This document summarizes recent advances in the diagnosis and genetic causes of cerebellar ataxia. It discusses how neuroimaging can identify patterns of cerebellar atrophy associated with different forms of ataxia. Genetic testing for autosomal dominant spinocerebellar ataxias and autosomal recessive cerebellar ataxias is important to establish a diagnosis. The mechanisms of various genetic mutations that cause spinocerebellar ataxia are described, including polyglutamine expansions and intronic repeat expansions.

1. Recent Advances in the
Cerebellar Ataxia
Dr. Bhawesh Kumar

5. NEUROIMAGING FOR CEREBELLAR
ATAXIA
Cerebellar cortical atrophy is the most common finding,
(degree of the cerebellar atrophy in different cerebellar
lobules and in vermis, paravermis, and hemisphere).
Prominent CSF space between cerebellar folia and
enlarged fourth ventricle is often associated with
cerebellar atrophy.
The cerebellum is divided into motor (predominantly
anterior) and nonmotor (predominantly posterior) regions
(Stoodley and Schmahmann, 2010).

6. Patients with prominent atrophy in the posterior lobules
of the cerebellum associated with cognitive dysfunction
and emotional liability.
Speech and gait ataxia is associated with vermal
atrophy, whereas appendicular ataxia is associated with
paravermal atrophy.
Certain forms of ataxia have predominant sensory
neuropathy in the early stage (e.g., Friedreich ataxia,
ataxia with vitamin E deficiency and POLG-ataxia);
therefore, no obvious cerebellar atrophy on the brain MRI.

7. Specific changes associated with certain forms of cerebellar ataxia.
1.Fragile X–associated tremor and ataxia syndrome has T2-
hyperintensity in the bilateral middle cerebellar peduncles.
2.Wernicke encephalopathy has T2 hyperintensity in the mamillary
bodies, periaqueductal gray, and paraventricular thalamus.
3.Adult-onset Alexander disease can have prominent subcortical
white matter changes.
4.POLG-ataxia, adult-onset Alexander disease, and ataxia with
gluten sensitivity can have T2 hyperintensity in the bilateral inferior
olivary nucleus.

8. 5.Multiple system atrophy can have either a hot-cross-bun sign (a T2
hyperintense cross sign in the pons, associated with the cerebellar
type, or linear T2 hyperintensity along the outer rim of the striatum
(associated with the parkinsonism type ).
6.Superficial siderosis has hypointensity along the surface of the
cerebellum and brainstem in the gradient echo sequence (GRE).
7.CJD has cortical ribboning and double hockey stick sign on the
diffusion-weighted imaging (DWI)
8.ARSACS- Atrophy of the vermis accompanies T2-hypointense
stripes in the central pons, diffuse T2-hyperintensity in the lateral
pons, and thickened middle cerebellar peduncles on brain MRI of
greater than 90% of ARSACS patients

10. OTHER DIAGNOSTIC TESTS FOR
ATAXIA
Autonomic nervous tests,orthostatic hypotension and/or
urinary disturbance together with a sleep study to
demonstrate RBD suggest the diagnosis of MSA.
 EMG and NCS can assess the associated motor-sensory
neuropathy.
Diagnosis of POLG-ataxia can be supported by muscle
biopsy, demonstrating increased succinate dehydrogenase
(SDH) expression as the result of mitochondrial proliferation.
In patients with CJD, an EEG may show typical periodic
sharp-wave complexes, and brain biopsy may demonstrate
spongiform changes.

13. GENETIC CAUSES FOR
ATAXIA
 Screening for repeat expansions, then sequencing.
Family history is frequently lacking in autosomal
recessive cerebellar ataxias (ARCAs).
The absence of family history may be attributable to
early death of the affected parent or separation from
them.

14. ARCAs are usually, but not always, early onset.
 The prevalence of ARCA may have been underestimated in
late- onset ataxic disorders and commonly overlooked.
 A recent study showed that an autosomal recessive
mutation with intronic pentanucleotide repeat expansions
causing cerebellar ataxia, neuropathy, vestibular areflexia
syndrome (CANVAS) and related disorders may account for
up to 20% of unexplained ataxias (Cortese et al., 2019).

15. If family history is negative, genetic testing of common ataxias should
be done.
 Common SCAs, and for ARCA, Friedreich ataxia and several other
common recessive ataxias should be tested.
 Expanded repeats are not readily detectable by whole exome
sequencing (WES) or whole genome sequencing (WGS).So,a panel of
repeat expansion mutations should be done first.
If these diagnoses are excluded, then WES is considered.
If the WES result includes only variations of unknown significance
(VUS), pedigree analysis needed in determining the pathogenicity.

16. Similar genetic testing approaches should be
considered for apparently sporadic disorders if secondary
causes (especially those that are treatable) of ataxia are
excluded.
The remaining sporadic ataxias may be classified into
two major types by clinical manifestations:
(1) Idiopathic late-onset cerebellar ataxia (ILOCA), and
(2) multiple system atrophy—cerebellar type (MSA-C;
Ashizawa et al., 2018;)

17. Autosomal Dominant Cerebellar
Ataxias
Spinocerebellar ataxias (SCAs) are a group of
autosomal dominant disorders presented with ataxia
variably accompanied by extracerebellar manifestations.
 Most SCAs are progressive adult-onset
neurodegenerative disorders affecting the cerebellum and
its afferent and efferent pathways.
In the genetic nomenclature, SCAs are numbered in the
order of discovery of the genetic locus, and the number
has recently reached 48.

18. Genotype-Phenotype Correlation

19. Cerebellar cognitive affective syndrome (CCAS or
Schmahmann syndrome) (Schmahmann, 2004), which
consists of underrecognized cognitive impairments may
be present in patients with SCAs.
The onset of most SCAs is typically with balance loss
and gait ataxia, although oculomotor abnormalities may
be present early on examination.

20. Anticipation
Progressively earlier onset of the disease in successive
generations with increasing severity within a family,
known as genetic anticipation, is a hallmark of most
polyQ SCAs.
Anticipation is attributed to
a) intergenerational increase of the number of CAGs.
b) juvenile-onset disease and
c) de novo cases of polyQ SCAs.
The small size of CAG repeat expansion in SCA6 and
CAA interruptions within the expanded CAG repeat of
SCA17 make the mutant expanded allele stable, leading
to the lack of anticipation in these SCAs.

21. Anticipation has also been reported in SCA5, SCA10,
and SCA31.
The instability of repeat size would explain anticipation
in SCA10 and SCA31

22. Regional and Ethnic Distributions
of Spinocerebellar Ataxia
The collective prevalence of all known types of SCAs
has been estimated as 1.0–5.6 in 100,000.
SCAs 1, 2, 3, 6, 7, and 8 are most common in the
United States and Europe, while geographic predilection
of specific SCAs and distinctive founder effects exist in
various parts of the world.
High prevalence has been found for SCA1 in Poland;
SCA2 in Cuba, Mexico, and Italy; SCA6 in UK, Germany,
and Japan; SCA7 in South Africa, Mexico, and
Venezuela; SCA10 in Latin America;
SCA2 and12 in India ;SCA 12 in Italy;
while SCA3 is the most common SCA worldwide.

23. World wide distribution

24. Autosomal dominant CAs (ADCAs) are classified into two
groups on the basis of their genetic mutations,
1.ADCAs caused by microsatellite repeat expansions and
2. ADCAs caused by point mutations.
The former is furthermore categorized into two types,
ADCAs induced by
a) polyglutamine-coding CAG repeat expansions and
b) those induced by non-protein-coding repeats.

26. Genetic Mutations in
Spinocerebellar Ataxia
SCA 1, 2, 3, 6, 7, 17 and DRPLA - CAG repeat
expansion encoding a polyQ peptide in respective genes.
SCA8 -expanded CTG repeat in the 3′ untranslated
region (3′UTR) of the ATXN8OS gene, while the same
repeat on the opposite strand encodes polyQ in the
ATXN8 gene.
SCA10, SCA31, and SCA37 are caused by a large
expanded intronic pentanucleotide repeat.
SCA36 is the only SCA caused by an hexanucleotide
repeat expansion.

27. Pathogenic mechanism
PolyQ SCAs - toxic gain of function by the mutant protein
products.
SCAs caused by intronic repeat expansions are thought to be
caused by toxic untranslated RNAs that contain large repeats.
Remaining SCAs are missense mutations,either toxic gain of
function of the mutant protein or dominant negative effect.
There are a handful of SCAs caused by deletions (SCA15/16
and SCA14), translocation (SCA27), and duplications (SCA20),
of which SCA15/16 and SCA27 show loss of function of the gene
(haploinsufficiency).

28. These mechanisms have important implications in the
ongoing and future development of disease-modifying
molecular therapy.
Repeat expansion and missense mutations are
generally good targets of RNA silencing therapy,
while haploinsufficiency would be addressed by gene
replacement therapy or transcription enhancers to
increase the lacking protein.

31. Mechanisms underlying SCA

32. Polyglutamine SCA

33. Genetic diagnosis of SCA

34. Autosomal Recessive
Cerebellar Ataxias
ARCAs comprise a group of disorders with cerebellar
and spinal cord degeneration typically presenting in
childhood, adolescence, or early adulthood.
Often accompanied by other neurological and systemic
manifestations.
ARCAs often affect siblings, but parents are usually
asymptomatic heterozygous carriers.
With the increasing availability of WES, the number of
ARCAs now exceeds 90, and an equivalent number of
additional autosomal recessive disorders show ataxia as
a part of the phenotypic spectrum.

35. In adults, a recent report described a new late-onset
ARCA ,CANVAS caused by a biallelic intronic AAGGG
repeat expansion in the replication factor C subunit 1
(RFC1) gene.

36. Autosomal Recessive Cerebellar Ataxias Caused by
Expansion of Intronic Repeats - Friedreich ataxia and
CANVAS.
Autosomal Recessive Cerebellar Ataxias Caused by Conventional
(Non-Repeat Expansion) Mutations- Synofzik and colleagues recently
classified mutated genes in ARCAs in groups
1.involved in mitochondrial functions,
2.DNA repair, and
3.complex lipid metabolism,
to delineate pathogenic pathways that may be targeted by future
therapeutics.

37. Autosomal Recessive Cerebellar Ataxias with Abnormal
Mitochondrial Function
a. Autosomal Recessive Spastic Ataxia of Charlevoix–
Saguenay (ARSACS)
b. Spastic Paraplegia Type 7
c. POLG Ataxia- MIRAS and SANDO
ARCAs with impaired DNA repair
a. Ataxia Telangiectasia
b. Ataxia with oculomotor apraxia type 1 (AOA1), AOA2,
and AOA4.

38. Autosomal recessive cerebellar ataxias with complex
lipid metabolism abnormalities.
a. Niemann-Pick C
b. Cerebrotendinous Xanthomatosis
c. Ataxia with Vitamin E Deficiency
 Autosomal recessive cerebellar ataxias with
cytoskeleton protein. SYNE1 ataxia accounts for
about 5% of recessive ataxias.

41. Cerebellar ataxia neuropathy vestibular
areflexia syndrome (CANVAS) and related
late-onset ataxias
Cortese and colleagues (2019) identified homozygous
intronic AAGGG repeat expansion in RFC1 gene at
chromosome 4p14 as a common cause of late-onset
ataxia (the mean age at onset 54 ± 9 years).
 Some patients showed typical CANVAS syndrome
while others often lacked either sensory neuropathy or
vestibulopathy; some patients lacked both and were
presented as ILOCA (i.e., isolated cerebellar ataxia).
Sensory ataxia and vestibulopathy appear to result from
large-fiber neuropathy and ganglionopathy.

42. Chronic cough and autonomic dysfunctions may be
seen in 25%–35% of patients. Cognitive and motor
functions are generally spared.
Bilateral vestibular areflexia may be detected as
diminished vestibulo-ocular reflex gain on the head
impulse test, abnormal dynamic visual acuity, and
abnormal occlusive fundoscopy.
NCS-sensory neuropathy, and brain MRI shows
cerebellar atrophy in most cases.

43. Idiopathic Late-Onset Cerebellar
Ataxia(ILOCA)
ILOCA was first used by Harding for all nonhereditary
progressive cerebellar ataxias with no identifiable
secondary causes (Harding, 1981).
 MSA-C was included at the time and later separated
from ILOCA.
 Unlike MSA-C, which has a distinct pathology feature of glial
cytoplasmic inclusion (Gilman et al., 2008; Quinn, 1989), ILOCA does
not have a signature pathology finding.
Patients with ILOCA have cerebellar ataxia as the core
clinical feature,Scanning speech,Cerebellar Ocular
findings.

44. Pyramidal tract involvement.
Bladder dysfunction may be seen in about 30% of ILOCA
patients, making it more difficult to distinguish ILOCA and
MSC-C.
 Imaging- isolated cerebellar atrophy or possibly
concomitant brainstem or spinal cord atrophy.
Despite extensive efforts to distinguish ILOCA from MSA-C, about 30%
of patients who were initially diagnosed as ILOCA eventually develop into
MSA-C, demonstrating the difficulty of making the diagnosis.

45. Recent advance in treatment
Ataxias of secondary causes require treatment of the
underlying disorders.
However, for symptomatic treatments of genetic or
degenerative ataxias, few pharmacological agents have
shown benefits.
Many medications targeting polyQ have been tested in
animal models with a wide range of mechanisms,
including histone deacetylation inhibitor, adenosine
receptor antagonist, autophagy inducer, serotonin
reuptake inhibitor, and modulators of chaperone
functions. (Ashizawa et al., 2018; Buijsen et al., 2019).

46. Treatment options
1.Pharmacotherapy
2.Molecular therapy-ASO/RNAi
3. Neuromodulation Therapies: Therapies Enhancing the
Cerebellar Reserve
a. Motor Rehabilitation, Cognitive Rehabilitation
b.Non-Invasive Cerebellar Stimulation-
transcranialmagnetic stimulation (TMS) and transcranial
direct current stimulation (tDCS).

47. However, most agents have no proven benefit clinically.
The 2018 American Academy of Neurology guideline
reviewed the literature extensively and deemed that only
4- aminopyridine, riluzole, valproic acid, and thyrotropin-
releasing hormone may improve symptoms of ataxia in
selected population of patients.

48. 4-Aminopyridine
Acts through blocking potassium channel prolong the
duration of the action potential and increase the action
potential hyperpolarization.
Therefore restoring the pacemaking precision of
purkinje cells in episodic ataxia type 2.The median
monthly attack frequency was significantly reduced.

49. Valproic acid
Histone acetyltransferases (HATs) is one of affected
regulatory proteins in polyQ SCA.
Valproic acid, a histone deacetylases inhibitor,
assumed to restore acetylation/deacetylation balance,
rescued polyQ-mediated toxicity in SCA type 3 model
cells and mouse.
A recent clinical trial showed valproic acid improved
stance in patients with SCA 3 at 12 weeks.

50. Thyrotropin releasing hormone
A clinical trial conducted before cerebellar ataxia was
routinely genetically diagnosed showed that thyrotropin
releasing hormone possibly improves speech,gait and
standing in patient with cerebellar ataxiain 10-14 days.

51. Riluzole and its precursor
It had been shown to improve ataxia symptoms for
several SCA at 8 weeks and 12 months.this rationale is
supported by normalisation of firing pattern of purkinje
cells in brain slice in SCA 3 mice.
 Riluzole acts through modulating SK channel activites
to correct burst firing of purkinje cells.
Trigriluzole/Troriluzole has better CNS penetrance.

52.  Lithium carbonate - 62 ambulatory pts with SCA3/MJD
for 48 weeks, but no difference was seen in mean
scores of the neurological scale for ataxia.
 Varenicline was anecdotally- beneficial effects in
patients with ataxia subsequently tested in patients with
SCA3/MJD, but its use was associated with a 40%
dropout rate owing to side effects.

53. Therapies targeting DNA and RNA—
Antisense oligonucleotides (ASOs):
Antisense oligonucleotides (ASOs) have an RNA-like
structure. In gain-of-function disorders, the main purpose
is to decrease the mutated mRNA expression by use of
single-stranded ASOs, by blocking translation or by a
direct silencing effect.
In a mouse model of SCA2 the administration of
intrathecal ASOs decreased the levels of the mutated
protein,improving the firing of Purkinje neurons as well as
motor tasks. Comparable findings have been described in
the SCA3 mouse model.

54. RNA interference
RNA interference is a physiological mechanism, that
permits to eukaryotic cells to control gene expression; this
process involves small RNA(RNAs)which have a length
lesser than 30 bases.
Often the concerning RNAs is a double-strained small
RNA (dsRNA). dsRNA less than 21–22 bases pairs (bp),
which are recognized by enzymatic cascade of RNAi, are
known as small interfering RNA (siRNA). The chemical
bond between a siRNA and a mRNA can inactivate the
expression of the mRNA target.

55. RNA interference (RNAi):
The goal of RNA interference (RNAi) in
polyglutaminopathies is to inhibit the synthesis of
defective polyglutamine-proteins resulting from mutated
genes.
 Polyglutaminopathies – pharmacotherapy as well as
ASO/RNAi
ADCAs Induced by Toxic RNAs- ASO/RNAi
 ADCAs Caused by Point Mutations- ASO/RNAi

59. Neuromodulation Therapies: Therapies
Enhancing the Cerebellar Reserve
Motor Rehabilitation- Ample evidence suggests that
conventional motor rehabilitation is effective in patients
with limited lesions (e.g.,cerebral infarction ,hemorrhage,
or trauma).
However,this is uncertain in patients with degenerative
Cas of progressive nature.
Two recent large-scale and case-control designed
studies demonstrated the therapeutic benefits of motor
rehabilitation.

60. Cognitive Rehabilitation
In 1998, Schmahmann and Sherman described the
cerebellar cognitive affective syndrome (CCAS or
Schmahmann syndrome).
Ch/ by executive dysfunctions, impaired visuo-spatial
cognition, personality changes, and language deficits.
Overall, patients exhibit a dysmetria of thought and
impaired affect. There are no systemic studies on
cognitive rehabilitation.
Appropriate rehabilitation protocols and their outcomes
remain unclear.

61. Non-Invasive Cerebellar
Stimulation
Transcranialmagnetic stimulation (TMS) and
transcranial direct current stimulation (tDCS)) improves
motor deficits in CAs.
Studies showed that non-invasive cerebellar stimulation improves
the clinical scores of SARA ,gait ataxia measured using 8–10 m
walking test, limb ataxia, tremor, blood flow in the cerebellar
hemisphere, and electroencephalogram in ataxic patients.
Show durable effect after administration of several
sessions (4–12 weeks after the last session).
Improvement moderate,so,Need for the development of
more efficient protocols.

62. THANK YOU