ZEESHAN GAUHAR PhD SCHOLOR-BIOTECHNOLOGY 14-ARID-4978

ZEESHAN GAUHAR

PhD SCHOLOR-BIOTECHNOLOGY

14-ARID-4978

HEREDITARY ATAXIA

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

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HEREDITARY ATAXIA

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

Dysarthria

Sensory deficits

Spasticity

Retinopathy and optic atrophy

Parkinsonian features

Epilepsy

Clinical manifestations

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 dominant2. autosomal recessive3. X- linked manner 4. Mitochondrial inheritance

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

Autosomal dominant cerebellar ataxia

Mutations associated with the ADCAs include; point mutations duplications deletions nucleotide expansions

Molecular genetic testing

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

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

Other repeat expansions

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

Prevalence

Autosomal recessive hereditary ataxias

One parent has ataxia and one parent is a carrier

Both parents are carriers

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

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

Autosomal recessive hereditary ataxias

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

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/

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

FXN YAC transgenic mouse models

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

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.

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

Body weight analysis

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

Therapeutic approaches

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

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

References

THANKS