SPINOCEREBELLAR ATAXIA

Biology

Amelia Gelz

Tina Ma

Michele Zhang

Tina Dhaliwal

OVERVIEW What is ataxia? What is spinocerebellar ataxia? What are the genetics of spinocerebellar

ataxia?Genes and chromosomes that affected Inheritance Pedigree of a family with spinocerebellar

ataxia How is it diagnosed?

Symptoms and onset of symptomsHow is it diagonosed?

What is the prognosis?Therapy and treatmentHope for the future

WHAT IS ATAXIA? Ataxia is not a specific disease or

diagnosis Ataxia is a word used to describe certain

symptoms related to movement, such as:Unsteady walkingDifficulty with balanceLoss of coordinationSlurred speech

Ataxia may be temporary or progressive and permanent

Spinocerebellar ataxia is one form of permanent ataxia

SPINOCEREBELLAR ATAXIA: A CLOSER LOOK

Spinocerebellar ataxia (SCA) is a rare genetic disease that affects the cerebellum, brain stem and spinal cord

There are 29 different types of SCA These 29 types are linked by common causes

and symptoms, but they each have acquired symptoms unique to that type

Out of these 29 types, SCA1 is one of the most common along with SCA2 and SCA6

SPINOCEREBELLAR ATAXIA: A CLOSER LOOK

SCA1 affects the cerebellum located near the back of the brain

The cerebellum is the region of the brain that is involved in: Motor control Balance and equilibrium The precision, timing

and coordination of movements

The cerebellum is actually a continuous layer of neural tissue

An important layer of the cerebellum is the Purkinje Layer, where Purkinje cells control the output of all motor coordination

SPINOCEREBELLAR ATAXIA: A CLOSER LOOK

The cerebellum gradually deteriorates due to a harmful mutation

The loss of Purkinje cells in the cerebellum causes a loss of balance and coordination

This leads to SCA1

Above: 2 MRI scans of a man with a normal

cerebellum and a man with spinocerebellar

ataxia

THE GENETICS OF SCA1

Above: the ataxin-1 protein

SCA1 is caused by the ATNX1 gene mutation on chromosome 6

A sequence of 3 bases, CAG, are replicated many times

This causes an excessive production of the ataxin-1 protein, which causes SCA1

The diseased allele can contain between 41-81 CAG repeats where normally there would only be 6-39 repeats

The longer the expansion, the more severe the disease becomes

THE GENETICS OF SCA1 Although the exact function of ataxin-1 is

unknown, scientists do know that: Ataxin-1 is attracted to certain parts of the

cerebellum and eventually will destroy the layers, causing atrophy (shrinking) of the cerebellum

A toxic buildup of ataxin-1 causes damage to the cerebellum Purkinje cells, which blocks messages to the brain concerning motor coordination

The polyglutamine expansions often vary in size and are very unstable

They usually increase in size which is passed onto successive generations

INHERITANCE

SCA1 is passed on through autosomal dominant inheritance

This means both affected parents have a 50% chance of passing on the mutated gene

However, if the CAG triplets in the offspring repeats in a normal range, the child might not have the disease

Every 1 in 100,000 people will suffer from SCA1

PEDIGREE

Above is a pedigree of a family with SCA1. This shows autosomal dominant inheritance with one of the

females diagnosed with SCA1.

SYMPTOMS Early symptoms:

Walking, balance and coordination problems (gait difficulty)

Precision, timing and coordination of movements significantly decreases

Later symptoms:Difficulty swallowing (dysarthria)Difficulty judging the distance between

objects (dysmetria)Neuropathy (loss of feeling and reflexes in

legs and feet)Spasticity

ONSET OF SYMPTOMS In SCA1, the number of CAG repeats

determined 64% of onset variability From the onset of the symptoms, the

duration of SCA1 is from 10 to 30 years The onset of symptoms usually appear in

adulthood (ranging from 20’s to late 30’s) If the onset of symptoms appear before

the age of 13, the disease is usually much more severe and the progression more rapid

DIAGNOSIS How is it diagnosed?

A neurological examination is conducted and will determine whether an individual has symptoms typical of SCA1

A blood test is conducted to detect the abnormal gene

DNA tests to analyze any gene mutations on the 6th chromosome

MRI scan of the brain

PROGNOSIS Unfortunately there is no cure for SCA1 The loss of muscle control will worsen until

the patient cannot eat or breathe Scientists have not yet found a way to

prevent neurons from dying a premature cell death

Scientists have also not found a way to restore neuronal populations that have already been lost

THERAPY AND TREATMENTS

However a number of different therapies are available to help affected individuals cope their disease: Physical therapy Speech therapy Emotional therapy and support

Conveniences: Installing grab bars, ramps and raised

toilets at home Canes, crutches, walkers and wheelchairs

to help walking Computer communication devices Weighted eating tools

HOPE FOR THE FUTURE:STEM CELLS AND SCA1

Stem cells are cells found in all multi-cellular organisms and can change into a wide range of specialized cell types

Stem cell tissues can be cultured into cells with the characteristics of the cells of tissues, muscles and nerves

In adults, stem cells can act as a repair system replenishing specialized cells

The goal is to coax stem cells to become nerve cells to replace dopamine-producing cells that have been lost in the brain

STEM CELL RESEARCH IN THE UNITED KINGDOM

The Institute of Clinical Neurosciences at the University of Bristol conducted a study on the use of bone marrow stem cells to treat degenerative ataxias

To test this theory, cerebellar cells were taken from rodents, grown in a culture and subjected to toxins

The effect of stem cells on the survival of the nerve cells was tested and scientists discovered: Nerve cells in the presence of the human bone

marrow derived stem cells were less likely to die These stem cells are able to protect nerve cells

that have been exposed to toxins

STEM CELL RESEARCH IN CHINA

Stem cell research is currently more advanced in China than in North American due to ethical issues

George Arruda was diagnosed with SCA1 and flew to China to receive stem cell injections that could potentially improve his condition

George experience significant improvements in his walking, balancing and coordination after the injections

SCA1 TREATMENT TESTING IN MICE

A study performed in 2005 showed that SCA1 pathology in transgenic mice can be reversed

The gene for ataxin-1 (ATNX1) was put into a tetracycline-sensitive promoter The administration of doxycycline (tetracycline) was

discovered to have the ability to shut off the activated gene Transgenic mice were given

doxycycline varying from 6, 12, 16 or 32 weeks and the general results were: 6 weeks: Purkinje cell pathology

was reversed 12 weeks: Restored motor

function 32 weeks: Significant

improvements in histopathology

OTHER THERAPIES UNDER INVESTIGATION

The National Institute of Neurological Disorders and Stroke are currently testing the use of the drug lithium carbonate Lithium injections have been tested on mice

diagnosed with SCA1 and have shown neurological improvement

The University of South Florida is testing the use of the drug varenicline (a drug used to smoking cessation) and the drug placebo Varenicline has shown substantial improvement in

patients with several inherited ataxias These drugs are targeted towards SCA3 but

because all types of SCA are linked by common symptoms, this may also provide helpful research in the treatment of SCA1

AN INSPIRATION Aya Kito was born on July

19, 1962 in Japan At the age of fifteen she

was diagnosed with spinocerebellar ataxia type 1

She slowly lost her ability to walk and talk and spent the rest of her life in a hospital bed

Aya wrote a diary documenting her personal experiences with spinocerebellar ataxia

Her diary was published on February 25th, 1986 and was titled 1 Litre of Tears

Aya Kito died on May 23rd 1988

THANK YOU FOR WATCHING

REFERENCES http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=

gene&part=sca1 http://www.ataxia.org/pdf/NAF%20Web%20Content%

20Publication%20SCA1.pdf http://clinicaltrials.gov/ct2/show/NCT00683943?term

=spinocerebellar+ataxia+1&rank=2 http://www.mdvu.org/emove/article.asp?ID=788 http://www.medicalnewstoday.com/articles/29733.ph

p http://stemcellschina.net/ http://myweb.tiscali.co.uk/ataxia.pages/index.htm#A

TAXIAPAGE-Understanding_Genes http://www.ataxia.org.uk/publications_and_pictures/

Degenerative%20ataxias%20and%20the%20potential%20for%20stem%20cell%20neuroprotection.pdf

http://www.uniprot.org/uniprot/P54253