1. HEREDITARY ATAXIA ZEESHAN GAUHAR PhD SCHOLOR-BIOTECHNOLOGY
14-ARID-4978
HEREDITARY ATAXIA

2. contents 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

3. HEREDITARY ATAXIA
Clinically and genetically heterogeneous group of disorders characterized by slowly progressive incoordination of gait, poor coordination of hands, speech, and eye movements

4. Clinical manifestations
Ataxia of gait
Dysarthria
Sensory deficits
Spasticity
Retinopathy and optic atrophy
Parkinsonian features
Epilepsy

6. 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

7. The hereditary ataxias can be inherited in
autosomal dominant
autosomal recessive
X- linked manner
Mitochondrial inheritance

8. Autosomal dominant cerebellar ataxia

14. Autosomal dominant cerebellar ataxia
Clinical features of ADCA
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

15. Molecular genetic testing
Mutations associated with the ADCAs include;
point mutations
duplications
deletions
nucleotide expansions

16. 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

17. Other repeat expansions
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

18. Prevalence 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

19. Autosomal recessive hereditary ataxias

20. One parent has ataxia and one parent is a carrier

21. Both parents are carriers

22. One parent is an unaffected carrier and the other is an unaffected non-carrier

25. Autosomal recessive hereditary ataxias
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

26. 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

27. 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.

29. FXN YAC transgenic mouse models
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

30. 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.

31. (a) Two TaqMan copy number assays were applied; Hs cn assay, represented in black, was designed to amplify a 106 bp fragment of FXN within intron 3 and Hs 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

32. 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.

33. 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).

34. 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.

35. Body weight analysis
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

36. Therapeutic approaches
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

37. 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 five- month study on the YG8R mice which confirmed the positive effects of HDAC inhibitors by reversing frataxin gene silencing

38. References
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: /journal.pone [PMC free article [PubMed

39. THANKS