Friedreich's ataxia is a hereditary disorder that affects the nervous system and heart, caused by defects in the frataxin gene. It most commonly affects Caucasians, with a prevalence of 1 in 29,000. Symptoms include difficulty walking, coordination issues, and an enlarged heart. As the disease progresses, symptoms worsen and include fatigue, loss of ability to walk, and cardiac failure. The lack of frataxin leads to oxidative stress that damages mitochondria and tissues over time. Potential treatments focus on reducing oxidative stress, chelating excess iron, and increasing frataxin levels through gene therapy or histone deacetylase inhibitors.

1. Friedreich’s ataxia and its Role in Altering Frataxin Expression
Introduction and Epidemiology Frataxin Deficiency and Oxidative Stess
Neurodegeneration by Frataxin Deficiency
Treatment and Therapy
Symptoms
● Friedreich’s ataxia (FRDA) is an
autosomal recessive hereditary
disorder that affects the nervous
system and the heart in
approximately 1 in 50,000
Caucasians.4
● It is caused by defects or mutations
in the frataxin gene causing a GAA
repeat in the DNA.7,13
● Overall, the FRDA carrier rate has
been estimated recently to be 1 in
60 to 1 in 90 with a disease
prevalence of 1 per 29,000.11
● Most prevalence is seen in
Europeans. FRDA is very rare in
descendants of Asian and African
cultures.18,19
Figure 1: This graph shows the GAA
frequency in four populations. In
comparison to the other populations,
caucasians have a higher GAA
frequency.
University of Washington | BIOL 119 A | AUTUMN 2014
Ken Steckler | Jessica Graves | Calina Daian | Shannon Kody
* A slow, slurred speech pattern
† The enlargement of chambers of the heart resulting in less efficient pumping
x Abnormal shape of foot
● Symptom Management:
○ Physical, occupational, and speech therapy
○ Bone deformity: surgery or bracing
○ Medication and diet for pain, heart disease [beta blockers and
ACE inhibitors], and diabetes [insulin and oral medication]7,18
● Major Treatments Under Trial:
Stage Symptom Cause
Early ● difficulty walking
● coordination issues
● diminished reflexes
Frataxin deficiency resulting in less
mitochondrial energy and build up of
toxins6
● scoliosis
● Pes Cavus×
Abnormal levels of use of certain
muscles resulting in extra stress on
bones in abnormal locations¹³
Late ● fatigue
● shortness of breath
● chest pain
● dysarthria*
● loss of ability to walk
Cardiac failure, specifically myocardial
fibrosis, hypertrophic cardiomyopia+
,
and arrhythmia6
Frataxin deficiency leads to damage to
cerebellum and peripheral nerves6
Mid
FIgure 2: Heart with hypertrophy in
comparison to regular heart. Main cause
of heart failure in patients.³
Figure 3: Patient experiencing Pes
Cavus, which results in pain and
abnormal gait.¹¹
Figure 4: There is a negative correlation between
the FXN level and GAA repeats1
● Frataxin is essential in oxidative
phosphorylation1,4,8
○ Makes ATP
● Frataxin production decreased in
FRDA5
● Pathogenesis due to Frataxin
deficiency12
● ROS (Reactive Oxygen
Species)
○ Superoxides, H2O2, etc.
○ Oxidative stress
○ Damages mitochondria
and DNA9
○ Vicious Cycle
Figure 5: Induction of Vicious Cycle by
oxidative stress1
1
GROUP
1
● Progressive degeneration of:
○ CNS and PNS8
● Lack of myelination of Dorsal
Root Ganglia and other
sensory/peripheral nerves8
● Oxidative stress affects Schwann
cells and myelinated neurons8
● Iron regulation altered and
affects cerebellum8
Figure 6: Iron accumulation and
degradation of cerebellum (top)
and normal cerebellum (bottom)2,8
Figure 7: Reflex arc being affected due to lack of
myelination of the DRG.
8
Dorsal Root Ganglion
● Sensory neuron not
integrated or response is
slow14
○ Antioxidants (vitamin E, coenzyme Q10, idebenone): protect,
improve energy from mitochondria
○ Iron chelation: decrease iron levels and enlargement of heart
○ EPI-A0001: improve energy from mitochondria
○ Erythropoietin: inject natural protein production stimulant
○ Gene and protein therapy: reach cell mitochondria16
○ Histone deacetylase inhibition: keep acetyl groups on genes10,15
Figure 8: Increasing progression of FA research treatments and their treatment focuses5
1. Astrid C. Haugen, Nicholas A, Di Prospero, Joel S. Parker, Rick D. Fannin, Jeff Chou, Joel N. Meyer, Christopher Halweg, Jennifer B. Collins,
Alexandra Durr, Kenneth Fischbeck, Bennett Van Houten. 2010. Altered Gene Expression and DNA Damage in Peripheral Blood Cells from
Friedreich's Ataxia Patients: Cellular Model of Pathology. 1000812.
2. Boddaert, N., K. H. Le Quan Sang, A. Rotig, A. Leroy-Willig, S. Gallet, F. Brunelle, D. Sidi, J.-C. Thalabard, A. Munnich, and Z. I. Cabantchik.
"Selective Iron Chelation in Friedreich Ataxia: Biologic and Clinical Implications." Blood 110.1 (2007): 401-08.
3. “Diseases and Conditions.” Left Ventricular Hypertrophy. Mayo Clinic, n.d. Web. 27 Nov. 2014.
4. Drake, Kelly. 2007. The Nature of Friedreich’s Ataxia. Nov 14, 2014. Ataxia.http://library.radford.edu/archives/winesett/drake.pdf
5. Edison Pharmaceuticals. "What Is Friedreich's Ataxia?" FARA. Friedreich's Ataxia Research Alliance, June 2014. Accessed Nov. 18, 2014. 1. http:
//www.curefa.org/images/pipeline.png
6. Facts About Friedreich’s Ataxia. MDA, Muscular Dystrophy Association. Muscular Dystrophy Association, 2011. Web.
7. Friedreich's Ataxia. Better Health. State Government of Victoria, 1 June 2012. Accessed Nov. 18, 2014. http://www.betterhealth.vic.gov.
au/bhcv2/bhcarticles.nsf/pages/Friedreich's_ataxia
8. Gomes, C., Santos, R. 2013. Neurodegeneration in Friedreich's Ataxia: From Defective Frataxin to Oxidative Stress. Oxid Med Cell Longev. 2013:
487534.
9. Gonzalez-Cabo, P., Palau, F. 2013. Mitochondrial pathophysiology in Friedreich’s ataxia. Journal of Neurochemistry 126 (1) 53-64.
10. Gottesfeld, J., Rusche, J., Pandolfo, M. 2013. Increasing Frataxin Gene Expression with Histone Deacetylase Inhibitors as a Therapeutic Approach for
Friedreich's Ataxia. J. Neurochem. 126(1): 147-154.
11. Holland, Mark, Dr. "Pes Cavus." Radiopaedia. UBM Medica, 8 Sept. 2012. Web. 27 Nov. 2014.
12. Jasvinder Chawla. 2013. Friedreich Ataxia. Nov 28, 2014. http://emedicine.medscape.com/article/1150420-overview#a0199
13. Office of Communications and Public Liaison, National Institute of Neurological Disorders and Stroke, National Institutes of Health. 2010.
Friedreich's Ataxia Fact Sheet, NIND. No. 10-87. Accessed October 28 2014. http://www.nlm.nih.gov/medlineplus/friedreichsataxia.html.
14. Pandolfo M; Friedreich Ataxia. Arch Neurol. Oct. 2008; 65(10):1296-303.
15. Pandolfo, M., Hausmann, L. 2013. Deferiprone for the treatment of Friedreich’s ataxia, Journal of Neurochemistry 126 (1): 142-146.
16. Perdomini, M., Belbellaa, B., Monassier, L., Reutenauer L., Messaddeq, N., Cartier, N., Crystal, R., Aubourg, P., Puccio, H. 2014. Prevention and
reversal of severe mitochondrial cardiomyopathy by gene therapy in a mouse model of Friedreich's ataxia. Nature Medicine. Macmillan Publishers
Limited. Accessed October 28, 2014. http://www.nature.com/nm/journal/vaop/ncurrent/full/nm.3510.html?message-global=remove.
17. Rajagopala N., Garcia MJ., Rodriguez L., Murray RD., Aperson-Hansen C., Stugaard M., Thomas JD., Klein AL. 2001. Comparison of new Doppler
echocardiographic methods to differentiate constrictive pericardial heart disease and restrictive cardiomyopathy. American Journal of Cardiology. 87
(1): 86-94.
18. Ramirez-Montealegre D, Mink JW. Ataxias. In: Kliegman RM, Behrman RE, Jenson HB, Stanton BF, eds.Nelson Textbook of Pediatrics. 19th ed.
Philadelphia, Pa: Saunders Elsevier; 2011:chap 590.1.
19. Vankan, Pierre. "Prevalence Gradients of Friedreich’s Ataxia and R1b Haplotype in Europe Co-localize, Suggesting a Common Palaeolithic Origin in
the Franco- Cantabrian Ice Age Refuge." Journal of Neurochemistry 126 (1): 11-21.
References
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