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Friedreich's Ataxia FRIEDREICH’S ATAXIA: A RARE NEURODEGENERATIVE CONDITION Item Type Electronic Thesis; text Authors Kalil, Danielle Citation Kalil, Danielle. (2020). FRIEDREICH’S ATAXIA: A RARE NEURODEGENERATIVE CONDITION (Bachelor's thesis, University of Arizona, Tucson, USA). Publisher The University of Arizona. Rights Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author. Download date 29/09/2021 16:56:08 Item License http://rightsstatements.org/vocab/InC/1.0/ Link to Item http://hdl.handle.net/10150/651346 FRIEDREICH’S ATAXIA: A RARE NEURODEGENERATIVE CONDITION By DANIELLE KALIL ____________________ A Thesis Submitted to The Honors College In Partial Fulfillment of the Bachelors degree With Honors in Neuroscience THE UNIVERSITY OF ARIZONA M A Y 2 0 2 0 Approved by: ____________________________ Dr. Torsten Falk Department of Neurology Abstract Friedreich’s ataxia is a rare neuromuscular condition that affects 1 in 50,000 individuals in the United States (“Friedreich’s Ataxia Guide,” 2020). Friedreich’s ataxia, otherwise known as FA, is an autosomal recessive disorder that targets progressive degeneration of nerve cells and cardiac cells through a GAA trinucleotide expansion on the ninth chromosome (“Friedreich’s Ataxia Guide,” 2020). While unaffected individuals tend to have this repeat less than 30 times, FA patients will show the GAA sequence anywhere from 100 to 1,000 times (Power & Bidichandani, 2018). While most patients typically start showing symptoms between 5 and 15 years old, the onset of the condition and the severity of symptoms are linked to the length of the GAA expansion (“Friedreich’s Ataxia Guide,” 2020). This expansion triggers the onset by impairing frataxin production in the cells. Frataxin is a mitochondrial protein that is essential for regular energy production and iron regulation throughout one’s body (González-Cabo & Palau, 2013). FA patients tend to have high levels of excess iron, which can lead to oxidative stress and nerve cell damage (González-Cabo & Palau, 2013), Since Friedreich’s ataxia is so rare, diagnosing the condition can be a long and difficult process. Typically, medical professionals will look for symptoms that come with Friedreich’s ataxia such as loss of coordination, fatigue, scoliosis, diabetes mellitus, or an abnormal heart condition (“Friedreich’s Ataxia Fact Sheet,” 2018). While there is currently no cure, treatments for FA include physical therapy/exercise, occupational therapy, and pharmaceutical drug trials with antioxidants and non-antioxidants, as well as gene therapy research are ongoing (Flavell, 2017). This paper identifies and discusses current known causes, symptoms, treatments, and research of Friedreich’s ataxia in greater depth. What is Friedreich’s Ataxia? Friedreich’s ataxia is a progressive neuromuscular condition that results in severe nerve cell degeneration (“Friedreich’s Ataxia Guide,” 2020). Friedreich’s ataxia, also known as FA, is an autosomal recessive disorder that affects 1 in 50,000 individuals in the United States (“Friedreich’s Ataxia Guide,” 2020). Though it was originally recognized and discovered by German pathologist Nikolaus Friedreich in 1863, it took over 120 years for researchers to understand the genetics of the disease (Schulz & Pandolfo, 2013). As a result, research has increased tenfold in the last 25 years. Friedreich’s ataxia was the first inheritable ataxia to be identified from various locomotor ataxias and accounts for more than half of all autosomal ataxias (Schulz & Pandolfo, 2013). Typically, onset of the condition tends to be between 5 and 25 years old for 85% of patients (“Friedreich’s Ataxia Guide,” 2020). Both men and women are equally susceptible to inheriting FA and though people all over the world suffer from the condition, studies show that it is most commonly inherited by those with European, North African, Middle Eastern, or Indian descent (“Friedreich’s Ataxia Guide,” 2020). Causes of Friedreich’s Ataxia Friedreich’s ataxia results from mutations in the FXN gene on a portion of the DNA that includes what is called a guanine-adenine-adenine (GAA) trinucleotide repeat. This genetic GAA segment on chromosome 9 typically repeats less than 30 times in unaffected individuals (Al- Mahdawi et al., 2018). In individuals with a defective FXN gene, the GAA sequence continues to repeat anywhere from 100 to 1,000 times, with the majority having more than 400 repeats (Power & Bidichandani, 2018). The severity of symptoms and onset is associated with the number of GAA sequence repeats. FA individuals with less than 400 GAA repeats generally have later age of onset and slower progression of symptoms (Power & Bidichandani, 2018). Patients with longer genetic expansions are typically diagnosed younger and experience faster, more severe progression of the disease (Power & Bidichandani, 2018). For those with FA, the abnormally high amount of GAA repeats disrupts the production of the protein frataxin, which is essential for normal nerve and muscle cell function (Konanz, 2020). As a mitochondrial protein, frataxin plays an important role in energy production throughout the body by driving iron-cluster biosynthesis and regulating iron in the mitochondria (Pastore & Puccio, 2013). Frataxin regulates iron levels to prevent cells from experiencing oxidative stress, which is essentially an imbalance of reactive oxygen species (ROS) and the body’s ability to detoxify these harmful free radicals (Lupoli, Vannocci, Longo, Niccolai, & Pastore, 2017). When this imbalance occurs and the body goes into a state of oxidative stress, an individual is vulnerable to neurodegeneration and several pathologies such as FA, Alzheimer’s disease, cancer, and diabetes (Lupoli, Vannocci, Longo, Niccolai, & Pastore, 2017). When an individual has low frataxin levels, their cells are unable to produce sufficient iron-sulfur clusters, which causes excessive iron to float around the mitochondria (González-Cabo & Palau, 2013). The excess iron interacts with oxygen to produce a byproduct known as free radicals, which are toxic to cell development and throughout the body (“Friedreich’s Ataxia Fact Sheet,” 2018) When Frataxin is low and these toxic free radical byproducts accumulate, an individual’s body goes into an unstable state known as oxidative stress (“Friedreich’s Ataxia Fact Sheet,” 2018). The lack of frataxin disrupts regular energy production in the mitochondria and damages both nerve cells and heart muscle cells throughout the body (González-Cabo & Palau, 2013). These cell abnormalities ultimately result in a thinner spinal cord, hypertrophy in cardiac muscle, impaired speech, altered eye movements, and misregulation of blood sugar in the pancreas (“Friedreich’s Ataxia Guide,” 2020). Individuals who carry one copy of a functional FXN gene and one copy of the mutated gene with a GAA expansion are known as carriers and are not at risk of developing the orthopedic, neurological, cardiac, or diabetic issues that are associated with the disease (Konanz, 2020).Therefore, carriers only need one functional gene to remain healthy since there are no personal risks for being a carrier. This is substantial for treatment research, explains the director of The UCLA Ataxia Center Dr. Perlman, because a cure for FA does not have to restore frataxin levels completely. Researchers believe that a treatment that can restore frataxin levels up to 45- 50% could successfully silence the condition (Konanz, 2020). Diagnosing Fredrich’s Ataxia Diagnosing Friedreich’s ataxia can be a long and difficult process due to the rarity of the condition and the variability in symptoms and progression. In a typical diagnosis, a medical professional will complete a clinical examination by assessing a patient’s symptoms, medical history, and family history (“Friedreich’s Ataxia Fact Sheet,” 2018). To identify Friedreich’s ataxia symptoms, the medical staff will particularly look for lacking sensation in joints and muscles, loss of reflexes, impaired balance, and cardiac problems (“Friedreich’s Ataxia Fact Sheet,” 2018). Patients are then given a more formal diagnosis after completing a genetic test or various medical examinations. Typically, less than 5% of FA diagnoses are done with genetic testing for the GAA sequence repeat or point mutation (Konanz, 2020). Most diagnoses are done through a combination of diagnostic tests. Doctors use nerve conduction studies to assess whether nerve cell deterioration has hindered the speed of transmission for nerve cell impulses (“Friedreich’s Ataxia Guide,” 2020). Other common diagnostic tests include electromyograms to detect muscle damage and electrocardiograms to observe abnormalities in a patient’s heartbeat (“Friedreich’s Ataxia Guide,” 2020). Echocardiograms, on the other hand, are used in FA diagnosis to view the position and motion of cardiac muscles. This is important for analyzing heart function, heart muscle thickness, and heart chamber size (“Friedreich’s Ataxia Guide,” 2020). Magnetic Resonance Imaging (MRI) and Computed Tomography (CT) scans provide detailed images of the brain and spinal cord to detect deterioration and thinning of the spinal cord (“Friedreich’s Ataxia Guide,” 2020). MRI and CT exams are often used to rule out other neurological conditions during the diagnosis (“Friedreich’s Ataxia Fact Sheet,” 2018).
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