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ZEESHAN GAUHAR
PhD SCHOLOR-BIOTECHNOLOGY
14-ARID-4978
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Hereditary Ataxia
Clinical manifestations
Autosomal dominant hereditary ataxia
Clinical features of ADCA
Molecular genetic testing
Other repeat expansions
Prevalence
Autosomal recessive hereditary ataxia
Friedreich ataxia (FRDA)
FXN YAC transgenic mouse models
Therapeutic approaches
References
Clinically and genetically heterogeneous group of
disorders characterized by slowly progressive
incoordination of gait, poor coordination of
hands, speech, and eye movements

Ataxia of gait
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Dysarthria

Sensory deficits
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Spasticity
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Retinopathy and optic atrophy
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Parkinsonian features
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Epilepsy
http://drugline.org/medic/term/ataxia/
Figure 1 Coronal brain MRI showing atrophy of both cerebellar
hemispheres (arrows) in a 28-year-old woman with SCA2. MRI,
magnetic resonance imaging; SCA, spinocerebellar ataxia
The hereditary ataxias can be inherited in
1.
autosomal dominant
2.
autosomal recessive
3.
X- linked manner
4.
Mitochondrial inheritance
Clinical features of ADCA
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Pyramidal signs (hyperreflexia and spasticity) in SCA1
and SCA3.
Cognitive impairment in SCA2, SCA12, SCA13,
SCA17.
Chorea in SCA17
Parkinsonism or motor neuron disease in SCA2
Mutations associated with the ADCAs include;
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point mutations
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duplications
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deletions
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nucleotide expansions
SCA1, SCA2, SCA3, SCA6, SCA7, SCA12, SCA17
and DRPLA are all caused by CAG repeats which
results elongated polyglutamine tract in the protein.
 The sizes of the normal CAG repeat allele and of the
full-penetrance disease-causing CAG expansion vary
among the disorders
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SCA8 has a CTG trinucleotide repeat expansion in
ATXN8OS.
The pathogenesis of the SCA8 phenotype also involves
a (CAG)n repeat in a second overlapping gene, ATXN8.
SCA10 has a large expansion of an ATTCT
pentanucleotide repeat in ATXN10
Prevalence of these rare diseases is not widely known.
◦ ADCAs in the Netherlands is estimated to be at
least 3:100,000.
◦ DRPLA is more common in Japan
◦ SCA3 in Portugal, Japan and Germany
◦ SCA2 is common in Korea
13 typical autosomal recessive disorders in which ataxia
is a prominent feature
Friedreich ataxia (FRDA)
The most common autosomal recessive ataxia with a
population frequency of 1–2:50,000
 Caused by a GAA repeat expansion mutation within
intron 1 of the FXN gene
 Result in reduced levels of frataxin protein
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The reduction in frataxin expression leads to oxidative
stress, mitochondrial iron accumulation and
consequential cell death with the primary sites of
neurons of the dorsal root ganglia and the dentate
nucleus of the cerebellum
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Normal individuals have 5 to 40 GAA repeat
sequences
affected individuals have approximately 70 to more
than 1000 GAA triplets
Typically associated with depressed tendon reflexes,
dysarthria, Babinski responses, and loss of position
and vibration senses.
http://drugline.org/medic/term/ataxia/
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To investigate FRDA molecular disease mechanisms
and therapy, three human FXN YAC transgenic mouse
models
• Y47R, containing normal-sized (GAA)9 repeats
• YG8R, containing expanded GAA repeats of 120–220 units
• YG22R, containing 170–260 units
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First the difference in the FXN transgene copy number
in YG8R, YG22R and Y47R lines were investigated
and found that the YG22R and Y47R lines had a single
copy of the FRDA transgene while the YG8R line had
two copies of the FRDA transgene.
(a) Two TaqMan copy number assays were applied; Hs05092416-cn assay,
represented in black, was designed to amplify a 106 bp fragment of FXN within intron
3 and Hs02407730-cn assay, represented in grey, was designed to amplify an 80 bp
fragment of FXN within intron 1 and exon 2. Wild type (WT) served as a negative
control with no copy number
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YG22R and YG8R FRDA mice expressed
comparatively decreased levels of human frataxin in
comparison to the endogenous mouse levels.
To determine the effect of reduced frataxin level,
coordination ability of YG8R and YG22R mice was
assessed
The YG8R and YG22R showed a significant decline in
their motor function compared to B6 and Y47R
controls, though, the degree of impairment was more
significant in YG8R mice.
YG22R and YG8R FRDA mice show a coordination deficit compared to B6 and Y47R controls when (a) both male and female values were taken
together (n = 10 mice per genotype) or (b) male alone (n = 5 mice per genotype) or (c) female alone (n = 5 mice per genotype).
Resons
 Firstly, lower body weight of the females may have
contributed to the improved function of these mice.
 Secondly, females may be more capable of adapting to
the experimental environment and conditions compared
to the male mice.
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body weight analysis of YG22R and YG8R
demonstrated an increase in weight compared to B6
GAA repeat instability in the brain and cerebellum of
both YG22 and YG8 transgenic mice
Consistent reduction in the levels of frataxin mRNA
and protein in the brain and liver samples of YG8R and
YG22R mice compared to Y47R mice
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Interferon gamma (IFNγ), a cytokine involved in
multiple aspects of iron metabolism and the immune
response , has been shown to increase frataxin levels in
both cell and animal models of FRDA
It has been reported that in vivo treatment of YG8R
mice with IFNγ enhances both locomotor activity and
motor coordination, and induces the upregulation of
cellular frataxin
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Use of HDAC inhibitors as potent candidates to prevent
deacetylation of histones and increase FXN gene
transcription through relaxation of chromatin
conformation
These studies are supported by the results from a fivemonth study on the YG8R mice which confirmed the
positive effects of HDAC inhibitors by reversing
frataxin gene silencing
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Cellular, Molecular and Functional Characterisation of YAC Transgenic Mouse Models of
Friedreich Ataxia Virmouni SA et al (2014)
Hereditary ataxias: overview Suman Jayadev, MD1 and Thomas D. Bird, MD (2013)
Sandi C, Sandi M, Jassal H, Ezzatizadeh V, Anjomani-Virmouni S, et al. (2014) Generation
and characterisation of friedreich ataxia YG8R mouse fibroblast and neural stem cell models.
PLoS One 9: e89488.doi: 10.1371/journal.pone.0089488[PMC free article [PubMed
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