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Inherited Genetic Disorders in Humans Introduction

Friediech’s Ataxia (FA) has been the most frequent type of ataxia occurring at a

mean age of 16 years old in Singapore. The aim of this proposal is to highlight this

growing trend in Singapore and to request the Members of the Parliament in Singapore to provide funds for biotechnological research on Friediech’s Ataxia, thereby treating patients with such disease in the future.

Background

Friediech’s Ataxia is an inherited disease caused by a defective gene known as X25, located on chromosome 9 which prevents the body from producing a normal amount of "frataxin" (a cellular protein). This disease can be inherited through autosomal recessive (common cases) or autosomal dominant (rare cases). Autosomal recessive requires both parents to each have a faulty gene which means they are carriers of FA. 50% of their children would become carriers and 25% would contract the disease. The remaining 25% would be a normal child (as shown in Fig 1.1)

Inherited Genetic Disorders in Humans Introduction Friediech’s Ataxia (FA) has been the most frequent type of

Fig 1.1

Autosomal dominant only requires one of the parents to have an abnormal gene in its 22 autosomal (non sex) chromosomes where this gene is dominant. This would result in 50% of their children to be carriers of FA (as shown in Fig 1.2).

Autosomal dominant only requires one of the parents to have an abnormal gene in its 22

Consequences

Fig 1.2

Friediech’s Ataxia deteriorates nerve cells called neurons in the brain and spinal cord, preventing smooth transfer of electrical signals between neurons. This would lead to a gradual loss of muscle coordination. To a 3 rd party, the affected person may look like drunk. It would also degenerate cardiac muscles, resulting in abnormal heart beats (palpitation) and heart failure which eventually leads to death. Currently, there is no cure, but the symptoms can be managed with medication and physical therapy.

Current Solutions

Exercising for example swimming Avoid resting on bed as it may aggravate walking problems Maintain an acceptable weight • Orthopaedic aids (wheelchair, walking sticks) • Physiotherapy • Medication to reduce muscle tremors and spasms

e.g. idebenone, 5-hydroxytryptophan & placebo.

• Medication to treat heart palpitations • Surgery to correct abnormal spine curvatures.

Effectiveness of Current Medications

5-hydroxytryptophan (drug) is more useful than placebo (substance lacking specific action on the disease under consideration) in improving neurological symptoms in patients with FA. On the other hand, Idebenone (drug) is more effective than placebo in preventing the progression of cardiomyopathy (heart muscle disease) related to FA, but is unable to improve neurological impairment. However, its stabilizing effect on neurological dysfunction was present only in the paediatric population, mainly before puberty, suggesting that the age for idebenone treatment is an important factor in the effectiveness of the therapy.

Latest Research

Currently, Interferon-gamma (IFNγ) has shown to increase production of frataxin. In FA research mice, treatment with interferon gamma preserved sensory neurons, improved muscle function and coordination, and enhanced movement ability (Amy Madson 2012).

Furthermore, researchers have tested the protein with cancer cells from a variety of different cultured human cell lines. After 24 hours of exposure to interferon gamma, frataxin level has increased in a dose-dependent manner (higher levels at higher doses) in all three types of cells. A similar dose-dependent upregulation of frataxin occurred in cells taken from healthy volunteers and from FA affected people.

(Amy Madson 2012). These data suggest that interferon gamma which is naturally produced in our immune system may be the possible treatment for FA in the future.

(Amy Madson 2012). These data suggest that interferon gamma which is naturally produced in our immune

Future Research Needed to Develop Treatment

Further research in interferon gamma would probably be useful and effective in coming up with a cure for FA in the future since experimental results with mice and human cells have proved that IFNγ increases frataxin expression. Therefore, I would like to request the members of the parliament to help provide grants for future research in this potential niche area so as to cure FA patients in Singapore.

Plans for Future Research

1) Funds would be used to develop a “humanised” mouse model which will enable scientists to better understand the molecular causes of FA and provide a better subject to test out potential FA therapeutics (Sarsero 2011). 2) Funds would also be used to analyse the role of altered iron metabolism in cellular energy factories known as mitochondria so that iron can be transported into the mitochondria that is easily utilized for the processes which are lacking when frataxin levels are not enough. (Richardson 2011). 3) More research would be conducted on interferon gamma and how it can be administered into a drug form that is effective and harmless to humans in the long run.

References

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Trujillo-Martín MM, Serrano-Aguilar P, Monton-Alvarez F, Carrillo-Fumero R. (2009). Effectiveness and Safety of Treatments for Degenerative Ataxias. Movement Disorder Society, 24(8):1111-24. Review. PubMed PMID:

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Scriba PC (2012). Placebo and the Relationship between Doctors and Patients, 55(9):1113-7. PubMed PMID: 22936478.

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Tomassini et al (2012). Interferon Gamma Up Regulates Frataxin and

Corrects the Functional Deficits in a Friedreich Ataxia Model. Epub 2012, 21(13):2855-61. PubMed PMID: 22447512.

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Amy Madson (2012). FA: Immune System Drug Strengthens Mice

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