levodopa 25–600 mg/day* NKX2.1- associated disease, Nausea, drowsiness, hallucinations
SQSTM1, Lesch–Nyhan
Dopamine receptor antagonists (DRA)
 Haloperidol 4–5 mg/day tid Sydenham chorea Dystonia, akathisia, parkinsonism, tremor, TD,
NMS
 Risperidone 0.5–4 mg/day bid SLE, APS Similar to other DRA
 Pimozide 0.05–0.2 mg/kg/day Sydenham chorea, FOXG1-mut Similar to other DRA, EKG changes (check
CYP2D6)
Antiepileptics
 Valproic acid 15–40 mg/kg/day Sydenham chorea Drowsiness, tremor, weight gain
 Carbamazepine 10–20 mg/kg/day Sydenham chorea Drowsiness, dizziness, nausea, vomiting, ataxia
 Clobazam 0.2 mg/kg ADCY5- mut Drowsiness, fatigue, aggression, ataxia,
insomnia
 Topiramate 25–400 mg/day GNAO1-mut., PRRT2 mut Changes in taste perception, paresthesia, ano-
rexia, lithiasis
 Phenytoin 4–8 mg/kg/day PRRT2 mut Gingival hyperplasia, nystagmus, ataxia, seda-
tion
 Levetiracetam 14–60 mg/kg/day bid PRRT2 mut Nervousness, mood swings, headache, ataxia
Benzodiazepines
  Clonazepam 0.01–0.20 mg/kg ADCY5-mut Sedation, hypotonia, fatigue ataxia
Beta-blockers
 Propranolol 10–40 mg tid ADCY5-mut Fatigue, bradycardia, vivid dreams, hypergly-
cemia
Stimulants
 Methylphenidate IR 5–30 mg/day NKX2-1 mut., ADCY5-mut Hypersensitivity reactions, decreased appetite,
 Methylphenidate SR 36–54 mg/day NKX2-1 mut., ADCY5-mut insomnia, agitation, tachycardia, dyskinesia
including choreoathetosis (both preparations)
Other
 Acetazolamide 5–8 mg/kg/day Glut1-deficiency syndromes Paresthesia, anorexia, nausea, diarrhea, polyuria
Diet
 Ketogenic-diet 3:1 fat to protein and CHO Glut1-deficiency syndromes May exacerbate chorea and other MDs
 Triheptanoin 1 g/kg/day in 3–4 intakes Glut1-deficiency syndromes Replenish the pool of metabolic intermediates;
it can produce C5-ketones

*Doses may be higher depending on body weight

APS antiphospholipid syndrome, CAPS cryopyrin-associated periodic syndromes, CHO carbohydrates, mut mutation, NMS neuroleptic malig-
nant syndrome, TD tardive dyskinesia, SLE systemic lupus erythematosus, SC subcutaneous injection

deficiency syndromes is based on ketogenic diet supple-
mented with l-carnitine. However, this therapy may be more
efficient for seizures than for MDs, and low compliance is
not uncommon, particularly in adults. In these instances,
triheptanoin, an odd-chain triglyceride, has proven effective
in a small trial (Friedman et al. 2006; Mochel et al. 2016).
Attacks of exercise-induced dyskinesia are usually resistant
to treatment with levodopa or AEDs, but may improve with
acetazolamide (Strzelczyk et al. 2011; Ramm-Pettersen et al.
2013). The MDs of FOXG1 respond poorly to antidyskinetic

13

drugs, although pimozide has provided anecdotic benefit
(Cellini et al. 2016). Chorea in patients with GNAO1 muta-
tions seems to be progressively refractory to tetrabenazine
or antidopaminergic therapy, although anecdotic improve-
ment with topiramate was reported (Sakamoto et al. 2017).
GPi DBS has been reported to improve the exacerbations of
MDs in these cases (Kulkarni et al. 2016; Koy et al. 2018;
Waak et al. 2018).
GPi DBS has proven beneficial in childhood chorea with
poor response to pharmacological therapy (Elia et al. 2018).
This therapy can improve functional disability, pain, and
quality of life in patients with DCP (Vidailhet et al. 2009).
GPi DBS has provided robust benefit in some disorders such
as ADCY-5-related dyskinesia (Dy et al. 2016), but limited
success in others including JOHD (Ferrea et al. 2018).
Concluding remarks
Chorea in children has a wide variety of etiologies, identi-
fying the cause is important in order to provide appropri-
ate treatment and prognosis. As these patients may survive
into adulthood and have persistent chorea, the topic is criti-
cal for clinicians taking care of patients with hyperkinetic
movements.
Author contributions  Dr. Baizabal-Carvallo: research project—con-
ception, organization, execution; manuscript—writing of the first
draft, review and critique. Dr. Cardoso: research project—conception,
organization, execution; statistical analysis: review and critique; manu-
script—review and critique.
Funding None.
Compliance with ethical standards  tional movement disorders. Mov Disord Clin Pract 7:182–187
Conflict of interest  Dr. Baizabal-Carvallo has received royalties from
Medlink Neurology, Dr. Baizabal-Carvallo serves as Associated Editor
in BMC Neurology. Dr. Cardoso has received honorarium for advisory
board of Roche. The authors declare that they have no conflict of in-
terests.
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