Chorea 9

Chorea REVIEW ARTICLE

By Pichet Termsarasab, MD C O N T I N U UM A U D I O
I NT E R V I E W A V A I L AB L E
ONLINE

ABSTRACT VIDEO CONTENT
PURPOSE OF REVIEW: Thisarticle provides an overview of the approach A V AI L A B L E O N L I N E
to chorea in clinical practice, beginning with a discussion of the

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phenomenologic features of chorea and how to differentiate it from

other movement disorders. The diagnostic approach, clinical features of
important acquired and genetic choreas, and therapeutic principles are
also discussed. Practical clinical points and caveats are included.
CITE AS:
CONTINUUM (MINNEAP MINN)
RECENT FINDINGS: C9orf72 disease is the most common Huntington disease 2019;25(4, MOVEMENT DISORDERS):
1001–1035.
phenocopy, according to studies in the European population. Anti-IgLON5
disease can present with chorea. The role of immunotherapies in
Address correspondence to
Sydenham chorea has increased, and further clinical studies may be useful. Dr Pichet Termsarasab,
Benign hereditary chorea is a syndrome or phenotype due to mutations in Ramathibodi Hospital, Mahidol
University, Bangkok, Thailand,
several genes, including NKX2-1, ADCY5, GNAO1, and PDE10A. New-generation [email protected].
presynaptic dopamine-depleting agents provide more options for
symptomatic treatment of chorea with fewer adverse effects. Deep brain RELATIONSHIP DISCLOSURE:
Dr Termsarasab serves as
stimulation has been performed in several choreic disorders, but features associate editor of the Journal
other than chorea and the neurodegenerative nature should be taken into of Clinical Movement Disorders
consideration. Studies on genetic interventions for Huntington disease and on the editorial board
of Brain Science Journal.
are ongoing. Dr Termsarasab has received
personal compensation for
SUMMARY: Clinical features remain crucial in guiding the differential speaking engagements for the
American Academy of
diagnosis and appropriate investigations in chorea. Given the complexity Neurology and Novartis AG and
of most choreic disorders, treating only the chorea is not sufficient. A receives publishing royalties
comprehensive and multidisciplinary approach is required. from MedLink Neurology.
UNLABELED USE OF
PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
INTRODUCTION
Dr Termsarasab discusses the
C
horea is derived from the Greek word χορεία, meaning dance. unlabeled/investigational
It is characterized by the random and flowing quality of the use of the current
recommended treatments of
movements, giving it a dancelike appearance. Randomness is the chorea, none of which are
key phenomenologic feature in the identification of chorea. The approved by the US Food and
movements typically flit from one body region to another in an Drug Administration except the
use of deutetrabenazine for the
unpredictable fashion. treatment of chorea associated
The differential diagnosis of chorea is broad. However, with clinical features with Huntington disease and
including demographic data, time course, associated medical and neurologic tardive dyskinesia,
tetrabenazine for the treatment
features, and known prevalence, the search for the etiology of chorea can be of chorea associated with
performed efficiently. A “shotgun approach” can be reserved for when no diagnostic Huntington disease, and
valbenazine for the treatment of
clues are present. This article discusses the general diagnostic approach to chorea,
tardive dyskinesia.
clinical clues to common and important choreic disorders, and therapeutic principles.
The first section of the article discusses general phenomenologic features of
chorea and how to differentiate chorea from other movement disorders. The next © 2019 American Academy
section covers the general approach to chorea, beginning with the three body of Neurology.
CONTINUUMJOURNAL.COM 1001
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

CHOREA
distributions that can be an important clue. A proposed practical approach to

chorea is presented, and how other clinical information can serve as diagnostic
clues is discussed. Selected important acquired and genetic etiologies of chorea
are discussed in subsequent sections, and paroxysmal movement disorders that
can present with chorea are also briefly discussed. Therapeutic principles of
chorea are delineated in the final section.
PHENOMENOLOGIC FEATURES OF CHOREA

In addition to the two main phenomenologic features of randomness and a
flowing quality, patients with chorea often blend or incorporate the chorea into
their normal movements, as if they are attempting to hide it. This phenomenon
is called parakinesia. For example, when chorea is present in the arm, a patient
may try to blend chorea by lifting or moving the arm to a target in the same
direction as the choreic movements.
Another feature of chorea is motor impersistence. This is not only seen in
Huntington disease (HD) or Sydenham chorea but also in other causes of chorea.
It is defined by an inability to perform sustained motor activities. Two tasks that
should be examined clinically include tongue protrusion and handgrip. Tongue
protrusion cannot be maintained, and the tongue retracts back into the mouth after
several seconds. For handgrip, when a patient attempts to squeeze an examiner’s
fingers, waxing-and-waning grip strength (called milkmaid’s grip) can be felt.
Ballism is a variant of chorea characterized by large-amplitude flinging
movements involving proximal extremities (VIDEO 6-1, links.lww.com/CONT/A351).
The diagnostic and treatment approaches for ballism are the same as for chorea.
Athetosis (“without fixed position”), originally described in 1871 by William
Hammond, remains controversial. While some experts categorize athetosis as a
variant of chorea, it has been argued to be a form of dystonia by others.1 Athetosis is
characterized by slow writhing movements typically involving distal extremities,
although other body parts, such as the face, can be involved. When dystonia, such
as dystonic hand posturing, coexists with flowing movements, it is sometimes
difficult to separate athetosis from dystonia, resulting in the so-called
dystonic-choreoathetoid movements seen in cerebral palsy.
The velocity of chorea can vary. The flowing component of chorea is usually faster
than that of dystonia but not as fast as the jerking component of myoclonus. However,
when chorea has a quick velocity along with low amplitude, it may appear quite
jerky and can be mistaken as myoclonic jerks. Chorea has a wide variation of severity;
patients with a mild degree can appear fidgety, and thus chorea may be overlooked.
Therefore, it is important to observe patients with their socks off and legs hanging from
the examination table to examine small choreic movements in the feet and toes.
DIFFERENTIATING CHOREA FROM OTHER ABNORMAL MOVEMENTS

Dystonia can have motor overflow mimicking the flowing movements of chorea,
but an abnormal posturing typically coexists. In addition, dystonia produces
patterned movements that are predictable, in contrast to the randomness of
chorea. Sensory tricks, a null point, and mirror movements are supportive
features of dystonia. Dystonic tremor that is usually irregular and jerky, when
present, is clinically distinct from the flowing quality of chorea.
As mentioned earlier, chorea with a quick velocity may resemble myoclonic
jerks, but the randomness of chorea distinguishes the two. In addition, the
jerks in chorea are not as brief as those in myoclonus, which are “lightninglike”
1002 AUGUST 2019

because of typical burst durations of less than 200 milliseconds. Stimulus KEY POINTS
sensitivity, if present, also supports the identification of myoclonus. However,
● Randomness is the key
when the jerks are frequent, stimulus sensitivity may be difficult to assess, and phenomenologic feature of
spontaneous jerks should not be mistaken as stimulus sensitive. chorea.
Common movement patterns and body distribution, such as eye blinking or
shoulder shrugging, help identify tics. However, with uncommon patterns of ● Chorea with quick
velocities may look jerky,
tics, the presence of a premonitory urge and suppressibility will help distinguish
resembling myoclonic jerks.
them from chorea.
Stereotypies, as seen in anti–N-methyl-D-aspartate (NMDA) receptor
encephalitis or tardive syndrome with orobuccolingual involvement, can have a
flowing quality similar to chorea. However, its stereotypic pattern, as if the same
video is running in a repetitive loop, distinguishes it from chorea.
Large-amplitude cerebellar outflow tremor with proximal extremity
involvement may look similar to chorea. However, regular oscillation around the
axis and activation of the tremor with movements (postural and kinetic
components) distinguish it from chorea.
APPROACH TO CHOREA
Given an extensive differential diagnosis, chorea can be challenging to many
clinicians. Nevertheless, there are some important clinical features that can
serve as diagnostic clues to the specific diagnosis. These include three body
distributions and other crucial features.
FIGURE 6-1
Body distribution as a phenomenologic clue in chorea. The differential diagnoses are
demonstrated in each distribution.
PKAN = pantothenate kinase–associated neurodegeneration.
a
Locations outside the subthalamic nucleus can also be involved.

CHOREA
Body Distribution as a Clue

While the list of disorders presenting with generalized chorea is extensive, three
body distributions carry a more limited number of possible diagnoses and serve
as useful diagnostic clues (FIGURE 6-1). These include hemichorea,
orobuccolingual, and forehead distributions.
HEMICHOREA. Lesions leading to hemichorea are classically localized to the

contralateral subthalamic nucleus. However, the lesions are not restricted to the
subthalamic nucleus and can be located in other anatomic locations, such as the
contralateral basal ganglia or corona radiata.2 Systemic disorders, such as
nonketotic hyperglycemia and polycythemia vera, can also present with
hemichorea or very asymmetric involvement.3,4 Sydenham chorea can also have
a very asymmetric presentation or even hemichorea. Therefore, systemic
CASE 6-1 A 77-year-old woman presented with abnormal movements of her left
arm, left leg, and left face. She had a history of type 2 diabetes mellitus
and poor compliance. She had run out of her medications and not taken
them for 2 weeks before developing abnormal flinging movements of her
left arm upon waking up in the morning, followed a few days later by
movements in her left leg and left face. The movements had gradually
become worse over the week, prompting her to seek medical attention.
On presentation to the hospital, examination revealed left
hemichorea/hemiballism involving her left arm, left leg, and left face
(VIDEO 6-2, links.lww.com/CONT/A352). The chorea abated during sleep.
Blood testing on presentation showed a glucose level of 445 mg/dL and
hemoglobin A1c of 12%. She had no ketosis.
The diagnosis of left hemichorea/hemiballism secondary to nonketotic
hyperglycemia was made, which was initially managed by IV and
subcutaneous insulin. Her oral diabetic medications were resumed, with
improvement in her blood glucose level. MRI of the brain revealed a
hyperintense signal on T1-weighted images in the right (contralateral)
putamen (FIGURE 6-2A). A faint hyperdense signal could also be seen on a
CT scan without contrast in the same region (FIGURE 6-2B).
Her chorea was not adequately improved with blood glucose control
alone, and haloperidol was started at 0.5 mg/d with about 50%
improvement in her hemichorea. The dose was then increased to 0.5 mg
2 times a day with further improvement. She required low-dose
haloperidol for several weeks before the chorea subsided.
COMMENT The acute temporal profile in this patient is suggestive of an acquired cause
of chorea. Hemichorea/hemiballism can be a manifestation of systemic
disorders such as nonketotic hyperglycemia or polycythemia vera.
Nonketotic hyperglycemia is common among Asian populations, especially
women (this patient was from Thailand). Blood glucose control serves as a
specific treatment, but most patients will also need symptomatic
therapies, as chorea may take several weeks or months to resolve.
1004 AUGUST 2019

etiologies should always be kept in the differential diagnosis, especially when
neuroimaging does not reveal any structural lesions.
Nonketotic hyperglycemia–induced hemichorea is common in Asians,
especially women. With a high index of suspicion, diagnosis can easily be made
by blood glucose testing, even in patients with no previous history of diabetes
mellitus.5 MRI of the brain typically demonstrates a hyperintense signal in the
putamen and caudate nuclei on T1-weighted images, usually more prominent on
the side contralateral to hemichorea. While blood sugar control is the therapeutic
mainstay, symptomatic treatment of chorea for at least several weeks or a few
months is also often needed (CASE 6-1).
OROBUCCOLINGUAL INVOLVEMENT. Choreic movements in the orobuccolingual
or lower cranial region are classically seen in tardive syndrome and acquired
FIGURE 6-2
Imaging of the patient in CASE 6-1 with nonketotic hyperglycemia. A, Axial T1-weighted MRI
shows hyperintense signal in the right putamen (red arrow), contralateral to the side of
hemichorea. B, CT scan of the same patient demonstrates mild hyperdensity in the same
region (white arrow).

CHOREA
hepatocerebral degeneration. Of note, in tardive syndrome with orobuccolingual

involvement, stereotypy may be a more precise phenomenologic term, since
the movements are often repetitive. Lateral lingual movements, as if the patient
has candy in his or her cheek (called the bonbon sign), can be seen in patients with
orobuccolingual involvement in tardive syndrome. Levodopa-induced dyskinesia
in multiple system atrophy tends to involve the orobuccolingual region, as
opposed to limb dyskinesia in classic Parkinson disease.
In some choreic disorders, dystonia (not chorea) in the orobuccolingual
region can coexist. These include neuroacanthocytosis syndromes,
neurodegeneration with brain iron accumulation disorders such as pantothenate
kinase–associated neurodegeneration and neuroferritinopathy, X-linked
dystonia-parkinsonism (also known as Lubag disease), Wilson disease, and
Lesch-Nyhan syndrome.
Neuroacanthocytosis syndromes are a group of disorders in which progressive
neurodegeneration is associated with acanthocytes.6 The two main disorders
are chorea-acanthocytosis (autosomal recessive inheritance) and McLeod
syndrome (X-linked inheritance). Chorea-acanthocytosis can present with
severe tongue protrusion dystonia, especially when eating, or feeding dystonia,
which can interfere with appropriate oral intake and cause lip and tongue biting.
In contrast, orobuccolingual involvement, including feeding dystonia, is much
less commonly seen in McLeod syndrome. Of note, when considering disorders
that can present with oromandibular dystonia and self-mutilating behavior,
Lesch-Nyhan syndrome is also in the differential diagnosis, in addition to
chorea-acanthocytosis. Lesch-Nyhan syndrome is an X-linked recessive disorder
that typically has an onset within the first few years of life, whereas onset of
chorea-acanthocytosis is usually in early adulthood.
FOREHEAD CHOREA. Forehead muscles are often involved in HD, in which

wiggling of the eyebrows or activation of the frontalis muscle can be seen.7
Forehead involvement can be a useful supportive clinical feature to distinguish
HD from tardive dyskinesia, in which the forehead is usually spared. However,
cases of HD without forehead chorea and cases of tardive dyskinesia with
forehead involvement can sometimes be seen.
DIAGNOSTIC APPROACH
Useful diagnostic clues include demographic data (eg, age, gender, and
ethnicity); family history; coexisting movement phenomenology such as
dystonia, myoclonus, or tics; and associated clinical features, such as seizures,
neuropathy, and myopathy. Given the broad differential diagnosis of chorea, the
clinical approach can be challenging to clinicians. A proposed practical clinical
approach is illustrated in FIGURE 6-3. The three most crucial features are time
course, age group, and known prevalence.
As a general rule, acquired or sporadic causes of chorea usually present with
an acute or subacute temporal profile, whereas genetic causes are chronic
(longer than 1 year in duration). It is crucial to identify acquired causes, as many
of them are treatable. Autoimmune etiologies should always be included in the
differential diagnosis, especially in subacute presentations; these disorders
typically respond to immunotherapies, including IV immunoglobulin (IVIg),
steroids, other immunosuppressive agents, and plasma exchange. In recent
years, the number of autoimmune neurologic disorders has been expanding
with advances in neuroimmunology and identification of novel autoantibodies.
1006 AUGUST 2019

KEY POINTS
● Chorea in one of three

body distributions
(hemichorea,
orobuccolingual
involvement, and forehead
chorea) can serve as a clue
to narrow down the
differential diagnoses.
● Structural lesions and

systemic disorders (such as
nonketotic hyperglycemia
and polycythemia vera) can
cause hemichorea.
● Sydenham chorea can

present with hemichorea or
very asymmetric
involvement.
FIGURE 6-3 ● The time course can help

Diagnostic approach to chorea. classify chorea into acquired
BHC = benign hereditary chorea; SCA17 = spinocerebellar ataxia type 17. and genetic etiologies.
a
The association between the temporal profile and sporadic versus genetic causes of chorea is only a
general rule. In clinical practice, overlaps (ie, genetic chorea with temporal profile of less than 1 year) can ● Age group and known
occur, but these are not common. prevalence are very
important diagnostic clues
in chorea.
Age group and known prevalence are also crucial diagnostic clues in chorea. In
the pediatric population, Sydenham chorea is the most common cause of ● The most common
acquired chorea and the most common among all choreic disorders, excluding acquired chorea in children
choreoathetoid cerebral palsy. In adults, HD is by far the most common genetic is Sydenham chorea.
cause, whereas C9orf72 disease is the second most common according to studies
● The most common
in the European population8 and spinocerebellar ataxia type 17 (SCA17) is the genetic chorea in adults is
third. Before the discovery of the C9orf72 gene, SCA17 was thought to be the Huntington disease,
second most common genetic cause of chorea. In 2011, C9orf72 gene mutations followed by C9orf72 disease
with the GGGGCC hexanucleotide repeat expansion were discovered in familial and spinocerebellar ataxia
type 17.
frontotemporal dementia with amyotrophic lateral sclerosis. Subsequently, the
clinical spectrum has broadened, and studies in HD phenocopies (patients with ● The most common
negative HD gene testing) revealed that C9orf72 disease is even more common than genetic chorea in children is
SCA17. The most common genetic cause of chorea in children is benign hereditary benign hereditary chorea.
chorea. It is important to note that when a child presents with chorea, the diagnosis
● A negative family history
is very unlikely to be HD, since juvenile HD typically presents with parkinsonism does not exclude genetic
(also known as the Westphal variant), dystonia, and seizures, rather than chorea. causes of chorea.
While family history can be a helpful diagnostic clue, a negative family history
does not exclude the possibility of having a genetic chorea. This can be due to
nonpaternity, incomplete penetrance, de novo mutations, or undiagnosed
affected parents with symptoms, such as depression or suicidality, incorrectly
attributed to other causes. Common genetic causes of chorea, including HD,
C9orf72 disease, SCA17, and benign hereditary chorea, are autosomal dominant.
In most repeat expansion disorders such as HD, larger numbers of repeats occur
in successive generations and are associated with earlier age at onset. This
phenomenon is called anticipation and has been reported in C9orf72 disease9 but
much less frequently in SCA17. Absence of male-to-male transmission is a

CHOREA
TABLE 6-1 Acquired Causes of Choreaa
Category Examples
Structural lesion Vascular causes: ischemic and hemorrhagic strokes,

vascular malformation (eg, Moyamoya syndrome)
Tumors
Demyelinating lesions
Metabolic/endocrine Nonketotic hyperglycemia
Hypoglycemia
Hypocalcemia
Hyponatremia/hypernatremia
Uremia
Acquired hepatocerebral degeneration
Hyperthyroidism
Hypoparathyroidism/hyperparathyroidism
Infectious Toxoplasmosis
HIV encephalopathy
Prion diseases
Drug-induced Levodopa
Cocaine (“crack-dancing”)
Amphetamine
Anticonvulsants
Lithium
Anticholinergics
Neuroleptic withdrawal
Autoimmune/paraneoplastic Sydenham chorea
Rheumatologic diseases: systemic lupus erythematosus,

antiphospholipid antibody syndrome, systemic sclerosis
Autoimmune neurologic syndromes: anti–CRMP-5,

anti-NMDA, anti-Hu (ANNA-1), anti-Yo, anti-LGI1, anti-
CASPR2, anti-GAD65, anti-IgLON5
Other Polycythemia vera
Postpump chorea
ANNA-1 = antineuronal nuclear antibody type 1; CASPR2 = contactin-associated proteinlike 2;

CRMP-5 = collapsin response mediator protein-5; GAD65 = glutamic acid decarboxylase 65; HIV = human
immunodeficiency virus; LGI1 = leucine-rich glioma inactivated 1; NMDA = N-methyl-D-aspartate.
a
Modified with permission from Termsarasab P.11 © 2017 American Academy of Neurology.
1008 AUGUST 2019

hallmark of X-linked disorders, examples of which include McLeod syndrome KEY POINTS
and Lesch-Nyhan syndrome. Notably, while much more common in males,
● Huntington disease–like 2
females can also be affected because of skewed inactivation of X chromosomes. is almost exclusively seen in
Ethnicity can be an important diagnostic clue. For example, Huntington patients with African
disease–like 2 (HDL2) is almost exclusively seen in patients with African ancestry ancestry.
and has been reported to be a common cause of HD phenocopies in South African
● Autoimmune chorea
patients with African ancestry.10
should be included in the
differential diagnoses of
ACQUIRED CAUSES OF CHOREA chorea with a subacute
The list of acquired causes of chorea is extensive but can be grouped into at least temporal profile.
six categories, including structural, metabolic/endocrine, infectious, drug-
induced, autoimmune/paraneoplastic, and others (TABLE 6-111). Among these,
levodopa-induced chorea (or dyskinesia) is the most common acquired cause
encountered in movement disorders clinics.
Chorea can be an initial presentation in several disorders, such as
polycythemia vera, systemic lupus erythematosus (VIDEO 6-3, links.lww.com/
CONT/A353), antiphospholipid antibody syndrome, and diabetes mellitus (with
nonketotic hyperglycemia). Therefore, an absence of a known underlying medical
problem should not dissuade clinicians from considering that particular etiology.
Autoimmune and paraneoplastic etiologies are considered “don’t miss,”
diagnoses, especially when a patient presents with a subacute time course, since
they can be treated with immunotherapies. In adults, autoimmune etiologies
include anti-Hu, anti–collapsin response mediator protein-5 (CRMP-5),
anti-NMDA receptor encephalitis, anti–leucine-rich glioma inactivated 1 (LGI1),
anti–contactin-associated proteinlike 2 (CASPR2), and antistriational antibody
diseases.12 With more clinical recognition of anti-NMDA receptor encephalitis in
the past decade, a variety of associated movement disorders, including chorea,
dystonia, and myoclonus, have been reported. Stereotypic movements in
orobuccolingual muscles, arms, and legs are characteristic. A 2018 study found that
dystonia, chorea, and stereotypies are the most common abnormal movements in
this disorder.13 Some patients may have been misdiagnosed with tardive
dyskinesia, but important clues are an encephalopathic clinical picture and no
previous history of neuroleptic use. It is crucial to search for an underlying tumor
or malignancy in some of these autoimmune/paraneoplastic disorders (eg, ovarian
teratoma in women with anti-NMDA receptor encephalitis).
Anti-IgLON5 disease has recently been described.14,15 Clinical features
include obstructive sleep apnea, rapid eye movement (REM) and non-REM
parasomnias, dementia, chorea, and vertical supranuclear gaze palsy. Parasomnia can
manifest as finalistic behaviors during sleep in which a patient acts as if he or she is
performing work activities, such as installing an antenna or threading electrical wires.
Despite being an autoimmune disorder, most patients with anti-IgLON5 disease have
a chronic temporal profile longer than 1 year. Earlier detection may be possible when
the disorder is better recognized. Interestingly, neuropathologic studies of anti-IgLON5
disease also demonstrated neurodegeneration with mixed 3-repeat and 4-repeat
tauopathy.16 Further studies may provide insight on the link between autoimmunity
and neurodegeneration and determine which is primary in the pathogenesis.
In children, Sydenham chorea (VIDEO 6-4, links.lww.com/CONT/A35417)
is the most common autoimmune chorea. When considering rheumatic heart
disease in the era of antibiotics, it remains a health care burden worldwide with
higher prevalence in some geographic distributions. In the United States,

CHOREA
Sydenham chorea is still the most common cause of chorea in the pediatric
population, after choreoathetoid cerebral palsy. Patients typically develop
chorea 2 to 3 months after group A β-hemolytic streptococcal throat infection.
Therefore, when chorea is already present, throat culture is usually negative
and not helpful. Furthermore, antibody testing usually performed in clinical
practice (including antistreptolysin O [ASO] and antideoxyribonuclease B [anti-
DNase B]), although having higher diagnostic yields than throat culture, does not
have high sensitivity. In addition to chorea, patients may have tics and
neurobehavioral features, such as anxiety, irritability, attention deficit
hyperactivity disorder, and obsessive-compulsive behaviors, that can sometimes
be disruptive. Thus, the term Sydenham disease has been proposed to cover the
entire spectrum of its clinical features. Some patients have severe hypotonia
along with florid chorea, called chorea paralytica.
Recognition of Sydenham chorea is important, since patients will require a cardiac
workup, particularly echocardiography, and secondary antibiotic prophylaxis
with long-term penicillin, the duration of which depends on the severity of
carditis. Treatment of Sydenham chorea is discussed further in the treatment
section of this article. Sydenham chorea can recur in 20% to 50% of patients, and
persistent symptoms after 2-year follow-up have been reported in up to 50%.18
Chorea gravidarum refers to chorea that initially emerges, reemerges, or
exacerbates during pregnancy. It is a descriptive terminology rather than specific
diagnostic entity, as underlying etiologies such as HD, systemic lupus
erythematosus, antiphospholipid antibody syndrome, and hyperthyroidism should
always be sought. Patients with a history of Sydenham chorea in childhood can have
reemergence of chorea during pregnancy. However, thorough investigations for
other potential underlying causes of chorea in these patients should not be
neglected. Another hormonal-related chorea is chorea that may emerge or reemerge
during the use of oral contraceptive pills, and the same principles should be applied.
Chorea gravidarum can improve spontaneously in the third trimester or shortly
after the patient gives birth,19 and treatment may not be required. Nevertheless, the
most crucial “don’t-miss” step is searching for an underlying etiology.
The workup for acquired causes of chorea can be extensive. If diagnostic clues
are present, a targeted approach can be pursued. In clinical practice, if no
diagnostic clues are present, the first-tier testing includes complete blood cell
count, thyroid function tests, liver function tests, serum electrolytes, serum
calcium, antinuclear antibody, anti–double-stranded DNA antibody, lupus
anticoagulant, and antiphospholipid antibody syndrome workup. When patients
present with a subacute temporal profile, antibody testing in both serum and CSF
should be considered in addition to routine CSF studies.
GENETIC CAUSES OF CHOREA

The most common genetic cause of chorea in adults is HD. Other genetic disorders
that can mimic HD (ie, HD phenocopies) will subsequently be discussed.
Benign hereditary chorea is the most common genetic chorea in children.
Huntington Disease
HD is by far the most common genetic chorea in adults (TABLE 6-2). Geographic
variability is seen, with higher prevalence in some regions because of founder
effects, such as in Venezuela around Lake Maracaibo. Clinical features can be
grouped into three major categories: movement disorders, cognitive impairment,
1010 AUGUST 2019

and neuropsychiatric features. It is important not to overlook the latter two KEY POINTS
domains, which can be more debilitating than chorea itself. Regarding motor
● Neuropsychiatric features
symptoms, chorea is the main phenomenology in adults but not in children. The such as irritability, attention
forehead is usually involved, and forehead chorea can be useful to distinguish HD deficit hyperactivity
from tardive dyskinesia. In addition to chorea, other abnormal movements, disorder, and obsessive-
including dystonia, myoclonus, and ataxia, can coexist. While dystonic compulsive behavior
can be seen in Sydenham
components such as pelvic tilting can be apparent during walking, the gait
chorea.
pattern is quite complex and probably attributed to more than just a combination
of chorea and dystonia.20 During the natural course of the disease, the severity of ● It is important to search
chorea increases and then plateaus. Subsequently, in later stages, chorea for an underlying etiology in
gradually subsides and parkinsonian features become more prominent.21 hormonal-related chorea,
including chorea gravidarum
Hyperkinetic movements transition into an akinetic-rigid syndrome in the later and estrogen-induced
stages. One implication of this evolution is that symptomatic treatment of chorea chorea.
in HD requires periodic revision over the course of the disease (CASE 6-2).
Cognitive dysfunction in HD includes subcortical dementia, impaired frontal ● Nonmotor features in
Huntington disease are
executive function, disinhibition, difficulty with multitasking, and short-term often more debilitating than
memory impairment. Neuropsychiatric features include depression, suicidal chorea itself.
ideation, anxiety, irritability, apathy, aggression, psychosis, obsessive-
compulsive behaviors, and reduced awareness of deficit.22 ● Chorea is gradually
replaced by parkinsonian
Another important diagnostic clue is eye movement abnormalities. Delayed
features in later stages of
initiation of saccades is a hallmark oculomotor abnormality in HD.23 Other Huntington disease; thus,
choreic disorders with delayed initiation of saccades include ataxia-telangiectasia the treatment regimen
and oculomotor apraxia types 1 and 2. However, these disorders typically present requires revision
at a younger age, and coexisting neuropsychiatric features are uncommon. periodically.
Another eye movement abnormality in HD is an impaired antisaccade task. This ● Delayed initiation of
can be seen by asking the patient to look to the side contralateral to the side on saccades is a hallmark eye
which the examiner is holding up a finger. Patients with HD tend to look to the movement abnormality in
ipsilateral side, reflecting frontal disinhibition. Huntington disease.
HD is an autosomal dominant disorder due to CAG repeat expansion in the
● Senile chorea should not
HTT (also known as IT15) gene on chromosome 4p encoding the huntingtin be used as a diagnosis, and
protein. Individuals with 40 or more CAG repeats have complete penetrance an underlying etiology
(FIGURE 6-4), with an inverse correlation between the number of repeats and the should be sought.
age at onset. Individuals with between 36 and 39 CAG repeats are manifesting
● Children with Huntington
carriers with incomplete penetrance; not all individuals with CAG repeats in this disease typically do not
range will develop HD manifestations during their lifetime. Patients with lower present with chorea but
numbers of repeats tend to have presentation of chorea in late life, which has rather parkinsonism,
been called senile chorea. However, this term is considered obsolete and should dystonia, and seizures.
not be used as a diagnosis. A careful search for underlying etiologies, including ● Age at onset in
HD, should be conducted. Generally, individuals with fewer than 36 CAG repeats Huntington disease is
(35 or fewer) will not manifest the symptoms or signs of HD. Nevertheless, rare determined by the number
case reports exist of manifest HD with an intermediate number (27 to 35) of CAG of CAG repeats, genetic
modifiers, and
repeats. Anticipation tends to occur when unstable CAG repeats are inherited
environmental factors.
from the father, because of CAG-repeat instability during spermatogenesis.
Children with manifest HD typically have 50 to 60 CAG repeats or more. In
contrast to the adult-onset form, juvenile HD (onset at younger than 20 years of
age) typically presents with parkinsonism (also known as the Westphal variant)
and dystonia rather than chorea, as well as seizures. Nevertheless, not only the
number of CAG repeats but also genetic modifiers and environmental factors
contribute to the age at onset24; therefore, the age at onset in an individual cannot
be accurately predicted exclusively from the number of CAG repeats.

CHOREA
TABLE 6-2 Genetic Causes of Chorea That Primarily Present in Adulthooda
Pattern of Gene (Protein Selected Clinical Clues

Disorder Inheritance Encoded) (Other Than Chorea) Remarks/Caveats
Huntington disease Autosomal CAG repeat expansion Chorea (forehead involvement Founder effect in
dominant in HTT (also known as common), psychiatric (anxiety, some regions (eg,
IT15) gene (huntingtin) depression, obsessive-compulsive Venezuela around
disorder) and cognitive features Lake Maracaibo)
36–39 repeats:
but found
reduced penetrance Delayed initiation of saccades,
worldwide
abnormal antisaccade task
≥40: full penetrance
Consider genetic
Motor impersistence (tongue
>60: juvenile counseling before
and milkmaid’s grip)
Huntington disease genetic testing,
(Westphal variant) Hung-up and pendular knee jerks especially
predictive testing
Patients can have dystonia
and parkinsonism
Parkinsonism becomes more
prominent upon progression
(when chorea “dies out”)
Gait can be complex
Children: parkinsonism
(Westphal variant) and
seizures; typically no chorea
C9orf72 disease Autosomal GGGGCC repeat Phenotypic variability: some Recently found
dominant expansion in C9orf72 patients have frontotemporal to be the most
gene (C9orf72) dementia-amyotrophic lateral common cause
sclerosis of Huntington
disease
Pyramidal features (hyperreflexia)
phenocopies
SCA17 (HDL-4) Autosomal TBP (TATA-box binding Ataxia, dystonia The second most
dominant protein) common cause of
Cognitive impairment,
Huntington
neuropsychiatric features
disease
phenocopies after
C9orf72 disease
Huntington Autosomal CTG/CAG repeat African ancestry Acanthocytes can

disease–like dominant expansion in JPH3 be present in 10%
Can also present with
2 (HDL-2) (junctophilin 3) of patients
parkinsonism without chorea
Neuropsychiatric features
CONTINUED ON PAGE 1013
1012 AUGUST 2019

CONTINUED FROM PAGE 1012

Neuroacanthocytosis Special technique
syndromes required to detect
acanthocytes in
peripheral blood
smear
Acanthocytes not
specific to these
disorders (refer to
TABLE 6-3)
Chorea- Autosomal VPS13A (chorein) Dystonia with predilection

acanthocytosis recessive to lower cranial region
Characteristic “feeding”
(tongue protrusion) dystonia
Self-mutilation: lip and
tongue biting (mimicking
Lesch-Nyhan syndrome)
Myopathy (with elevated
creatine kinase), neuropathy,
seizure
Psychiatric features (depression,
anxiety, obsessive-compulsive
disorder)
Head drop, rubber man gait
Compared to Huntington disease
(anecdotally), delayed saccade
initiation is less impaired at the
same stage of neuropsychiatric
abnormalities
MRI: atrophy of caudate nuclei,
similar to Huntington disease
McLeod syndrome X-linked XK (Kx antigen) Cardiomyopathy in two-thirds Patients can

benefit from
Seizure, neuropathy, myopathy
autologous blood
Feeding dystonia rare banking because
of the risk of
transfusion
reaction

CHOREA

Dentatorubral- Autosomal ATN1 (atrophin 1) Generally manifests with High prevalence in
pallidoluysian atrophy dominant choreoathetosis if age at Japan but can also
onset >20 years be seen in other
populations
Adult-onset: ataxia, dystonia,
parkinsonism, dementia Reported as “Haw
River syndrome” in
Childhood-onset: epilepsy,
an African
myoclonus
American family in
MRI: pontocerebellar atrophy, North Carolina
white matter T2 hyperintensities
Neurodegeneration Pantothenate
with brain iron kinase–associated
accumulation neurodegeneration
is rarely reported to
cause chorea
Neuroferritinopathy Autosomal FTL (ferritin light chain) Dystonia with predilection to lower
dominant cranial region
Low serum ferritin (not all cases)
MRI gradient recalled echo
(GRE), or susceptibility-weighted
imaging (SWI): cystic degeneration
in caudate and putamen; “pencil
sign” (cortical lining of iron) has
also been reported
Aceruloplasminemia Autosomal CP (ceruloplasmin) Dystonia, ataxia, diabetes mellitus,

recessive retinal degeneration, anemia
Absent serum ceruloplasmin (as
opposed to low level in Wilson
disease)
Iron accumulation on GRE or SWI MRI
sequences in the striatum, thalami,
and dentate nuclei
HDL = Huntington disease–like; MRI = magnetic resonance imaging; SCA17 = spinocerebellar ataxia type 17.
a
1014 AUGUST 2019

Genetic testing in HD is a complex and sensitive issue. Genetic results can
impact not only a patient but also an entire family; therefore, great caution
should be exercised before ordering genetic testing. Appropriate counseling
should be performed by geneticists or genetic counselors, especially for
predictive genetic testing in asymptomatic individuals.25,26
The current clinical and research diagnostic criteria of HD are based on the
presence of unequivocal motor symptoms and signs including chorea, not solely
on the number of CAG repeats. However, attempts have been made to
incorporate cognitive and more subtle motor features to identify patients with
HD at a prodromal stage.27 Identification of individuals at premanifest and
prodromal stages may be useful for subject recruitment into natural history
An 83-year-old woman presented with an 18-month history of abnormal CASE 6-2

movements. The movements initially started in both her hands and feet,
later spreading to the proximal arms and legs. The movements were
absent during sleep. In addition, in the past 8 months, her family
members noted she had developed irritability and inappropriate
jocularity. She denied memory problems, depression, or suicidal
ideation. She had no significant family history.
Examination revealed moderate generalized chorea with choreic gait
(VIDEO 6-5, links.lww.com/CONT/A355). Upper facial chorea, seen as
activation of the frontalis muscle and eyebrow wiggling, was also
present. She demonstrated impulsivity and frontal disinhibition, including
making inappropriate jokes during the examination. She had delayed
initiation of saccades, more prominent in the horizontal than vertical
directions, and blinked her eyes or thrust her head to generate saccades.
Antisaccade tasks were also abnormal. She also had motor impersistence
including inability to maintain tongue protrusion and milkmaid’s grip.
Hung-up jerks, demonstrated as prolonged knee extension upon
quadriceps reflex testing, were present.
She was initially diagnosed with “senile chorea.” Complete blood cell
count, thyroid function tests, serum calcium, and parathyroid hormone
were normal. CT of the brain revealed mild to moderate bilateral caudate
atrophy. After appropriate genetic counseling, genetic testing was
performed, revealing 40 CAG repeats in the HTT gene. Risperidone
0.5 mg/d was initiated for symptomatic control of chorea.
A chronic course (longer than 1 year) is suggestive of a genetic etiology of COMMENT

chorea, the most common of which in adults is Huntington disease (HD). HD
manifests not only with chorea but also cognitive and neuropsychiatric
features that can sometimes be more debilitating than the chorea itself.
Senile chorea, which she had previously been diagnosed with, should
not be used as a diagnosis, and an underlying etiology, such as HD,
hyperthyroidism, or autoimmune causes should be sought. An individual
with a low number of expanded CAG repeats in the HTT gene typically has
a late-onset presentation, as in this patient.

CHOREA
studies and clinical trials for disease-modifying therapies; however, ethical issues
and impact on patients and families should be taken into consideration.
Huntington Disease Phenocopies

HD phenocopies refers to a group of disorders with clinical features like HD. Given
the much higher prevalence of HD compared to HD phenocopies, HD is often
excluded by genetic testing in these patients before HD phenocopies are
considered.
C9ORF72 DISEASE. According to studies in Europe, the most common HD
phenocopy is C9orf72 disease, followed by SCA17.8,28 However, these data
cannot be simply applied to other populations since the prevalence of these
choreic disorders may differ among various ethnic groups. In addition to chorea,
other movement disorders in C9orf72 disease include ataxia and myoclonus. One
important diagnostic clue is upper motor neuron signs or pyramidal features.
Pathologic studies revealed transactive response DNA-binding protein 43
(TDP-43) pathologies in this disorder. Of note, these repeat expansion disorders
can be missed in next-generation sequencing techniques. Therefore, when
suspecting these disorders, clinicians should ensure that the test panels and
genetic techniques used cover these disorders appropriately.
SPINOCEREBELLAR ATAXIA TYPE 17. SCA17 (also known as Huntington
disease–like 4 [HDL4]) is due to CAG/CAA repeat expansion in the TBP gene
encoding TATA-box binding protein. In addition to ataxia and chorea, patients can
also have psychiatric features or cognitive impairment. Of note, chorea can also
be a presentation in SCA1, SCA2, SCA3, SCA8, and SCA12. However, these SCAs
are less common than SCA17 among HD phenocopies.
FIGURE 6-4
Relationship between CAG repeat length and Huntington disease phenotype.
Figure courtesy of Thananan Thammongkolchai, MD.
1016 AUGUST 2019

DENTATORUBRAL-PALLIDOLUYSIAN ATROPHY. Dentatorubral-pallidoluysian KEY POINTS
atrophy (DRPLA), an autosomal dominant disorder due to CAG repeat expansion in
● Genetic counseling
the ATN1 gene encoding atrophin 1, can also present with chorea. The prevalence is should be considered
high in Japan, but it has also been reported in other populations. In the United States, before ordering genetic
DRPLA was initially reported in an African American family in North Carolina and testing for Huntington
was called Haw River syndrome29; it has almost exclusively been seen in patients with disease.
African ancestry. In an early-onset form (younger than 20 years of age), patients
● Autosomal recessive
with DRPLA usually have epilepsy and myoclonus, whereas chorea, ataxia, ataxia syndromes can
dystonia, parkinsonism, and dementia are features of the late-onset form. present with a variety of
hyperkinetic movement
AUTOSOMAL RECESSIVE ATAXIA SYNDROMES. In addition to the autosomal disorders, including chorea.
dominant SCAs mentioned above, several autosomal recessive ataxia syndromes
with typical onset in childhood can present with a variety of hyperkinetic movement
disorders, including chorea, dystonia, and myoclonus.30 Examples include Friedreich
ataxia, ataxia-telangiectasia, ataxia with oculomotor apraxia types 1 and 2,
abetalipoproteinemia, and ataxia with vitamin E deficiency.
HUNTINGTON DISEASE–LIKE 2. HDL2 (VIDEO 6-6, links.lww.com/CONT/A356) is

an autosomal dominant disorder due to CTG/CAG repeat expansion in the JPH3
gene encoding junctophilin 3. Clinical features, including neuropsychiatric
features and cognitive impairment, can be similar to HD. Ethnicity is an
important diagnostic clue, as it is almost exclusively seen in patients with African
ancestry. Parkinsonism can be a presentation in some patients. Interestingly,
acanthocytes can be found in about 10% of patients with HDL2. Of note, HDL1
and HDL3 are even rarer than HDL2. HDL1 is a prion disease, and HDL3 has been
reported in only a few families.
NEUROFERRITINOPATHY AND ACERULOPLASMINEMIA. Among all

neurodegeneration with brain iron accumulation disorders, chorea is more
commonly seen in neuroferritinopathy and aceruloplasminemia. Chorea is, in
fact, rare in pantothenate kinase–associated neurodegeneration, the most
common neurodegeneration with brain iron accumulation disorder, which
typically presents with pure dystonia without chorea. Serum ferritin (reduced in
neuroferritinopathy) and ceruloplasmin (absent, not just reduced, in
aceruloplasminemia) can be helpful in the diagnosis. MRI can also be a useful
diagnostic clue (eg, bilateral symmetric cystic change in the basal ganglia or
“cortical pencil lining” in neuroferritinopathy [FIGURE 6-532–34]).
NEUROACANTHOCYTOSIS SYNDROMES. Acanthocytes can be present in a

number of movement disorders 35 :
u Chorea-acanthocytosis
u McLeod syndrome
u HDL2 (in approximately 10% of patients)
u Pantothenate kinase–associated neurodegeneration (in approximately 10% of patients)
u Abetalipoproteinemia (Bassen-Kornzweig syndrome)
u Aceruloplasminemia
The two main disorders in this group are chorea-acanthocytosis and McLeod
syndrome. Chorea-acanthocytosis is due to mutations in the VPS13A gene

CHOREA
FIGURE 6-5
Neuroimaging in choreic disorders. A, Axial T2* MRI shows hypointensity in the bilateral
striatum (red arrows), thalami (yellow arrowheads), and cortical surface (green arrow),
representing iron accumulation in a patient with aceruloplasminemia. B, Axial T2-weighted
MRI shows cystic degeneration of the bilateral basal ganglia (blue arrows) and hyperintense
signal with a hypointense rim at the bilateral thalami (red arrowheads) in a patient with
neuroferritinopathy. C, Axial susceptibility-weighted imaging (SWI) shows “cortical pencil
lining” representing superficial iron accumulation in a patient with neuroferritinopathy.
Panel A reprinted with permission from Fujita K, et al, Neurology.32 © 2013 American Academy of Neurology.
Panel B reprinted with permission from Ohta E, Takiyama Y, Neurol Res Int.33 © 2012 The Authors. Panel C
reprinted with permission from Batla A, et al, Neurology.34 © 2015 American Academy of Neurology.
encoding for chorein. However, because of the large size of the gene with 76 exons,
gene sequencing is not feasible. Using Western blot to detect chorein deficiency is
another diagnostic method. McLeod syndrome is due to mutations in the XK gene
on the X chromosome encoding for the Kx antigen on the surface of red blood
cells. The mutations lead to absent Kx antigen and reduced Kell antigen. Kx is not a
part of the Kell antigen system, but molecular structural interaction between these
two proteins leads to reduction of Kell protein when Kx antigen is absent. The
McLeod phenotype can be discovered in blood banks during blood screening and
can be detected by using anti-Kx and anti-Kell antibodies.
While acanthocytes are a hallmark of these disorders, three caveats are
important to note here. First, acanthocytes are not specific to these two disorders
and can also be seen in others as noted above. These disorders have also been
included under the umbrella of neuroacanthocytosis syndromes.36 Second, a
special technique using a wet unfixed preparation of an isotonically diluted blood
sample, as described in detail by Storch and colleagues,37 is required for higher
sensitivity of acanthocyte detection in peripheral blood smear. Although the yield
of acanthocyte detection from routine peripheral blood smear is lower, it should
still be examined, with an understanding of its limitations. Third, even with the
appropriate technique, acanthocytes can be absent in neuroacanthocytosis
syndromes; thus, the absence of acanthocytes on peripheral blood smear does not
exclude these disorders.
In chorea-acanthocytosis, dystonia has a predilection to involve the lower
cranial region, and feeding dystonia is one of the characteristic features. This can
lead to poor nutritional status. Lip and tongue biting can be due to feeding
dystonia and possibly coexisting obsessive-compulsive behaviors. Intermittent
1018 AUGUST 2019

head drop has been observed.31 Delayed saccade initiation, similar to HD, can be KEY POINTS
a feature of chorea-acanthocytosis but anecdotally appears or becomes more
● In addition to chorea-
obvious in the later stages as compared to HD.23 The classic “rubber man” gait is acanthocytosis and McLeod
characterized by intermittent truncal flexion, extension spasms, and, sometimes, syndrome, acanthocytes
knee flexion during walking. The phenomenology of this gait appearance can also be seen in 10% of
remains unclear, but dystonia has been proposed.38,39 Similar to HD, chorea can Huntington disease–like
2 and pantothenate
gradually be replaced by parkinsonian features in the later stages of the disease
kinase–associated
(CASE 6-3). neurodegeneration as well
Clinical features of chorea-acanthocytosis and McLeod syndrome include not as abetalipoproteinemia and
only motor features but also neuropsychiatric features similar to HD, including aceruloplasminemia.
depression, anxiety, and obsessive-compulsive behaviors.
● Patients with McLeod
Associated medical and neurologic features can be helpful diagnostic clues in syndrome can benefit from
neuroacanthocytosis syndromes. Coexisting neuropathy, myopathy, and seizures cardiac surveillance and
can be seen in both chorea-acanthocytosis and McLeod syndrome. Serum creatine autologous blood
kinase and nerve conduction studies and EMG are useful investigations. Elevated transfusion.
serum creatine kinase is suggestive of coexisting myopathy, and nerve conduction ● Caudate atrophy is not
studies and EMG may show evidence of neuropathy or myopathy, or both. specific to Huntington
One of the major clinical differences between chorea-acanthocytosis and disease and can also be seen
McLeod syndrome is that in the latter, cardiomyopathy can be present in more in other disorders, such as
chorea-acanthocytosis and
than 70% of patients but feeding dystonia is rare. Recognition of McLeod
Huntington disease–like 2.
syndrome is of particular importance, since patients can benefit from cardiac
surveillance and autologous blood transfusion. Allogeneic blood transfusion can ● Benign hereditary chorea
potentially lead to severe life-threatening blood transfusion reaction, since syndromes can be due to
antibodies to Kx and Kell antigens are produced after the first exposure of these multiple mutations; the
classic benign hereditary
antigens to blood without the McLeod phenotype. chorea is due to NKX2-1
Atrophy of the caudate nuclei on neuroimaging is not specific to HD and (TITF) mutations. Some
can also be seen in other disorders, including chorea-acanthocytosis and patients with NKX2-1–
HDL2 (FIGURE 6-631). related benign hereditary
chorea can paradoxically
respond to levodopa.
Benign Hereditary Chorea Syndromes
Benign hereditary chorea is the most common genetic cause of chorea in children
(TABLE 6-3). The “classic” benign hereditary chorea is an autosomal dominant
disorder due to mutations in the NKX2-1 (formerly known as TITF-1) gene
encoding thyroid transcription factor-1. Chorea usually begins in infancy or early
childhood, and usually no or minimal progression occurs, with plateauing in
adulthood; rare remission is seen. Other associated clinical features include
ataxia, dystonia, hypotonia, and delayed motor milestones. Cognitive function
is usually normal, but intellectual disability can occur. Given that the NKX2-1
gene also has a role in lung and thyroid development, neonatal respiratory
distress, interstitial lung disease, congenital hypothyroidism, or thyroid agenesis
can coexist and serve as useful diagnostic clues. NKX2-1–related benign
hereditary chorea is also called brain-lung-thyroid syndrome; however,
involvement of all three organs is seen in only 30% to 40% of the patients
(CASE 6-4).40,41
Although indicated in the name as “benign,” it is not always benign. Some
patients may have learning disabilities, attention deficit hyperactivity disorder,
pituitary cysts, recurrent pulmonary infection, pulmonary fibrosis, and
malignancies, such as lung cancer, bladder cancer, or leukemia.42
In addition to the NKX2-1 gene, benign hereditary chorea or benign
hereditary chorea–like phenotypes have been reported in other genes,

CHOREA
CASE 6-3 A 36-year-old woman presented for an evaluation of her progressive

neurologic symptoms. At age 22, she had developed generalized
tonic-clonic seizures that required multiple antiepileptic medications to
control, including lamotrigine, gabapentin, and zonisamide. During one
episode, she spilled boiling water on herself and required a burn unit
admission and skin graft placement. At age 32, she developed speech
and swallowing problems. She said that her tongue involuntarily pushed
food out when eating, and she also had frequent choking, once requiring
the Heimlich maneuver. She bit her lips and tongue and wore a bite block
24 hours per day. Her family had difficulty understanding her speech over
the phone. At age 35, she developed flinging movements of her arms,
trunk, and legs. She had difficulty walking and experienced multiple falls.
She had developed depression, memory loss, and irritability around age
22 but denied obsessive-compulsive behavior. Family history was
negative.
Examination revealed a mild parkinsonian appearance with facial
dystonia, especially in the lower facial region (VIDEO 6-7, links.lww.com/
CONT/A357). She had moderate dysarthria. Eye examination revealed
delayed initiation of vertical saccades with more limited range of
downgaze than upgaze. She had mild intermittent chorea in her
extremities and trunk as well as some dystonic posturing of the left arm.
Her gait was complex and partially composed of choreic and dystonic
components. She had some hyperextension and circumduction of the left
leg when walking. Deep tendon reflexes were absent throughout.
Acanthocytes were found on a routine peripheral blood smear. Her
creatine kinase was 790 U/L. A previous MRI brain reportedly showed no
caudate atrophy but was not available for review. Western blot of her
blood sample revealed absence of chorein protein. The diagnosis of
chorea-acanthocytosis was confirmed. Her care was managed by a
multidisciplinary team, including physical, occupational, and speech
therapists.
COMMENT Chorea, along with feeding dystonia, seizures, and coexisting neuropathy
or myopathy (evidenced by absent or reduced deep tendon reflexes and
elevated creatine kinase) are very suggestive of chorea-acanthocytosis, an
autosomal recessive form of neuroacanthocytosis syndromes. Although
present in this patient, acanthocytes in the peripheral blood smear are not
always seen even with a special technique using a wet unfixed preparation
of an isotonically diluted blood sample. Delayed initiation of saccades,
similar to that seen in Huntington disease, can be seen in chorea-
acanthocytosis; however, it usually comes in the later stages compared to
Huntington disease. Vertical supranuclear gaze palsy is an unusual feature
in chorea-acanthocytosis. Therapies for choreic disorders are not
restricted to the treatments of chorea. Although specific therapies are not
yet available, and symptomatic treatment is not required if chorea is mild
and nonbothersome, patients such as this one could benefit from
multidisciplinary care by a physical medicine and rehabilitation specialist
and physical, occupational, and speech therapists.
1020 AUGUST 2019

FIGURE 6-6
Choreic disorders with bilateral caudate atrophy on neuroimaging. A, CT scan showing bilateral
caudate atrophy in Huntington disease (white arrowheads). B, Coronal T1-weighted MRI in a
patient with Huntington disease–like 2 (red arrowheads). C, Axial fluid-attenuated inversion
recovery (FLAIR) MRI in a patient with chorea-acanthocytosis (yellow arrowheads).
Panel B reprinted with permission from Margolis RL, Holmes SE, Clin Neurosci Res.31 © 2001 Nature Press.
including ADCY5,43,44 PDE10A,45,46 GNAO1,47 and SLC16A2 (associated with

Allan-Herndon-Dudley syndrome).48 Therefore, benign hereditary chorea
represents the clinical syndromes, rather than one specific disorder. The term
benign hereditary chorea syndromes has been used to represent the entire group
of patients with clinical features compatible with or similar to benign hereditary
chorea as described above regardless of the underlying genetic defects, whereas
the term classic benign hereditary chorea specifically denotes NKX2-1–related benign
hereditary chorea. While no consensus definition or distinct clinical boundary of
benign hereditary chorea syndromes exists, this term may be useful for searching
for other underlying genetic defects when encountering patients with clinical
pictures similar to or mimicking NKX2-1–related benign hereditary chorea.
Unfortunately, this terminology has not been consistently used in the literature or
clinical practice; thus, whether benign hereditary chorea represents only the classic
form or the benign hereditary chorea syndromes should always be clarified.
In addition to general symptomatic therapies for chorea, patients with
NKX2-1–related benign hereditary chorea can paradoxically respond to levodopa
for unknown reasons. In the author’s experience, this responsiveness can be
seen in some, but not all, patients.
ADCY5-related dyskinesia, previously known as familial dyskinesia with facial
myokymia,49 is an autosomal dominant disorder due to mutations in the ADCY5
gene encoding adenylate cyclase 5. Patients may have clinical features mimicking
NKX2-1–related benign hereditary chorea, but mixed movement disorders,
including chorea, dystonia, and myoclonus, often occur.43,44 One diagnostic
clue is facial dyskinesia, which cannot be perfectly categorized into any
previously described movement disorder phenomenology. Facial myokymia
was a misnomer, since subsequent electrophysiologic studies did not reveal
evidence of myokymia.50 Other clinical features include hypotonia, delayed
motor milestones, and exacerbation of dyskinesia during transitions between
wakefulness and sleep including drowsiness and sleep arousal.51 In some patients,
the movements may be paroxysmal.

CHOREA
TABLE 6-3 Genetic Causes of Chorea That Primarily Present in Childhooda
Selected Clinical
Pattern of Gene (Protein Clues (Other
Disorder Inheritance Encoded) Than Chorea) Remarks/Caveats
Choreoathetoid NA NA Dystonia often Included in this

cerebral palsy coexists with chorea table as it is likely
composed of a
Flowing component
mixed bag of
may sometimes be
genetic/
difficult to
neurometabolic
differentiate
disorders, in
between dystonia
addition to hypoxic
and choreoathetosis
brain injury, which
Dystonic hand have to be ruled out
posturing typically carefully before
not painful; it is making this diagnosis
unique and difficult
for healthy person to
mimic
Benign hereditary Can be due to

chorea syndromes mutations in several
genes, including
NKX2-1, ADCY5,
PDE10A, GNAO1,
SLC16A2 (Allan-
Herndon-Dudley
syndrome)
Classic benign Autosomal NKX2-1 (formerly Also called Some may have
hereditary chorea dominant known as TITF-1) brain-lung-thyroid paradoxical
syndrome or gene (thyroid syndrome (or BLT response to
NKX2-1–related transcription factor-1) syndrome) levodopa
benign hereditary
Hypothyroidism and
chorea
pulmonary disease
(eg, respiratory
distress or interstitial
lung disease) can
coexist
Typically
nonprogressive, but
not always benign
(considered
relatively more
benign, compared to
Huntington disease)
Patients may have
developmental
delay or short
stature
1022 AUGUST 2019

Selected Clinical
ADCY5-related Autosomal ADCY5 (adenylate Phenotypic Previously called

dyskinesia dominant cyclase 5) variability familial dyskinesia
with facial
Mixed movement
myokymia, but the
disorders, including
facial movements
chorea, dystonia,
are, in fact, not
myoclonus
myokymia, based on
Movements can be EMG studies
paroxysmal
Lesch-Nyhan X-linked HPRT1 (hypoxanthine- Often associated Females can less

syndrome recessive guanine with dystonia with commonly be
phosphoribosyltransferase) predominant lower affected because of
cranial involvement skewed inactivation
of X chromosome
Self-mutilation
May resemble
chorea-
acanthocytosis, but
age group is typically
younger in Lesch-
Nyhan syndrome
Hyperuricemia
Wilson disease Autosomal ATP7B (ATP7B) Varieties of

recessive movement
dystonia,
parkinsonism, ataxia,
tremor (including
classic wing-beating
tremor, a form of
cerebellar tremor
but not common)
Kayser-Fleischer
rings (pay attention
to upper and lower
corneal limbi); when
in doubt, refer for
slit-lamp examination
Low serum
ceruloplasmin, low
serum copper, high
24-hour urine copper

CHOREA
Selected Clinical
Autosomal Most autosomal

recessive ataxia recessive ataxias
with onset in
childhood can
present with
hyperkinetic
movement
dystonia, chorea,
and myoclonus
Friedreich ataxia Autosomal FXN due to GAA Dystonia, ataxia, pes

recessive repeat expansion cavus, hyporeflexia,
and/or mutations diabetes mellitus,
(frataxin) cardiomyopathy,
scoliosis
Eye movement
examination:
macrosaccadic
oscillations,
hypermetric
saccades
Relatively preserved
cerebellar size on
MRI until late stages
Variants (these two
overlap):
Friedreich ataxia
with retained reflex
or hyperreflexia,
often late onset
Late-onset
Friedreich ataxia
Ataxia with Autosomal APTX (aprataxin) Oculomotor apraxia Differential

oculomotor apraxia recessive (delayed initiation of diagnoses of
type 1 (AOA1) saccades) oculomotor apraxia
associated with
Neuropathy
ataxia include ataxia-
Low serum albumin, telangiectasia, AOA1
high cholesterol and AOA2
Ataxia with Autosomal SETX (senataxin) Age group is α-Fetoprotein can

oculomotor apraxia recessive typically older than also be elevated in
type 2 (AOA2) AOA1 ataxia-telangiectasia
(almost all cases)
Oculomotor apraxia
Neuropathy
High α-fetoprotein in
almost all cases
1024 AUGUST 2019

Selected Clinical
Metabolic disorders Autosomal Multiple Can also present Differential

(eg, organic recessive with dystonia diagnoses include
acidemia) methylmalonic
Hyperintense signals
acidemia and
at bilateral lentiform
glutaric aciduria type
nuclei on T2-
I, among others
weighted MRI
Check plasma amino
acids and urine
organic acids
Mitochondrial Mitochondrial or Mitochondrial/nuclear May also present Start by checking for

disorders (eg, Leigh autosomal gene mutations with dystonia high lactate level in
syndrome or MELAS) recessive (if serum and CSF
MRI in Leigh
attributed to
syndrome:
nuclear
hyperintense signal
mutations)
at bilateral basal
ganglia and/or
brainstem on T2-
weighted sequences
MELAS can have
basal ganglia
calcification (CT is
useful to
demonstrate)
CSF = cerebrospinal fluid; CT = computed tomography; EMG = electromyography; MELAS = mitochondrial encephalomyopathy, lactic acidosis,
and strokelike episodes; MRI = magnetic resonance imaging; NA = not applicable.
a

CHOREA
Other rarer genes related to benign hereditary chorea syndromes are discussed
here only briefly. PDE10A mutations can be either autosomal dominant or
recessive. The dominant forms or de novo mutations typically present with
chorea at around 5 to 10 years of age and show bilateral striatal hyperintense
signals on MRI (hence, also called childhood-onset bilateral striatal necrosis), but
no intellectual impairment is seen.45 The recessive forms are more severe.
Clinical features include infantile-onset chorea and motor and language
developmental delay but, interestingly, no striatal hyperintensity on MRI.46
Gain-of-function mutations in the GNAO1 gene can present with chorea,47
whereas loss-of-function mutations cause Ohtahara syndrome, a form of early
infantile epileptic encephalopathy. Relatively new genes reported in chorea
associated with epilepsy include FOXG1 (in which patients can have prominent
orofacial chorea/dyskinesia),52 GRIN153,54 and FRRS1L.55
CASE 6-4 A 6-year-old boy came to the clinic for follow-up of his choreic disorder.
He was born full term without any prenatal and perinatal complications.
However, during the first 2 years of life, he was diagnosed with
hypothyroidism and “asthma.” Around 4.5 years of age, he was evaluated
in the movement disorder clinic because of abnormal movements
compatible with generalized chorea, which had gradually become more
noticeable in the past 1.5 years. Multiple family members on his maternal
side had thyroid problems and asthma; however, no abnormal movement
was reported in these family members. The diagnosis of benign
hereditary chorea was suspected, and it was confirmed by the mutation
in the NKX2-1 (formerly known as TITF-1) gene. He had mild intellectual
disability and had participated in a special school program. His chorea
had been stable in the past 2 years. He was trialed on levodopa at the age
of 6 years up to 5 mg/kg/d for symptomatic control of chorea. However,
because no improvement was seen, it was subsequently discontinued.
Examination revealed mild to moderate generalized chorea involving
all extremities, trunk, neck, and lower facial region, as well as mild
bilateral foot dystonia demonstrated as mild foot inversion when
walking. The dystonic component was much less prominent than chorea.
Treatment options, including tetrabenazine, were discussed with his
parents.
COMMENT This patient’s chronic temporal profile is suggestive of a genetic cause of

chorea, the most common of which in children is benign hereditary chorea.
Benign hereditary chorea syndrome can be due to several mutations. The
“classic” benign hereditary chorea syndrome is due to NKX2-1 (TITF-1)
mutations, which can also cause lung and thyroid problems (hence the term
brain-lung-thyroid syndrome), as in this patient. While seen in this patient,
involvement of all three organs is present in only 30% to 40% of patients.
Benign hereditary chorea is not always “benign”; for example, this patient
has intellectual disability. Some, but not all, patients with this disorder can
respond to levodopa.
1026 AUGUST 2019

CHOREA IN PAROXYSMAL MOVEMENT DISORDERS
This special group of disorders can be divided into two main categories: primary
and secondary paroxysmal dyskinesias. Based on the triggers, primary
paroxysmal dyskinesias can be further classified into paroxysmal kinesigenic
dyskinesia, paroxysmal nonkinesigenic dyskinesia, and paroxysmal exercise-
induced dyskinesia. Although dystonia is common during the paroxysmal
attacks, chorea can also be seen. When encountering patients with paroxysmal
chorea, these disorders should be considered. Paroxysmal kinesigenic dyskinesia
typically has exquisite response to low-dose antiepileptic medications, especially
carbamazepine. In patients with paroxysmal exercise-induced dyskinesia,
glucose transporter 1 deficiency syndrome, which is treatable, should be
excluded. With advances in genetics, the number of genes associated with each
phenotype has been expanding.56–58 A detailed discussion about paroxysmal
movement disorders is beyond the scope of this article.
TREATMENT
The first question before initiating treatment is “Does chorea need to be treated?”
(TABLE 6-4). When chorea is mild and nonbothersome and does not interfere
with a patient’s daily activities, symptomatic treatment is not required. In some
choreic disorders, such as HD, lack of awareness of the deficit by patients as a
possible coexisting neuropsychiatric feature may limit evaluation of chorea
severity solely from patients’ reports. Thus, the clinician’s and family’s
evaluation of chorea severity should also be incorporated into clinical decisions.
When clinicians decide to treat, two main categories of therapies should be
considered: specific therapies and symptomatic therapies (TABLE 6-5).
Specific Therapies
Many acquired choreas are treatable, so correct diagnosis of these “don’t-miss”
disorders is a crucial step before using corresponding specific therapies.
Examples include blood sugar control in nonketotic hyperglycemia, phlebotomy
and hydroxyurea in polycythemia vera, antibiotics in central nervous system
(CNS) infection such as CNS toxoplasmosis, and immunotherapies in
autoimmune choreas, including systemic lupus erythematosus.
Symptomatic Therapies
Symptomatic therapies include pharmacologic treatment and deep brain
stimulation (DBS).
Principles of Chorea Treatment TABLE 6-4
Step 1: Does chorea need to be treated? When it is mild and nonbothersome, treatment is not
required.
Step 2: Is specific treatment available?
Step 3: If chorea is not controlled by specific treatment or specific treatment is not available,
what symptomatic therapies should be selected?
Step 4: Are there any other symptoms than chorea that require treatment or surveillance?
Patients can benefit from multidisciplinary approach.
Step 5: Does any family member need further evaluation or genetic counseling?

CHOREA
TABLE 6-5 Therapeutic Options in Chorea
Specific Therapies
◆ Blood sugar control in nonketotic hyperglycemia
◆ Phlebotomy and hydroxyurea in polycythemia vera
◆ Treatment for hyperthyroidism
◆ Immunotherapies in autoimmune choreas
Symptomatic Therapies
◆ Pharmacologic therapies
◇ Presynaptic dopamine depletors
→ Tetrabenazine and reserpine
→ New-generation vesicular monoamine transporter 2 inhibitors
– Deutetrabenazine
– Valbenazine
◇ Postsynaptic dopamine receptor blockers (dopamine receptor blocking agents,
neuroleptics or antipsychotics)
→ Typical antipsychotics
– Haloperidol
→ Atypical antipsychotics
– Olanzapine
– Risperidone
– Quetiapine
– Clozapine
◇ Others
→ Antiepileptics
– Valproic acid
– Carbamazepine
Deep Brain Stimulation
◆ Reported in Huntington disease, chorea-acanthocytosis, and some acquired choreas
Multidisciplinary Approach
◆ Psychiatrist; physical medicine and rehabilitation specialist; physical, occupational, and
speech therapists
◆ Geneticist, genetic counselor
◆ Social worker
1028 AUGUST 2019

PHARMACOLOGIC THERAPIES. As a general principle, the “start low, go slow” KEY POINTS
strategy should be followed. Medications should be started at a low dose and
● Patients with choreic
gradually titrated over time to reach the effective dose to avoid side effects. If disorders can benefit from a
side effects occur, tapering the medications and monitoring are required. If multidisciplinary approach.
medications need to be discontinued for any reason, slow tapering should be Associated features and
considered to avoid withdrawal side effects. comorbidities, such as
cognitive and
Given a hyperdopaminergic state as a general hypothesis of the pathophysiology
neuropsychiatric features,
of chorea, the strategy for symptomatic therapies is to reduce the amount of should be taken into
dopamine or its effect within the CNS. The main pharmacologic targets are consideration when treating
dopaminergic synapses, either at presynaptic or postsynaptic sites (FIGURE 6-7). chorea. Mild and
nonbothersome chorea
MEDICATIONS TARGETING THE PRESYNAPTIC SITE (PRESYNAPTIC DOPAMINE- does not require treatment.
DEPLETING AGENTS). Presynaptic dopamine-depleting agents include Immunotherapies are
treatment options in
tetrabenazine and reserpine. Both drugs inhibit vesicular monoamine Sydenham chorea.
transporter (VMAT) 2 in the CNS, thereby preventing packaging of dopamine
into presynaptic vesicles. Dopamine is then degraded by a monoamine oxidase B ● The main pharmacologic
enzyme. Tetrabenazine is a selective VMAT2 inhibitor, whereas reserpine also targets of chorea are
dopaminergic synapses,
inhibits VMAT1 in the peripheral nervous system and can lead to hypotension.
either at presynaptic or
Tetrabenazine is widely used in clinical practice and was approved by the US postsynaptic sites
Food and Drug Administration (FDA) for chorea associated with HD in 2008,
based on the TETRA-HD (Efficacy, Safety, and Dose Tolerability of
FIGURE 6-7
Sites of action of the main pharmacologic therapies in chorea. 1, Presynaptic dopamine-
depleting agents are vesicular monoamine transporter 2 (VMAT2) inhibitors. 2, Postsynaptic
dopamine receptor blocking agents (DRBAs) act by blocking mainly D2 receptors.
Figure courtesy of Thananan Thammongkolchai, MD.

CHOREA
Tetrabenazine for Chorea in Huntington Disease) study.59 In addition to HD,

tetrabenazine has been used off-label for other indications, including chorea
from other etiologies and various hyperkinetic movement disorders such as tics
and Tourette syndrome.60,61 Because of presynaptic monoamine depletion, side
effects include parkinsonism, depression, and akathisia. Because of the potential
risks of depression and suicidality, tetrabenazine carries an FDA boxed warning.
Its active metabolites are degraded by the CYP2D6 enzyme. When the dose is
greater than 50 mg/d, CYP2D6 enzyme testing is currently recommended to
determine whether patients are poor, intermediate, or extensive metabolizers.
Extensive metabolizers may require higher doses.
The new-generation selective VMAT2 inhibitors include deutetrabenazine and
valbenazine. Deutetrabenazine was approved by the FDA for chorea associated
with HD in April 2017 and for tardive dyskinesia in August 2017, based on the
FIRST-HD (First Time Use of SD-809 in Huntington Disease)62 and AIM-TD
(Addressing Involuntary Movements in Tardive Dyskinesia)63 studies, respectively.
Six hydrogen atoms in tetrabenazine are replaced by deuterium or “heavy
hydrogen” atoms in deutetrabenazine. This leads to pharmacokinetic advantages,
including longer plasma half-life (9 to 10 hours for deutetrabenazine compared to
5 to 7 hours for tetrabenazine) and less plasma level fluctuation of the drug, and
thus fewer side effects, especially sedation. In addition, deutetrabenazine can be
administered 2 times a day, instead of 3 times a day as with tetrabenazine. Despite
no statistical difference in depression and suicidality between the treatment and
control groups in the FIRST-HD study, deutetrabenazine carries an FDA boxed
warning for depression and suicidality in patients with HD.
Valbenazine is a prodrug of one of the isomeric metabolites of tetrabenazine.
It is slowly metabolized into (+)-α-dihydrotetrabenazine. The pharmacokinetic
advantage of valbenazine and its metabolite is long plasma half-life (16 to
22 hours), so the medication can be administered once daily. It was approved
for tardive dyskinesia in adults in April 2017, based on the KINECT-3 (A Phase
3 Study of NBI-98854 for the Treatment of Tardive Dyskinesia) study.64
Valbenazine has not been studied in chorea associated with HD. Side effects
of valbenazine include sedation, headache, and QTc prolongation. It is
contraindicated in patients with underlying congenital prolonged QT
syndrome or arrhythmias with prolonged QT interval.
α-Methyl-p-tyrosine (metyrosine) depletes presynaptic dopamine by
inhibiting tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis.
However, this drug is not available in the United States and most other countries.
MEDICATIONS TARGETING THE POSTSYNAPTIC DOPAMINERGIC SITES. Medications

that target the postsynaptic dopaminergic sites are mainly dopamine receptor
blocking agents (also called antipsychotics or neuroleptics). The dopamine
receptor blocking agents effective for treatment of chorea typically have a
mechanism of action at the D2 receptor, which also contributes to the risk of
developing tardive dyskinesia. The “cleaner” dopamine receptor blocking
agents, such as clozapine and quetiapine, have also been used but may not be as
effective as dopamine receptor blocking agents with higher affinity to D2
receptors, such as the typical antipsychotics, in particular, haloperidol, and
atypical antipsychotics such as olanzapine and risperidone While clozapine is
relatively the “cleanest” with regard to the risk of tardive dyskinesia, the need
for frequent blood monitoring limits its use, especially in the setting of
1030 AUGUST 2019

coexisting cognitive impairment or poor compliance, which may not be
uncommon in patients with chorea. Because of the risks of tardive dyskinesia,
many clinicians, especially clinicians in the United States, prefer the presynaptic
dopamine-depleting agents to dopamine receptor blocking agents. According to
a 2011 international survey,65 treatment preferences for chorea in HD differed
between Europe and America. In Europe, clinicians preferred antipsychotics to
tetrabenazine, whereas in the United States, preferences were roughly equally split
between antipsychotics and tetrabenazine. However, there may be a trend to use
more presynaptic dopamine-depleting agents in current clinical practice.66
Other associated clinical features or comorbidities should be taken into
consideration when selecting treatment for chorea. Antipsychotics may be
preferable to presynaptic dopamine-depleting agents when one or more of the
following exists: (1) coexisting psychosis or aggression, which can be seen in
some choreic disorders such as HD and chorea-acanthocytosis; (2) coexisting
depression and suicidal risks that preclude the use of presynaptic dopamine-
depleting agents; and (3) noncompliance.65 Given the higher cost of presynaptic
dopamine-depleting agents and their limited availability, antipsychotics remain
the only or more preferable choice in many regions of the world.
Dopamine receptor blocking agents, especially olanzapine and risperidone,
can cause metabolic syndromes, including weight gain, which can be a beneficial
effect in patients with significant weight loss and poor nutritional status.
Blood chemistries, including lipid profile and glucose, should be monitored
periodically. Other symptomatic therapies for chorea include antiepileptic drugs
such as valproic acid and carbamazepine (eg, in Sydenham chorea), and
levodopa (in benign hereditary chorea).
Treatment of Sydenham chorea deserves some specific discussion here. For
symptomatic treatment of the chorea, antiepileptic drugs, including valproic acid
and carbamazepine, have been found to be effective.67 Antipsychotics can pose
risks of drug-induced parkinsonism in Sydenham chorea and thus have to be
used with caution, typically as second-line treatment.68 Immunomodulatory
therapies (which serve as specific rather than symptomatic therapies), including
IVIg, IV steroids, and plasma exchange, have been increasingly employed in
Sydenham chorea,69 although more evidence from clinical trials is needed. This
option can be considered in patients with severe Sydenham chorea such as chorea
paralytica or as second-line treatment in patients with inadequate response to
conventional symptomatic therapies.
DEEP BRAIN STIMULATION. DBS in chorea remains a moving target. Most studies
have been done in HD70 and chorea-acanthocytosis.71 These are mostly case
reports or small case series,72 which can pose some biases, as cases with poor
outcome are unlikely to be reported. The most common target is the globus
pallidus internus (GPi), and stimulation at the ventral GPi is known to have an
antidyskinetic effect from extensive DBS experience in Parkinson disease.
Further clarification on DBS efficacy, candidacy, and appropriate targets can be
elucidated from future studies and randomized controlled trials.
Factors other than chorea also should be considered when selecting DBS as a
treatment. First, coexisting cognitive and neuropsychiatric features can even be
more debilitating than chorea and other motor features and are unlikely to be
responsive to DBS. Secondly, chorea in HD and chorea-acanthocytosis can
gradually be replaced by parkinsonism in the later stages of the diseases. Thus, the

CHOREA
natural history of the disease can contribute to chorea reduction, and different
stimulation or programming strategies may be required in different stages (eg, more
dorsal electrodes in GPi to control parkinsonism). Experimental genetic therapies,
especially huntingtin-lowering treatment, are under active investigation,73,74
and more data will be required before application to clinical practice.
A holistic approach is also crucial in the care of patients with chorea. Many patients
with chorea experience not only motor symptoms but also cognitive and
neuropsychiatric features as well as psychosocial issues. A multidisciplinary team
approach that includes psychiatrists, physical medicine and rehabilitation specialists,
physical therapists, occupational therapists, speech therapists, social workers, and
geneticists and genetic counselors can be beneficial. Furthermore, in some disorders,
especially HD, the unit of treatment is an entire family rather than an individual patient.
Caregiver burden and the stress of at-risk family members should also be supported.
CONCLUSION
The etiology of chorea can be categorized into acquired and genetic causes.
Among the most useful features in the diagnostic approach are time course, age
group, and known prevalence in the population. Other clinical diagnostic clues
can help guide the investigation. Genetic counseling should be considered before
sending genetic testing in chorea. Management should include not only
symptomatic treatment of chorea but also other associated medical, neurologic,
and psychiatric aspects. Family and caregiver support should be also taken into
consideration when caring for patients with chorea.
VIDEO LEGENDS
VIDEO 6-1 VIDEO 6-4
Hemiballism secondary to central nervous system Sydenham chorea. Video shows an 8-year-old boy
toxoplasmosis. Video shows a 54-year-old man with Sydenham chorea who presented with an
with left hemiballism exhibiting large-amplitude acute temporal profile of severe generalized
movements involving the predominantly proximal chorea. He also displays hypotonia and milkmaid’s
arm and leg. On MRI, fluid-attenuated inversion grip. He is unable to stand unassisted.
recovery (FLAIR) images show numerous multifocal links.lww.com/CONT/A354
hyperintense lesions that also involve the basal
ganglia. Reproduced with permission from Frucht SJ.17
links.lww.com/CONT/A351 © 2013 Springer Science+Business Media.
Courtesy of Steven Frucht, MD.

© 2019 American Academy of Neurology. VIDEO 6-5
Huntington disease. Video shows the 83-year-old
VIDEO 6-2 woman described in CASE 6-2. She has Huntington
Hemichorea secondary to nonketotic disease and exhibits generalized chorea including
hyperglycemia. Video shows the 77-year-old upper and lower facial involvement, parakinesia,
woman described in CASE 6-1. She has hemichorea motor impersistence involving the tongue,
secondary to nonketotic hyperglycemia and milkmaid’s grip, and choreic gait. Hung-up knee jerk
demonstrates left hemichorea involving the face, is also shown.
arm, and leg as well as hemichoreic gait. links.lww.com/CONT/A355
links.lww.com/CONT/A352
© 2019 American Academy of Neurology.
VIDEO 6-3
Lupus chorea. Video shows a 29-year-old woman
with acute generalized chorea and encephalopathy
as her first presentation of systemic lupus
erythematosus. Both chorea and her mental status
improved after 3 days of treatment with IV steroids
and tetrabenazine 75 mg/d.
links.lww.com/CONT/A353
Courtesy of Steven Frucht, MD.
1032 AUGUST 2019

VIDEO 6-6 VIDEO 6-7
Huntington disease–like 2. Video shows a Chorea-acanthocytosis. Video shows the
56-year-old woman exhibiting generalized chorea 36-year-old woman with chorea-acanthocytosis
and tongue impersistence. She is originally from described in CASE 6-3. The first video segment
Barbados with African ancestry. Genetic testing for demonstrates severe tongue protrusion and
Huntington disease is negative, and she is feeding dystonia. In the second segment, she
genetically confirmed to have mutations in JPH3 exhibits a mild parkinsonian appearance and lower
diagnostic of Huntington disease–like 2. facial and left arm dystonia, but only mild truncal
links.lww.com/CONT/A356 chorea. She walks with stutter steps and has
circumduction of the left leg.
Courtesy of Steven Frucht, MD. links.lww.com/CONT/A357
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Chorea REVIEW ARTICLE

to chorea in clinical practice, beginning with a discussion of the

phenomenologic features of chorea and how to differentiate it from

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distributions that can be an important clue. A proposed practical approach to

PHENOMENOLOGIC FEATURES OF CHOREA

DIFFERENTIATING CHOREA FROM OTHER ABNORMAL MOVEMENTS

1002 AUGUST 2019

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Body Distribution as a Clue

HEMICHOREA. Lesions leading to hemichorea are classically localized to the

1004 AUGUST 2019

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

hepatocerebral degeneration. Of note, in tardive syndrome with orobuccolingual

FOREHEAD CHOREA. Forehead muscles are often involved in HD, in which

1006 AUGUST 2019

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● Chorea in one of three

● Structural lesions and

● Sydenham chorea can

FIGURE 6-3 ● The time course can help

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TABLE 6-1 Acquired Causes of Choreaa

Structural lesion Vascular causes: ischemic and hemorrhagic strokes,

Metabolic/endocrine Nonketotic hyperglycemia

Acquired hepatocerebral degeneration

Autoimmune/paraneoplastic Sydenham chorea

Rheumatologic diseases: systemic lupus erythematosus,

Autoimmune neurologic syndromes: anti–CRMP-5,

Other Polycythemia vera

ANNA-1 = antineuronal nuclear antibody type 1; CASPR2 = contactin-associated proteinlike 2;

1008 AUGUST 2019

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

GENETIC CAUSES OF CHOREA

1010 AUGUST 2019

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TABLE 6-2 Genetic Causes of Chorea That Primarily Present in Adulthooda

Pattern of Gene (Protein Selected Clinical Clues

Huntington Autosomal CTG/CAG repeat African ancestry Acanthocytes can

CONTINUED ON PAGE 1013

1012 AUGUST 2019

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Pattern of Gene (Protein Selected Clinical Clues

Chorea- Autosomal VPS13A (chorein) Dystonia with predilection

McLeod syndrome X-linked XK (Kx antigen) Cardiomyopathy in two-thirds Patients can

CONTINUED ON PAGE 1014

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CONTINUED FROM PAGE 1013

Pattern of Gene (Protein Selected Clinical Clues

Aceruloplasminemia Autosomal CP (ceruloplasmin) Dystonia, ataxia, diabetes mellitus,

1014 AUGUST 2019

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An 83-year-old woman presented with an 18-month history of abnormal CASE 6-2

A chronic course (longer than 1 year) is suggestive of a genetic etiology of COMMENT

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.