REVIEW

CLINICAL PRACTICE

Movement Disorders in Genetic Pediatric

Ataxias
Simone Gana, MD1 and Enza Maria Valente, MD, PhD1,2,*

ABSTRACT: Background:
Background Genetic pediatric ataxias are heterogeneous rare disorders, mainly inherited as
autosomal-recessive traits. Most forms are progressive and lack effective treatment, with relevant
socioeconomical impact. Albeit ataxia represents the main clinical feature, the phenotype can be more
complex, with additional neurological and nonneurological signs being described in several forms.
Results In this review, we provide an overview of the occurrence and spectrum of movement
Methods and Results:
disorders in the most relevant forms of childhood-onset genetic ataxias. All types of hypokinetic and
hyperkinetic movement disorders of variable severity have been reported. Movement disorders occasionally
represent the symptom of onset, predating ataxia even of a few years and therefore challenging an early
diagnosis. Their pathogenesis still remains poorly defined, as it is not yet clear whether movement disorders
may directly relate to the cerebellar pathology or result from an extracerebellar dysfunction, including the basal
ganglia.
Conclusion Recognition of the complete movement disorder phenotype in genetic pediatric ataxias has
Conclusion:
important implications for diagnosis, management, and genetic counseling.

The word “ataxia” derives from the Greek language, meaning
"lack of order," and defines a clinical picture characterized by
unsteadiness, imbalance, clumsiness, and slurred speech attributed
to lack of muscle control during voluntary activity. Gait and bal-
ance problems often progress to the point at which patients
become wheelchair bound and, in general, the level of disability
progresses at the cost of functional independence. Cerebellar
ataxia is caused by dysfunction of the complex circuitry con-
necting the basal ganglia, cerebellum, and cerebral cortex,
whereas the less frequent form of sensory ataxia refers to a dys-
function of the proprioceptive sensory activity at the level of the
peripheral nerves or the posterior columns of the spinal cord.
Ataxic syndromes are characterized by wide clinical and
genetic heterogeneity, with dominant, recessive, or mitochon-
drial inheritance. To date, more than 100 hereditary disorders
have ataxia as the predominant sign (so called primary or pure
ataxias), and the number of genetic disorders that can occasion-
ally feature ataxia as part of their clinical spectrum is even
higher.1,2 For most ataxic disorders, therapeutic strategies are lac-
king or result only in limited improvements in quality and
expectancy of life. Thus, ataxias have a strong social impact and
high economic costs that often rest largely on the patients’
families.
Ataxia is especially debilitating in the pediatric age, as children
are still developing and learning motor competency; moreover,
its recognition can be particularly difficult in early childhood,
delaying diagnosis and management. In a child suspected of hav-
ing ataxia, a detailed clinical assessment is mandatory to rule out
any other developmental, physical, neurological, or behavioral
disorders, as clumsiness, imbalance, and lack of motor control
can be key features of many conditions. For instance, the so-
called Developmental Coordination Disorder is characterized by
similar features presenting in children with preserved intellectual
abilities and in the absence of any physical, sensory, or neurologi-
cal abnormalities, and its early identification and diagnosis is cru-
cial to establish prompt educational interventions and avoid
negative consequences on activities of daily living, particularly
school learning.3 Similarly, a suggestive perinatal history and the
co-occurrence of pyramidal and/or extrapyramidal signs can be
indicative of a disorder of central origin such as cerebral palsy.

1
IRCCS Mondino Foundation, Pavia, Italy; 2Department of Molecular Medicine, University of Pavia, Pavia, Italy
*Correspondence to: Dr. Enza Maria Valente, Department of Molecular Medicine, University of Pavia, via Forlanini 14, 27100 Pavia, Italy;
E-mail: enzamaria.valente@unipv.it
Keywords: pediatric ataxias, hereditary ataxias, movement disorders, extrapyramidal, genetics.
Relevant disclosures and conflicts of interest are listed at the end of this article.
Received 19 November 2019; revised 24 February 2020; accepted 8 March 2020.
Published online 6 April 2020 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mdc3.12937

MOVEMENT DISORDERS CLINICAL PRACTICE 2020; 7(4): 383–393. doi: 10.1002/mdc3.12937

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© 2020 International Parkinson and Movement Disorder Society
 REVIEW MOVEMENT DISORDERS IN PEDIATRIC ATAXIAS

TABLE 1 Differential diagnosis of the most common forms of primary pediatric ataxias
Clinical and Imaging
Disease Gene Onset (Years) Features Laboratory Features Refs.

FA FXN 2nd decade Cardiomyopathy, axonal #Frataxin level in 18–21

(4–40) sensory neuropathy, leucocytes
Babinski sign,
diabetes
ARSACS SACS Childhood Spasticity, Abnormally fused 30–33
demyelinating or mitochondrial
axonal neuropathy, network in fibroblasts
typical imaging at
brain MRI
AOA1 APTX 1st–2nd decade Oculomotor apraxia, #albumin, "cholesterol, 35–37, 39, 41
axonal normal α-FP
sensorimotor neuropathy
AOA2 SETX 2nd decade (7–25) Oculomotor apraxia, "α-FP, "cholesterol, "CK 43, 44, 46, 49
axonal (occasionally), "serum
sensorimotor neuropathy IgG/IgA
AT ATM 1st decade Oculomotor apraxia "α-FP, #serum IgG/IgA, 50, 51, 53, 54
telangiectasias, chromosomal
immunodeficiency, instability
cancer susceptibility
AVED TTPA 2nd decade (2–52) Similar to FA, head ##Plasma vitamin E 61, 62, 64, 67
titubation, pigmentary
retinopathy
SCA28 AFG3L2 1st–6th decade Nystagmus, ptosis, – 68
ophthalmoparesis,
increased tendon
reflexes
SCA29 ITPR1 Early childhood Mild cognitive – 72, 75
impairment
FA, Friedreich ataxia; ARSACS, autosomal recessive spastic ataxia of Charlevoix–Saguenay; AOA1, ataxia with oculomotor apraxia type 1; AOA2,
ataxia with oculomotor apraxia type 2; AT, ataxia telangiectasia; AVED, ataxia with vitamin E deficiency; SCA28, spinocerebellar ataxia type 28;
SCA29, spinocerebellar ataxia type 29; MRI, magnetic resonance imaging; α-FP, α-fetoprotein; CK, creatin kinase; Refs., references.

Lastly, disorders of the peripheral neuromuscular system should
be envisaged in the presence of muscle weakness or abnormal
stretch reflexes.
The overall prevalence of childhood ataxias in Europe has
been estimated to be 26 per 100,000 children, with genetic
forms accounting for the majority of cases (14.6 per 100,000
children). Yet these figures are probably underestimated, and the
true worldwide prevalence is likely higher.4
Autosomal dominant ataxias usually manifest in adulthood,
and pediatric presentations are rare. Conversely, recessive forms
present typically during childhood or teens and often with com-
plex phenotypes that can include neuropathy, pyramidal, and
extrapyramidal involvement, ophthalmoplegia, cognitive/behav-
ioral impairment, seizures, retinopathy, and other nonneurologic
signs. All types of hypokinetic and hyperkinetic movement disor-
ders are also commonly observed in pediatric patients with
hereditary ataxias. Their severity can vary from mild to severe,
and in some cases, involuntary movements may represent the
dominant or presenting feature, challenging the diagnosis.
Here we aim to provide an overview of the occurrence of
movement disorders in pediatric genetic ataxias. We divide this
review into 3 sections. First, we briefly discuss the pathophysiol-
ogy underlying the link between ataxia and movements disor-
ders, referring to specific reviews for a more in-depth revision of
this topic. Second, we review the spectrum of involuntary
movements in the 5 best characterized and frequent autosomal
recessive primary pediatric ataxias and in some rarer autosomal
dominant forms (summarized in Table 1 and Fig. 1). Finally, we
briefly summarize movement disorders in episodic ataxias and in
neurometabolic diseases having ataxia as a relevant feature.
Pathophysiology
of Movement Disorders
in Ataxic Syndromes
Classically, the cerebellum has been suggested to modulate
movement control through its influence on the primary motor
cortex. It is now clear that the cerebellum works in concert with
both the cortex and the basal ganglia in regulating motor and
cognitive tasks of various complexity. Indeed, numerous evi-
dences demonstrate that the cerebellum and the basal ganglia
receive input from and send output to different cortical areas
through multisynaptic loops, and studies on different animal
models clearly showed that the cerebellum and basal ganglia are
directly connected by bidirectional pathways.5 These observa-
tions indicate that the basal ganglia and cerebellar motor net-
works are not independent systems but may exchange
information in real time to provide appropriate inputs to the
frontal cortex. In mice, under physiological conditions, it has

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S. GANA AND E.M. VALENTE REVIEW

FIG. 1. Summary of movement disorders reported in the most relevant forms of genetic pediatric ataxias. The thickness of the bars correlates
with the frequency of the observed movement disorder. ARSACS, autosomal recessive spastic ataxia of Charlevoix–Saguenay; AOA1, ataxia
with oculomotor apraxia type 1; AOA2, ataxia with oculomotor apraxia type 2; AVED, ataxia with vitamin E deficiency; SCA28, spinocerebellar
ataxia 28; SCA29, spinocerebellar ataxia 29; GLUT-1 DS, Glucose Transporter Type 1 deficiency syndrome; MD, movement disorder.

been demonstrated that stimulation of dentate neurons evokes
short-latency responses in about half of the striatal neurons all-
owing the basal ganglia to incorporate time-sensitive cerebellar
information (facilitating optimal motor control) and permitting
cerebellar modulation of corticostriatal plasticity. Conversely,
under pathological conditions, the same pathway allows for the
transfer of aberrant cerebellar activity to the basal ganglia causing
movement disorders such as dyskinesia and dystonia.6 Therefore,
the interconnections between the cerebellum and the basal gang-
lia provide the neural basis for cerebellar involvement in disor-
ders typically associated with the basal ganglia as well as in
normal basal ganglia functions, such as reward-related learning.5
As an example, we present an overview of the growing body
of studies suggesting that the cerebellum may play a significant
role in dystonia. First, studies on animals indicate that altered cer-
ebellar signaling, such as abnormal burst patterns in Purkinje cell
firing, along with dysfunctional interactions with basal ganglia
activity and alterations in Purkinje cell morphology or cerebellar
synaptogenesis, are all putative mechanisms involved in generat-
ing dystonic-like motor behaviors. Second, several clinical and
pathologic observations indicate that dystonia may occur in com-
bination with other movement disorders, including ataxia, and
may be related to anatomic lesions of the cerebellum or its path-
ways as a result of cerebrovascular disorders or posterior fossa
tumors. Third, both neuroimaging studies and functional mag-
netic resonance imaging (MRI) have provided insight into the
role of cerebellar involvement in dystonia. Fourth, cerebellar
abnormalities in dystonia were also proven through several neu-
rophysiologic techniques, opening an interesting scenario in
which the cerebellar dysfunction may lead to ataxia or dystonia,
depending on the integrity of multiple networks.7,8 Fifth, the
silencing of glutamatergic signaling at olivocerebellar synapses in
a mouse model resulted in severe dystonia that could be reduced
by deep brain stimulation of the cerebellar nuclei.9 Sixth, a study
exploring the expression pattern of genes involved in primary
dystonia and spinocerebellar ataxia demonstrated that they share
many molecular pathways, mainly related to synaptic transmis-
sion and neurodevelopment. Interestingly, the overlapping genes
encode ion channels and a number of proteins necessary for reg-
ulation of neurotransmitter synthesis, synapse formation, and
vesicular structures.10
Of note, evidence from clinical and neuroimaging studies also
demonstrated an involvement of the cerebellum in the patho-
physiology of tremor, both in Parkinson’s disease and in essential
tremor,11,12 and in that of cortical myoclonus.13 Whether the
cerebellum is involved in the primary pathologic process or
whether the abnormalities are secondary features that compensate
for deficient basal ganglia functioning (eg, increased activity in
the cerebellum) is still debated.14
On the other hand, it has been observed that basal ganglia
may be implicated in some way in the pathogenesis of ataxic
syndromes. Neuropathological abnormalities of the basal ganglia
have been shown in several spino-cerebellar ataxias, such as spi-
nocerebellar ataxia (SCA) 1, SCA2, SCA3, and SCA17 (which
can occasionally present with a Parkinson disease–like pheno-
type).15 Moreover, in adults with ataxia-telangiectasia, functional
neuroimaging studies measuring regional brain glucose metabo-
lism showed hyperactivity of the globus pallidus indicative of
basal ganglia involvement, besides the expected decrease in cere-
bellar metabolism.16
In conclusion, although a definite consensus statement on
how the cerebellum works in synergy with the basal ganglia and

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 REVIEW
cortical areas has not yet been reached, there is now a general
agreement on the importance of studying the cerebellar function
from an integrative perspective taking into account the interplay
between cerebellar, cortical, and basal ganglia networks.5
Autosomal Recessive
Pediatric Ataxias
In childhood, autosomal recessive ataxic disorders are far more
frequent than their dominant counterparts. In Western countries,
Friedreich’s ataxia (FA) represents the most common form,
accounting for about half of all genetically defined conditions.
Rarer recessive forms include spastic ataxia of Charlevoix–
Saguenay (ARSACS), ataxia with oculomotor apraxia (AOA;
mainly types 1 and 2), and ataxia telangiectasia (AT), each
accounting for 2% to 10% of all autosomal recessive forms. The
many other autosomal recessive ataxias subtypes are generally
very rare, albeit ataxia with vitamin E deficiency (AVED) is also
worth mentioning as this is a treatable condition.17
Friedreich’s Ataxia
FA has a global prevalence rate of 1 in 50000, with a carrier fre-
quency reaching 1 in 90 in the white population. The classic phe-
notype is characterized by the onset of symptoms in the second
decade (before 25 years of age), with progressive gait and trunk
ataxia, dysarthria, loss of deep tendon reflexes and of position
sense, and progressive motor weakness as a result of axonal neu-
ropathy.18 Nonneurological complications include diabetes, hyper-
trophic cardiomyopathy, scoliosis, and pes cavus. Occasional
patients have atypical phenotypes with later onset, less severe man-
ifestations, and slower progression.19,20 Neuroimaging is often
normal in the early stages of the disease, whereas atrophy of the
cervical spinal cord and cerebellum may be observed later.
FA is a genetically homogeneous disorder: up to 98% of
patients carry homozygous expansions of a GAA trinucleotide
repeat within intron 1 of the FXN gene on chromosome
9q13-21, whereas the remaining 2% are compound heterozygous
for the GAA expansion on 1 allele and a distinct FXN point
mutation or deletion on the other allele.
Normally there are fewer than 36 GAA repeats, although the
expansions associated with FA vary from 44 to 1700 repeats with
most abnormal alleles ranging from 600 to 900 GAAs.21 However,
the exact demarcation between normal and pathological alleles has
not been clearly determined. The GAA repeat length on the
shorter allele correlates inversely with the age of onset and directly
with the clinical severity.21
With the exception of tremor, other hyperkinetic movement
disorders are rarely predominant in patients with FA. However,
these have not been well characterized and could be more com-
mon than expected.22 For instance, in a 29-patient series, pos-
tural tremor of the upper limbs or head was reported in 17% of
affected individuals and upper limb dystonia in 45%. Yet in these
cases dystonia was not a functionally important symptom, and
386 MOVEMENT DISORDERS CLINICAL PRACTICE 2020; 7(4): 383–393. doi: 10.1002/mdc3.12937
MOVEMENT DISORDERS IN PEDIATRIC ATAXIAS
most patients were not even aware of its presence.23 In other FA
series, generalized or focal dystonia has been only occasionally
reported.22,24,25
Interestingly, scoliosis is found in >60% of FA patients and
frequently requires surgical intervention.26 Although the mecha-
nism underlying this deformity largely remains unclear, it was
suggested that, at least in some patients, scoliosis could result
from truncal muscle spasms and axial dystonia.22
Chorea is rarely observed in FA although it may be the
presenting features in the absence of cerebellar signs.27–29 In a
sporadic case, a 4-year-old child, myoclonus was the presenting
feature besides chorea.27
Autosomal Recessive Spastic
Ataxia of Charlevoix–Saguenay
ARSACS has long been considered as exceptionally rare outside
the region of Quebec in Canada, but recent studies have
consistently demonstrated that this condition can also be found
elsewhere, likely representing the second most common
autosomal recessive ataxia after FA.17
This chronic disorder is caused by mutations in the SACS
gene, located on chromosome 13q12.12. Symptoms usually
develop early, before 10 years of age, and are represented by the
typical triad of slowly progressive cerebellar ataxia, lower limb
spasticity, and demyelinating or axonal polyneuropathy.30 Brain
MRI demonstrates cerebellar atrophy and highly specific linear
hypointensities within the pons.31
ARSACS is rarely complicated by movement disorders. For
instance, in one of the largest published series to date, dystonia was
observed only in 2 of 47 patients.30 Mild dystonia was also rare in
other 2 studies, occurring in 3 of 23, and in 1 of 13 cases, respec-
tively.32,33 Myoclonus was reported only in 1 case as a complicating
feature of classic ARSACS in addition to supranuclear gaze palsy.34
Ataxia with Oculomotor Apraxia
AOA is defined by childhood or adolescence onset of progressive
cerebellar ataxia, commonly followed by oculomotor apraxia and
peripheral neuropathy. Most patients become wheelchair bound,
and some may show cognitive impairment.
To date, 4 types have been described (AOA1–4), respectively
caused by biallelic pathogenic variants in the APTX, SETX,
PIK3R5, and PNKP genes. As the last 2 forms have only occasion-
ally been reported, we focus here on AOA1 and AOA2.
AOA Type 1
Patients with AOA1 present at a mean age of 7 years with slowly
progressive cerebellar ataxia, oculomotor apraxia that progresses
to external ophthalmoplegia, and severe motor peripheral neu-
ropathy, leading to quadriplegia with loss of ambulation within
7 to 10 years from onset. Optic atrophy and cognitive impair-
ment may be present.35,36 Cerebellar atrophy on MRI is a con-
stant feature. The diagnosis is based on clinical findings and is
S. GANA AND E.M. VALENTE
confirmed by molecular testing, which reveals biallelic mutations
in the APTX encoding aprataxin.37,38
Movement disorders are not rare in AOA1 and mainly feature
chorea and dystonia. At onset, chorea may affect as many as 80% of
cases, but it tends to resolve with time, being detectable in about half
of patients with long-term disease duration.35,36,39,40 Chorea com-
monly involves the face, larynx, pharynx, and limbs, sometimes lead-
ing to erroneous initial clinical diagnoses of juvenile Huntington’s
disease, Sydenham chorea, or benign hereditary chorea.
Upper limb dystonia was reported in approximately 36% to
50% of AOA1 patients, sometimes being the presenting feature
and resulting in delayed diagnosis.35,40–42 Other movement dis-
orders reported in a series of 11 AOA1 patients include tremor
(36%), myoclonus (18%), and parkinsonism (9%).40
AOA Type 2
Besides cerebellar ataxia and oculomotor apraxia (the latter not
always present), patients with AOA2 feature sensorimotor axonal
neuropathy, pyramidal signs, mild cognitive impairment, and
skeletal deformities, with onset in the second decade of life. Cere-
bellar atrophy and elevated alpha-fetoprotein are early features of
this condition.43,44 The genetic defect is represented by biallelic
mutations in the SETX gene (9q34) coding for senataxin.45
Similar to AOA1, hyperkinetic movement disorders such as
dystonia and chorea have been reported in several AOA2 cases.
In a 90-patient series, dystonia was observed in 14%, head tremor
in 14%, and chorea in 10% of patients.43 In a smaller cohort,
movement disorders were more frequent (44%) and consisted
mainly of dystonic posturing of the hands (28%), choreic move-
ments (22%), and head or postural tremor (17%), occasionally in
combination. In this latter group, the initial symptom was usually
gait ataxia, but it was preceded by dystonia or postural tremor in
11% patients.46 Other extrapyramidal disorders have rarely been
reported as the initial sign in AOA2. For instance, mild chorei-
form movements of trunk and face were the presenting feature
in 2 siblings, whereas isolated head tremor was noticed 2 years
before gait ataxia in a third patient.47,48
In contrast to AOA1, the severity of movement disorders is
known to remain generally stable.46 Yet there are some
exceptions, such as 2 Italian patients with movement disorders
(choreiform head movements and truncal dystonia or head
tremor), which rapidly disappeared as the disease progressed.49
Interestingly, in a large AOA2 cohort, the frequency of dystonia
was much higher (42%) for missense mutations in the helicase
domain of SETX, whereas it significantly dropped for missense
mutations out of the helicase domain (7%) and for deletions
or truncating mutations (9%), supporting possible genotype–
phenotype correlates.43
Ataxia Telangiectasia
AT is a clinically complex disorder accounting for about 3% to
5% of all patients with autosomal recessive ataxia.
Onset is usually before the age of 5 years,50 but adolescent-
onset and adult-onset presentations have been increasingly
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REVIEW
recognized, with ataxia starting in the third to fourth decade.51
Progressive ataxia is typically accompanied by noncerebellar fea-
tures that include oculomotor apraxia (82%), telangiectasias of
the conjunctivae (usually evident by age 6 years, 84%), defects of
immune system (eg, reduced serum IgG/IgA levels) with recur-
rent sinopulmonary infections (67%), increased sensitivity to ion-
izing radiation, and strong predisposition to malignancy
(approximately 22% of patients will develop a cancer during the
course of their illness), particularly leukemia and lymphoma.50 In
childhood, however, many of these characteristic extracerebellar
features might not have developed yet, challenging the diagnosis.
On MRI, there is atrophy of the frontal and posterior cerebellar
vermis and both hemispheres.
AT is caused by homozygous or compound heterozygous
mutations in the ATM gene on chromosome 11q22.52 Severe
phenotypes are associated with total loss of ATM protein,
whereas milder phenotypes, characterized by slow neurological
progression or later onset, are associated with the presence of
residual ATM kinase activity, principally caused by non-
truncating variants.53
The disease is frequently complicated by a plethora of move-
ment disorders that tend to be progressive and may precede the
onset of ataxia by several years.51 In classical AT, these non-
cerebellar symptoms may remain mild compared with ataxia, but
in patients with atypical AT, progressive extrapyramidal move-
ments can represent the main motor feature.53,54
Choreoathetosis, being found in nearly all affected individuals
(up to 89%), has traditionally been defined as an AT feature almost
as typical as cerebellar ataxia and oculocutaneous telangiectasias
and represents the initial manifestation of illness in 10% of cases.50
Almost 90% of AT patients have dystonia during the course
of the disease, of whom 18% at onset.50 Dystonia usually mani-
fest in the second to third decade of life; however, onset can
occasionally be as young as 2 years.55 Interestingly, older age at
onset was found to correlate directly with the likelihood of
having cervical or axial dystonia as a presenting feature.50
Dystonia may be focal, multifocal, or generalized and may be
disabling56–58; moreover, phenotypes of dopa-responsive cervical
or generalized dystonia have been reported.59,60
Jerky movements are very frequent in AT, representing either
true myoclonus, jerky dystonia, tremor, or chorea, either alone or
in combination and mainly affecting the axial muscles and upper
limbs.57 Yet the real occurrence of myoclonus is difficult to ascer-
tain because few studies included proper diagnostic electrophysio-
logical assessments. Despite myoclonus or jerky movements as
presenting features of AT have never been reported, it has been
estimated that approximately 92% of affected patients may present
these abnormal movements during the course of their illness.50
Rest, postural, or kinetic tremors can develop in AT patients
and may be associated with cerebellar dysfunction, dystonia, or
parkinsonism. Overall, tremor was reported in 74% patients and
as initial manifestation in 4%. Finally, albeit parkinsonism has not
been reported as an early feature of AT, 41% of affected patients
seem to develop this movement disorder at some point during
their disease, which may worsen over time and contribute to the
overall disability.50
387
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Ataxia with Vitamin E Deficiency
AVED typically presents in late childhood or early teens with
progressive ataxia, areflexia, and loss of proprioceptive and vibra-
tory sense, resembling FA.61,62 Cerebellar atrophy is present in
approximately half of the patients. Laboratory examinations
reveal markedly reduced plasma vitamin E (α-tocopherol) levels
and a normal lipoprotein profile in the absence of known causes
of malabsorption. Identification of biallelic TTPA pathogenic
variants on molecular genetic testing confirms the diagnosis.63
An early diagnosis is imperative, as lifelong high-dose oral vita-
min E supplementation can halt or even reverse disease progres-
sion. Thus, clinicians should always test early vitamin E in the
assessment of patients presenting with progressive ataxia.
AVED is uncommonly complicated by extrapyramidal move-
ment disorders. In a relatively large series, dystonia was reported
only in 13% of the affected patients.64 Dystonia occurs most fre-
quently in the neck, followed by upper and lower limbs, trunk,
and face and can generalize in half of the patients.65 The
development of ataxia precedes dystonia in most cases with
highly variable latency (from 0 to 26 years).65,66
In 3 distinct series, head tremor occurred in 28% to 44% of
AVED patients, possibly representing cervical dystonic tremor in
some cases.62,64,67 In an 8-year-old patient with AVED, myoclonic
dystonia involving the head and trunk was the presenting symp-
tom, preceding the onset of typical features of more than 6 years.66
Autosomal Dominant
Ataxias
In general, autosomal dominant ataxias are less relevant to the
pediatric population, and pediatric neurologists should not con-
sider them in the absence of a well-demonstrated family history.
Yet, infantile and childhood onset has been described in many
spinocerebellar ataxias, including SCA2, SCA7, SCA10, SCA13,
SCA14, SCA21, SCA25, SCA28, SCA29, SCA42, SCA44,
and dentatorubral-pallidoluysian atrophy.68,69 Some cases can be
explained by the phenomenon of anticipation, with earlier onset
and more severe presentation in subsequent generations that is
typical of expansion-repeat disorders.68 In the uncommon situa-
tion of autosomal dominant ataxia presenting in childhood, the
phenotype tends to be more severe and complex than pure ataxia.
Presentations can include hypotonia, developmental delay, respi-
ratory difficulties, and apnoea in the neonatal period, and in some
SCA2 cases, retinopathy.
Only a few autosomal dominant ataxias are relevant to chil-
dren, particularly SCA28 and SCA29.69
Spinocerebellar Ataxia 28
SCA28 is a rare neurodegenerative disorder mainly characterized
by slowly progressive gait and limb ataxia and a plethora of neu-
rological symptoms. Age of onset can range from early childhood
to the sixth decade, and the course is slowly progressive without
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MOVEMENT DISORDERS IN PEDIATRIC ATAXIAS
impairment of functional autonomy even decades after onset.
Brain MRI shows cerebellar atrophy, predominantly in the supe-
rior vermis, with sparing of the brainstem.68 SCA28 is caused by
heterozygous mutations in the AFG3L2 gene,70 whereas homo-
zygous mutations of the same gene cause a form of autosomal
recessive spastic ataxia (SPAX5).71
Regarding movement disorders, parkinsonism or dystonia are
recognized in about 24% of SCA28 patients.68
Spinocerebellar Ataxia 29
SCA29 is an extremely rare condition characterized by gross
motor delay and hypotonia in infancy followed by a very slowly
progressive or nonprogressive ataxia and mild cognitive impair-
ment. Variable features include nystagmus, dysarthria, intention
tremor, and epilepsy, and brain imaging shows hypoplasia or par-
tial aplasia of the cerebellar vermis.72 SCA29 is caused by hetero-
zygous mutations in the ITPR1 gene and is allelic to SCA15,
which is distinguished by later age at onset, progressive course,
and normal cognition.73 Dominant or recessive variants in the
same gene may also cause Gillespie syndrome, another form of
pediatric ataxia associated to developmental delay, intellectual
disability, iris hypoplasia, and visual impairment.74
Extrapyramidal movement disorders do not represent relevant
complications of ITPR1-related conditions,72,75 and only a few
patients have been reported with myoclonus or dystonia.76
Primary Episodic Ataxias
Primary episodic ataxias (EAs) are a group of rare, dominantly
inherited disorders characterized by transient recurrent episodes
of incoordination and truncal instability, often triggered by phys-
ical exertion and emotional stress, and variably associated with
progressive baseline ataxia without evidence of metabolic abnor-
malities.77 In the great majority of patients, the age of onset of
ataxic episodes usually occurs in the first 2 decades of life (more
commonly during early childhood).77
At present, 8 EA syndromes are described according to their
associated genetic loci, and the causative genes have been clearly
established in 4 subtypes: KCNA1 for EA1, CACNA1A for
EA2, CACNB4 for EA5, and SLC1A3 for EA6.78 Because these
genes are related to transmembrane proteins, the prevailing path-
ophysiology hypothesis is that the EAs are channelopathies.
These conditions should be promptly recognized, as several
different drugs are known to improve symptoms. For instance,
carbamazepine, valproic acid, and acetazolamide have been effec-
tive for treating EA1, whereas acetazolamide, flunarizine, and
4-aminopyridine are used in EA2 patients.79
Among the 8 subtypes, EA1 and EA2 are the most common
and best characterized disorders. In these forms, ictal extrapyra-
midal movement disorders can unusually complicate the disease
course.
EA1 is clinically characterized by brief, sudden-onset (1–2
minutes) attacks of imbalance, incoordination, and slurred speech
triggered by exertion or excitement.80 During and between
attacks, patients with EA1 can have myokymia, manifesting
S. GANA AND E.M. VALENTE REVIEW

TABLE 2 Occurrence of specific movement disorders in 9 categories of inherited errors of metabolism

IEM category Ataxia, % Dystonia, % Chorea, % Myoclonus, % Tremor, % Parkinsonism, %

Disorders of nitrogen-containing compounds 60–70 50 30–40 10 30–40 20

Disorders of vitamins, cofactors, metals, 70–80 50 30–40 <10 20 20
and minerals
Disorders of carbohydrates >80 >80 30–40 30–40 70–80 60
Mitochondrial disorders of energy 70–80 60 30–40 20 30–40 20
metabolism
Disorders of lipids >80 30–40 10–20 20–30 20–30 10
Disorders of tetrapyrroles 60–70 30–40 30–40 <10 <10 <10
Storage disorders >80 30–40 10–20 50 10–20 20
Disorders of peroxisomes >80 60–70 <10 <10 10–20 <10
Congenital disorders of glycosylation 70–80 10–20 20 10 10 <10
Adapted from Figure 1, ref. 88.

clinically as undulating and rippling activity in the large and small
muscles of the face and hands. More sustained abnormal muscle
contractions may also occur and are referred to as neu-
romyotonia.80 This can cause a typical fixed hand posture resem-
bling carpopedal spasm and mimicking dystonia. Besides this, the
other reported movement disorder is choreoathetosis.80,81
EA2 patients typically present paroxysmal recurrent debilitat-
ing spells of unsteadiness, incoordination, vertigo, and slurring of
speech lasting hours to days, with variable baseline progressive
ataxia.77 The attacks may occur spontaneously or may be trig-
gered by physical exertion, fatigue, emotional distress, or excite-
ment. Besides ataxia, uncommon clinical features include
paroxysmal torticollis of infancy, blepharospasm, and other focal
dystonias.82,83
Metabolic Ataxias
Inborn errors of metabolism (IEMs) are a group of genetic disor-
ders characterized by dysfunction of an enzyme or other protein
involved in cellular metabolism that may cause localized or sys-
temic dysfunctions.84 The current nosology for IEMs includes
9 categories with 130 disease groups and 1,015 distinct
disorders.85
Most IEMs involve the nervous system (neurometabolic dis-
eases), but generally they do not present with an isolated neuro-
logic feature. Conversely, the clinical picture is usually complex,
with several neurologic features (such as seizures, extrapyramidal
movement disorders, developmental delay, ataxia, deteriorating
vision and hearing), behavioral problems and nonneurologic fea-
tures (such as dysmorphic features and eye, heart, or gastrointesti-
nal involvement).84
As normal movement requires appropriate neurochemical inter-
actions among brain regions involved in motor function, it should
not be surprising that ataxia and movement disorders are frequent
findings in IEMs.86 Indeed, about a third of patients with neuro-
metabolic disorders present with either ataxia, hyperkinetic or
hypokinetic-rigid phenotypes.87 All types of movement disorders
(except for tics and ballismus) have been described in up to
207 distinct forms of IEMs, with age of onset typically ranging
from neonatal period to adolescence. The most common symp-
toms were ataxia (73%), dystonia (47%), chorea/athetosis (24%),
hypokinetic-rigid syndrome (17%), tremor (15%) and myoclonus
(14%).88 The relative occurrence of specific movement
disturbances in the IEM categories is illustrated in Table 2 (modi-
fied from Ferreira and colleagues88).
Generally, in presence of a movement disorder, an underlying
IEM should be suspected in cases of (1) early age of onset (the ear-
lier the onset, the more likely a metabolic etiology), (2) associated
neurologic or extraneurologic signs and symptoms (motor distur-
bances rarely predominate the clinical presentation and are more
frequently part of a complex picture), (3) progressive course,
(4) consanguinity and/or positive family history of similar disorder,
(5) autonomic dysfunction, (6) paroxysmal episodic events, and
(7) acute or subacute onset with or without triggering factors.88
However, the diagnosis of IEMs can be challenging as children can
present with nonspecific pediatric problems, such as growth falter-
ing, recurrent vomiting, and developmental delay. In addition,
some neurometabolic disorders progress very slowly and can mimic
cerebral palsy or isolated developmental delay. The investigation of
these disorders requires specific metabolic screenings followed by
enzymatic and molecular evaluations.89,90 Recognizing the poten-
tially treatable causes of IEMs is critical not only to implement
targeted treatments but also to establish as early a treatment as possi-
ble to hopefully halt neurological deterioration or at least improve
outcome. Even for defects lacking specific therapeutic intervention,
a definite diagnosis can allow genetic counseling, prenatal diagnosis,
and where appropriate, screening of the wider family.
Discussing all types of treatable IEMs is beyond the scope of
this article; thus, in this section, we focus on movement disorders
occurring in 2 metabolic disorders of particular interest in which
ataxia is a prominent clinical sign and amenable to disease-
specific treatment: glucose transporter type 1(GLUT-1) defi-
ciency syndrome and primary coenzyme Q (CoQ)10 deficiency.
Supplementary Table S1 summarizes the list of the 37 treatable
IEMs featuring ataxia and movement disorders and their primary
treatment options (modified from Ferreira and colleagues88).
GLUT-1 Deficiency Syndrome
The classic phenotype of GLUT-1 deficiency syndrome is char-
acterized by infantile-onset seizures, delayed neurologic develop-
ment, acquired microcephaly, and complex movement
disorders.91–93 Although unspecific, the single most important
laboratory observation in GLUT-1 deficiency syndrome is
hypoglycorrhachia (cerebrospinal fluid glucose values below
60 mg/dL), with normal blood glucose concentration and the

MOVEMENT DISORDERS CLINICAL PRACTICE 2020; 7(4): 383–393. doi: 10.1002/mdc3.12937 389
 REVIEW
cerebrospinal fluid/blood glucose ratio ranging from 0.19 to 0.46
(average value 0.33).94 Diagnosis is confirmed by the detection
of heterozygous mutations, typically occurring de novo, in the
SCL2A1 gene, encoding for the main glucose transporter across
the blood–brain barrier.94 The establishment of a ketogenic
diet allows an alternative energy source for the brain and leads to
a significant clinical improvement.95
Movement disorders in GLUT-1 deficiency syndrome are
complex may include ataxia, dystonia, chorea, tremor, myoclo-
nus, and parkinsonism. They can be paroxysmal, continuous, or
with fluctuations related to environmental stressors. Paroxysmal
worsening often occurs before meals, during fasting, or with
infectious stress.92,95–97
Earliest symptoms are usually dominated by seizures and other
paroxysmal events. However, seizures gradually recede in early child-
hood and are replaced by dystonic postures as the dominant paroxys-
mal manifestation thereafter.95
In a series of 57 patients, movement disorders featured action
limb dystonia (86%), mild chorea (75%), and myoclonus (16%).
Nonepileptic paroxysmal events occurred in 28% patients, and
besides ataxia and weakness, they also included parkinsonism and
nonkinesigenic dyskinesias.92 The acute presentation of dystonia
has been also reported.98
Primary Coenzyme Q10
Deficiencies
Primary CoQ10 deficiencies constitute a very rare and heteroge-
neous group of autosomal recessive conditions with primary defi-
ciencies caused by mutations in genes encoding CoQ10
biosynthesis enzymes (secondary forms of CoQ10 deficiency are
related to mutations that indirectly affect CoQ10 biosynthesis).
Approximately 200 patients have been described in the literature
so far.99
CoQ10 is a lipid-soluble component located in the inner
mitochondrial membrane. In the mitochondrial respiratory chain,
CoQ10 is vital for the transport of electrons from complex I
(NADH-ubiquinone oxidoreductase) and complex II (succinate-
ubiquinone oxidoreductase) to complex III (ubiquinol-cytochrome
c reductase). It is also an antioxidant and a membrane stabilizer, and
its oxidized form serves as a cofactor for uncoupling proteins in
brown adipose tissue.100 Thus, the bioenergetic defect and the
increased reactive oxygen species production may have a pathoge-
netic crucial role.
To date, the following 10 different genes have been associated
with primary CoQ10 deficiency: PDSS1, PDSS2, COQ2,
COQ4, COQ5, COQ6, COQ7, COQ8A, COQ8B, and COQ9.
The age of disease onset is variable, ranging usually from birth
to adolescence (but can also occur in adults), and there is a marked
diversity in clinical symptoms as multiple organ systems can be
variably affected, including central nervous system (encephalopa-
thy, seizures, cerebellar ataxia, epilepsy, or intellectual disability),
peripheral nervous system, kidney (steroid-resistant nephrotic
syndrome), skeletal muscle (myopathy), heart (hypertrophic car-
diomyopathy), and sensory system (sensorineural hearing loss,
390 MOVEMENT DISORDERS CLINICAL PRACTICE 2020; 7(4): 383–393. doi: 10.1002/mdc3.12937
MOVEMENT DISORDERS IN PEDIATRIC ATAXIAS
retinopathy, or optic atrophy).99 Because of the small number of
patients harboring mutations in CoQ10 genes and the highly vari-
able multisystem involvement, genotype–phenotype correlations
are still scarce.
COQ8A and COQ8B are the most common mutated
genes.99 Although ataxia is not observed in patients with
COQ8B mutations, the phenotype associated to COQ8A muta-
tions is dominated by a slowly progressive childhood-onset gait
ataxia with cerebellar atrophy, frequently associated to seizures,
cognitive decline, and sometimes more systemic involvement
such as liver or kidney dysfunction.101 Until now, 48 patients
with COQ8A mutations have been reported.99,102 Among these,
tremor was observed in 18 (37.5%), myoclonus in 13 (27%),
dystonia in 10 (21%), and chorea in 2 (4%).
Very few patients with ataxia and mutations in PDSS2,
COQ4, COQ5, and COQ6 have been identified, and some of
them also presented with dystonia, myoclonus, or tremor.99,103
The diagnostic process in CoQ deficiency is particularly complex,
as there are no specific biomarkers, and there is no way to discrimi-
nate “a priori” between a primary or secondary defect. The most
reliable diagnostic test is the detection of reduced CoQ10 levels in
skeletal muscle by high-performance liquid chromatography.99
As for other treatable IEMs, early diagnosis is crucial because
high-dose CoQ oral supplementation was shown in most cases
to induce dramatic improvements, blocking the progression of
the disease in critical tissues such as the kidney or the central
nervous system.104 Alternatively, some 4-Hydrozybenzoate
analogs, such as vanillic acid and 3,4-dihydroxybenzoate, have
been proposed as potential bypass molecules increasing CoQ
bioavailability.99
Conclusions
In childhood, ataxia represents a relatively common disorder often
complicated by additional neurological and nonneurological signs;
except for some neurometabolic diseases, it usually lacks effective
treatments and bears a strong social impact. Movement disorders,
ranging from mild to severe, are among the most common non-
cerebellar features at least in some primary pediatric ataxias
(AT and AOA1), whereas they occur less frequently in others
(FA, ARSACS, AOA2, AVED). Patients may manifest 1 or more
movement disorders (eg, dystonia, myoclonus, chorea), which in
some cases may be the presenting or dominant feature, making
the diagnosis particularly challenging especially at disease onset.
Recognition of the complete movement disorder phenotype has
important implications for diagnosis, management, and genetic
counseling.
Acknowledgments
We acknowledge support from the Pierfranco and Luisa Mariani
Foundation (PADAPORT project) and the Italian Ministry of
Health (Ricerca Corrente 2020 and 5 per mille year 2016).
S. GANA AND E.M. VALENTE
Author Roles
(1) Research Project: A. Conception, B. Organization,
C. Execution; (2) Manuscript Preparation: A. Writing of the First
Draft, B. Review and Critique.
S.G.: 1A, 1B, 1C, 2A
E.M.V.: 1A, 1B, 1C, 2B
Disclosures
Ethical Compliance Statement: We confirm that patient
consent and the approval of an institutional review board were
not required for this work. We also confirm that we have read
the Journal’s position on issues involved in ethical publication
and affirm that this work is consistent with those guidelines.
Funding Sources and Conflict of Interest: The authors
declare to have no competing financial interests.
Financial Disclosures for the Previous 12 Months: The
authors declare no competing financial interests for the preceding
twelve months.
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