Cerebellar ataxias

Mario Manto and Daniele Marmolino

FNRS-Neurologie, Laboratoire de Neurologie
Experimentale, ULB, Bruxelles, Belgium
Correspondence to Dr Mario Manto, MD, Laboratoire
de Neurologie Experimentale, Fonds National de la
Recherche Scientifique ULB, 808 Route de Lennik,
1070 Bruxelles, Belgium
Tel: +32 2 555 39 92; fax: +32 2 555 39 92;
e-mail: mmanto@ulb.ac.be
Current Opinion in Neurology 2009, 22:419429
Purpose of review
The term cerebellar ataxias encompasses the various cerebellar disorders
encountered during daily practice. Patients exhibit a cerebellar syndrome and can also
present with pigmentary retinopathy, extrapyramidal movement disorders, pyramidal
signs, cortical symptoms (seizures, cognitive impairment/behavioural symptoms),
and peripheral neuropathy. The clinical diagnosis of subtypes of ataxias is complicated
by the salient overlap of the phenotypes between genetic subtypes. The identification
of the causative mutations of many hereditary ataxias and the development of
relevant animal models bring hope for effective therapies in neurodegenerative
ataxias.
Recent findings
We describe the current classification of cerebellar ataxias and underline the recent
discoveries in molecular pathogenesis. Cerebellar disorders can be divided into
sporadic forms and inherited diseases. Inherited ataxias include autosomal recessive
cerebellar ataxias, autosomal dominant cerebellar ataxias/spinocerebellar ataxia)
and episodic ataxias, and X-linked ataxias. From a motor control point of view, the
leading theories of ataxia are based on neural representations or internal models to
emulate fundamental natural processes such as body motion.
Summary
Recent molecular advances have direct implications for research and daily practice. We
provide a framework for the diagnosis of ataxias. For the first time, the therapeutic
agents under investigation are targeted to deleterious pathways.

Keywords
ataxias, cerebellum, dominant, dysmetria, recessive, X-linked

Curr Opin Neurol 22:419429

2009 Wolters Kluwer Health | Lippincott Williams & Wilkins
1350-7540

Introduction Sporadic and acquired ataxias

The terminology cerebellar ataxias comprises a wide The main sporadic and acquired nonhereditary ataxias
spectrum of neurological disorders with ataxia as the are given in the list below.
main symptom. Ataxia results from the involvement of
cerebellar structures themselves, or from a combination (1) Degenerative ataxias
of cerebellar and extra-cerebellar lesions, especially due (a) multiple system atrophy (MSA);
to brainstem involvement. We review the classification (b) idiopathic late-onset cerebellar ataxia (ILOCA);
and the recent advances in molecular pathogenesis of (2) acquired ataxias
cerebellar ataxias. (a) stroke (infarction, haemorrhage);
(b) toxic induced
(i) ethanol;
Cerebellar disorders in daily practice (ii) drugs (antiepileptic agents, lithium salts,
Making a correct diagnosis of ataxia may be a challenge, antineoplastics, cyclosporine, metronida-
given the overlap in phenotypes and the various modes of zole);
presentations of cerebellar ataxias. The advent of brain (iii) heavy metals;
MRI has revolutionized the morphological characteriz- (iv) solvents;
ation of cerebellar disorders, but the final diagnosis is (c) immune-mediated;
often based on combinations of biochemical and genetic (d) infectious/parainfectious diseases (abscess,
assessments. A diagnostic algorithm is proposed in Fig. 1. cerebellitis);
1350-7540 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI:10.1097/WCO.0b013e32832b9897

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 420 Movement disorders

Figure 1 Diagnostic algorithm of cerebellar ataxias (see text for details)

Cerebellar ataxia

Family history?
Yes No

Dominant X-linked
Recessive .Structural?
.Stroke?
Episodic? .FRDA? .Toxic?
.Mitoch. disease
.ALD .Immune?
.FXTAS .Infectious/parainfectious?
Yes No No .Traumatic?
.Neoplastic?
.Endocrine?
EA SCA Serum studies
.Blood smear No
.Vitamin E
Pure cerebellar Cerebellar .Cholesterol
syndrome ataxia-plus .Cholestanol Criteria of MSA?
.Phytanic acid
.Alpha-fetoprotein
SCA5,6,11,26 See Table 3 No Yes
.Immunological studies

Onset
+ Normal
< 50 years > 50 years
.AVED .EOCARR
.Abetalipoproteinemia .ARSACS
.CTX .MIRAS ILOCA
.Refsum disease .ATLD/ATM
.AOA1/AOA2
.SCAN1
.LOTSD

ALD, adrenoleukodystrophy; AOA, ataxia with oculomotor apraxia (type 12); ARSACS, autosomal recessive ataxia of Charlevoix-Saguenay; ATLD,
ataxia telangiectasia-like disorder; ATM, ataxia telangiectasia mutated gene; AVED, ataxia with vitamin E deficiency; CTX, cerebrotendinous
xanthomatosis; dominant, autosomal dominant; EA, episodic ataxia; EOCARR, early onset cerebellar ataxia with retained reflexes; FRDA, Friedreich
ataxia; FXTAS, fragile X-associated tremor/ataxia syndrome; ILOCA, idiopathic late-onset cerebellar ataxia; LOTSD, late-onset Tay-Sachs disease;
MIRAS, mitochondrial recessive ataxia syndrome; Mitoch., mitochondrial; MSA, multiple system atrophy; recessive, autosomal recessive; SCA,
spinocerebellar ataxia (type 130); SCAN1, spinocerebellar ataxia with axonal neuropathy; X-linked, chromosome X-linked.

(e) traumatic; Alcoholic cerebellar degeneration is the most common

(f) neoplastic disorder (cerebellar tumor, metastatic form of acquired toxic ataxia. The ataxia is typically more
disease); severe in lower limbs.
(g) endocrine (hypothyroidism);
(h) structural disease (Chiari malformations, agen- Immune-mediated cerebellar ataxias are summarized
esis, hypoplasias, dysplasias). below.

(1) Multiple sclerosis;

MSA is the most common nonhereditary degenera- (2) cerebellar ataxia with anti-glutamic acid decarboxylase
tive ataxia. The disease usually starts around 55 years. (GAD) antibodies;
The latest criteria retain the diagnostic categories (3) gluten ataxia;
of MSA with predominant parkinsonism and MSA (4) MillerFisher syndrome;
with predominant cerebellar ataxia to designate the (5) systemic lupus erythematosus;
predominant presentations of the disease [1]. (6) Sjogren syndrome;
(7) Cogan syndrome;
The diagnosis of ILOCA is considered when the patient (8) thyroiditis;
exhibits a sporadic progressive degeneration of the (9) paraneoplastic cerebellar syndrome.
cerebellum for which the underlying cause remains
not elucidated. Age of onset is usually between 40 and Gluten ataxia is triggered by the ingestion of gluten in
55 years. genetically susceptible individuals [2]. Gluten ataxia is

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 Cerebellar disorders Manto and Marmolino 421

defined as a sporadic cerebellar ataxia associated with the Table 1 Antibodies in paraneoplastic cerebellar degeneration
presence of circulating antigliadin antibodies in the ab- Antibody type Clinical picture Underlying cancer
sence of an alternative cause for ataxia [2]. Ataxia can
Anti-Yo Breast, gynaecological
occur in absence of the small bowel lesions characteristic Anti-Hu Encephalomyelitis SCLC, sarcoma,
of celiac disease (gluten sensitive enteropathy). Gluten Limbic encephalitis neuroblastoma
ataxia is characterized by an insidious onset of gait ataxia. Sensory neuronopathy
Autonomic dysfunction
Half of the patients have neurophysiological evidence of Anti-Ri Opsoclonusmyoclonus Neuroblastoma, breast,
a sensorimotor axonal neuropathy. The human leukocyte Brainstem encephalitis gynaecological
antigen system (HLA) class II type DQ2 (found in 90% Anti-Tr Hodgkins lymphoma
Anti-CV2 Polyneuropathy Thymoma, SCLC,
of patients with celiac disease) is overrepresented in (CMRP) tumours of testis
individuals with circulating antigliadin antibodies and Anti-Ma Limbic encephalitis Breast
normal small bowel biopsy. Brainstem encephalitis
Opsoclonusmyoclonus
Anti-PCA2 Limbic encephalitis SCLC
Paraneoplastic cerebellar degeneration (PCD) usually LambertEaton syndrome
presents as a subacute cerebellar syndrome. The most Autonomic and motor
neuropathy
commonly associated cancers are small-cell lung cancer
(SCLC), breast or ovarian cancer and lymphoma. Several SCLC, small-cell lung cancer.
antibodies have been identified in serum and cerebrosp-
inal fluid (CSF) (Table 1). Ataxia may precede the
detection of the underlying tumour. Brain imaging shows
a slowly progressive cerebellar atrophy.
both central and peripheral nervous system and in some
case other systems and organs (Table 2). Onset is usually
Autosomal recessive cerebellar ataxias before the age of 20 years [3]. ARCAs are divided into four
Autosomal recessive cerebellar ataxias (ARCAs) are a main groups: degenerative ataxias, congenital ataxias,
heterogeneous group of neurological disorders involving metabolic ataxias and ataxias with DNA repair defects.

Table 2 Autosomal recessive cerebellar ataxias

Type Protein Gene locus

Degenerative ataxias
Friedreich ataxia Frataxin 9q13
Coenzyme Q10 deficiency with cerebellar ataxia
Charlevoix-Saguenay spastic ataxia Sacsin 13q12
Early onset cerebellar ataxia with retained tendon reflexes (EOCARR) 13q11-12
Mitochondrial recessive ataxic syndrome (MIRAS) Polymerase g
MarinescoSjogren syndrome SILI 5q32
Congenital ataxias
Joubert syndrome (JBTS)
JBTS1 9q34
JBTS2 AHII 11p12-p13.3
JBTS3 6q23
JBTS4 2q13
JBTS5 Nephrocystin-6 12q21.32
Cayman ataxia Cayataxin 19p13.3
Metabolic ataxias
Ataxia with isolated vitamin E deficiency (AVED) Alpha-tocopherol transfer protein (a-TTP) 8q13
Refsums disease Phytanoyl-CoA hydroxylase 10pter-p11.2
Peroxisomal biogenesis factor-7 6q22-q24
Cerebrotendinous xanthomatosis (CTX) Sterol 27-hydroxylase 2q33-qter
Abetalipoproteinaemia Microsomal triglyceride transfer protein 4q22-q24
Metachromatic leucodystrophy Arylsulfatase 1 22q13
NiemannPick type C NPC1 protein 18q11-121
GM1 gangliosidosis Beta-galactosidase 3p21.33
GM2-gangliosidosis (Tay-Sachs disease) Hexosaminidase 1 15q23-24
Chorea-acanthocytosis Chorein 9q21
Wilsons disease ATPase Cu transporting beta-polypeptide 13q14-21
Aceruloplasminaemia Ceruloplasmin 3q23q24
Ataxias with DNA repair defects
Ataxia telangiectasia ATM 11q22.3
Ataxia with oculomotor apraxia 1 (AOA1) Aprataxin 9p13
Ataxia with oculomotor apraxia 2 (AOA2) Senataxin 9q34
Ataxia-telangiectasia-like disorder (ATLD) MREIIA 11q21
Spinocerebellar ataxia with axonal neuropathy (SCAN1) Tyrosyl-DNA phosphodiesterase 1 14q31

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 422 Movement disorders
Friedreich ataxia is the most common form of degenerative
recessive ataxia, with a prevalence varying between 2 to
4.5/100.000. Patients exhibit progressive deficits including
gait ataxia, limb ataxia, dysarthria, tendon areflexia, pro-
prioceptive loss and Babinski sign. Extra-neurological
deficits include cardiomyopathy and diabetes. Friedreich
ataxia is caused by an intronic GAA repeat expansion within
the frataxin gene, resulting in reduced frataxin levels
in several tissues. The reduction in frataxin is inversely
related to the size of the GAA repeat alleles. Long unin-
terrupted GAA tracts adopt triple helical structures, inhi-
biting transcription [4,5]. A small number of patients are
compound heterozygous for an expanded allele and a point
mutation within the coding sequence of the gene.
Coenzyme Q10 (CoQ) deficiency presents with various
phenotypes, in particular, an ataxic form, a myopathic
form, a severe infantile neurological syndrome associated
with nephritic syndrome, and Leigh syndrome [6]. The
ataxic form is characterized by a cerebellar syndrome with
onset in infancy or during adulthood. There is a partial to
profound CoQ deficiency in muscle and fibroblasts [6,7].
Ataxia with deficiency in vitamin E (AVED; serum vitamin
E values < 2.5 mg/l) is characterized by a progressive
sensory and cerebellar ataxia. The 744delA frameshift
mutation is the most common and is distributed as a result
of a founder effect. In AVED, clinical signs are similar to
those in Friedreich ataxia. However, cardiomyopathy and
glucose intolerance are much less frequent.
Abetalipoproteinaemia (ABL) is caused by mutations in
the gene of the large subunit of microsomal triglyceride
transfer protein, which allows the assembly of apolipopro-
tein-B containing very low-density lipoproteins (VLDLs)
and chylomicrons. Patients present with a malabsorption
syndrome, pigmentary degeneration of the retina and
progressive ataxic neuropathy. Red cells show a peculiar
deformation called acanthocytosis. The neurological
symptoms are related to the deficiency of vitamin E.
Ataxia telangiectasia is the most common recessive ataxia
in children under 5 years of age. Ataxia telangiectasia is
characterized by ataxia and oculocutaneous telangiec-
tases appearing between the age of 2 and 8 years. Ataxia
telangiectasia is associated with immunodeficiency lead-
ing to recurrent infections, endocrine and skin abnorm-
alities, radiation sensitivity, and a predisposition for
malignancies [8,9]. Ataxia telangiectasia is due to
mutations in the ataxia telangiectasia mutated gene
(ATM) involved in DNA repair.
Ataxias with oculomotor apraxia (AOAs) were probably
underdiagnosed in the past. Onset of AOAs is mostly in
childhood and early teens. The AOAs include AOA1
(ataxia with oculomotor apraxia type 1, ocular motor
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apraxia, and hypoalbuminaemia), which is most frequent
in Portugal and Japan, and AOA2 (ataxia with ocular
apraxia type 2, ataxia with ocular apraxia, and increased
alpha-fetoprotein levels) [10]. AOA1 and AOA2 are
associated with the aprataxin gene and the senataxin
gene, respectively.
Late-onset Tay-Sachs disease (LOTSD) is a GM2-gang-
liosidosis caused by a deficiency of b-hexosaminidase due
to a mutation in the HEXA gene [11]. The late-onset
phenotype is characterized by cerebellar dysfunction,
tendon areflexia, proximal muscle weakness, fascicula-
tions, and psychiatric/behavioural deficits. The late-onset
form can present as a Friedreich ataxia phenotype.
Cerebellar atrophy is marked on brain MRI.
Cerebrotendinous xanthomatosis (CTX) is caused by
mutation of CYP27 gene encoding for the mitochondrial
enzyme sterol 27-hydroxylase, resulting in increased
levels of serum cholestanol and bile alcohols [12,13].
Refsums disease presents with cerebellar ataxia, periph-
eral neuropathy, sensorineural deafness, retinitis pigmen-
tosa, anosmia, as well as skeletal abnormalities, ichthyosis,
renal failure, and cardiac myopathy/arrhythmias. Refsums
disease is caused by mutation of the gene for the perox-
isomal enzyme phytanoyl-CoA hydroxylase, PHYH [14].
SCA with axonal neuropathy (SCAN1) is a childhood-
onset disorder due to a mutation within the gene TDP1
encoding for the tyrosyl-DNA phosphodiesterase 1. Oxi-
dative stress and transcription deficits cause single-strand
breaks in the nervous system DNA [15,16].
Autosomal recessive spastic ataxia of Charlevoix-Saguenay
(ARSACS) was first identified in northeast Canada.
Recently, the disorder has been described in Europe,
Eurasia, North Africa, and Japan [17,18]. The disease
usually starts in the first decade. The geneimplicated in this
disorder (SACS) codes for the chaperone protein sacsin.
The infantile-onset spinocerebellar ataxia (IOSCA) is a
severe ataxic syndrome starting in the first 2 years of life.
The gene C10orf2 encodes for the protein twinkle, a
mitochondrial helicase involved in DNA replication [19].
Cayman ataxia is a childhood-onset disorder. The gene
mutated is called ATCAY and encodes for the protein
caytaxin, which interacts with a kidney-type glutaminase.
Mutations could affect glutamate synthesis at the synapse
level, causing abnormal neuron growth or neurotoxicity
[20].
MarinescoSjogren syndrome (MSS) is an infantile-onset
or childhood-onset syndrome due to a mutation of the
gene SIL1 encoding for a nucleotide exchange factor for
 Cerebellar disorders Manto and Marmolino 423

heat-shock protein 70 family member HSPA5. This Several identified mutations correspond to expansions of
factor works as a molecular chaperone during nascent repeated trinucleotides (CAG repeats in SCA1, SCA2,
protein folding and transport [21,22]. SCA3, SCA6, SCA7, SCA17, and DRPLA, CTG repeats
in SCA8). A pentanucleotide repeat expansion (ATTCT)
is associated with SCA10. In SCA1, SCA2, SCA3, SCA6,
Autosomal dominant ataxias SCA7, and SCA17, the triplet repeat codes for a poly-
This group includes the spinocerebellar ataxias (SCAs) glutamine tract in the respective proteins. DRPLA falls
and the hereditary episodic ataxias. also in this group of polyglutaminopathies. In SCA8,
SCA10, and SCA12, repeat expansions are found in the
Spinocerebellar ataxias noncoding regions of the genes. Point mutations are
The prevalence of SCAs is estimated to be 14 per responsible for SCA5, SCA13, SCA14, and 16q22-linked
100 000. However, values can be much higher in some autosomal dominant cerebellar ataxia (ADCA).
regions of the world due to a founder effect [23]. Symp-
toms of SCA1, SCA2, SCA3, SCA7, SCA8, SCA12, SCA1, 2, and 7 are prototypes of a degeneration pattern
SCA13, SCA17, and SCA25 may start in the first decade, previously designated as olivopontocerebellar atrophy
whereas ataxia can start after 65 years in SCA6. A child- with degeneration of the cerebellar cortex, pontine
hood onset with severe phenotype resulting from marked nuclei, and inferior olives [24].
anticipation is observed in SCA2, SCA7, and SCA17.
The following clinical features have some specific values MRI is widely used to visualize atrophic processes occur-
for predicting a gene defect (see Table 3): slowing ring in SCAs [25]. The recommendation is now to inves-
of saccades in SCA2, ophthalmoplegia in SCA1, SCA2, tigate through the application of three-dimensional (3D)
and SCA3, pigmentary retinopathy in SCA7, spasticity volumetric methods and voxel-based morphometry
in SCA3, dyskinesias associated with a mutation in (VBM) [26].
the fibroblast growth factor 14 (FGF14) gene, cognitive
impairment/behavioural symptoms in SCA17 and denta- Episodic ataxias
torubral-pallidoluysian atrophy (DRPLA), seizures in Hereditary episodic ataxia represents a group of mono-
SCA10, SCA17, and DRPLA, peripheral neuropathy in genic disorders characterized by recurrent episodes of
SCA1, SCA2, SCA3, SCA4, SCA8, SCA18, and SCA25. vertigo and ataxia, variably associated with progressive
ataxia [27]. The number of phenotypes and genotypes is
Table 3 Clinical presentations of spinocerebellar ataxias expanding (Table 4). Nearly all episodic ataxia mutations
Pure cerebellar syndrome SCA5, SCA6, SCA11, SCA26 identified so far occur in individuals with onset early in
Cerebellar ataxia plus: life [27,28].
Cognitive impairment/ SCA1, SCA2, SCA3, SCA10,
behavioural symptoms SCA12, SCA13, SCA14,
SCA17, SCA19, SCA21, EA2 is the most common episodic ataxia. EA2 is allelic
SCA-FGF14, DRPLA with familial hemiplegic migraine type 1 (FHM1) and
Seizures SCA10, SCA17, DRPLA spinocerebellar ataxia type 6 (SCA6). Attacks are typically
Eyes/oculomotor deficits
Slow saccades SCA1, SCA2, SCA3, SCA7, SCA28 brief (seconds to minutes) in EA1 and more prolonged in
Down-beat nystagmus SCA6 EA2 or in EA7 (hours to days) [29,30].
Ophthalmoparesia SCA1, SCA2, SCA3, SCA28,
SCA30
Ocular dyskinesia SCA10
Pigmentary retinopathy SCA7 X-linked cerebellar ataxias
Movement disorders Fragile-X tremor ataxia syndrome (FXTAS) is represen-
Parkinsonism SCA1, SCA2, SCA3, SCA12,
SCA17, SCA21 tative of this group. The disorder starts usually after
Dystonia SCA3, SCA14, SCA17 50 years. Patients exhibit combinations of kinetic tremor,
Tremor SCA8, SCA12, SCA16, SCA19, ataxia of gait, parkinsonism, autonomic dysfunction,
SCA20
Dyskinesias SCA-FGF14 polyneuropathy, and cognitive deficits [31,32]. The age
Myoclonus SCA2, SCA14, SCA19, DRPLA of onset of tremor or ataxia inversely correlates with the
Chorea SCA1, SCA17, DRPLA repeat size (CGG triplet). Brain MRI in FXTAS shows, in
Myokymia SCA5
Pyramidal signs SCA1, SCA2, SCA3, SCA4, particular, hyperintense lesions in the middle cerebellar
SCA7, SCA8, SCA10, SCA11, peduncles on T2-weighted sequence.
SCA12, SCA13, SCA14, SCA15,
SCA28, SCA30
Peripheral neuropathy SCA1, SCA2, SCA3, SCA4, SCA6,
SCA8, SCA-FGF14, SCA12, Mitochondrial disorders
SCA18, SCA22, SCA25 Mitochondrial disorders refer to a group of diseases
DRPLA, dentatorubral-pallidoluysian atrophy; FGF14, fibroblast growth associated with abnormalities of the mitochondrial
factor 14. energy metabolism, mainly the oxidative phosphorylation

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 424 Movement disorders

Table 4 Main episodic ataxias

Episodic ataxia Phenotype Onset Triggering Mutation/locus

EA1 Interictal myokymia Early childhood Physical exertion KCNA1 (12q13)

Emotional stress
Startle
EA2 Interictal nystagmus Childhood or adolescence Exertion CACNA1A (19p13)
Rarely in adulthood Stress
Alcohol
EA3 Episodic vertigo, tinnitus, and ataxia Linked to 1q42
No baseline deficit
EA4 Episodic vertigo Late-onset
Interictal nystagmus
No response to acetazolamide
EA6 Attacks of hemiplegia and migraine
EA7 Seizures Before the age of 20 Exertion 19q13
Attacks of vertigo, weakness, and slurring Excitement

(OXPHOS) [33]. The respiratory chain depends on two associated with a progressive external ophthalmoplegia
genetic systems: the nuclear and the mitochondrial and the severe hepatocerebral disturbances seen in
genomes. Mitochondrial DNA mutations can mimick Alpers syndrome. Furthermore, these mutations can
autosomal dominant, recessive or X-linked transmis- produce autosomal recessive ataxic syndromes [35].
sion due to heteroplasmy and threshold effects [34].
In addition, insertions and deletions may appear as
sporadic forms. The main diseases classically associated Molecular mechanisms of cerebellar ataxias:
with cerebellar deficits are given in Table 5. an overview
Our understanding of the defects in pathways critical for
survival of neurons of the cerebellum has increased
DNA polymerase g disorders including dramatically these past 10 years. The main molecular
mitochondrial recessive ataxia syndrome mechanisms of cerebellar ataxias are summarized in
Several neurodegenerative disorders are associated with a Fig. 2. Neurons of the cerebellum are particularly
mutation of the POLG gene, encoding for the mitochon- vulnerable, and neuronal death may result from various
drial DNA polymerase g catalytic subunit. This group is combinations of deficits at the DNA/RNA level such as
DNA repair or transcriptional dysregulation, accumu-
Table 5 Mitochondrial diseases associated with cerebellar lation of toxic proteins or reduced clearance of abnormal
deficits proteins, oxidative stress and N-methyl-D-aspartate
Disorder Extra-cerebellar signs Other signs (NMDA)-mediated excitotoxicity, caspase activation,
and apoptosis. In case of expanded polyglutamine, the
KearnsSayre Progressive ophthalmoplegia Poor growth
syndrome Pigmentary neuropathy Heart block
mutant protein is associated with misfolding and aberrant
Muscle weakness conformations leading to insoluble aggregates in the
MELAS Stroke-like episodes nuclei, which lead to neuronal dysfunction and eventually
Lactic acidosis
Dementia cell death. Intranuclear insoluble inclusions contain
Recurrent headache chaperones and components of the ubiquitinproteasome
Seizures system, such as ubiquitin and proteasome subunits, indi-
Deafness
Muscle weakness cating that the misfolded protein might trigger a stress
MEERF Myoclonus response to reduce the amount of mutant protein.
Epilepsy
Muscle weakness/wasting
Deafness Therapies of cerebellar ataxias
Dementia
NARP Sensorimotor neuropathy Therapies of cerebellar ataxias are summarized below.
Pigmentary neuropathy
MayWhite Myoclonus Specific therapies for nonhereditary ataxias
syndrome Deafness Intoxications and endocrine disorders may respond to
MNGIE Ophthalmoparesia Gastrointestinal specific therapies. Ataxia associated with thyroiditis
Peripheral neuropathy symptoms
Leigh syndrome Psychomotor delay Recurrent vomiting responds to steroids if detected at an early stage.
Pyramidal signs
Dystonia There is no curative treatment for MSA.
Respiratory deficits
MEERF, myoclonus epilepsy with ragged-red fibres; MELAS, mitochon- Supplements of vitamin B1 are recommended for alco-
drial encephalopathy, lactic acidosis and stroke-like episodes; MNGIE,
mitochondrial neurogastrointestinal encephalomyopathy; NARP, neuro- holic cerebellar degeneration. Abstinence is mandatory to
pathy, ataxia and retinitis pigmentosa. avoid further deterioration.

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 Cerebellar disorders Manto and Marmolino 425

Figure 2 Molecular pathogenesis of cerebellar ataxias

The pathways/sites affected by the various mutations causing ataxias are illustrated. Not all the processes occur in the same cell types. The precise
mechanism remains unknown in some cases (?). Processes occurring within or in association with a specific subcellular structure are depicted near the
respective organelle. 1, transcription; 2, processing; 3, transport; 4, DNA repair; 5, replication; 6, glycosphingolipid metabolism; 7, unfolded protein
response (PR); 8, autophagy; 9, autolysosome; 10, Ca2 activated voltage-gated K channel; 11, translation; 12, protein folding; 13, lipoprotein
assembly; 14, fatty acid metabolism; 15, protein import; 16, non-NMDA receptor; 17, NMDA receptor; 18, voltage-gated Ca2 channels; 19, DNA
repair/replication; 20, mitochondrial impairment; 21, Krebs cycle; 22, chaperones; 23, axonal transport and vesicle trafficking; 24, aggregation; 25,
Ca2 homeostasis; 26, synaptic function; ABL, abetalipoproteinaemia; ACO, aconitase; AoA (type 12), ataxia with oculomotor apraxia (type 12);
ARSACS, autosomal recessive ataxia of Charlevoix-Saguenay; AT, ataxia telangiectasia; AVED, ataxia with vitamin E deficiency; CA, Cayman ataxia;
Ca2, calcium ions; CI, respiratory chain complex I; CII, respiratory chain complex II; CIII, respiratory chain complex III; CIV, respiratory chain complex IV;
cQ, coenzyme Q; cQ10, coenzyme Q10; CTX, cerebrotendinous xanthomatosis; Cu, copper; cytC, cytochrome C; DRPLA, dentatorubral-
pallidoluysian atrophy; EA (type 16), episodic ataxia (type 16); ER, endoplasmic reticulum; FA, Friedreich ataxia; Fe2, ferrous iron; FGF14,
fibroblast growth factor 14; FeS, ironsulfur cluster; FXTAS, fragile X-associated tremor/ataxia syndrome; Glu, glutamate; HEME, the prosthetic
group of hemoglobin, myoglobin, and the cytochromes; IscU, ironsulfur cluster scaffold protein; IOSCA, infantile-onset spinocerebellar ataxia; K,
potassium ions; LOTSD, late-onset Tay-Sachs disease; Na, sodium ions; MELAS, mitochondrial encephalopathy, lactic acidosis and stroke-like
episodes; MEERF, myoclonus epilepsy with ragged-red fibres; MIRAS, mitochondrial recessive ataxia syndrome; MSS, MarinescoSjogren syndrome;
NARP, neuropathy, ataxia and retinitis pigmentosa; OH, hydroxyl radical; Q, glutamine; RD, Refsums disease; RNA, ribonucleic acid; ROS, reactive
oxygen species; SCA (117), spinocerebellar ataxia (type-117); SCAN1, spinocerebellar ataxia with axonal neuropathy; Ub, ubiquitin.

The benefits of a gluten-free diet in the treatment
of patients with celiac disease are well established.
However, there are very few studies on of the effect
of gluten-free diet on the neurological manifestations of
gluten sensitivity. The most reliable marker of adher-
ence to a gluten-free diet is serological evidence of
elimination of circulating antigliadin antibodies [2].
Patients with gluten ataxia in absence of enteropathy
may improve with intravenous immunoglobulins. Treat-
ment with immunosuppressants should be considered
if strict gluten-free diet has not resulted in improvement
of ataxia after a year or if the ataxia is rapidly progressive
[2].
It is still unclear whether i.v. (intravenous) immunoglo-
bulin and plasmapheresis improve patients outcomes in
MillerFisher syndrome [36].
When a PCD is suspected, careful search of an underlying
cancer is mandatory. Tumour treatment may stabilize the
cerebellar deficits.
Autosomal recessive cerebellar ataxias
Pilot studies with vitamin E, coenzyme Q10, or idebe-
none have shown the potential effects of antioxidant
therapies for Friedreich ataxia. Idebenone plays a
protective effect against cardiomyopathy [37], but the
general neurological function remains unmodified in
adults. If iron chelators such as desferrioxamine are to
be used, they must be able to enter in the mitochondria in
order to reduce the mitochondrial iron overload. Beta-
blockers at high doses could provide benefits in patients
with heart disease. The use of recombinant human
erythropoietin (EPO) in the treatment of Friedreich

Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
 426 Movement disorders

ataxia is based on the increased frataxin protein expres-
sion in response to EPO [38].
Patients with primary CoQ deficiency may benefit
from CoQ supplementation (3003000 mg/day). CoQ
deficiency is probably the mitochondrial encephalomyo-
pathy with the best clinical response to supplementation
[6].
Ataxia with vitamin E deficiency (AVED) is improved by
vitamin E supplementation. Administration to adults of
800 mg a-tocopherol twice daily increases plasma levels
of a-tocopherol and improves the clinical status.
Treatment of Refsums disease is based on dietary
restriction of phytanic acid. Treatment of CTX includes
oral administration of chenodeoxycholic acid and statins
such as pravastatin to inhibit hydroxy-methylglutaryl
(HMG)-CoA reductase.
Spinocerebellar ataxias
Limitations of the previous trials are related to their small
size, the generally short time periods to assess treatment,
the advanced disease in some studies and the selection of
therapeutic agents that are not targeted to one of the
deleterious pathways [39]. Some benefits regarding ataxic
symptoms have been reported with 5-hydroxytrypto-
phan, buspirone or tandospirone, sulfamethoxazole/tri-
methoprim or lamotrigine in SCA3, acetazolamide in
SCA6, NMDA modulators or antagonists, and deep brain
stimulation in SCA2 with tremor. Amantadine/levodopa/
dopamine agonists may improve extra-cerebellar symp-
toms in SCA2/SCA3. Baclofen/tinazidine improves spas-
ticity. Dystonia can be treated with botulinum toxin.
Restless legs and periodic leg movements in sleep usually
respond to dopaminergic treatment. Muscle cramps may
be disabling, especially in SCA3, and may respond to
magnesium, quinine, or mexiletine. Urinary urgency is
improved with spasmolytics or adrenergic a-receptor
blockers. Acetazolamide remains the mainstay of
treatment for episodic ataxia. Doses vary from 125 up
to 500 mg twice daily as needed or as tolerated [27]. An
alternative is the use of 4-aminopyridine 15 mg/day.
X-linked ataxias
High doses of coenzyme Q10 as well as other antioxidants
such as N-acetylcysteine are used in maternally inherited
mitochondrial diseases, but the efficacy is often not
established.
General recommendations in ataxias
Speech rehabilitation and regular physiotherapy/occu-
pational therapy are recommended. Most patients will
have some improvements with the use of orthosis, sticks,
or strollers. Many patients will become wheelchair bound
during the course of their illness. Gastrostomy is usually
recommended when swallowing difficulties worsen.
Therapies under investigation
New drugs are currently tested in transgenic models.
New strategies are summarized in Table 6. Therapeutic
strategies successful for Huntingtons disease are being
considered for SCAs, including RNAi therapies with
the goal of inhibiting polyglutamine-induced neuro-
degeneration. Transplantation of stem cells is another
approach. Prevention of protein misfolding and aggrega-
tion by overexpressing chaperones, such as heat-shock
protein HSP70 or DNAJ1, and application of histone
deacetylase inhibitors (HDACi), capable of reversing
heterochromatin formation, are being assessed.
Advances in our appraisal of the nonmotor
functions of the cerebellum
During the past 3 decades, there has been increasing
debate about the possible nonmotor roles of the cerebellar
circuitry. Clinical descriptions of ataxias report cogni-
tive deficits to variable extents and are confirmed by

Table 6 Strategies under investigation in progressive ataxias

Strategies Experimental results

Reducing the oxidative stress
Acting on the excitotoxic cascade
Silencing gene expression via RNAi
Enhancing the clearance of the mutant protein
Targeting the toxicity of the protein via
modulation of phosphorylation
Acting on chaperones
Inhibition of transglutaminases
Acting on transcriptional regulation
Inhibition of caspase activation
Transplantation
DRPLA, dentatorubral-pallidoluysian atrophy; NMDA, N-methyl-D-aspartate.
Increased aggregation and cell death under oxidative stress in human mutant
ataxin-1-expressing cells
NMDA receptor antagonists improve survival in mouse models of Huntingtons disease
Improvements in mouse models of SCA1
Rescue in cell, fly, and mouse models of Huntington disease
Favourable effect on ataxia in SCA1 mice
Overexpression of HSP70 decreases the toxicity of ataxin 1 in cells, flies, and mice
Transglutaminase inhibitors decrease toxicity in cell models of DRPLA and mouse
models of Huntington disease
Mutant polyglutamine-expanded ataxin 7 inhibits the histone acetyltransferase function
Improved neuropathology and motor phenotypes in fly and mouse models of
Huntingtons disease treated with histone deacetylase inhibitors
Favourable effects of caspase inhibitors in mouse models of Huntingtons disease
Graft survival and behavioural improvements in SCA-1 transgenic mice

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neuropsychological studies. Deficits in ataxic patients fall
in the following domains: executive control, attention,
memory and learning, visuo-spatial abilities, and language.
The confrontation with imaging investigations and neu-
ropathological studies, the comparison of the symptoms
found in the various ataxias as well as data obtained in
animals suggest that these deficits result from disruption of
cerebro-cerebellar networks and the communication
between cerebellar modules and brain cortical areas.
Pathogenesis of cerebellar dysmetria
The cerebellum plays fundamental roles in action control
and motor learning [40,41]. Current theories of ataxia
take into account the division of cerebellum in micro-
circuits and the connectivity of the different cerebellar
regions with the motor/prefrontal cerebral cortex, the
thalamus, the brainstem, and the spinal cord. The leading
theories are summarized in Table 7.
The intrinsic time delay of sensory feedback associated
with motor commands is a central issue in motor control.
Sensory-motor delays vary according to the modality and
context and may be in the order of 50400 ms. Such delays
imply that in-flight updating of motor commands using
sensory feedback can never be optimal. The cerebellum
has therefore been proposed to contain neural representa-
tions or internal models to emulate fundamental natural
processes such as body motion. This theory is supported by
fMRI studies, transcranial magnetic stimulation (TMS)
experiments, and psychophysical studies. The motor cor-
tex can perform an accurate movement using an internal
feedback instead of the external feedback from the real
control object [42]. The internal feedback is closely linked
to the internal model of the object, built in the cerebellum
Table 7 Main theories of cerebellar functions
Theory Assumptions
Adaptative filter Based upon MarrAlbus theory. Transformation
hypothesis of sets of signals into other sets.
Components are weighted individually and
then recombined to minimize the errors in
performance because of noise
Internal models The cerebellum contains neural representations
to emulate movement. Internal models
reproduce the dynamic properties of body
segments
Forward model The model predicts the upcoming state given
the current state and the motor command
Inverse model The model inverts the system by providing the
motor command that will cause the desired
change in state
Tonic reinforcer The cerebellum tunes the intensities of
agonist/antagonist/synergist muscles.
Cerebellum generates a facilitatory drive
upon extra-cerebellar targets, especially
brainstem and thalamic nuclei
Cerebellar timer Cerebellum is the main site of temporal
representation of action
Sensory processor The cerebellum monitors and adjusts the
acquisition of sensory information
Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Cerebellar disorders Manto and Marmolino 427
in close cooperation with the cerebral cortex (Fig. 3a).
Accurate predictions would decrease the dependence on
time-delayed sensory signals. Cerebellar circuitry would
be necessary to learn making appropriate predictions using
error information about the discrepancies between the
actual and predicted sensory consequences, not only for
limb movements but also for postural adjustments. Some
of the most convincing evidence that the central nervous
system (CNS) uses internal forward models in human
motor behaviour comes from studies dedicated to the
control of grasping forces during manipulation of objects.
The rate of grip force development and the balance
between the grip and load forces when grasping/lifting
an object are programmed in order to meet the require-
ments due to physical object properties, such as weight,
surface friction, or shape. Cerebellar patients generate
excessive grip forces in relation to loads, suggesting a
distorted predictive force control in cerebellar disorders.
Clumsiness in cerebellar patients and dysmetria are due to
abnormal predictivefeedforwardcontrol andto a disorderin
the accurate appraisal of the consequences of motor com-
mands.
According to the theory of inverse models, the input to the
cerebellum would be the aimed trajectory, and the output
would be a motor command. In order to train this type of
model, error information would best be characterized in
motor coordinates in three directions. The fact that
cerebellar patients exhibit difficulties in adapting to exter-
nal force field is in agreement with the inverse dynamics
hypothesis [43,44]. The majority of Purkinje cells do not
exhibit any modulation in the patterns of discharges as a
function of force type or load. In addition, the spatial
tuning pattern seems unaffected, strengthening the idea
of uncoupling between Purkinje cell firing and electro-
myographic (EMG) activity in limbs. One of the differ-
ences between cerebellar simple spike responses and
those of motor cortical cells is the nonuniform distribution
of preferred directions and the extensive overlap in the
timing of the correlations. These differences suggest that
Purkinje cells handle kinematic information in a different
way as compared with motor cortical neurons.
Figure 3b summarizes the mechanisms of cerebellar dys-
metria. Both the abnormal excitability of the motor cortex
and the abnormal feedforward control result in an inability
to update programming based on sensory events. Errors in
predictions generate errors in superimposition of motor
activities, errors in timing and rhythmicity, and abnormal
modulation of the magnitude of muscle discharges in
responses to inertial and damping changes at the joint level.
Conclusion
Our understanding of the molecular pathogenesis
of several ataxic disorders has improved dramatically in
 428 Movement disorders

Figure 3 An internal model of the real control object, built in the cerebellum in close cooperation with the cerebral cortex

(a) Primary motor cortex

Thal. Motor
command

Copy

Cerebellar nuclei
Cerebellar cortex Error signal Inferior
olive
Predicted
(corollary discharge)

Reafference
Spinal cord

Muscles/joints

Sensory signals
Movement

(b) Cerebellar disorder

Impaired excitability Abnormal feedforward

of the motor cortex control

Errors in motor
predictions

Inability to update
programming based Inability to superimpose Errors in timing Deficit in adaptation Abnormal compensation
upon sensory events motor activities Errors in rythmicity to inertia of damping

Abnormal tuning of magnitudes

of muscle responses

Cerebellar dysmetria

(a) Communication flows for information processing in forward models of motor coding. Cerebellar circuitry receives an efference copy of motor
commands via the corticopontocerebellar tract. This allows the cerebellum to make appropriate predictions. Reafference signals and corollary
discharges reach the inferior olive. This latter works as a comparator, generating an error signal to update the plastic cerebellar microcircuits. Expected
sensory outcomes are conveyed to the primary motor cortex via excitatory connections and to the inferior olive via inhibitory pathways. (b) Mechanisms
of cerebellar dysmetria.

the last years. New strategies of treatment are being

References and recommended reading
investigated. The novelty is that therapeutic agents are Papers of particular interest, published within the annual period of review, have
now targeted to the deleterious pathways. been highlighted as:
 of special interest
 of outstanding interest
Additional references related to this topic can also be found in the Current
World Literature section in this issue (pp. 446448).
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