Review Article

Metabolic and genetic disorders mimicking cerebral palsy

Wejdan S. Hakami, MD, Khaled J. Hundallah, MD, Brahim M. Tabarki, MD.

ABSTRACT C erebral palsy (CP) is a group of disorders that

affect movement, tone or posture, causing activity
limitation, that are attributed to non-progressive
‫الشلل الدماغي هو متالزمة تشمل مجموعة كبيرة من اضطرابات‬ disturbances that occurred in the immature developing
‫احلركة واجللسه لدى األطفال التي تنجم عن آفة حتدث في الدماغ‬ brain, most often before birth.1,2 The CP should be
‫ ميكن للعرض السريري للعديد من احلاالت األيضية‬.‫في طور النمو‬ better considered as a descriptive syndrome because
‫ أن حتاكي الشلل‬،‫ وخاصة في املجموعات شديدة االقارب‬،‫واجلينية‬ it is not a specific disease, pathological or etiological
‫ الهدف من هذه املقالة هو التعرف‬.‫الدماغي خاصة في سن مبكرة‬ entity. The motor component abnormality in CP is
‫على السمات السريرية التي يجب أن تنبه الطبيب إلى إمكانية‬ often associated with epilepsy, intellectual disability,
‫ والعالمات املهمه السريرية‬،‫حدوث اضطرابات تشبه الشلل الدماغي‬ movement disorders, visual and hearing impairments,
and musculoskeletal problems which contribute to
‫ وتسليط الضوء على بعض احلاالت االستقالبية‬،‫والتصوير العصبي‬ the clinical heterogeneity of CP. The presence of these
‫ في حالة‬.‫ وخلل احلركة‬،‫ والترنح‬،‫واجلينية التي قد تظهر مع التشنج‬ additional features can make the diagnostic process
‫ فإن إجراء تشخيص دقيق مهم بشكل‬،‫االضطراب األيضي أو الوراثي‬ sometimes difficult and challenging. A growing group
.‫خاص إلمكانية العالج والتشخيص الدقيق واالستشارات الوراثية‬ of metabolic and genetic disorders is being recognized,
mainly due to the advancement in the area of metabolic
Cerebral palsy is a syndrome that encompasses a large and genetic investigations, to present with exactly the
group of childhood movement and posture disorders same symptoms and signs as CP.3-12 These CP mimickers
that result from a lesion occurring in the developing are common, particularly in highly consanguineous
brain. The clinical presentation of many metabolic populations, as in Saudi Arabia, and can be easily
and genetic conditions, particularly in highly missed, mainly in countries lacking national newborn
consanguineous populations, can mimic cerebral
screening programs or advanced metabolic and genetic
palsy particularly at early age. The aim of this review
article is to identify the clinical features that should
investigations.13 The possibility of a treatable metabolic
alert the physician to the possibility of disorders that or genetic etiology of CP, together with a more accurate
resemble cerebral palsy, the clinical and neuroimaging diagnosis and genetic counseling, emphasizes the
red flags, and highlight some metabolic and genetic importance of being particularly vigilant in determining
conditions which may present with spasticity, ataxia the etiology.3 The objective of this review is to provide
and dyskinesia. In the case of metabolic or genetic a practical diagnostic approach to a child with motor
disorder, making a precise diagnosis is particularly delay early in life suggestive of CP, and to summarize
important for the possibility of treatment, accurate the most common metabolic and genetic conditions,
prognosis and genetic counseling. focusing on treatable diseases, that may be misdiagnosed
as CP.
Neurosciences 2019; Vol. 24 (3): 155-163 A brief overview of a CP. Historically, the term CP
doi: 10.17712/nsj.2019.3. 20190045 was used to describe the neurological consequences
Division of Pediatric Neurology, Department of Pediatrics, Prince of an adverse antenatal event (prematurity causing
Sultan Military Medical City, Riyadh, Kingdom of Saudi Arabia an intraventricular or periventricular hemorrhage)
Received 22nd June 2018. Accepted 27th June 2019.
and was later expanded to include other adverse
antenatal and perinatal events (cerebral dysgenesis,
Address correspondence and reprint request to: Dr. Brahim M. Tabarki, intracranial infection, and hypoxic-ischemic brain
Division of Neurology, Department of Pediatrics, Prince Sultan injury).1,2 By definition, the cerebral insult occurred
Military Medical City, Riyadh, Kingdom of Saudi Arabia. E-mail:
[email protected] in the developing fetal or infant brain, with infancy
ORCID ID: https://orcid.org/0000-0001-6240-0489 spanning from birth to one or even 2 years of age.5
The most common causes of CP are hypoxic-ischemic

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 Mimics of cerebral palsy … Hakami et al

insult, complications of prematurity, bilirubin toxicity, to the possibility of CP mimic: absent history of any
trauma, and infection.1,2 The prevalence of CP is 2-3 risk factors leading to brain injury, such as prematurity,
per 1000 live births;1,2 slightly higher in Saudi Arabia, perinatal or infantile hypoxic ischemic insult,
4-5 per 1000 live births.13 Although the highest risk intracranial bleeding, kernicterus, cerebral vascular
(40-100 per 1000 live births) is among very preterm accident, infection or head injury, family history of
and low birth weight babies, most CP patients are CP, progressive neurological symptoms, regression of
born term or near to term.13 Insults are antenatal in milestones, diurnal variation of symptoms or symptoms
approximately 80% of all cases of CP, perinatal in fluctuation in relation to activity or fasting. Dysmorphic
10%, and occur in infancy in 10% of cases.2 The CP features, isolated motor dysfunction (hypotonia without
is grouped according to the most predominant pattern dystonia or spasticity or isolated ataxia), peripheral
of motor disturbance as spastic (diplegia, tetraplegia, nervous system abnormalities (sensory sign or absent
hemiplegia), dyskinetic (dystonia, choreoathetosis) or reflexes), eye movement abnormalities (paroxysmal
ataxic, although the overall clinical picture is not always saccadic eye-head movements, oculogyria, or
pure.1,2 Neuroimaging, mainly MRI, is considered as oculomotor apraxia), and optic atrophy or retinopathy
a standard investigation in all children with CP.14 The are atypically seen in CP children.
most common cerebral abnormalities observed in these The following criteria were described by Person
children are periventricular white matter injury (19%), et al6 to diagnose a child with a motor features
diffuse gray matter insult (14%), cerebral malformation consistent with CP: symptom onset before 2 years of
(11%), and cerebral vascular accident (11%).14 age, nonprogressive clinical course with no milestone
Interestingly, in around 18% of patients with CP, the regression, and exclusion of disorders that present
MRI findings are nonspecific, or even normal in 15%
with predominant cognitive impairment, autism,
of cases.14
encephalopathy, or seizure.
Metabolic and genetic disorders that mimic CP.
Inherited metabolic and genetic diseases are common Brain MRI is recommended as a first-line
in highly consanguineous populations. Their clinical investigation in all children with a clinical feature
presentation may be nonspecific or very slowly suggestive of CP.6 If the findings are normal or
progressive, especially in the early age. They can nonspecific, other investigations should be carried out
therefore be misdiagnosed as CP. to rule out an underlying metabolic or genetic disease.
Prevalence of metabolic and genetic disorders that Investigations. Most of the metabolic/genetic
mimic CP. A growing number of metabolic and genetic diseases have overlapping or unspecific phenotypes.
disorders may present with symptoms and signs that The utility of next-generation sequencing in the clinical
resemble a CP phenotype.3-12 In a systematic review, field has been widely demonstrated in different groups
Leach et al3 found that at least 54 treatable inborn errors of diseases, mainly in metabolic/genetic diseases.15
of metabolism mimicking CP. Whole exome sequencing Those metabolic and genetic diseases may present
was performed by McMichael et al9 and Mattews et al11 with various phenotypes, some of them resembling
in 183 and 60 CP patients respectively. The CP-causing CP. The first approach should be based on the history,
variant were found in 14% and 65% of their patients clinical examination and neuroimaging findings. Based
respectively.9,11 on a detailed clinical phenotyping and neuroimaging
Red flags in the history, examination and findings, 2 phenotypes can be proposed:
neuroimaging when another diagnosis should be Scenario 1. The phenotype is highly suspected
considered. Table 1 & Table 2 summarize the clinical and based on the clinical and neuroimaging findings.
neuroimaging features that should alert the physician to In these cases, a targeted biomarker analysis or
a possible underlying metabolic or genetic disorder that single gene analysis may facilitate the diagnostic
mimic CP. Thorough history and a careful neurological process of a treatable disorders and the initiation of
examination are essential in the evaluation of a patient disease specific treatment. For examples, infant with
suspected to have CP. hypotonia, nystagmus, and dystonia, and MRI showing
The following elements in the patient’s medical hypomyelination (Figure 1). This picture is highly
history are not typical for CP and are an important clue suggestive of PLP1-related dysmyelinating disorders.
Another example, patient with macrocephaly, severe
dystonia/ opisthotonos, and MRI showing widening of
Disclosure. Authors have no conflict of interests, and the the Sylvian fissures and basal ganglia abnormalities; this
work was not supported or funded by any drug company. picture is highly suggestive of glutaric aciduria type 1
(Figure 2).

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 Mimics of cerebral palsy … Hakami et al

Table 1 - Red flags in the history and examination that should prompt the consideration of another diagnosis

History
No risk factors for CP such as: prematurity, low birthweight, multiple births, hypoglycemia, jaundice and kernicterus, intrapartum asphyxia, intracranial
hemorrhage, infection, stroke, or head injuries
Positive family history of CP
Fluctuation in motor symptoms
Paroxysmal symptoms in relation to time of day, diet/fasting, or activity
Progressive neurological symptoms
Regression of milestones
Examination
Dysmorphic features
Isolated motor dysfunction such as isolated ataxia or isolated hypotonia without dystonia or spasticity
Peripheral nervous system abnormalities: absent reflexes, sensory signs
Eye movement abnormalities (e.g., oculogyria, oculomotor apraxia, or paroxysmal saccadic eye-head movements)
Optic atrophy/retinopathy
CP- cerebral palsy

Table 2 - Red flags in the MRI brain findings that should prompt consideration of another diagnosis.

Normal neuroimaging
Nonspecific abnormalities, such as isolated globus pallidus involvement, which can suggest methylmalonic aciduria
Imaging may demonstrate specific lesions that are inconsistent with perinatal brain injury, but characteristic of a particular genetic disorder, such as
leukodystrophies, features of glutaric aciduria type 1, or features of Joubert syndrome

Table 3 - Common metabolic and genetic disorders that mimic CP according to the prominent motor dysfunction.

Disorders with prominent spasticity Disorders with prominent dyskinesia Disorders with prominent ataxia
- Hereditary spastic paraglegias - Dopa-responsive dystonia - Glucose transporter deficiency type 1
- Arginase deficiency - Sepiapterin reductase deficiency - Ataxia telangiectasia
- COL4A1-Related spastic CP - Glutaric aciduria type 1 - Pelizaeus-Merzbacher disease
- Biotinidase deficiency - Glucose transporter deficiency type 1 - Hereditary ataxias
- Aicardi-Goutières syndrome - Neurodegeneration with brain iron - Joubert syndrome
- Sulfite oxidase deficiency/ accumulation - Mitochondrial cytopathies (mainly 8993
Molybdenum cofactor - Cerebral creatine deficiency syndrome mutation)42
deficiency22 - Lesch Nyhan syndrome - Pontocerebellar hypoplasia36
- Leukodystrophies, - Cerebral folate deficiency - Cockayne syndrome43
such as metachromatic - ADCY5-related dyskinesia - Niemann-Pick disease type C44
leukodystrophy,23 - PCDH12-related dyskinesia34 - Angelman syndrome12
adrenoleukodystrophy,24 Sjorgen - NKX2-1 related ataxic dyskinetic - Gangliosidosis type 1 , juvenile and adult
Larsson syndrome25 CP35 forms45
- TSEN54 Gene-related - Non-ketotic hyperglycinemia3
pontocerebellar hypoplasia type 236 - Maple syrup urine disease3
- NKX2-1 related ataxic dyskinetic CP35
CP- cerebral palsy

Scenario 2. The clinical and neuroimaging findings Common metabolic and genetic disorders that mimic
are non-specific and no specific cause is suspected: the CP. The metabolic and genetic disorders that may
role of next generation sequencing. In recent years, misdiagnosed as CP are outlined in Table 3, classified
advanced genetic testing techniques have become by the most predominant motor pattern, although in
efficient strategies to diagnose rare disease-causing many conditions the clinical features are not always
mutations in children with neurodevelopmental pure.
disorders.4 This methodology was recently applied to Common metabolic/genetic diseases with
an atypical CP: Zouvelou et al4 recently analyzed 47 predominant spasticity. Several neurometabolic
patients with atypical CP and found 23 pathogenic disorders can resemble spastic CP, resulting in
mutations explaining the clinical/MRI phenotype. misdiagnosis Table 3 & Figure 3.16-25

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 Mimics of cerebral palsy … Hakami et al

Figure 1 - Axial T2-weighted brain magnetic resonance image of a 5-year- Figure 2 - Axial T2-weighted brain magnetic resonance image of a
old child with Pelizaeus-Merzbacher disease shows bilateral 9-months-old child with glutaric aciduria type1 shows
subacute right frontoparietotemporal subdural hematoma
symmetrical hyperintensity of the deep, periventricular and with mass effect, diffuse brain atrophy with widening of
subcortical white matter including the posterior limbs of the sylvian fissures bilaterally and secondary ventriculomegaly and
internal capsules. increased signal intensity of basal ganglia bilaterally.

Figure 4 - Axial T1-weighted brain magnetic resonance image of a

1-year-old child with Joubert syndrome shows the classical
Figure 3 - Axial T2-weighted brain magnetic resonance image of a molar tooth sign.
2-year-old child with molybdenum cofactor deficiency shows
extensive brain damage, signifiant loss of white matter with
cystic changes, ex vacuo dilatation of ventricles and mushrom-
shaped gyri. described so far, associated with HSP.16 According to
the clinical phenotype, mode of inheritance and the
affected gene, the HSP syndromes are classified into: (1)
Hereditary spastic paraplegias (HSPs) constitute “uncomplicated” HSPs, which exhibit pure progressive
a wide and heterogeneous group of genetically lower-extremities spastic weakness, typically occur in
determined neurodegenerative disorders that share a the third decade of life, but may start as early as 10 years
common clinical feature of lower limb spasticity and of age, and are inherited in an autosomal dominant
muscle weakness. There is considerable phenotypic and fashion; and (2) “complicated” HSPs, where spastic
genetic heterogeneity; there are more than 80 genes, paraplegia is associated with other neurologic and

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 Mimics of cerebral palsy … Hakami et al

Biotinidase deficiency is an autosomal recessive

inherited form of multiple carboxylase deficiency.
The clinical presentation is usually in infancy with
neurological manifestations (hypotonia, seizures, ataxia,
and developmental delay), metabolic acidosis, and optic
atrophy, in addition to dermatological abnormalities
(such as skin rashes and alopecia). Patients with a
delayed onset-biotinidase deficiency may develop motor
limb weakness and spastic paresis attributed to spinal
cord involvement, commonly misdiagnosed as CP.19
The MRI shows signal abnormality in the white matter
of the spinal cord. Diagnosis of biotinidase deficiency
is confirmed by demonstration of deficient enzyme on
a dried blood spot which is included in the newborn
screening in many countries, or by analyzing the BTD
gene.6 Early treatment with biotin results in resolution of
the cutaneous and neurological manifestations, whereas
the audiological and ophthalmological manifestations,
are more resistant to treatment.19
Arginase deficiency is an autosomal recessive urea
Figure 5 - Axial T2-weighted brain magnetic resonance images of a cycle disorder. Patients between one and 3 years of
2-year-old child with mitochondrial leukoencephalopathy,
caused by ISCA2 gene mutation shows leukodystrophy with
age may present with developmental delay, motor
supra and infra tentorial predominantly deep white matter and cognitive regression, slowly progressive spastic
involvement and central areas of cavitation (arrows). paresis, acquired microcephaly and failure to thrive.20
Ataxia and seizures may also develop. Arginase
non-neurologic signs (peripheral neuropathy, cognitive deficiency can be confirmed by elevated serum arginine
impairment, extrapyramidal manifestations, ataxia, and concentrations and through the identification of a
mutation on the ARG1 gene. Early diagnosis and early
brain imaging abnormalities); they usually present in
and sustained treatment with a low arginine diet and
early to mid-childhood, and are usually inherited in an
‘nitrogen-scavenger’ drugs may ameliorate some of the
autosomal recessive pattern.16 Most HSP patients but not
impairments associated with the disorder.
all, have a slowly progressive weakness.6 Some HSPs may
Aicardi-Goutières syndrome is a genetically
be non-progressive, as observed in infantile-onset HSP inherited autoimmune-mediated encephalopathy. It is a
cases with de novo mutations in SPG3-related spastic heterogeneous group of disorder characterized by increase
paraplegia or DDHD2-related spastic paraplegia.17 cerebrospinal fluid (CSF) white cells and interferon-
Those patients are commonly misdiagnosed as having alpha level, negative serologic screen for prenatal
spastic diplegic/paraplegic CP. Brain and spinal MRI infections, cerebral calcifications and white matter
may appear normal or show specific findings suggestive abnormalities.21 Neurological manifestation usually
of an HSP syndrome, such as brain atrophy, thin corpus appear in early infancy, with progressive microcephaly,
callosum, spinal cord atrophy and a lipid peak, as spasticity, dystonia, and severe psychomotor retardation.
observed in DDHD2 mutation.17 Non-neurological features include hepatosplenomegaly,
COL4A1-related spastic CP is a collagen vascular elevated hepatic transaminases and thrombocytopenia.
disorder which may cause an antenatal or perinatal Phenotypic variability in Aicardi-Goutières syndrome
cerebrovascular insult, resulting in a neonatal is well recognized. There are reports of patients that
stroke syndrome that manifests as hemiplegia or have presented with only mild spasticity and had been
quadriplegia.18 Screening for the mutation in COL4A1 diagnosed as CP.21 Genetic heterogeneity is common
gene should be undertaken in all neonates and infants with mutations identified in the following genes:
with a stroke syndrome in the absence of any antenatal TREX1, RNASEH2A, RNASEH2B and RNASEH2C.21
injury, prematurity, or with MRI features that are not Common metabolic/genetic disorders with
characteristic of periventricular leukomalacia or cerebral predominant dyskinesia. Dyskinesia is defined as
infarction in the distribution of the anterior or middle abnormal involuntary movements, with fluctuating
cerebral artery.18 patterns of tone and posture. The dyskinesia can be

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 Mimics of cerebral palsy … Hakami et al

categorized as dystonia, tremor, chorea, athetosis, Patients typically present with an intellectual disability,
ballism, tic, akathisia and orofaciolingual dyskinesia. severe speech delay and abnormal behavior. Additional
Table 3 lists some of the disorders mimicking dyskinetic features include seizures, ataxia dystonia and/or chorea.
CP.26-36 The brain MRI is usually nonspecific; however, MR
GCH1-related dopa-responsive dystonia is spectroscopy shows absent creatine peak, which is the
commonly misdiagnosed as CP.26 It is inherited marker of the disease. The diagnosis is based on the
an autosomal dominant metabolic disorder of the analysis of creatine, creatinine and guanidoacetate
dopamine synthetic pathway. Typically, they present in the urine and blood, and is confirmed by genetic
at childhood with gait disorder due to foot dystonia, analysis in the GAMT, AGAT, or SLC6A8 genes.30
diurnal fluctuation and improvement with rest or Treatment consists of oral supplementation with
sleep. Patients have a normal intellectual and cognitive high-dose creatine for all 3 cerebral creatine deficiency
function. The confirmation of diagnosis is by molecular syndromes. Arginine-restricted diet with high-dose
testing of the GCH1 gene. Levodopa, usually at ornithine is additionally used in GAMT deficiency.
low dose, is the mainstay of therapy with complete Supplementation with arginine and glycine has been
resolution of symptoms.26 used additionally to treat SLC6A8 deficiency.30
Sepiapterin reductase deficiency is an autosomal Cerebral folate deficiency typically presents between
recessive disorder caused by mutation in the sepiapterin 4-6 months as an infantile form, mainly in form of
reductase gene. The triad of oculogyric crises, paroxysmal behavior changes and refractory epilepsy, whereas
stiffening and hypotonia is the hallmark of the disease after one year of age it presents with a spastic-ataxic
in the early stages.27,28 These features have typical syndrome that can mimic CP, progressing to dystonia
diurnal fluctuations with sleep disturbance. In some and schizophrenic syndrome in adolescence.31
patients, the clinical manifestations are nonspecific, The diagnosis is based on the low CSF levels of
and they misdiagnosed as CP with hypotonia or 5-methyltetrahydrofolate and normal plasma folate
dystonia.28 Neuroimaging is generally normal. Analysis levels, and is confirmed by FOLR1 gene analysis . Folic
of CSF neurotransmitters and SPR gene confirm the acid therapy results in significant improvement of the
diagnosis. It is a treatable neurometabolic disorder clinical symptoms, brain abnormalities and function.31
and early treatment with a combination of L-dopa and Lesch-Nyhan syndrome is a rare X-linked recessive
5-hydroxytryptophan results in a good neurological disorder of purine metabolism, caused by mutation
outcome.27,28 in the HPRT gene, encoding hypoxanthine-guanine
Glutaric aciduria type 1 is a rare autosomal recessive phosphoribosyltransferase. The characteristic clinical
metabolic disorder caused by alteration in the glutaryl- features are motor disability, self-injurious behavior and
CoA dehydrogenase gene (GCDH).29 Most untreated cognitive impairment. The motor symptoms typically
affected children present with an encephalopathic start at the age of 3-6 months of life, subsequently,
crisis, mainly triggered by a febrile illness, in the first between the ages of 6-24 months, generalized dystonia
6 years of life. These crises will cause striatal injury emerges. Other extrapyramidal and pyramidal signs
and consequent dystonic movement disorder. Other may occur.32 Children with Lesh-Nyhan syndrome
affected individuals may present within the first year of may misdiagnosed initially with dyskinetic CP.32
life with delayed milestone, macrocephaly, hypotonia, Neuroimaging is usually normal or shows nonspecific
choreoathetosis or dystonia. The typical MRI finding brain atrophy.6 Molecular genetic testing for HPRT1
in glutaric aciduria type 1 is the presence of a widening gene confirms the diagnosis. Current treatments are
of the Sylvian fissures and basal ganglia abnormalities only symptomatic.
(Figure 2). Diagnosis can be made by urine organic acids ADCY5-related dyskinesia is a significant genetic
analysis and genetic study of the GCDH gene which cause of early-onset non-progressive hyperkinetic
is confirmatory. Early treatment with a diet restriction, movement disorders. Typically, the onset is around 6
riboflavin, carnitine therapy, and aggressive emergency months of age in a patient known to have hypotonia
treatment during catabolism improve the neurological or motor delay.33 The movement disorder, in form
outcome.29 of dystonia, chorea or choreoathetosis, is typically
Cerebral creatine deficiency syndromes are a group episodic and sleep-related. Dyskinesia may exacerbate
of the creatine synthesis and transport with 3 recognized upon awakening, falling asleep or during intercurrent
syndromes: guanidinoacetate methyltransferase illnesses for few minutes up to days.6 The exacerbation
(GAMT), arginine glycine amidinotransferase (AGAT), of dyskinesia in relation to sleep should prompt
and X-linked creatine transporter deficiency (SLC6A8).30 consideration of an underlying ADCY5 mutation.33

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They may have normal cognitive function or mild fetoprotein and absent immunoglobulin A. Analysis of
intellectual disability and normal Brain MRI.6 the ATM gene confirms the diagnosis.38
Patients with ADCY5-related dyskinesia are frequently Pelizaeus-Merzbacher disease (PMD) is an X-linked
misdiagnosed as hypotonic or dyskinetic CP.33 inherited disorder of myelination, due to mutations
Common metabolic/genetic disorders with in the PLP1 gene encoding the proteolipid protein.
predominant ataxia and/or mixed motor signs. Up to Patients with PLP mutations exhibit phenotypic
10% of patients with CP are diagnosed with the ataxic variability, ranging from the less involved spastic
type.1,2 Interestingly, isolated ataxia is rare feature in paraplegia type 2 to the more sever classical PMD.39
a patients with CP associated with birth asphyxia.6 Classic PMD present during early infancy with head
Therefore, further investigation for metabolic/genetic bobbing, nystagmus, psychomotor retardation, tremor,
causes should be strongly considered in any patient ataxia, and progressive spasticity. Dystonia and athetosis
who presents with predominant ataxia, especially with may also occur.6 Regarding neuroimaging, all forms are
normal brain MRI.6 Clinically it may be difficult to associated with central hypomyelination (Figure1).39
recognize ataxia in the first year of life and initially PMD can be misdiagnosed as CP in early stages because
they may present with motor developmental delay and the spasticity is slowly progressive and the MRI findings
truncal hypotonia. Ataxia may also frequently coexist may not appreciate abnormalities during the first year
with other involuntary movements. Table 3 lists some of life.39
disorders mimicking ataxic/hypotonic CP.37-45 Hereditary ataxias are a large group of genetic disorders
Glucose transporter deficiency type 1 (Glut1 that are commonly characterized phenotypically by gait
deficiency syndrome) is a disorder of the brain energy ataxia, pyramidal tract signs (often spastic diplegia), and
metabolism caused by mutations in the SLC2A1 incoordination of eye movements. The MRI typically
gene, which encodes a glucose transporter protein shows cerebellar atrophy. The dominant forms are termed
type 1 (Glut1) that is required for glucose to cross the spinocerebellar ataxias, and are usually with an adult
blood-brain barrier.37 Two main phenotypes can be onset. The autosomal recessive forms include different
identified. The classic phenotype manifests with an
diseases, mainly Freiderish ataxia, Refsum disease,
early onset intractable epilepsy, delayed development,
ataxia with vitamin E deficiency, cerebrotendinous
acquired microcephaly, and movement disorder
xanthomatosis, and coenzyme Q10 deficiency. Few of
(ataxia, spasticity, and dystonia). The non-classic Glut1
these disorders are amenable to effective treatment.40
phenotype (10-15% of patients) manifests mainly with
paroxysmal dyskinesias, including intermittent ataxia, Joubert syndrome is genetically heterogeneous
dystonia, exercise-induced dyskinesia, and alternating group of disorders with an autosomal recessive or
hemiplegia. The latter is the phenotype that may be X-linked inheritance. Characterized by hypoplasia
misdiagnosed as CP.37 Ataxia and involuntary movements of the cerebellar vermis and classified in the group of
often fluctuate in severity, getting worse with fasting ciliopathies.41 Clinically, ataxia is the predominant
or exercise which is an important clue. Brain MRI is neurological sign; however, the initial presentation
normal or may shows mild cerebral atrophy or subtle is typically with a hypotonia, oculomotor apraxia
white matter abnormalities. The diagnosis is confirmed and breathing dysregulation, features that have been
by a low CSF glucose concentration in the absence misdiagnosed as CP.45 The neurological features may be
of low blood sugar, and analysis of the SLC2A1 gene. associated with variable multiorgan involvement mainly
Treatment is based on the ketogenic diet or modified the retina, kidneys, liver and skeleton. The hallmark
Atkins diet which is highly effective in controlling the diagnosis of this condition is a pathognomonic
seizures and improving gait disturbance.37 midbrain-hind brain malformation on brain MRI
Ataxia-telangiectasia is a multisystem autosomal “molar tooth sign” (Figure 4).41 Diagnosis may be
recessive inherited disorder, caused by mutations confirmed by the identification of a mutation in one of
in the ATM gene.38 It presents with progressive the numerous genes associated with the condition.
ataxia, oculomotor apraxia, and oculocutaneous Mitochondrial disorders, one of the most common
telangiectasia. Dyskinesia occur frequently, dystonia neurometabolic diseases, are characterized by
and choreoathetosis may be more prominent than ataxia impaired energy production. They usually manifest
at onset:38 thus, this condition can be misdiagnosed as multi-organ disorder, often with neurological
as ataxic-dyskinetic CP. Additional features of ataxia dysfunction and are rapidly progressive. Early isolated
telangiectasia include immunodeficiency and risk of ataxia, dystonia, or hypotonia with slow course can be
malignancy. Brain MRI shows progressive cerebellar observed and confused as CP.42 Mitochondrial disorders
atrophy. Blood tests show high levels of alpha- affect a wide range of brain structures, including the

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predominant bulbar and oromotor dysfunction. Psychiatry 2015; 20: 176-182.
Classically, bulbar and oromotor dysfunction, including 10. Carecchio M, Mencacci NE. Emerging monogenic complex
speech and feeding difficulties, are not a major feature hyperkinetic disorders. Curr Neurol Neurosci Rep 2017; 17: 97.
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