ataxia cerebelosa

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CURRENT
OPINION Cerebellar ataxias: an update
Mario Mantoa,b
, Jordi Gandinia
, Katharina Feilc
, and Michael Struppc
Purpose of review
Providing an update on the pathophysiology, cause, diagnosis and treatment of cerebellar ataxias. This is
a group of sporadic or inherited disorders with heterogeneous clinical presentation and notorious impact
on activities of daily life in many cases. Patients may exhibit a pure cerebellar phenotype or various
combinations of cerebellar deficits and extracerebellar deficits affecting the central/peripheral nervous
system. Relevant animal models have paved the way for rationale therapies of numerous disorders affecting
the cerebellum.
Recent findings
Clinically, the cerebellar syndrome is now divided into a cerebellar motor syndrome, vestibulocerebellar
syndrome and cerebellar cognitive affective syndrome with a novel clinical scale. This subdivision on three
cornerstones is supported by anatomical findings and neuroimaging. It is now established that the basal
ganglia and cerebellum, two major subcortical nodes, are linked by disynaptic pathways ensuring
bidirectional communication. Inherited ataxias include autosomal recessive cerebellar ataxias (ARCAs),
autosomal dominant spinocerebellar ataxias and episodic ataxias and X-linked ataxias. In addition to the
Movement Disorders Society genetic classification of ARCAs, the classification of ARCAs by the Society for
Research on the Cerebellum and Ataxias represents major progress for this complex subgroup of cerebellar
ataxias. The advent of next-generation sequencing has broadened the spectrum of cerebellar ataxias.
Summary
Cerebellar ataxias require a multidisciplinary approach for diagnosis and management. The demonstration
of anatomical relationships between the cerebellum and basal ganglia impacts on the understanding of the
cerebello-basal ganglia-thalamo-cortical system. Novel therapies targeting deleterious pathways, such as
therapies acting on RNA, are under development.
Keywords
ataxias, biomarker, cerebellum, classification, next-generation sequencing, scale, therapy
INTRODUCTION
Cerebellar ataxias represent a group of disorders
with heterogeneous clinical presentation [1]. They
are characterized by a salient overlap of the pheno-
types between genetic subtypes. Patients may
exhibit a pure cerebellar phenotype or various com-
binations of cerebellar deficits and extracerebellar
signs, such as pigmentary retinopathy, extrapyrami-
dal movement disorders, pyramidal signs, cortical
symptoms (seizures, cognitive impairment/behav-
ioral symptoms) and peripheral neuropathy. Loss
of balance, lack of coordination and slurred speech
are common symptoms. Cerebellar ataxias are
increasingly recognized, and the field of ataxiology
has grown substantially. It also now covers essential
tremor, on the basis of neuropathological findings
demonstrating defects in the cerebellar cortex, espe-
cially at the Purkinje cell level [2].
Relevant animal models have been developped,
so that our understanding of the molecular
mechanisms behind cerebellar ataxias has improved
substantially. For many cerebellar ataxias, we have
now experimental evidence of the molecular path-
ways involved. A typical example is represented by
autosomal recessive cerebellar ataxias (ARCAs; refer
to the ‘RECESSIVE ATAXIAS: CLASSIFICATION AND
PATHOGENESIS’ section).
a
Cerebellar Ataxia Unit, Department of Neurology, CHU-Charleroi, Char-
leroi, b
Department of Neuroscience, University of Mons, Mons, Belgium
and c
Department of Neurology and German Center for Vertigo and
Balance Disorders (DSGZ), Ludwig Maximilians University, Munich,
Germany
Correspondence to Mario Manto, MD, PhD, Cerebellar Ataxia Unit,
Department of Neurology, CHU-Charleroi, Charleroi, Belgium; Service
des Neuroscience, University of Mons, Mons, Belgium. E-mail: mman-
to@ulb.ac.be
Curr Opin Neurol 2019, 32:000–000
DOI:10.1097/WCO.0000000000000774
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REVIEW
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The diagnosis of cerebellar ataxias: finding
the way in the labyrinth
For many clinicians, the diagnosis of cerebellar
ataxias remains challenging during daily practice.
The clinical diagnostic approach to a patient pre-
senting cerebellar ataxia is illustrated in Fig. 1. More
specific blood studies (Table 1) and brain MRI are
essential tools. Conventional MRI can be comple-
mented with volumetric studies of the cerebellum,
diffusion tensor imaging/tractography to assess in
vivo the organization of cerebellar afferent and effer-
ent tracts passing through the inferior, middle and
superior cerebellar peduncles including in children,
and magnetic resonance spectroscopy [3].
The impact of advances in genetic techniques
The number of genes implicated in cerebellar ataxias
is constantly increasing. The advent of next-genera-
tion sequencing (NGS: targeted gene-panel sequenc-
ing, WES: whole exome sequencing – analysis of the
most coding regions of the 20 000 human genes,
WGS: whole genome sequencing) has revolution-
ized the field of clinical genetics [4]. Indeed, NGS
allows simultaneously sequencing of hundreds of
thousands of different DNA fragments, improving
the speed and costs of analysis. The neurological
community has learnt that NGS requires a thought-
ful approach and careful genetic counseling. The
interpretation of WES/WGS results is often not
straight-forward, requiring sophisticated facilities
and skills. The following need to be taken into
account: analysis/interpretation of single nucleo-
tide variants, insertions and deletions, copy number
variants (CNVs), structural variants and intronic
variants (introme). Genetic pleiotropy (the same
mutation can produce different diseases) is another
factor which is increasingly recognized. It should be
kept in mind that WES does not detect trinucleotide
repeat expansion disorders (requiring PCR amplifi-
cation, electrophoresis, triplet repeat primed PCR)
and mitochondrial DNA mutations. In addition,
large structural variants are missed. DNA sequencing
techniques are not suitable to unravel dynamic
mutations. Bioinformatic progress is ongoing, for
instance to detect CNVs. The ethical issues raised by
genome-wide sequence data must be addressed dur-
ing counseling before and after the analysis [4].
The following current guidelines are proposed
for the diagnosis of cerebellar ataxias [5
&&
]:
(1) Test for single genes sequencing when the phe-
notype/paraclinical tests are suggestiveor in pop-
ulations with a high prevalence of a given
disorder. Sanger sequencing remains the gold
standard for small genes and founder mutations.
(2) Move to NGS if the result is negative:
(a) Multigene panel: a priori selection from
existing knowledge. Regular updates of pan-
els are required. The flexibility of gene pan-
els’ approach and the cost-effectiveness are
clear advantages.
(b) Targeted or WES: the diagnostic yield varies
from 18 to 80% (highest values in case of
early-onset and consanguinity).
(c) WGS: however, the diagnostic yield still
remains uncertain.
CEREBELLO-CEREBRAL NETWORKS:
NOVEL ANATOMIC FINDINGS
The recent full characterization of the neuroanat-
omy of the cerebello-basal ganglia-thalamo-cortical
system has important implications for our under-
standing of the functions of the cerebellum, the
roles of cerebellar afferent/efferent circuits, the over-
all contribution of the cerebellum to brain activities,
and the neurobiological basis of brain disorders [6].
It was initially thought that the cerebellum was
exclusively involved in motor control by receiving
information from multiple neocortical areas and by
returning the information to the primary motor
cortex. It is now established that the cerebellum
projects to numerous cerebral cortical areas, with
a segregation of outputs from dentate nuclei: the
dorsal region (motor domain of the nucleus) proj-
ects to M1/premotor areas and the ventral region
(nonmotor domain of the nucleus) projects to pre-
frontal cortex, parietal cortex and temporal cortex.
Converging data show that functional subre-
gions within the cerebellum underlie motor, cogni-
tive and affective behaviors [7]. The sensorimotor
homunculi in the anterior lobe and lobule VIII are
associated with the cerebellar motor syndrome
(CMS). The cerebellar posterior lobe, including ver-
mal and hemispheric regions of lobules VI and VII, is
KEY POINTS
A dedicated clinical scale of Schmahmann syndrome/
cerebellar cognitive affective syndrome has
been validated.
The clinical cerebellar syndrome gathers three
elemental pieces.
Cerebellum communicates with basal ganglia.
The classification of recessive ataxias has
been reshaped.
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reciprocally connected with cerebral association
and paralimbic cortices. Lobule VII comprises
48% of the cerebellar cortex in humans. Lobule
VII includes Crus I, Crus II and VIIB. This posterior
lobe region of the cerebellum has a distinct connec-
tivity pattern as compared with the anterior lobe/
lobule VIII: lobule VII connects with parietal and
prefrontal cortices, providing the anatomical sub-
strate for a key-role for the cerebellum in a wide
range of cognitive tasks [7,8
].
In addition to the well known convergence of
basal ganglia and cerebellar output at the level of the
cortical motor areas, it is now accepted that the
cerebellum and basal ganglia are directly connected
by bidirectionnal pathways [9
]. The cerebellum
sends a projection to the striatum via the thalamus
and subthalamic nucleus projects to the cerebellum
via the pontine nuclei (Fig. 2). Furthermore, basal
ganglia and cerebellar output also converge on the
red nucleus at the brainstem level. Impaired cere-
bellar plasticity is incriminated in the pathogenesis
of dystonia, Parkinson’s disease and addiction.
Moreover, the cerebellum impacts on striatal plas-
ticity. Compelling evidence has been provided by
experimental manipulations in animal models of
dystonia, especially the genetically dystonic rat
and the tottering mice [10]. Genetic silencing of
olivocerebellar synapses causes dystonic-like motor
disturbances in mice [11
].
In addition to its anatomical communication
with the thalamic nuclei, basal ganglia and cerebral
cortex, the cerebellum is heavily connected with the
spinal cord (spinocerebellar systems). Corticospinal
tracts are heavily connected with spinal
FIGURE 1. General diagnostic algorithm of cerebellar ataxias. The diagnosis is reached in successive steps and often requires a
multidisciplinary team. A genetic cause is considered when there is a family history, a chronic course and suggestive clinical
signs. Importantly, a negative family history does not exclude a genetic disease for the following reasons: pseudo-sporadic cases
may be due to a recessive or mitochondrial inheritance, genetic anticipation, de novo mutations, error in the paternity, gonadic
mosaicism or failure to obtain a detailed phenotype from the family members. Obtaining details on the family may be time-
consuming but remains very informative. A three-generation pedigree should be obtained. In children, the differential diagnosis of
cerebellar ataxias includes infections (viral, bacterial, cerebellar abcess), autoimmune-mediated diseases (Miller-Fisher Syndrome,
Bickerstaff encephalitis), metabolic/toxic causes (e.g. drug intoxication, mitochondrial cytopathies), space-occupying lesions (e.g.
tumour, hydrocephalus), acute demyelinating syndromes (e.g. acute disseminated encephalomyelitis ADEM, CIS/MS), hereditary
channelopathies, inner ear diseases and acute labyrinthitis, epilepsy (Joubert et al., 2018). ADEM, acute diffuse
encephalomyelitis; ALD, adrenoleukodystrophy; ASAT, ataxia with sideroblastic anemia; CIS/MS, clinically isolated syndrome/
multiple sclerosis; FXTAS, fragile X-associated tremor/Ataxia syndrome; MRXSCH, Christianson type of X-linked syndromic mental
retardation; MS, multiple sclerosis; MSA, multiple system atrophy; SCA, spinocerebellar ataxia; SPG7, spastic paraplegia 7.
An update on cerebellar ataxias Manto et al.
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interneurons which are involved in the spinocere-
bellar circuits [9
]. These circuits ensure a continu-
ous monitoring of the activity in spinal cord.
The cerebellum is organized into modules con-
necting the cerebellar cortex, cerebellar nuclei and
the inferior olivary complex [8
]. Despite a remark-
ably homogeneous cytoarchitecture, the cerebellum
is functionally heterogeneous with topographically
arranged cerebellar connections with sensorimotor,
association and paralimbic areas of the cerebral
hemispheres as well as with the brainstem and
spinal cord [7]. The cerebello-cerebral loops run in
parallel with two important features now being
recognized: the Purkinje neurons are chemically
heterogeneous and the modules show plastic mech-
anisms [8
].
CEREBELLAR COGNITIVE AFFECTIVE
SYNDROME: WHERE DO WE STAND?
The classical mediolateral subdivision of the cere-
bellum into a vermal part (in connection with fas-
tigial nuclei), an intermediate zone (in connection
with the interpositus nuclei) and a lateral zone
(communication with dentate nuclei) has been
replaced by a subdivision based upon the 10 cere-
bellar lobules (Larsell’s classification) and their con-
nectivity. This novel approach to the functional
anatomy of the cerebellum is the basis of the current
subdivision of the cerebellar syndrome into three
domains:
(1) CMS: A primary sensorimotor region is located
in the anterior lobe and the adjacent part of
lobule VI. A second sensorimotor region is
located in lobule VIII. Motor-related cortices
project to the caudal half of the pons, which
itself projects to the contralateral anterior lobe.
The anterior lobe projects back to the motor
cortices via thalamic nuclei. CMS is composed
of various combinations of dysmetria, kinetic
tremor, action tremor, impaired muscle tone
(hypotonia, cerebellar fits), decomposition of
movement, adiadochokinesia.
(2) Vestibulocerebellar syndrome (VCS): The flocculo-
nodular lobe receives projections from the
Table 1. Blood studies in cerebellar ataxiasa
Blood parameters Cerebellar disorder
Reduced level of thiamine
Reduced level of transketolase
Wernicke encephalopathy
Raised levels of alpha-foetoprotein AT (60 mg/l), AOA1 (7–20 mg/l), AOA2 (15–65 mg/l), AOA4, Riddle syndrome (50 mg/l)
Reduced levels of ATM Ataxia-telangiectasia
Reduced levels of vitamin E AVED
Reduced levels of cholesterol
Reduced levels of LDL/VLDL
Reduced levels of vitamins E, A, D, K
Acanthocytes
Anemia
Abetalipoproteinemia
Reduced levels of ceruloplasmin
Near absence of ceruloplasmin
Wilson’s disease
Aceruloplasminemia
Hypercholesterolemia
Hypoalbuminemia
AOA1, SCAN1
Increased levels of phytanic acid Refsum’s disease
Raised levels of VLCFA ALD
Increased levels of oxysterols Niemmann-pick type C
Decreased levels of arylsulfatase A MLD
Decreased activity of GALC Krabbe disease
Decreased activity of HEXA GM2 gangliosidosis
Increased levels of lactate Mitochondrial ataxias
Decreased levels of gonadotrophins Gordon-Holmes syndrome
Increased levels of cholestanol CTX
Reduced activity of GBA1 Gaucher disease
Abnormal serum transferrin glycoforms Congenital disorders of glycosylation
ALD, adrenoleukodystrophy; AOA, ataxia with oculomotor apraxia; AT, ataxia-telangiectasia; AVED, ataxia with vitamin E deficiency; CTX, cerebrotendinous
xanthomatosis; MLD, metachromatic leukodystrophy; SCAN1, spinocerebellar ataxia with axonal neuropathy type 1.
a
See also Table 2.
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vestibular nuclei. Three main areas have been
identified: the flocculus–paraflocculus, the nod-
ulus–ventral uvula (lobules IX and X), and the
dorsal oculomotor vermis (lobules V–VII). The
vestibulocerebellar and vestibulospinal systems
are closely linked. VCS can present as fixation
deficits(flutter, macrosaccadicoscillations,opso-
clonus), ocular misalignment, downbeat nystag-
mus, rebound nystagmus, period alternating
nystagmus, central positional nystagmus,
impaired smooth pursuit and gaze-holding, dys-
metria of saccades, and rarely skew deviation and
ocular tilt reaction. A clinically very relevant
entity is cerebellar dizziness; practically every
patient with cerebellar dizziness has one or more
of these clinical signs [12].
(3) Cerebellar cognitive affective syndrome (CCAS):
Cognitive impairment is observed in numerous
cerebellar disorders at various severities, from
subtle and overlooked symptoms to a severe
clinical pseudopsychiatric picture. Executive
functions, visuospatial skills and verbal memory
are particularly impaired. In some patients, lin-
guistic processing and affect regulation are par-
ticularly affected. The CCAS is observed in
patients showing lesions of the cerebellar poste-
rior lobe (so-called cognitive cerebellum: lobules
VI, VII and possibly lobule IX). The CCAS is the
manifestation of dysmetria of thought, repre-
senting the cognitive equivalent of the motor
dysmetria characterized by hypermetria (positive
symptoms) and hypometria (negative symp-
toms) [13]. A particularly severe form of CCAS
is posterior fossa syndrome (cerebellar mutism)
which is mainly observed in children after sur-
gery for midline tumors of the posterior fossa
such as a medulloblastoma [14
]. The clinical
presentation is characterized by delayed onset
(1–10 days after surgery) of mutism/reduced
speech associated with behavioral symptoms
such as emotional lability, high-pitch crying,
apathy, autistic-like behavior [15]. Hypotonia,
oropharyngeal dysfunction/dysphagia and other
signs of brain stem dysfunction may occur.
Although the speech disorder is transient, its
recovery may take months or years and patients
often retain some cognitive/affective/motor def-
icits. None of the ‘higher-level’ language, work-
ing memory, spatial or executive tasks reported
here are associated with activation of the anterior
lobe of the cerebellum. Whereas language is
right-lateralized, spatial processing is associated
with a greater activation of left hemisphere.
Similar operational mechanisms likely subserve
both motor processing and cognitive operations of
the cerebellum. The leading theory of internal mod-
els suggests that the cerebellum provides a forward
model for motor and mental operations of the cere-
bral cortex. In other words, the cerebellum predicts
the current and future states of the body, both from
the motor and cognitive stand-point [16].
Routine scales aiming to detect dementia [Mini
Mental State Examination (MMSE), Montreal Cog-
nitive Assessment (MoCA)] are not sensitive/specific
enough to demonstrate a cognitive involvement in
FIGURE 2. Bidirectionnal communication between the cerebellum and basal ganglia. The two disynaptic pathways between
the cerebellum and basal ganglia are shown with gray arrows: the cerebellum projects to the basal ganglia via the thalamus
and the subthalamic nucleus projects to the cerebellum via pontine nuclei. Adapted from [9
,10].
An update on cerebellar ataxias Manto et al.
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cerebellar ataxias. Therefore, an office/bedside scale
to screen and follow cerebellar patients was devel-
oped [17
]. The scale was first applied to an explor-
atory cohort and subsequently to a validation
cohort. The scale is particularly useful for detecting
dysexecutive function (working memory, flexibility
in mental tasks, abstract reasoning). The scale has
three components: first, a pass/fail diagnostic cutoff
for each item; second, a pass/fail for the scale as a
whole; and third, a scale total raw score. Possible,
probable and definite CCAS are defined. Sensitivity
ranged from 46 (definite CCAS) to 95% (possible
CCAS) in the validation cohort, contrasting with
normal scores for MMSE and MoCA. The CCAS scale
covers the deficits both in pure cerebellar lesions
and in complex cerebellar disorders affecting also
extracerebellar regions, showing that the cerebellar
involvement itself is sufficient to generate the cog-
nitive dysmetria. This new scale fills a gap in clinical
ataxiology. Clinicians have now validated scales to
quantify the CMS (international cooperative ataxia
rating scale, scale for assessment and rating of ataxia
(SARA), brief ataxia rating scale, friedreich ataxia
rating scale) and the CCAS.
Mentalization refers to the process of identifying
other persons’ intentions, beliefs, emotions and
personality traits based on behavioral descriptions.
Recent studies have uncovered that the cerebellum
is a key-node of the social brain network [18]. There
is a robust activation of the cerebellum during social
judgments and there is a strong neural interaction
between the cerebellum and cerebrum during
social mentalizing. The connectivity between the
posterior cerebellum and cortical mentalizing
areas includes the medial prefrontal cortex and
the temporoparietal junction, with a distinct default
network in the cerebellum directly connected to
the default network in the cerebrum that largely
overlaps with cerebellar activation during social
mentalizing. Sequencing appears as an elemental
mechanism underlying mentalizing. This has impli-
cations in our understanding of neuropsychiatric/
neurodevelopmental disorders such as autistic spec-
trum disorders, attentional deficit and hyperkinetic
disorder, as well as schizophrenia [19].
IMMUNE-MEDIATED CEREBELLAR
ATAXIAS
Immune-mediated cerebellar ataxias (IMCAs) include
gluten ataxia, GAD65 antibody-associated cerebellar
ataxia, primary autoimmune cerebellar ataxia, the
cerebellar form of Hashimoto’s encephalopathy, para-
neoplastic cerebellar degeneration, postinfectious cer-
ebellitis, Miller-Fisher syndrome and opsoclonus-
myoclonus syndrome. Rarely, cerebellar ataxia occurs
in patients presenting with systemic lupus erythema-
tosus, Behçet disease or sarcoidosis.
In a large study dedicated to the cause of cere-
bellar ataxias in the United Kingdom [20
], 30%
had a definite IMCAs. The clinical presentation is
acute/subacute. This is a hallmark. IMCA should be
suspected in the context of recent infection, signs of
cerebrospinal fluid (CSF) inflammation such as ele-
vated protein or cell count, detection of autoanti-
bodies targeting intracellular or surface antigens
(Table 2) and clinical response to steroids or immu-
nosuppressants [21].
DOMINANT ATAXIAS: RECENT
ADVANCES
The prevalence of spinocerebellar ataxias (SCAs)
varies between 2 and 4/100 000 according to the
region of the world. So far, 47 SCAs have been
reported with identification of 35 genes. World-
wide, the most common SCAs are polyglutamine
expansion disorders: SCA1 (ATXN1), SCA2 (ATX2),
SCA3 (ATX3), SCA6 (CACNA1A), SCA7 (ATXN7),
SCA17 (TBP) and DRPLA (ATN). Rare SCAs are
caused by nonrepeat mutations. The symptoms usu-
ally start between the 2nd and the 4th decade, with
an inverse correlation between the size of CAG
repeat expansion (CAG trinucleotide repeats encode
Table 2. Antibodies associated with cerebellar ataxiaa
Antibody Associated CA
Antigliadin (IgG/IgA)
Anti-TG 2/6
Gluten ataxia
Anti-GAD65 Anti-GAD65 Ab-associated ataxia
Anti-TPO Hashimoto’s encephalopathy
Anti-Yo PCD (breast, uterus, ovarian cancer)
Anti-Hu PCD (SCLC)
Anti-CV2/CRMP5 PCD (SCLC, thymoma)
Anti-Ri PCD (lung, breast), OMS
Anti-Ma2 PCD (testis, lung cancer)
Anti-Tr PCD (Hodgkin’s lymphoma)
Anti-VGCC
(P/Q type)
PCD (SCLC), PACA
Anti-MAP1B PCD (SCLC)
Anti-CARP VIII PCD (melanoma, ovary)
Anti-ITPR1 PCD (Breast cancer)
AntimGluR1,
Anti-PKC g
Neoplasm (hematological, prostate,
NSCLC, gall bladder carcinoma)
Anti-Homer-3 Neoplasm, postinfectious cerebellitis, PACA
Anti-GluRd2 Postinfectious cerebellitis, PACA
CA, cerebellar ataxia; PACA, primary autoimmune cerebellar ataxia; PCD,
paraneoplastic cerebellar degeneration.
a
Data from [21].
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polyglutamines) and the age of onset and a genetic
anticipation due to instability of expanded alleles.
The normal range of repeats is usually below 40.
Pathological expansions rarely exceed 100 (as in
SCA1, SCA3, SCA6, SCA12, SCA17). However,
expansions may reach the 200–450 repeats (as in
SCA2, SCA7, SCA8). Furthermore, repeats may
reside within introns, promoters, 50
or 30
untrans-
lated regions and are much larger in size, from
hundreds to thousands bp, as found in SCA10,
SCA36, as well as in FRDA (see ARCAs). A ‘premu-
tation range’ of expansions (between the normal
repeat range and the fully expanded range causing
the disease at full penetrance) can result in lower
penetrance or milder phenotypes. Premutation
alleles also tend to further expand during meiosis.
The premutation and full mutation range may
slightly overlap, rendering the prediction in terms
of clinical outcome difficult. Patients worsen at
different rates according to the SCA (annual pro-
gression on SARA scores: 2.11 in SCA1, 1.56 in SCA3,
1.49 in SCA2 and 0.8 in SCA6). Patients often show
combinations of cerebellar and extrapyramidal
symptoms. Risk factors for death include in particu-
lar a high SARA score and dysphagia [22].
Biomarkers: In terms of biomarkers, neuroimag-
ing studies have demonstrated specific patterns of
brain atrophy, including at the premanifest stage.
MRI spectroscopy detects abnormal metabolic pro-
files [23]. Functional MRI is being investigated as a
potential biomarker with the goal of extracting
patterns of cerebral reorganization at rest and during
activation tasks. Oculomotor biomarkers include
slow horizontal saccades in SCA2, with preclinical
carriers showing a decreased saccade velocity and
antisaccade task errors. Slowing of horizontal sac-
cade velocity is correlated with the degree of pon-
tine atrophy, whereas the progression of
oculomotor deficits is correlated with CAG repeat
size [24
]. This is particularly relevant to address the
issue of the power of clinical trials.
There is a clear need to identify blood/CSF
markers in SCAs. These biomarkers should be robust
enough to be used for the diagnosis and disease
management, including disease progression and
prognosis. In SCA3, investigations are ongoing to
assess SIRT1 mRNA levels (SIRT1 encodes for sirtuin-
1 involved in cell cycle, apoptosis and autophagy) as
a biomarker. The activity of gluthatione peroxidase
(involved in oxidative stress regulation), the levels
FIGURE 3. Subdivision of autosomal recessive cerebellar ataxias in two groups according to the presence/absence of
sensorimotor involvement. Adapted from [30].
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of IL6 mRNA (brain from SCA3 patients show
enhanced inflammation) are also being considered
[25,26]. Promising data are emerging from studies
on serum levels of neurofilament light chain (Nfl
are present in the neuron cytoskeleton and blood
level increase indicates axonal damage) in polyglu-
taminopathies [27]. Nfl represent a potential bio-
marker for Huntington’s disease in terms of
prediction of disease onset and progression of the
disease [28].
RECESSIVE ATAXIAS: CLASSIFICATION
AND PATHOGENESIS
ARCAs are characterized by a high phenotypic het-
erogeneity and complex phenotypes. None of them
presents with a pure cerebellar syndrome. They
often start in childhood or early adulthood, with
an incidence of about 3–5/100 000. Friedreich ataxia
(FRDA) remains the most common ARCA. More
than 200 genes have been identified [29
]. Except
for FRDA, which results from a noncoding repeat
expansion in majority of cases, almost all other
ARCA mutations identified so far constitute
conventional mutations.
Classification of autosomal recessive
cerebellar ataxias: looking for clarity for
current clinical practice
The classification of ARCA is still highly challenging
due to the high number of genes identified, the
phenotypic overlap and due to metabolic/develop-
mental diseases which present occasionally with
ataxia [29
,30]. A first clinical approach is based
on the presence of a sensorimotor deficits in the
phenotype (Fig. 3).
The current Classification of the Movement
Disorder Society is based on the gene name associ-
ated with a phenotypical prefix [31]. It covers a list
of 92 gene-defined recessive disorders and an
exhaustive list of disorders that may occasionally
present with ataxia. The classification is particu-
larly useful from a genetic standpoint to design a
gene panel and to guide the interpretation of
exome/genome sequencing results. The society
for research on cerebellum and ataxias classifica-
tion aims to guide the neurologist during daily
practice and to identify shared mechanisms
between the various ARCAs [5
]. The classification
takes into account regional differences in the prev-
alence of ataxias. The classification considers 59
Table 3. Classification of autosomal recessive cerebellar ataxias in three groupsa
(a) Most prevalent ataxias (b) Rare ataxias (c) Metabolic/Complex disorders
ATX-FXN PHARC Joubert syndrome
ATX-ATM SPAX5 CDG
ATX-APTX (AOA1) Cayman ataxia Wilson disease
ATX-SETX (AOA2) CAMRQ3 SPG26
ATX/HSP-SACS (ARSACS) SPG76 Biotidinase deficiency
POLG (MIRAS, SANDO) SCAN3 Aceruloplasminemia
ATX-SYNE1 (ARCA1) COX20 Unverricht–Lundbog disease
HSP/ATX-SPG7 SCAR17 Lafora disease
COQ8A (ARCA2) SPG5A Giant axonal neuropathy
ATX-ANO10 (ARCA3) SCAR18 Tay–Sachs disease
ATX-TTPA (AVED) SCAR13 Alpha mannosidosis
ATX-CYP27A1 (CTX) SeSAME syndrome Niemann-Pick type C
ATX-SIL1 (MSS) SPAX4 Behr syndrome
TWNK (IOSCA) SCAR2 Wolfram syndrome
AOA4
4H syndrome
ATX-RNF216
CAMRQ2
ARCA, autosomal recessive cerebellar ataxia; AOA, ataxia with oculomotor apraxia; ARSACS, autosomal recessive spastic ataxia of Charlevoix Saguenay; ATM,
ataxia-telangiectasia; AVED, ataxia with vitamin E deficiency; CAMRQ, cerebellar ataxia, mental retardation and dysequilibrium syndrome; CDG, congenital
disorder of glycosylation; CTX, cerebrotendinous xanthomatosis; FXN, Friedreich ataxia; IOSCA, infantile-onset spinocerebellar ataxia; MIRAS, mitochondrial
recessive ataxia syndrome; MSS, Marinesco–Sjögren syndrome; PHARC, polyneuropathy, hearing loss, ataxia, retinitis pigmentosa and cataracts; SANDO,
sensory ataxic neuropathy with dysarthria and ophthalmoparesis; SCAN, spinocerebellar ataxia with axonal neuropathy; SPAX5, autosomal recessive spastic
ataxia-5; SPG7, spastic paraplegia 7; SYNE1, spectrin repeat-containing nuclear envelope protein 1.
a
Data from [5
,30].
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primary recessive ataxias and 44 disorders which
are less common and reported only in some pop-
ulations. Disorders in which ataxia is a secondary
nonspecific observation are excluded. The classifi-
cation considers three groups of ARCAs (Table 3
and Fig. 4):
(1) Primary autosomal recessive ataxias: a group of
15 disorders.
(2) Rare ataxias or reported in only a few families.
(3) Metabolic or complex disorders with ataxia as
an associated feature.
Some ARCAs have a low incidence/prevalence
but are treatable. Therefore, they must be kept in
mind and need to be included in the procedure of
testing of gene panels.
The age of onset allows a first guess: infancy: AT,
ARSACS; childhood/teenage: FRDA, AOA1, AOA2,
POLG; and adulthood: SYNE-1 (ARCA1), ARCA3,
SPG7. There are exceptions. For instance, FRDA
may present after the age of 25 (late-onset Friedreich
ataxia) or 40 (very late onset Friedreich ataxia).
THERAPIES IN CEREBELLAR ATAXIA
Therapies are based on the following principles:
rehabilitation; immunotherapies for IMCAs; supple-
mentation of vitamins in ataxia with vitamin E
deficiency, coenzyme Q10 deficiency, abetalipopro-
teinemia; chelators in Wilson’s disease; 4-amino-
pyridines in episodic ataxias and cerebellar
dizziness due to downbeat [32,33]; and symptom-
atic therapies for extrapyramidal and pyramidal
FIGURE 4. Phenotypic presentation of the most frequent autosomal recessive cerebellar ataxias worldwide. Adapted with
permission [5
] under CC-BY.
An update on cerebellar ataxias Manto et al.
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10. CE: Swati; WCO/330112; Total nos of Pages: 11;
WCO 330112
symptoms. Therapies in development include treat-
ments targeting RNA [34].
CONCLUSION
The cerebellar deficits encountered during daily
practice are now gathered into three cornerstones
(CMS, VCS, CCAS) on the basis of the anatomy and
neuroimaging. Within two centuries, the clinical
neuroscience of the cerebellum has moved from
the initial mediolateral subdivision of clinical defi-
cits to an anatomo-functional categorization. CCAS
now has a dedicated scale, helping the clinician in
the fast detection of the cognitive symptoms in
cerebellar ataxias. Cerebellum and basal ganglia
communicate bidirectionally. These findings will
impact deeply on our appraisal of both cerebellar
disorders and basal ganglia disorders in the next
decades. The classification of the growing group
of ARCAs has been clarified.
Acknowledgements
None.
Financial support and sponsorship
None.
Conflicts of interest
M.M. is Chief Editor of The Cerebellum, Chief Editor of
Cerebellum and Ataxias, Deputy Editor of the Journal of
NeuroEngineeing and Rehabilitation, Editor of Contem-
porary Clinical Neurosciences. He has received royalties
from Cambridge University Press, Springer, Lavoisier
Medicine, Elsevier, Morgan and Claypool.
M.S. is Joint Chief Editor of the Journal of Neurology,
Editor in Chief of Frontiers of Neuro-otology and Section
Editor of F1000. He has received speaker’s honoraria
from Abbott, Actelion, Auris Medical, Biogen, Eisai,
Grsunenthal, GSK, Henning Pharma, Interacoustics,
Merck, MSD, Otometrics, Pierre-Fabre, TEVA, UCB.
He is a shareholder of IntraBio. He acts as a consultant
for Abbott, Actelion, AurisMedical, Heel, IntraBio and
Sensorion.
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