REVIEW

Genetic Mimics of Cerebral Palsy

Toni S. Pearson, MBBS,1* Roser Pons, MD,2 Roula Ghaoui, MBBS, FRACP, PhD3 and
Carolyn M. Sue, MBBS, FRACP, PhD4*

1
Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA
2
First Department of Pediatrics, National and Kapodistrian University of Athens, Aghia Sofia Hospital, Athens, Greece
3
Department of Neurology, Royal Adelaide Hospital, Adelaide, South Australia, Australia
4
Department of Neurogenetics, Kolling Institute, Royal North Shore Hospital and University of Sydney, St Leonards, NSW, Australia

A B S T R A C T : The term “cerebral palsy mimic” is used to
describe a number of neurogenetic disorders that may pre-
sent with motor symptoms in early childhood, resulting in a
misdiagnosis of cerebral palsy. Cerebral palsy describes a
heterogeneous group of neurodevelopmental disorders
characterized by onset in infancy or early childhood of
motor symptoms (including hypotonia, spasticity, dystonia,
and chorea), often accompanied by developmental delay.
The primary etiology of a cerebral palsy syndrome should
always be identified if possible. This is particularly important
in the case of genetic or metabolic disorders that have spe-
cific disease-modifying treatment. In this article, we discuss
clinical features that should alert the clinician to the
possibility of a cerebral palsy mimic, provide a practical
framework for selecting and interpreting neuroimaging,
biochemical, and genetic investigations, and highlight
selected conditions that may present with predominant
spasticity, dystonia/chorea, and ataxia. Making a precise
diagnosis of a genetic disorder has important implications
for treatment, and for advising the family regarding prog-
nosis and genetic counseling. © 2019 International
Parkinson and Movement Disorder Society
Key Words: ataxia; cerebral palsy; dystonia; inborn
errors of metabolism; spasticity

The term cerebral palsy (CP) describes a group of perma- predominant spasticity, the body distribution: diplegia,
nent disorders of the development of movement and pos- hemiplegia, or quadriplegia. In addition, motor symptoms
ture, causing activity limitation, that are attributed to are frequently accompanied by a variety of nonmotor neu-
nonprogressive disturbances that occurred in the develop- rological features, such as intellectual disability, behavioral
ing fetal or infant brain.1 Motor features may include symptoms, and seizures.
hypotonia, spasticity, weakness, and involuntary move- Historically, patients with CP have been classified based
ments (most commonly dystonia or chorea), either alone on physical characteristics rather than etiology. Some his-
or in combination. Clinical characterization involves a torical perspective is worth bearing in mind when consider-
description of the motor features, and in the case of ing how our usage of the term “cerebral palsy” evolved.
The English surgeon William Little is credited with the first
-*Correspondence
- - - - - - - - - - - - - - -to:- - Dr.
- - - Toni
- - - -S.- -Pearson,
- - - - - - - -Department
- - - - - - - - - of- - Neurology,
----------- description, in 1843, of musculoskeletal complications
Washington University School of Medicine, 660 S. Euclid Ave, Campus
Box 8111, St. Louis, MO 63110, USA; E-mail: tpearson@wustl.edu
arising from injury to the infantile central nervous system
Dr. Carolyn M. Sue, Department of Neurogenetics, Kolling Institute, (CNS).2 Other 19th century researchers described the clini-
Royal North Shore Hospital and University of Sydney, Pacific Highway, cal features that distinguished the cerebral palsies from the
St Leonards, NSW 2065, Australia; E-mail: carolyn.sue@sydney.edu.au
flaccid paralysis of poliomyelitis.3 A classification scheme
Relevant conflicts of interest/financial disclosures: Nothing to
report. based on the body distribution of motor symptoms devel-
Full financial disclosures and author roles may be found in the online
oped: hemiplegia, diplegia (bilateral hemiplegia), and para-
version of this article. plegia.4,5 A century later, in the 1980s, further delineation
Received: 26 July 2018; Revised: 4 February 2019; Accepted: 10 of the clinical motor syndrome based on the predominant
February 2019 type of motor involvement—spastic, ataxic, dyskinetic, or
Published online 00 Month 2019 in Wiley Online Library hypotonic—was adopted.6 The variety of possible underly-
(wileyonlinelibrary.com). DOI: 10.1002/mds.27655 ing etiologies has been acknowledged since the 19th

Movement Disorders, 2019 1

P E A R S O N E T A L
century,5 but a universal etiological classification system
for CP remains elusive to this day. Given the manner in
which technological advances in neuroimaging and genetic
testing in the early 21st century have transformed our diag-
nostic capability, the contemporary meaning and usage of
cerebral palsy deserves some contemplation.
CP is best considered a descriptive, rather than a diagnos-
tic, label. We would argue that, as neurologists, we should
not be satisfied with CP as a stand-alone diagnosis for any
child with nonprogressive motor symptoms. Rather, it
should be conceptualized as a syndrome with an underlying
primary etiology in every case. The use of CP as a quasi-
diagnostic label is likely to endure for several reasons,
including its long-standing history, broad recognition by
the lay community, and the practical consideration that
many non-neurological specialists are typically involved in
the care of children with chronic motor disability.
This brings us to the question: what should be considered
a “CP mimic?” If one considers CP to be a syndrome rather
than a diagnosis, genetic diagnoses are not necessarily
excluded. But, in practice, CP is often considered to be syn-
onymous with long-term neurological sequelae of a perina-
tal or infantile brain injury: complications of prematurity
such as intraventricular hemorrhage and periventricular
leukomalacia, neonatal hypoxic-ischemic encephalopathy,
CNS infection, or trauma. For the purposes of this review,
we consider a CP mimic to be a condition that manifests
with a clinical syndrome consistent with CP, in the absence
of documented risk factors or neuroimaging findings con-
sistent with a history of brain injury or a congenital cerebral
malformation.
A number of genetic and metabolic disorders may pre-
sent with clinical features that fit a CP phenotype. Some of
these disorders may be thought of as developmental (symp-
tomatic from birth and nonprogressive), while others are
neurodegenerative (onset at variable intervals postnatally,
with progressive symptoms). A precise etiological diagnosis
should always be sought because, while symptomatic treat-
ments may be prescribed independent of the primary diag-
nosis, the confirmation of a genetic diagnosis has important
implications for the patient and family. Critically, some
neurometabolic conditions have disease-specific treatments
that may dramatically improve symptoms and develop-
mental outcome. Determination of a genetic diagnosis can
lead to an improvement of quality of life for the patient and
family, independent of treatment options, by relieving pos-
sible feelings of ambivalence or guilt.7 Genetic counseling
may prevent disease recurrence in a potential future sibling
and provide information to other family members at risk.
The purpose of this review is to discuss the approach to
diagnosis in a child with a nonprogressive motor syndrome
consistent with CP, and to describe selected genetic condi-
tions that may present as CP mimics. We have included
conditions with the following criteria:
2 Movement Disorders, 2019
1. Symptom onset before age 2 years. In the great majority
of children with CP, initial symptoms appear in infancy,
and the diagnosis of CP is made between the ages of
12 and 24 months.8
2. Stable clinical course with no developmental regres-
sion. The existence of a nonprogressive lesion or dys-
function of the immature brain is a core feature of
CP.9,10 This results in relatively stable neurological fea-
tures, but it is recognized that symptoms may evolve
over time with growth and development even in the face
of a static brain insult.11 For example, spasticity and
weakness may functionally increase as a result of body
growth, and dystonia may emerge years after the initial
brain injury.12,13 We do include some slowly progres-
sive conditions in which progression may not be evident
in the first years of life because of the interaction
between disease progression and normal development.
Some, but not all, CP registries re-evaluate patients
through age 5 years to confirm the diagnosis of CP, per-
mitting the detection of both patients with progressive
disorders, and patients with mild symptoms that were
not evident at an earlier age.8,14
3. Normal or nonspecific neuroimaging findings. Although
neuroimaging is not required to diagnose CP, it is of great
assistance in the recognition of the etiology and patho-
genesis.14 It is known that over 80% of patients with CP
attributed to acquired brain injury show evidence of
brain abnormalities on neuroimaging,15 with white mat-
ter injury being the most common imaging pattern
(19–45%), followed by gray matter injury (21–25%),
focal vascular insults (10–13%), malformations
(11–17%), and miscellaneous findings (4–22%).15,16
Characteristic lesions described in patients with typi-
cal CP attributed to acquired brain injury include per-
iventricular leukomalacia (PVL), thalamic and basal
ganglia ischemic lesions, cerebral hemorrhage or
ischemic stroke, and cerebral dysgenesis.
4. Exclusion of conditions that typically present with
predominant intellectual disability, autism, encepha-
lopathy, or epilepsy. We do, however, discuss some
of the epileptic-dyskinetic encephalopathies in which
motor phenotypes with absent or mild epilepsy have
been described in a number of patients.
We aim to add our perspective to two previously publi-
shed systematic reviews on the topic of genetic and metabolic
disorders that may resemble CP17,18 by providing a practical
framework for the clinician to consider when a patient pre-
sents with an undiagnosed, early-onset, apparently non-
progressive movement disorder suggestive of CP. Selected
common examples are outlined below, grouped according
to the often predominant or distinguishing motor feature,
while recognizing that many conditions present with com-
bined and variable features.

Approach to Diagnosis
It is not possible to provide a comprehensive diagnostic
algorithm, but here we suggest a general approach (Fig. 1)
and outline some specific clinical and imaging features that
may orient the clinician toward an initial diagnostic testing
strategy.
History and Examination
Establishing the primary etiology of a CP syndrome
begins with a careful history and neurological examina-
tion. Clinical features that should prompt the clinician to
consider further investigation for a genetic or metabolic
disorder are summarized in Table 1. The medical history
should first clarify details of the pregnancy and birth to
determine whether a clear cause for perinatal brain injury
may be present, including birth gestation, delivery compli-
cations, Apgar scores, and need for admission to neonatal
intensive care. Additional important details of the medical
history are the age of symptom onset, the time-course of
FIG. 1. General diagnostic approach to the patient with an infantile-onset, apparently non-progressive motor disorder. Studies are grouped by predom-
inant clinical presentation; it may be appropriate to consider investigations from more than one group depending on the specific clinical context. a See
examples in Table 2 b CSF studies: glucose (+serum glucose), lactate, pyruvate, neurotransmitter metabolites (biogenic amines + GABA), pterins,
5-methyltetrahydrofolate.
C E R E B R A L P A L S Y M I M I C S
symptoms, age at which early developmental milestones
were achieved, and family history. A family history of con-
sanguinity, or of a sibling or other relative with similar neu-
rological symptoms, may suggest the possibility of a
genetic condition.
Absence of Risk Factors for Acquired Brain Injury
Classic CP results from acquired pre-, peri-, or postnatal
processes leading to brain injury.10 The most frequent causes
include complications of prematurity, intrapartum asphyxia,
intracranial hemorrhage, infection, stroke, kernicterus, or
trauma.9 When a specific etiology is unclear, a combination
of two or more risk factors is often identifiable from the med-
ical history.8
Inconsistent Clinical Course
Motor symptoms in CP tend to be relatively stable from
moment to moment. A history of marked symptom fluctu-
ation or paroxysmal symptoms in relation to time of day,
activity, or fasting is atypical for CP, and is an important
Movement Disorders, 2019 3
P E A R S O N E T A L
TABLE 1. Clinical features that should prompt evaluation
for genetic and metabolic conditions in a patient presenting
with symptoms of CP
Absent history of any perinatal risk factor for brain injury
Family history of sibling with similar neurological symptoms
Motor symptom onset after an initial period of normal development
Developmental regression
Progressive neurological symptoms
Paroxysmal motor symptoms or marked fluctuation of motor symptoms
Clinical exacerbation in the setting of a catabolic state (e.g., febrile illness)
Isolated generalized hypotonia
Prominent ataxia
Signs of peripheral neuromuscular disease (reduced or absent reflexes,
sensory loss)
Eye movement abnormalities (e.g., oculogyria, oculomotor apraxia, or
paroxysmal saccadic eye-head movements)
clue to a possible underlying metabolic disorder. Examples
of treatable metabolic diseases that may present with these
features are the neurotransmitter disorders associated with
impaired synthesis of the biogenic amines dopamine and
serotonin and glucose transporter type 1 (Glut1) deficiency
syndrome. Prompt diagnosis is important because early ini-
tiation of treatment may markedly improve symptoms and
developmental outcome.
Children with CP often have developmental delay, but
do not typically regress developmentally in the early child-
hood years. In contrast, motor symptom onset after normal
attainment of early motor milestones, such as independent
sitting and walking, is a red flag and may point to an under-
lying genetic disorder. In infants and young children, this
information can be accurately collected in most cases.
In adult patients, early historical details are sometimes
unavailable, particularly if neither parent is available to
provide them. This is one potential pitfall that can lead to
misdiagnosis of CP in an older patient with a slowly pro-
gressive condition that started in childhood after a period
of normal development in infancy.
Inconsistent Clinical Examination Findings
On examination, it is helpful to be aware of clinical
features that are not typically observed in children with CP
attributed to brain injury. These include eye movement
abnormalities (e.g., oculomotor apraxia in ataxia-telangi-
ectasia)19 or episodic repeated eye-head gaze saccades in
Glut1 deficiency syndrome,20 isolated ataxia or isolated
generalized hypotonia (without spasticity or dystonia),
myoclonus or myoclonic epilepsy, and dysmorphic fea-
tures (Table 1). In the presence of these signs, clinicians
need to maintain a high index of suspicion, particularly
when there is no history of risk factors for perinatal brain
injury, and neuroimaging findings are unremarkable.
Brain Imaging
Brain MRI is a first-line investigation in a child or adult
with an undiagnosed motor disorder suggestive of CP. Brain
4 Movement Disorders, 2019
MRI demonstrates evidence of white matter or basal ganglia
injury in the vast majority of patients with spastic CP and
approximately two-thirds of patients with dyskinetic CP.21
In the assessment of bilateral cerebral abnormalities, such as
white matter injury or basal ganglia lesions, it is helpful
to be aware of the typical MRI appearance of common
patterns of injury observed in patients with CP. For exam-
ple, PVL (associated with preterm birth) may appear as
multifocal T2-hyperintense white matter lesions in the acute
phase, but residual findings in the chronic phase may consist
only of white matter volume loss and ventricular dilatation
with evidence of scarring around the ependyma.22 The most
common pattern of deep gray matter injury in term infants
with CP is involvement of the thalamus, putamen, and
globus pallidus.15
Some children with a CP phenotype have a cerebral mal-
formation as the primary cause of their neurological syn-
drome, which is readily recognized on brain imaging. There
are now a number of causative genes associated with disor-
ders of neuronal migration and cortical development, such
as lissencephaly, polymicrogyria, schizencephaly, and focal
cortical dysplasia.23,24 In severe cases, associated clinical fea-
tures typically include seizures and intellectual disability.23
Aside from cerebral malformations, brain imaging may
reveal two main types of findings that should prompt fur-
ther investigation for a genetic disorder. First, the brain
MRI may be completely normal. Second, imaging may
demonstrate specific lesions that are inconsistent with peri-
natal brain injury, but characteristic of a particular genetic
disorder or group of disorders (Table 2). Most of these con-
ditions with characteristic imaging findings will not be fur-
ther discussed below.
TABLE 2. Brain MRI findings suggestive of selected genetic
CP mimics
Finding Selected Conditions
Hypomyelination PLP1-related dysmyelinating disorders
H-ABC (TUBB4A mutation)
AGS (may also have basal ganglia and WM
calcification)
GM1 gangliosidosis
Demyelination Krabbe disease
Metachromatic leukodystrophy
Thin corpus HSP (i.e., SPG4, SPG11, SPG15, and others)
callosum
Globus pallidus T2-hypointense: NBIA (SN also involved in BPAN,
lesions MPAN), fucosidosis
T2-hyperintense: MMA, PDH deficiency, creatine
deficiency syndromes
Focal atrophy or Glutaric aciduria type 1 (frontotemporal),
hypoplasia H-ABC (cerebellum  putamen),
Joubert syndrome (cerebellum)
AGS, Aicardi-Goutières syndrome; BPAN, beta-propeller protein-associated
neurodegeneration; H-ABC, hypomyelination with atrophy of the basal gang-
lia and cerebellum; MMA, methylmalonic aciduria; MPAN, mitochondrial
membrane protein-associated neurodegeneration; NBIA, neurodegeneration
with brain iron accumulation; PDH, pyruvate dehydrogenase; WM, white
matter.
 C E R E B R A L P A L S Y M I M I C S

Screening Metabolic Investigations clinical and radiological features are nonspecific, however,
An important consideration early in the diagnostic pro- a more comprehensive testing approach is appropriate.
cess is whether the patient may have a treatable metabolic Comparative genomic hybridization (CGH) microarray
disorder. While it is now more common for next-generation to detect chromosomal microdeletions and -duplications is
sequencing (NGS) molecular genetic tests to be performed recommended as a first-tier investigation for infants and
before lengthy and comprehensive metabolic studies, there children who present with developmental delay, intellec-
remains a role for screening biochemical investigations. The tual disability, autism, and/or congenital anomalies. Facial
finding of a positive biomarker may expedite diagnosis of a dysmorphism and congenital microcephaly are additional
treatable condition and facilitate initiation of disease- features that should prompt CGH microarray analysis.
specific treatment (Table 3). Cerebrospinal fluid (CSF) anal- Pathogenic de novo copy number variants were detected
ysis is strongly recommended in the case of an infant or in 7% to 17% of patients with CP in several recent small
young child presenting with marked symptom fluctuation studies.25-27
in relation to time of day, exertion, or fasting—features that Tests based on NGS techniques, including multigene
may suggest a metabolic disease such as monoamine neuro- panels and when accessible, whole-exome and -genome
transmitter disorder or Glut1 deficiency syndrome. sequencing (WES and WGS) may be pursued if the
diagnosis remains uncertain. When the syndrome is
clinically or radiologically distinct (e.g., hereditary spas-
tic paraplegia or leukodystrophy), it may be appropri-
Genetic Testing ate to perform a targeted, multigene panel first. When
The appropriate genetic testing strategy depends on the the features are nonspecific or mixed, WES or WGS
patient’s age, clinical syndrome, brain imaging findings, (including trio analysis with parental samples, if avail-
and results of any screening biochemical investigations that able, to increase diagnostic yield) are likely to be a
may have been performed. If a specific syndrome or imag- more efficient and cost-effective strategy. This is fre-
ing abnormality is evident, confirmatory molecular genetic quently the case in infants and young children, recog-
testing may be targeted at a small number of genes. If the nizing that their disease features may not yet have had
time to fully evolve, and also that we do not yet know
TABLE 3. Screening laboratory investigations for treatable the full phenotypic spectrum of most genetic disorders.
metabolic disorders that may present as CP mimics Test findings should be interpreted in the context of the
patient’s clinical features, and with the support of a
Test Sample Conditions
geneticist and/or genetics counselor, given the potential
Monoamine neurotransmitter CSF BH4 deficiencies, TH for detecting variants of unknown significance.
metabolites, pterins deficiency, AADC
deficiency, DNAJC12
deficiency
5-Methyltetrahydrofolate CSF Cerebral folate
deficiency
Selected Disorders
Glucose CSF, plasma Glut1 deficiency with Prominent Spasticity
Lactate CSF, plasma Mitochondrial disease,
organic acidurias, Spastic CP is characterized by spasticity, weakness, and
thiamine deficiency
hyperreflexia and can affect both upper and lower limbs as
Pyruvate CSF, plasma Pyruvate dehydrogenase
deficiency well as the neck and trunk. It may be worse in the lower
Amino acids Plasma, CSF Arginase deficiency, limbs when compared to the upper limbs and may be either
BH4 deficiencies unilateral or bilateral.28 Several neurological conditions
(CSF: glycine can masquerade as spastic CP resulting in misdiagnosis of
encephalopathy,
some patients. Some examples are the hereditary spastic
serine deficiency)
Ammonia Plasma Arginase deficiency paraplegias (HSPs), arginase deficiency, and multiple car-
Acylcarnitines Plasma Organic acidurias boxylase deficiency. Disorders that typically present with
Biotinidase activity Plasma Biotinidase deficiency spasticity in combination with other neurological features,
Thyroid stimulating hormone Plasma Brain-lung-thyroid including Glut1 deficiency, Pelizaeus-Merzbacher disease,
syndrome (benign
and some dopamine synthesis defects, are discussed in
hereditary chorea)
Uric acid Plasma Lesch-Nyhan syndrome other sections below. Disorders that are usually associated
Creatine and Plasma, urine Creatine deficiency with a clearly progressive disease course, and/or symptom
guanidinoacetate onset after a period of normal early development, such as
Organic acids Urine Organic acidurias, lysosomal storage diseases, cerebral folate deficiency, and
multiple carboxylase
cerebrotendinous xanthomatosis, will not be discussed
deficiency
here because the course of symptom progression is incon-
AADC, aromatic L-amino acid decarboxylase; TH, thyroid hormone. sistent with CP.

Movement Disorders, 2019 5

P E A R S O N E T A L
HSP Syndromes
There are over 60 genes associated with HSP, a group of
disorders that share the core feature of lower limb spasticity
associated with weakness, each to a varying degree. The
upper limbs may only become involved late in the disease
course. HSP syndromes are categorized into two broad
groups: “uncomplicated” (pure spastic paraplegia pheno-
type) and “complicated” (variable other neurological and
systemic manifestations such as peripheral neuropathy, cog-
nitive impairment, ataxia, and brain imaging abnormalities).
There is considerable genetic and phenotypic heterogeneity,
and many of the genes may be associated with both uncom-
plicated and complicated phenotypes.29
Most, but not all, patients with HSP have slowly progres-
sive weakness. Specifically, infantile-onset HSP may be non-
progressive, as observed in cases with de novo mutations
in SPG3A/atlastin.30 As a consequence, patients with HSP
may be misdiagnosed as having spastic diplegic CP. HSP
can usually be distinguished from spastic diplegic CP by the
absence of perinatal risk factors for brain injury and normal
brain imaging or specific findings suggestive of an HSP
syndrome, such as thin corpus callosum.31 Other associated
features that may accompany HSP, such as parkinsonism,
dystonia, ataxia, ptosis, posterior column signs, ophthalmo-
plegia, amyotrophy, and a thin corpus callosum, may alert
the clinician to consider a diagnosis of HSP.
Arginase Deficiency
Arginase deficiency is an autosomal-recessive disorder
of the urea cycle caused by mutations in ARG1. This
results in argininemia and intermittent moderately raised
plasma ammonia concentrations. Unlike other urea cycle
defects, which typically manifest with hyperammonemia
and encephalopathy, arginase deficiency may present with
progressive spastic paraplegia. Onset is usually in late
infancy, and may be insidious, leading to misdiagnosis
with CP.32 Additional clinical features are epilepsy and
intellectual disability.33,34 A careful history elucidating the
presence of slowly progressive symptoms, or an acute pre-
sentation with encephalopathy and vomiting associated
with hyperammonemia, if one occurs, help to distinguish
this disorder from CP. The diagnosis is suggested by raised
arginine concentrations on plasma amino acid analysis,
and now typically confirmed with molecular genetic anal-
ysis.35 The mainstay of treatment has been to reduce the
production of nitrogenous waste and lower the ammonia
levels by providing a low-protein diet supplemented with
citrulline and/or arginine and preventing endogenous
catabolism through dietary restrictions.34,36
Multiple Carboxylase Deficiency
Multiple carboxylase deficiency is characterized by defi-
cient activity of the biotin-dependent carboxylation
enzymes, and may result from deficiency of either bio-
tinidase or holocarboxylase synthetase. These disorders
6 Movement Disorders, 2019
respond to treatment with biotin. Holocarboxylase syn-
thetase deficiency typically presents in early infancy with
severe lactic acidosis. Clinical manifestations include a
seborrheic skin rash, seizures, and encephalopathy that
can progress to coma, but the chronic neurological fea-
tures of hypertonia and developmental delay may be mis-
interpreted as CP.37 Biotinidase deficiency is more
common than holocarboxylase synthetase deficiency and
usually presents later in infancy with hypotonia, develop-
mental delay, seizures (often myoclonic), ataxia, and meta-
bolic acidosis, in addition to skin rash and alopecia.38
Some patients with biotinidase deficiency develop spastic
paraparesis or tetraparesis attributed to myelopathy.39,40
Patients with multiple carboxylase deficiency have raised
concentrations of lactate, 3-methylcrotonylglycine, and
3-hydroxyisovaleric acid in the blood and urine. Bio-
tinidase deficiency can be confirmed by enzyme assay on
dried blood spot and is included on newborn screening
panels in many countries. Treatment with biotin results in
resolution of the skin rash and the organic aciduria,41 and
prevention of long-term neurological disability if treat-
ment is initiated early in life.42
Selected Disorders with Prominent
Dystonia and/or Chorea
Monoamine Neurotransmitter Disorders
The primary monoamine neurotransmitter disorders are a
group of conditions characterized by deficient synthesis
or transport of biogenic amines, including catecholamines
(dopamine, noradrenaline, and adrenalin) and serotonin.
Clinical symptoms can be variable and range in severity. The
most severe forms present in early infancy with profound
hypotonia, akinesia, oculogyric crises, dystonia, irritability,
and autonomic features such as ptosis, gastrointestinal
dysmotility, temperature instability, and excessive sweating.
In some patients, encephalopathy and seizures may also
occur. More moderate forms, for example, classic dopa-
responsive dystonia attributed to autosomal-dominant GTP-
cyclohydrolase deficiency, may present in childhood with
developmental delay, hypotonia, dystonia, parkinsonism, or
spastic diplegia.43-45
Accurate diagnosis requires the analysis of CSF metabo-
lites and is essential given that most neurotransmitter disor-
ders are treatable. Neuroimaging is generally normal.
Depending on the specific condition, treatment may in-
clude variable combinations of supplementation with the
cofactor, tetrahydrobiopterin (BH4), the neurotransmitter
precursors, levodopa and 5-hydroxytryptophan, dopami-
nergic medications, including dopamine agonists, and
anticholinergics.46,47
Patients can be misdiagnosed with CP because of the
nonprogressive nature of the motor manifestations. There
are, however, characteristic clinical features in this group
of disorders that should prompt their suspicion. The first is

oculogyric crises, or paroxysmal dystonic episodes of
ocular deviation with variable association of limb and/or
axial dystonic posturing, which typically present during
infancy. Consciousness is preserved and the episodes tend
to occur later in the day and subside with sleep. The sec-
ond characteristic feature, though not always present, is
diurnal variation, or a marked exacerbation of motor
symptoms late in the day and/or improvement with sleep.
In infants with severe phenotypes manifesting with
akinesia, this feature may not be noted, except for the pres-
ence of oculogyric crises later in the day as mentioned
above.
Benign Hereditary Chorea/NKX2-1–Related
Disorders
Benign hereditary chorea (BHC) is an autosomal-
dominant movement disorder that results from mutations
of the NK2 homeobox 1 gene (NKX2.1) encoding a tran-
scription factor that is essential for the development of the
lung, thyroid, and basal ganglia. It is characterized by non-
progressive chorea in variable association with thyroid and
respiratory involvement (brain-thyroid-lung syndrome).48
Patients usually present with hypotonia during infancy,
delayed walking, and chorea in early childhood. Chorea is
generalized and may also involve face, tongue, or trunk. It
improves during adolescence and stabilizes or may even
resolve completely in early adulthood. Approximately half
of patients develop other movement disorders such as dys-
tonia, ataxia, or intention tremor.49 Cognition is relatively
preserved and neuroimaging is normal. Various combina-
tions of brain, thyroid, and lung involvement occur, with
the full triad reported in 36% to 49% of cases. The most
frequent thyroid involvement is in the form of congenital
hypothyroidism, whereas lung involvement may manifest
with neonatal respiratory distress, recurrent pulmonary
infections, asthma, and lung cancer.50
Patients with BHC may be misdiagnosed with dyski-
netic CP, especially when there is lack of family history,
which occurs in approximately one-third of cases.50
Lesch-Nyhan Syndrome
Lesch-Nyhan syndrome (LNS) is a rare X-linked reces-
sive disorder of purine metabolism attributed to deficiency
of the purine salvage enzyme, hypoxanthine-guanine
phosphoribosyl transferase. LNS is characterized by uric
acid overproduction and a neurological disorder that
includes motor disability, cognitive impairment, and self-
injurious behavior.51
In LNS, the motor disorder manifests with hypotonia
and motor delay during infancy. Subsequently, between
the ages of 6 and 24 months, dystonia emerges, which is
generalized, with prominent involvement of cervical,
truncal, and oromandibular regions. Other involuntary
movements (choreoathetosis or ballismus) and pyramidal
signs may also occur.52,53 Neuroimaging is usually normal,
C E R E B R A L P A L S Y M I M I C S
although some patients have cerebral atrophy. The move-
ment disorder remains relatively static, and eventually
patients develop self-injurious behavior, most often biting
of the fingers, hands, lips, and cheeks, between the ages of
2 and 3 years, and at times even later.52,53
Children with LNS may initially be misdiagnosed
with dyskinetic CP. The development of self-injurious
behavior is often a distinct clue to the correct diagnosis.
Treatment includes allopurinol to control the over-
production of uric acid, but this has no effect on behav-
ioral or neurological symptoms.52,53
ADCY5-Related Dyskinesia
ADCY5-related dyskinesia is caused by heterozygous
mutations in the ADCY5 gene encoding adenyl cyclase 5, a
striatal-specific enzyme crucial for several molecular path-
ways.54 Patients typically present in infancy or early child-
hood with axial hypotonia, motor delay, and dyskinesia
(chorea, ballismus, and choreoathetosis) often with facial
involvement.55 Episodic exacerbations of the baseline dys-
kinesia upon awakening, when falling asleep or during
intercurrent illnesses, lasting minutes to hours, and even
days, is characteristic and may be the first disease manifes-
tation. Subsequently, the disease course is variable, from
stability to spontaneous improvement during adolescence.
Generalized dystonic spasms can also occur. Patients may
be cognitively normal or have mild intellectual disability.
Neuroimaging is normal.54,55
Patients with ADCY5-related dyskinesia are often mis-
diagnosed with hypotonic or dyskinetic CP.55 A specific
clue to the diagnosis is the episodic exacerbations of dys-
kinesia, particularly during drowsiness.
Other Hyperkinetic Movement Disorders
With the advent of NGS new genes associated with
hyperkinetic movement disorders have been identified
that can mimic dyskinetic CP, including PDE10A,56,57
PDE2A,58 GPR88,59 and GNB1.60,61
Epileptic-Dyskinetic Encephalopathies
The epileptic-dyskinetic encephalopathies are a group of
genetically and clinically heterogenous disorders character-
ized by early-onset epileptic encephalopathy associated
with hyperkinetic movement disorders. Related genes
include FOXG1, GNAO1, GRIN1, STXBP1, GABRA2,
ARX, TBC1D24, FRRS1L, PCDH12, CDKL5, SCN2A,
SETD5, ALG13, TBL1XR1, SCN1A, and SCN8A.62-65
The increasing application of next-generation technologies
has led to the realization that these disorders may present
with a remarkably broad range of phenotypes, including a
predominant motor disturbance with absent or mild epi-
lepsy, thus potentially mimicking dyskinetic CP.66
Movement Disorders, 2019 7
P E A R S O N E T A L
GNAO1-Related Disorders
GNAO1 encodes an α-subunit of heterotrimeric guanine
nucleotide-binding protein responsible for regulation of
gamma-aminobutyric acid B and α2-receptors and neuro-
transmitter release.67 GNAO1-related disorders range from
infantile epileptic encephalopathy to a static encephalopathy
without epilepsy characterized by infantile hypotonia,
global developmental delay, and the later emergence, in
some cases, of a hyperkinetic movement disorder (chorea,
ballismus, dystonia, and orofaciolingual dyskinesia) at vari-
able ages during childhood. Episodic exacerbations of cho-
rea, in combination with autonomic dysfunction, are often
triggered by infection or other stressors, and may last days
to weeks. Before the first exacerbation of chorea occurs, the
motor syndrome typically appears nonspecific, and patients
may be misdiagnosed with hypotonic or dyskinetic CP.68
The movement disorder phenotype without epilepsy has
mainly been reported in association with gain-of-function
mutations in codons 209 or 246.67,69,70
FOXG1-Related Disorders
The FOXG1 gene product is a transcription repressor
that plays a crucial role in fetal telencephalon development
and is an important component of the transcription regula-
tory network that controls proliferation, differentiation,
neurogenesis, and neurite outgrowth in the cerebral cortex,
hippocampus, and basal ganglia.63 Mutations in FOXG1
manifest in infancy or early childhood with severe develop-
mental delay, acquired microcephaly, profound intellectual
disability, epilepsy, and a hyperkinetic movement disorder.
Neuroimaging may show corpus callosum hypoplasia or
aplasia, delayed myelination, simplified gyration, and
frontotemporal abnormalities.71 Hyperkinetic movement
disorders in these patients include various combinations of
chorea, orolingual/facial dyskinesia, dystonia, myoclonus,
and hand stereotypies.72,73 Once more, expansion of the
clinical phenotype has been recognized in patients with
FOXG1 mutations. Patients with milder phenotypes may
be normocephalic, acquire independent ambulation and
speech, have minimal or no MRI abnormalities, and have
the hyperkinetic movement disorder as the major clinical
feature, thus mimicking dyskinetic CP. It appears that mis-
sense variants in the forkhead conserved site 1 are responsi-
ble for these milder phenotypes.72,73
Organic Acid Disorders
Organic acidurias are a group of inborn error of
metabolism leading to accumulation of toxic intermedi-
ates that can manifest early in life with episodes of
acute encephalopathy precipitated by catabolic states
(febrile illness, vomiting diarrhea, and fasting),
resulting in basal ganglia injury and variable neuro-
logic deficits. Generally, the medical history, the find-
ings on neuroimaging, and the abnormalities on
metabolic studies point to the diagnosis. Nevertheless,
8 Movement Disorders, 2019
at times, the acute encephalopathy may be misdi-
agnosed with a viral encephalitis, and the subsequent
neurological phenotype is characterized as postnatal
CP.74 Diagnosis is essential given that there is benefit
from treatment, including dietary restrictions and sup-
plements according to the enzyme deficiency.
Glutaric aciduria type 1 (GA-1) is an autosomal-recessive
disorder of the degradation of lysine, hydroxylysine, and
tryptophan, resulting from a defect of the enzyme, glutaryl-
CoA dehydrogenase.75 This enzyme deficiency results in an
accumulation of glutaric and glutaconic acid. Urine testing
for organic acids demonstrates increased urinary excretion
of glutaric acid and 3-hydroxyglutaric acid.76 The usual age
of presentation is 6 months to 2 years. Most children pre-
sent with a severe chronic dystonic-dyskinetic syndrome that
follows an acute encephalopathy resulting in permanent
striatal lesions. The most characteristic finding on neuroim-
aging is the presence of wide CSF spaces and enlarged
Sylvian fissures (“bat-wing” appearance).77 Patients may
also manifest within the first year of life with an insidious
clinical picture that is characterized by developmental delay,
hypotonia, mild-moderate choreoathetosis or dystonia,78
and dorsolateral putaminal lesions on brain MRI.79 Al-
though this disorder does not strictly fit the criteria of a CP
mimic because of the abnormal and characteristic neuroim-
aging findings, we have included it because it has been long
considered a CP masquerader. Early detection of GA-1 is
very important, given that diet restriction and riboflavin and
carnitine therapy can limit and to some extent even reverse
the neurological deficit.
Cerebral Creatine Deficiencies
Cerebral creatine deficiencies (CCDs) are inborn errors of
creatine metabolism that include arginine: glycine amidino-
transferase, guanidinoacetate methyltransferase (GAMT),
and X-linked creatine transporter deficiency (SLC6A8) that
are characterized by syndromic intellectual disability.
Patients typically present with developmental delay, and
additional clinical features include seizures (60%), hypoto-
nia (40%), ataxia (30%), and/or dystonia and chorea
(11%).80 Abnormal signal in the globus pallidus may be
noted on brain MRI.81
While the motor features are usually less prominent
than intellectual disability, behavior problems, and sei-
zures in these disorders, we have included them here
because they are treatable. Treatment strategies involve
oral supplementation of high-dose creatine mono-
hydrate for all three CCDs. Guanidinoacetate-reducing
strategies (high-dose ornithine, arginine-restricted diet)
are additionally used in GAMT deficiency. Supplemen-
tation of substrates for intracerebral creatine synthesis
(arginine, glycine) has been used additionally to treat
SLC6A8 deficiency.81-84 Early recognition is essential as
treatment improves outcome.

Cerebral Folate Deficiency
Cerebral folate deficiency (CFD) is associated with low
levels of 5-methyltetrahydrofolate in the CSF with normal
plasma folate levels. The most common cause of CFD
is blocking autoantibodies to the folate receptor that
inhibit methyltetrahydrofolate transport across the choroid
plexus.85 Symptoms typically present around 4 to 6 months
of age with delayed development, hypotonia, ataxia, cho-
reoathetosis, hemiballismus, spasticity, speech difficulties,
and often severe epilepsy.85 Development of progressive
neurological symptoms, followed by progressive vision and
hearing loss from around age 3 years if left untreated, distin-
guishes this syndrome from CP. Treatment with folinic acid
results in significant improvement of clinical symptoms and
a return of 5-methyltetrahydrofolate levels in the CSF to
normal. It is essential that patients with neurological disor-
ders of uncertain etiology are screened for this condition so
that the opportunity to treat it and minimize future disability
is not missed.86
Selected Disorders with Ataxia
and Mixed Motor Features
Fewer than 5% of patients in CP registries have ataxic
CP,21,87 and in our experience, isolated ataxia is a rare
finding in patients with CP associated with perinatal brain
injury. Therefore, investigation for genetic causes of ataxia
should be strongly considered in any patient who presents
with predominant ataxia, especially in the context of nor-
mal brain imaging. Autosomal-recessive ataxias, for
example, ataxia-telangiectasia, may present with initially
nonprogressive motor symptoms, and de novo dominant
point mutations in several different genes have been
reported in children with a diagnosis of ataxic CP.88
Ataxia may be one feature of a complex syndrome that
includes spasticity and/or dystonia.
Glut1 Deficiency Syndrome
Glut1 deficiency syndrome (DS) is a disorder of brain
energy metabolism caused by impaired glucose transport
into the brain mediated by the glucose transporter, Glut1.
Glut1 DS presents with a diverse phenotypic spectrum. The
classic phenotype of Glut1 DS manifests with infantile-
onset refractory epilepsy, developmental delay, acquired
microcephaly, varying degrees of intellectual disability, a
mixed movement disorder (spasticity, ataxia, and dystonia),
and paroxysmal neurological events, including paroxysmal
exertion-induced dyskinesia, paroxysmal eye-head move-
ments, migraines, dysphoria, and paroxysmal events with
prominent motor manifestations (ataxia, hemiplegia, and
dyskinesias).20,89,90
Up to 20% of patients with Glut1 DS manifest with non-
classic phenotypes, including benign epilepsy syndromes;
paroxysmal exercise-induced dyskinesia with or without
C E R E B R A L P A L S Y M I M I C S
epilepsy, and a neurodevelopmental disorder associated
with variable motor manifestations. The latter is the pheno-
type that may be misdiagnosed as CP. Patients’ symptom
onset is usually in infancy or early childhood. Spasticity
and ataxia are usually the most prominent early motor
findings, whereas dystonia tends to emerge in later child-
hood or adolescence.91
Patients with Glut1 DS have both persistent and episodic
motor findings. Spastic diplegia is typically a stable feature,
but an important diagnostic clue in Glut1 DS is that ataxia
and involuntary movements often fluctuate in severity,
worsening in the context of exercise or fasting.90,92 The
same environmental triggers may provoke other paroxys-
mal symptoms, often with prominent motor manifestations
such as weakness. The biochemical hallmark of the disease
is a low CSF glucose concentration in the setting of a nor-
mal serum glucose. The underlying genetic cause is a hetero-
zygous pathogenic variant in SLC2A1. If no pathogenic
variant is identified, 3-O-methyl-D-glucose uptake in eryth-
rocytes can be performed, with a value between 35% and
74% of control levels being diagnostic for the condi-
tion.92,93 Brain imaging is either normal or shows slight
brain atrophy, whereas in up to one-quarter of cases white
matter abnormalities are detected, including focal or diffuse
supratentorial hyperintensities, prominence of perivascular
Virchow Robin spaces, and delayed myelination.94,95 Criti-
cally, the ketogenic diet or modified Atkins diet often leads
to substantial symptom improvement.95,96
Ataxia Telangiectasia
Ataxia telangiectasia (A-T) is an autosomal-recessive
disease caused by mutations in the ATM gene.97 A-T is a
multisystem neurodegenerative and immunodeficiency
disorder. It manifests with progressive cerebellar ataxia,
oculomotor apraxia, oculocutaneous telangiectasia,
sinopulmonary infections, radiosensitivity, early aging,
and increased incidence of cancer.98 Dystonia and
choreoathetosis occur frequently in A-T, and may be more
prominent than ataxia at onset.99-101 Brain imaging is nor-
mal during the first 2 years of life, even though children are
already symptomatic. Between 2 and 8 years of age, virtu-
ally all children with the classic form develop cerebellar
atrophy, which is progressive and parallels the progression
of the pathology. A-T can be misdiagnosed in early child-
hood as ataxic-dyskinetic CP, given that symptom progres-
sion may not be evident in early childhood, and
telangiectasias usually appear after the onset of neurologi-
cal symptoms.102,103
Pelizaeus-Merzbacher Disease
Pelizaeus-Merzbacher disease (PMD) is an X-linked
recessive disorder affecting myelination of the CNS. It is
attributed to variants in the PLP gene encoding the
proteolipid-protein (PLP), which is a major component of
the myelin membrane. Patients with PLP mutations have a
Movement Disorders, 2019 9
P E A R S O N E T A L
wide spectrum of possible presentations ranging from the
less involved spastic paraplegia type 2 (SPG2) with pro-
gressive leg weakness and spasticity to the more severe clas-
sical PMD, which manifests in infancy with nystagmus,
hypotonia, developmental delay, tremor, ataxia, and pro-
gressive spasticity.104 In classic PMD, cognition is variably
impaired and dystonia and athetosis may also occur. In
classical PMD, brain MRI shows diffuse abnormal white
matter signal and prominently reduced white matter vol-
ume. Despite the fact that PMD is a neurodegenerative dis-
ease, it is considered a CP masquerader because the
spasticity progresses slowly and the neuroimaging findings
may not be appreciated during the first year of life.
Other Conditions Mimicking Ataxic
and Mixed CP
A number of neurometabolic disorders, such as mito-
chondrial disorders, coenzyme Q10 deficiency, congenital
disorders of glycosylation, or Nieman Pick Type C, may
present insidiously with ataxia associated with other
motor manifestations.105 The progressive nature may not
be evident in the first years of life, and patients potentially
can be misdiagnosed with CP. However, often times these
patients have multiple system involvement and neuroim-
aging demonstrates abnormalities suggestive of a genetic
or metabolic disorder.
Conclusion
This review has summarized some of the metabolic, neu-
rodegenerative, and developmental genetic disorders that
may present with a CP phenotype. Some of these disorders
are treatable and can be identified with minimally invasive
testing. Lumbar puncture should be considered to obtain
CSF for analysis of neurotransmitter metabolites and glu-
cose, particularly in infants and children with fluctuating
or paroxysmal motor symptoms. Other investigations,
including neuroimaging and molecular genetic testing, will
facilitate the diagnosis of the underlying pathophysiology
of these disorders. Considering the marked technological
advances in molecular genetic diagnosis that have occurred
in the past decade, a diagnosis of CP deserves reconsidera-
tion in any adolescent or adult patient who lacks a clear eti-
ology for their neurological syndrome. There are clear
benefits to identifying an etiological diagnosis, including
the ability to provide better counseling to patients and their
families about the cause of the disease, recurrence risk, and
prognosis; identify appropriate support groups; and, in
some conditions, provide disease-modifying therapy that
may improve symptoms and developmental outcome.
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