4. SPINOCEREBELLAR
ATAXIA
Autosomal dominantly inherited diseases.
>40 genetically distinct subtypes of SCA.
Each subtype is named SCA followed by a
number; the numbers
Represent the chronological order in which the
disease locus or causative gene of the subtype
was identified.
Involvement of the spinal cord and the
cerebellum in these diseases. However, the
spinal cord is unaffected in many SCAs, and
pathological changes occur in other regions of
the nervous system, including peripheral nerves
and the brainstem and basal ganglia.
11. Genetics
SCA12 - repeat is located in the 5′ untranslated
region of the gene - doesn’t encode polyglutamine
affect the expression - PPP2R2B, a brain- specific
regulatory subunit of protein phosphatase 2A.
The CTG repeat expansion- SCA8 is transcribed in
both directions, and transcription of the antisense
strand of DNA results in a CAG repeat
SCA10, SCA31, SCA36 and SCA37 — are caused by
repeat expansions in introns
Intronic mutation causing SCA10- 4,500 ATTCT
repeats, whereas the
Polyglutamine SCAs typically - 100 CAG repeats.
12. Neuropathology
Cerebellar Purkinje neurons is characteristic of SCA1,
SCA2 and SCA6 and Purkinje neuron degeneration
has also been described in some cases of
nonpolyglutamine SCAs at autopsy.
The loss of Purkinje neurons is typically accompanied
by retrograde degeneration of inferior olive neurons.
In SCA1 and SCA2, but not SCA6, there is also
degeneration of pontine nuclei in the brainstem.
By contrast, in SCA3/MJD, neuronal loss occurs less in
the cerebellar cortex and more in the dentate nucleus
and basal ganglia. However, loss of dopaminergic
neurons of the substantia nigra is an overlapping
feature of SCA2 and SCA3/MJD
13. Epidemiology
Prevalence of SCAs - of 2.7cases/100,000
Polyglutamine SCAs (SCA1, SCA2,
SCA3/MJD, SCA6, SCA7, SCA17 and
DRPLA) are the most commonly recognized
genetic forms of SCAs
SCA3/MJD is the most common SCA
worldwide
(20–50% of families with SCA)
SCA2 (13–18%)
SCA6 (13–15%)
In India most common genotype was SCA2
15. Pathophysiology
The pathology of SCAs ranges - pure cerebellar
involvement - SCA6 broader degeneration involving other
parts of the brain, the spinal cord and peripheral Nerves -
with SCA1, SCA2 or SCA3/MJD.
Clinical features can vary greatly even within a family -
dynamic repeat expansions
Longer repeats - disease with greater severity and an earlier
onset than shorter repeats
Disease symptoms often worsen from generation to
generation in a
Family - clinical anticipation.
Clinical anticipation - most common - SCA1, SCA2 and
SCA7
Paternal transmission: SCA7 & DRPLA
18. Polyglutamine mechanism
the aggregation of polyglutamine disease proteins in neuronal
processes - disrupt crucial cargo trafficking and trap other
proteins, potentially compromising various cellular processes
and cellular homeostasis.
Apart from SCA6, all of these proteins normally reside in the
cytoplasm or nucleus as soluble proteins.
The SCA6 disease protein is a cell surface transmembrane
protein that constitutes the pore- forming subunit of a
voltagedependent
P/Q- type calcium channel.
Because of to the cellular location of SCA6, at only 20–33
rpts cause disease
By contrast SCA1, SCA2 and SCA3/MJD are caused
by polyglutamine repeats of 38–85, 36–100 and 60–87
repeats, respectively.
19. the polyglutamine protein loses this flexibility,
with deleterious consequences for neurons
SCA1, SCA7, SCA17 and DRPLA, the disease
protein becomes heavily concentrated within
neuronal nuclei in susceptible brain regions,
including the cerebellum and brainstem.
20. RNA toxicity
At least four SCAs (SCA10, SCA31, SCA36
and SCA37) - introns
Repeat- containing transcripts accumulate in
RNA foci within neurons .
These foci sequester key RNA- binding
proteins and, as a result, splicing or other
RNA- dependent processes are perturbed.
21.
22. Channel dysfunction
SCAs caused - ion channels or regulatory
pathways
Slowly progressive
Relatively pure cerebellar involvement or they
can be associated with myoclonus, episodic
symptoms.
23. Age of onset
Most SCA - third or fourth decade of life but there is
Variation between genotypes, within genotypes and
even within families.
Age of onset - conventional mutations is earlier than
that of polyglutamine SCAs.
Childhood onset- conventional mutations(SCA5,
SCA12, SCA13, SCA21, SCA25, SCA29 and SCA47)
SCA6 and SCA31 - later adulthood
Because of large variation age , this information not
helpful in selecting appropriate genetic test
inversely correlates with the length of the expanded
repeat
24. Clinical features
The prominent clinical feature - progressive
ataxia. The ataxia in patients with
First abnormality: unsteadiness of gait,
progresses,
Incoordination of the extremities deteriorates,
resulting in difficulties with writing and the loss
of fine motor skills.
Almost all patients with an SCA also
experience speech and swallowing problems.
25. Non- ataxia symptoms – prominent in - SCA1, SCA2,
SCA3/MJD, SCA7, SCA17 and DRPLA
SCA6 - purely ataxic phenotype
In exceptional cases, non- ataxia symptoms may occur
before ataxia
For example, in SCA7 patients with expansions >59
repeats, visual loss is often the initial symptom.
Interrupted repeats with a length of <39 repeats in the
SCA2 gene are associated with parkinsonism rather
than ataxia.
26. SCA17 - initially with psychiatric symptoms and chorea
DRPLA - progressive myoclonus epilepsy,
choreoathetosis and dementia
SCA2 - increased risk ALS and are associated with
shorter survival times in ALS patients.
Cognitive decline resulting in manifest dementia is rare
in SCAs but may occur mainly in SCA17 and DRPLA
Depression affects 17–26% of SCA patients
27. O/E : Oculomotor abnormalities
broken- up smooth pursuit ,gaze- evoked nystagmus, dysmetric
saccades
Non- ataxia symptoms
Motor symptoms (namely, weakness, spasticity and amyotrophy),
Movement disorders (such as parkinsonism, dystonia and
chorea)
sensory symptoms, epilepsy, myoclonus, cognitive and intellectual
dysfunction and urinary symptoms.
Visual loss due to retinal degeneration is a characteristic feature
of
SCA7
Restless leg syndrome, rapid eye movement sleep behaviour
disorder,
excessive daytime sleep, insomnia
28.
29. SCA1
Progressive ataxia, speech and swallowing difficulties,
spasticity, and ophthalmoplegia
cognitive impairment (frontal executive dysfunction,
impaired verbal memory)
Saccadic velocity slows as the disease progresses, and
an
upgaze palsy may develop.
In advanced stages, muscle atrophy, hyporeflexia, loss
of proprioception, and bulbar dysfunction become
evident
Occult or clinically significant maculopathy has been
reported Bulbar symptoms, rigidity, tremor, and
30. Age at onset - third or fourth decade (childhood - late
adulthood depending on CAG repeat length)
Penetrance is age dependent.
Juvenile onset - severe, rapidly progressive brainstem
dysfunction in addition to cerebellar symptoms, leading
to death within 4–8 years.
Onset over age 60 years - pure cerebellar phenotype
Lifespan after onset varies from 10 to 30 years.
SCA1 - faster progression than SCA2 and SCA3
31. Brain magnetic resonance imaging (MRI) shows
pontocerebellar atrophy .
Cord atrophy occurs also
SCA1 is caused by a CAG repeat expansion in ATXN1
gene
Normal CAG segments are 4–39 repeats (abnormal
range: 40–80 repeats).
CAG repeat encodes a glutamine tract in ataxin-
1,Cytoplasmic and nuclear protein - transcription
regulation and RNA processing.
Correlation between the number of CAG repeats -
severity of disease
3,4-diaminopyridine is beneficial in mouse model of
SCA1
32. SCA2
Progressive ataxia, dysarthria, dysphagia, nystagmus
and slow hypometric saccades, hyporeflexia, and
sensory polyneuropathy
The symptoms, signs, and AO of SCA2 are similar, but
more heterogeneous than SCA1.
Individuals may exhibit leg cramps, dystonia, chorea,
and cognitive impairment
Symptoms may appear from childhood to late
adulthood.
In adult-onset SCA2 confinement to a wheelchair may
occur 10–20 years after onset, and death may occur 10–
30 years after onset.
33. Children with infantile-onset SCA2 have infantile
spasms, severe hypotonia, pigmentary retinopathy,
dysphagia, and failure to thrive, and usually die before 2
years of age.
Cuba has the highest prevalence of SCA2
PET studies show significantly reduced glucose
metabolism in the cerebellum, pons, parahippocampal
gyrus, and frontal cortex
Cerebellar fluorodeoxyglucose metabolism is severely
compromised in SCA2, compared to other SCAs
Magnetic resonance spectroscopy helps distinguish
SCA2 from other SCAs
34. SCA2 is caused by a CAG expansion in the ATXN2
Alleles with 33 or more pure CAG repeats or repeats
interrupted by a CAA repeat are pathogenic.
The size of the CAG repeat - larger - dystonia,
myoclonus, and myokymia.
Both CAG repeat length and duration of disease
influence muscle atrophy, fasciculations, decreased
tendon reflexes, and vibration sense in the lower
extremities and slow saccades.
35. SCA3 (Machado–Joseph
disease )
Slowly progressive cerebellar ataxia, with dysarthria,
dysphagia,
Brainstem signs (temporal and facial atrophy,
characteristic action-induced perioral twitches, tongue
atrophy and fasciculations, poor ability to cough and
clear secretions, extraocular movement disorders),
parkinsonism, Sensory/ motor neuropathies, vocal cord
paralysis, vestibular dysfunction, autonomic symptoms
,disabling sleep disturbances, rapid eye movement
sleep behavior disorder.
36. SCA3
Restless legs syndrome,chronic pain , impaired
executive and emotional function, and verbal fluency
and visual memory deficits.
The mean AO is 36 years
need for assistive devices 10–15 years after onset.
The mean survival after onset - 21 years
Classified SCA3 into several types
Type 1 (dystonic-rigid form),
Type 2 (ataxia with pyramidal signs)
Type 3 (peripheral amyotrophy).
37. SCA3
SCA3 is the most common SCA
Brain MRI shows pontocerebellar atrophy with
enlargement of the fourth ventricle
CAG repeat in the ATXN3 gene leading to an elongated
tract of glutamine residues within a nucleocytoplasmic
protein, ataxin-3.
The normal length is 13–44 with affected lengths
greater than 50
Paternal anticipation occurs
38. SCA-6
late-onset ADCA - by progressive ataxia, dysarthria,
dysphagia, and diplopia (50%).
Eye movement abnormalities, including gaze-evoked
and downbeat nystagmus, impaired smooth pursuit and
abnormal vestibulo-ocular reflex, are common.
Cognitive function is preserved .
AO ranges from 19 to 71 years (mean: 43–52 years)
Penetrance is 100% and symptoms may not appear
until the seventh decade.
Anticipation has been observed. Lifespan is not
shortened.
Disease severity seems to increase during pregnancy.
39. Brain MRI - demonstrates isolated cerebellar atrophy
with no brainstem involvement
Expansion in a CAG repeat in the CACNA1A gene
encoding the voltage-gated calcium channel subunit
a1A, which is involved in pre- and postsynaptic Ca2+
signaling and gene expression.
The CAG repeats range from (CAG)4 to (CAG)18 in
normal alleles. SCA6-associated alleles carry CAG
repeats ranging from (CAG)19 to (CAG)33.
EA2, SCA6, and familial hemiplegic migraine are not
only allelic disorders, but may be the same disorder with
great phenotypic variability.
40. SCA7
Cerebellar ataxia and a pigmentary macular
degeneration resulting in abnormalities in color vision
and central visual acuity.
In adults, visual symptoms may precede the cerebellar
symptoms.
Associated ophthalmoplegia (supranuclear in nature,
never ptosis), pyramidal or extrapyramidal signs, deep
sensory loss, and dementia are variable.
Ataxia progresses to wheelchair confinement in 5–10
years.
In the infantile-onset form there is rapidly progressive
cerebellar and brainstemdegeneration and visual loss
may be difficult to ascertain before death.
41. SCA7 - expansion of a CAG trinucleotide repeat within
the ATXN7 gene, which encodes a polyglutamine tract
within a protein, called ataxin-7.
Normal alleles - CAG repeat 4 to 27,
Abnormal alleles -37 to 200 repeats.
Gonadal instability in SCA7 was greater than that
observed in any of the known neurodegenerative
disorders caused by translated CAG repeat expansions.
42. SCA12
Prominent action tremor of the arms or head, minimal
gait ataxia and/or limb dysmetria, generalized
hyperreflexia, bradykinesia, pyramidal signs,cognitive
impairment, and sensory or sensorimotor neuropathy
(50%).
AO ranges from 8 to 62 years.
Action tremor is most prominent in the limbs, but can
occur in the trunk, neck, lips, and tongue .
Postural tremor and intention tremor are observed.
Disease progression is slow and does not impact on
longevity .
43. Brain MRI - shows cerebral and/or cerebellar atrophy
with relative sparing of the basal ganglia, thalamus, and
brainstem nuclei.
Second most common form of SCA in India.
A (CAG) repeat expansion located 133 nucleotides
upstream of the reported transcription start site of the
protein phosphatase 2 regulatory subunit beta gene
(PPP2R2B) is the cause of the disease.
PPP2R2B is a brain-specific regulatory subunit of the
protein phosphatase PP2A, an enzyme implicated in
awide array of cellular processes, including apoptosis.
44. SCA17
Extremely variable phenotype, including ataxia (95%),
dementia (90%), involuntary movements (70%, chorea
and dystonia, blepharospasm, torticollis, writer’s cramp,
foot dystonia), psychiatric symptoms, pyramidal signs,
parkinsonism, and multiple system atrophy-like
symptoms .
The AO ranges from 3 to 75 years.
SCA17 is also known as Huntington disease-like
disorder 4.
45. Brain MRI - shows variable atrophy of the cerebrum,
brainstem, and cerebellum.
MRI voxel-based morphometry studies revealed gray-
matter atrophy in the cerebellum and basal ganglia, as
well as in the frontal and temporal lobes.
Personality changes correlate with atrophy in the frontal
cortex and limbic areas.
The expansion of an imperfect CAG/CAA repeat in exon
3 of TBP gene, encoding the TATA box-binding protein,
is pathogenic in SCA17.
46. The correlation between the size of the CAG/CAA repeat
and the AO in SCA17 is not as strong as in other
disorders caused by expansion of a polyglutamine tract.
Anticipation is infrequently documented but larger
expansions were observed with paternal transmission
and age.
Selective neuronal degeneration suggests no significant
loss of protein function and transcriptional
downregulation of TRKA by mutant TBP may contribute
to SCA17 pathogenesis.
47. DENTATORUBRAL-PALLIDOLUYSIAN
ATROPHY
DRPLA is an autosomal-dominant triplet CAG repeat
ataxia.
Adult-onset presentations typically present with
cerebellar ataxia, chorea, athetosis, and dementia and
often DRPLA is a differential diagnosis of adult
choreiform disease.
Mild expansions of theCAGrepeat (below 55 repeats)
tend to present with mild ataxia and a later presentation
of
dementia, so both early- and late-onset cases can be
very
difficult to diagnose
53. Differential diagnosis –
Acquired, nongenetic causes of ataxia,
Alcoholism,
Vitamin deficiencies,
Multiple sclerosis,
Vascular disease,
Primary or metastatic tumors, or
Paraneoplastic diseases(occult carcinoma
of the ovary, breast, or lung
54. Sporadic ataxia
A diagnosis of SCA must also be considered-
sporadic
ataxia and without a family history of SCA;
Due to novel mutations, reduced penetrance of
the mutation , death of parent(Eg SCA 6),
anticipation or misattributed paternity.
A careful diagnostic work- up, including MRI and
laboratory tests, is essential to assess for non-
genetic causes of ataxia. If this workup is
negative, molecular genetic testing of patients for
SCAs is justified.
55. Disease progression
All SCAs are progressive disorders - disability
and premature death.
However, there is an enormous degree of
variability in progression rate both between
and within the different SCAs.
EUROSCA study : SCA1 has the fastest
progression rate, SCA2 and SCA3/MJD have
an intermediate progression rate and SCA6
has the slowest progression rate.
57. Disease progression
SCA1 - longer CAG repeat expansions - faster disease
progression
Whereas CAG repeat length was not found to influence
disease progression in other SCAs
SCAs caused by mutations other than CAG repeat
mutations tend to have slower progression and to take
a more benign course.
58. Pharmacological treatments for
SCAs
For treatment of ataxia : Riluzole, valproic
acid, varenicline and lithium carbonate were
tested but no definite evidence of benefit was
established.
59. In 55 patients with different types of genetic ataxias
(SCAs and Friedreich ataxia), riluzole decreased
SARA scores by 1.02 points in patients, compared
with a mean increase in SARA score of 1.66 in the
placebo group.
Change of 1.0 point in SARA score - clinically
relevant
larger studies in patients presenting more
homogenous genetic forms of ataxia are needed
to define the effectiveness of riluzole in clinical
practice.
SARA greatly influenced by the genetic subtype,
60. Valproic acid has been proposed as a pharmacological
treatment
in SCA3/MJD for its neuroprotective properties as a pan-
histone
deacetylaseinhibitor.
Assessed in 12 patients with SCA3/MJD that were randomly
assigned to receive high- dose valproic acid, low- dose
valproic
acid or placebo for 12 weeks.
The mean change in total SARA significantly greater in the
patients receiving a high dose (a 2.05 decrease in SARA
score; P = 0.021) than in patients in other treatment groups.
Small number of subjects in the study and the short period of
treatment did not allow conclusive statements
61. 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
63. Supportive treatments for SCAs
Rehabilitation improves function and mobility in
pts
Physiotherapy focused on improving gait,
balance,
coordination, posture and muscle strength is often
recommended.
Small studies showed improvement in SARA
scores with physiotherapy
Speech therapists - educate and train patients
and their relatives by recommending supportive
strategies and surveillance during swallowing to
prevent respiratory infections.
64.
65. Handbook of Clinical Neurology, Vol. 155 (3rd
series) The Cerebellum: Disorders and
Treatment
Primer neurology
Imaging in SCA-dohlinger
Bradley text book
