FRIEDREICH’S ATAXIA: A RARE NEURODEGENERATIVE CONDITION

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Authors Kalil, Danielle

Citation Kalil, Danielle. (2020). FRIEDREICH’S ATAXIA: A RARE NEURODEGENERATIVE CONDITION (Bachelor's thesis, University of Arizona, Tucson, USA).

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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). Doctors sometimes order blood tests and urinalysis during diagnosis to identify high blood sugar and Vitamin E levels in FA individuals (“Friedreich’s Ataxia Fact Sheet,” 2018). X-Ray images are sometimes utilized to test for scoliosis and spinal issues, which is associated with Friedreich’s ataxia symptoms (Konanz, 2020).Lastly, patients will complete a Holter monitor test by tracking their cardiac rhythm with an electrocardiogram for about 24 hours (“Friedreich’s Ataxia Guide,”

2020). This testing method will detect heartbeat abnormalities that are link to Friedreich’s Ataxia

(“Friedreich’s Ataxia Guide,” 2020).

Symptoms of Friedreich’s Ataxia

Traits of Friedreich’s ataxia include neuromuscular effects, neurological problems, bone abnormalities, cardiac symptoms, and markers of diabetes (Naqvi, 2017). Onset of FA typically appears between 5 and 15 years old with less than 15% of all patients developing late onset ataxia after 25 years (“Friedreich’s Ataxia Fact Sheet,” 2018). The rate of progression varies from person to person, but usually a patient who has a higher number of GAA trinucleotide repeats will show earlier onset and more aggressive progression of symptoms (Power &

Bidichandani, 2018). The first symptoms that appear in an FA patient tend to be awkward, shaky movements and impaired sensory functions (“Friedreich’s Ataxia Fact Sheet,” 2018). As the condition progresses, patients usually experience difficulty walking, poor balance, loss of usual reflexes, and loss of sensation in their arms and legs (“Friedreich’s Ataxia Fact Sheet,” 2018).

Other early signs of FA may include dysarthria, which is slowness or slurring of speech

(“Friedreich’s Ataxia Fact Sheet,” 2018). Patients may experience difficulties swallowing, loss of hearing, and deteriorating vision over time (“Friedreich’s Ataxia Fact Sheet,” 2018).

Additionally, FA patients often experience fatigue due to the inhibition of energy production caused by the lack of frataxin in mitochondrial cells (González-Cabo & Palau, 2013).

Many Friedreich’s ataxia patients will also develop bone defects of the feet and curvature of the spine as the condition progresses (Naqvi, 2017). This includes clubfoot, high-arched feet, and abnormal inversions in the toes and feet (Naqvi, 2017). About 63% of FA patients tend to have scoliosis, which often creates even more problems (Milbrandt, Kunes & Karol, 2008).

Patients are also susceptible to developing the symptoms of diabetes mellitus such as severe thirst, weight reduction, excessive urination, and blurry vision (Naqvi, 2017). Diabetes is common in FA individuals due to impaired mitochondrial function which is essential for regular

β cell functioning and insulin secretion (Cnop, Mulder & Igoillo-Esteve, 2013).

Patients with Friedreich’s ataxia are also vulnerable to various heart conditions, such as hypertrophic cardiomyopathy which can ultimately lead to heart failure (Hanson, Sheldon,

Pacheco, Alkubeysi & Raizada, 2019). The cardiac problems seen in FA patients result from mitochondrial breakdown and the loss of contractile proteins (Hanson, Sheldon, Pacheco,

Alkubeysi & Raizada, 2019). The left ventricle wall of a patient thickens and a patient’s develop cardiomyopathy and arrhythmias postmortem (Hanson, Sheldon, Pacheco, Alkubeysi & Raizada,

2019). Like most symptoms that rise with Friedreich’s ataxia, the severity of a patient’s cardiomyopathy is linked to the clinical age of onset for FA and the length of the GAA expansion in the mutated frataxin gene (Hanson, Sheldon, Pacheco, Alkubeysi & Raizada, 2019).

Treatments for Friedreich’s Ataxia

Physical Therapy / Exercise

While there is no cure for Friedreich’s ataxia, physical therapy and regular exercise is valuable for managing common symptoms, optimizing body function, and slowing FA progression as much as possible (Power James, 2007). Physical therapy is also used to retain locomotor skills that are used in daily activities (Power James, 2007). Friedreich’s Ataxia patients initially complete a detailed evaluation to assess balance, coordination, endurance, and reflexes (Powers James, 2007). Physical therapists will also test the patient’s walking behaviors, strength flexibility, energy, endurance, and posture (Mancini & Horak, 2010). The Berg Balance

Scale is a common assessment during an initial clinical evaluation to test for a patient’s functional balance and risk of falling (Powers James, 2007). Similarly, the Tinetti Gait

Assessment Tool is used to measure a FA patient’s balance and stability during daily activities

(Mancini & Horak, 2010).

Physical therapists focus on providing targeted exercises to help optimize function and hinder symptom progression in patients with Friedreich's ataxia. Low-intensity strengthening exercises are used to maintain function in the arms and legs while preventing immobility in a ‘use it or lose it’ fashion (Power James, 2007). To avoid injury or damage, FA parents should be careful when completing exercises by using low weights and taking adequate breaks throughout a workout. Patients can target their hips and shoulders to improve posture improvement or focus on their trunk and lower back to reduce pain by increasing blood flow (Power James, 2007).

Rhythmic stabilization and proprioceptive neuromuscular exercises are also common strengthening exercises used to work through FA symptoms (Power James, 2007). Stretching exercises are also completed by patients with FA to relax the spine and muscles that are neglected throughout the day or are targeted in scoliosis that appears with the condition (Power

James, 2007). Wheelchair bound patients also find value in stretching their hip flexors and hamstrings to prevent muscle deformities from developing (Power-James, 2007). Gait training is also very prominent in coping with Friedreich’s ataxia to manage the erratic walking behaviors that develop with the condition (Power James, 2007). Many patients will complete gait exercises with assistive devices, such as a rollator walker, to ensure safety throughout the exercise (Power

James, 2007). Coordination exercises are recommended to stimulate their sense of motion, position, and balance (Power James, 2007). When practicing these proprioception exercises, FA patients are encouraged to use a mirror to watch their movements to create better connections between their brains and their bodies (Power James, 2007). Coordination challenges rise in many daily activities so it is important for patients to focus on the movements that impact their daily function (Power James, 2007).

Balance exercises are used throughout physical therapy sessions for individuals with

Friedreich’s ataxia to maintain stability when sitting, walking, standing, and moving (Power

James, 2007). It usually consists of concentrating on balancing throughout a certain task and using repetition to improve stability (Power James, 2007). Finally, conditioning exercises are important in Friedreich’s ataxia regimes to promote cardiovascular health and prevent diabetes mellitus from developing over time (Power James, 2007). Patients often complete cardio exercises by using a stationary bike or completing pool exercises (Power James, 2007).

While physical therapy is a powerful tool for maintaining function and managing FA symptoms, there is also an emotional component of going to physical therapy that individuals with Friedreich’s ataxia often face. Since Friedreich’s ataxia is a progressive disorder, many FA individuals get discouraged and frustrated when they are tirelessly working to improve a symptom that will ultimately negatively progress (Harvey, 2018). Still, it is important to remain positive. In her blog “My Darling Disability,” FA patient Kendall Harvey explained, “I have to keep trying to stay mobile and strong while the scientists try to find a cure. That’s my job.”

Occupational Therapy

Occupational therapy is also a common treatment for symptom management in

Friedreich’s ataxia to promote patient independence as they cope with the condition.

Occupational therapists can help identify issues that are restricting a patient’s quality of life and advise adaptations that can help improve each situation (Flavell, 2017). Occupational therapy programs are usually tailored specifically to each patient’s lifestyle and needs since what is valuable for one person may not benefit another (Flavell, 2017). Since many FA individuals experience difficulties walking, occupational therapists often recommend FA patients with mobility devices to aid them in walking prior to using a wheelchair (Flavell, 2017). Occupational therapists also help teach their patients how to adapt to a certain device or transfer into using a wheelchair part-time or full-time (Flavell, 2017). Occupational therapists will also advise techniques to combat daily fatigue and risk of injuries in their personal lifestyle (Flavell, 2017). For example, patients who struggle with swallowing due to decreased coordination may be advised to use lidded cups, rocker knives, nonslip mats, or weighted cutlery (Flavell, 2017). FA individuals who struggle when typing on a keyboard may be advised to use a voice-activated software to complete their projects (Flavell, 2017). Occupational therapy serves as a valuable component of coping with Friedreich’s ataxia because individuals who are dealing with the condition can improve basic functioning in their daily activities and retain their personal independence.

Drug Trial and Pharmaceutical Treatments

While there is no cure for Friedreich’s ataxia, several antioxidants have slowed progression by reducing damage in the heart and nerve cells (Kearney, Orrell, Fahey,

Brassington & Pandolfo, 2016). One of the most common antioxidants, Coenzyme Q10, helps

FA patients by reducing the oxidation of proteins, lipids, lipoproteins, and DNA (Parkinson,

Schulz & Giunti, 2013). While Coenzyme Q10 is commonly known as a heart supplement in low doses (100 mg), the antioxidant is paired with vitamin E supplements in both high-dose groups (

600mg CoQ10 / 2100IU vitamin E) and low-does groups (30 mg CoQ10 / 24 IU vitamin E) in recent medical trials (Cooper & Schapira, 2007). In recent trials, Coenzyme Q10 has been shown to sustain or improve cardiac bioenergetics (Parkinson, Schulz & Giunti, 2013). Similarly,

Idebenone is a synthetic analog of coenzyme Q10 that has been popular in recent clinical trials associated with Friedreich’s ataxia (Kearney, Orrell, Fahey, Brassington & Pandolfo, 2016).

Many patients also take Vitamin E antioxidants to prevent peripheral neuropathy that comes with its deficiency in Friedreich’s ataxia (Kearney, Orrell, Fahey, Brassington & Pandolfo, 2016). N- acetylcysteine, commonly known as NAC, is a classical antioxidant that has been positive in Friedreich’s ataxia trials for protecting frataxin levels in various cell types (Petrillo, D’Amico,

La Rosa, Bertini & Piemonte, 2019). Selegiline is an antioxidant that has been used to increase energy levels and decrease fatigue by increasing catalase activity and protecting neurons from toxicity (Kearney, Orrell, Fahey, Brassington & Pandolfo, 2016). Selegiline is primarily a selective, irreversible inhibitor of monoamine oxidase B (MAO-B) (Kearney, Orrell, Fahey,

Brassington & Pandolfo, 2016).. It is used as a treatment for motor symptoms in Parkinson’s disease and as an antidepressant since it is able to slow the breakdown of specific neurotransmitters such as dopamine, serotonin, and norepinephrine (Kearney, Orrell, Fahey,

Brassington & Pandolfo, 2016). Alpha‐tocopheryl quinine EPI‐A0001 serves as a metabolic stimulator in Friedreich’s ataxia (Kearney, Orrell, Fahey, Brassington & Pandolfo, 2016).

Recently, medical trials with A0001 have shown to protect fibroblasts and increase mitochondrial function in individuals with the condition (Kearney, Orrell, Fahey, Brassington &

Pandolfo, 2016). Finally, pioglitazone is a common antioxidant that is used to treat diabetes mellitus in patients with Friedreich’s ataxia by increasing enzyme expression during mitochondrial metabolism (Kearney, Orrell, Fahey, Brassington & Pandolfo, 2016).

There are several important non-antioxidant pharmaceuticals that have been studied in various clinical trials to treat Friedreich’s ataxia. Many FA patients are prescribed to take medications that help reduce cardiac workload and stabilize a heart arrhythmia (Flavell, 2017).

Beta blockers, Angiotensin-converting enzyme (ACE) inhibitors, and diuretics are valuable for increasing heart function by decreasing its workload (Payne, 2011). Histone deacetylase

(HDAC) inhibitors have been positive in FA studies for restoring levels of frataxin protein by inhibiting acetyl group removal (Payne, 2011). Benzamides have showed positive results in drug trials for activating the expression of the frataxin gene in mice models but have also induced negative effects that halted progress in clinical trials (Sandi, et al., 2011) Deferiprone is a useful iron chelator that combats the effects of FA by binding iron and reducing oxidative stress, so it been efficient in slowing neurodegeneration (Pandolfo & Hausmann, 2013). Erythropoietin

(EPO) benefits the hearts of FA individuals by regulating the production of red blood cells

(Mariotti, et al., 2013).

Another researched treatment for Friedreich’s ataxia has been Exenatide, which is also used in research for patients with Parkinson’s disease (Igoillo-Esteve, et al., 2020). Exenatide improves glucose homeostasis in patients who have impaired frataxin levels by enhancing insulin production and pancreatic β cell secretion (Igoillo-Esteve, et al., 2020). Targeting nuclear factor erythroid 2-related factor 2 (NRF2) signaling to regulate mitochondrial function has also been a researched treatment to combat FA (Petrillo, D’Amico, Rosa, Bertini, & Piemonte, 2019). NRF2 signaling is severely impaired in Friedreich’s ataxia patients, so targeting NRF2 activation can improve mitochondrial efficiency and frataxin development in FA individuals (Petrillo,

D’Amico, Rosa, Bertini, & Piemonte, 2019). Finally, resveratrol is a natural compound with a multitude of effects being investigated, including support of heart health, and that is possibly targeting frataxin increase in cells. And lastly, interferon gamma-1b is a pharmaceutical treatment with known immunosuppressive action that also inhibits bone degradation in patients with Friedreich’s ataxia (Lynch, et al., 2019).

Gene Therapy Research

Since the underlying cause of Friedrich’s ataxia is a single gene mutation, many researchers are looking to gene therapy research and gene editing techniques as a promising cure for the condition (Inacio, 2017). Gene therapy involves correcting erroneous gene mutations with new genetic material to eliminate or silence the effects of the genetic abnormality (Inacio, 2017).

One technique to complete this is through gene augmentation therapy, where the mutated gene is replaced by a healthy gene (Inacio, 2017). Another strategy that scientists have been researching is gene inhibition therapy, which involved inactivating the mutated gene to silence its effects

(Inacio, 2017). A third common gene therapy strategy that is being studied deals with managing the damage caused by FA to help fight the disease instead of working to correct the underlying genetic mutation (Inacio, 2017). Regardless of the technique, gene therapy involves transferring a DNA sequence of new genetic material to a patient’s cells via a vector, such as a deactivated virus host (Inacio, 2017). There are also nonviral methods for transferring the genetic information, such as through electroporation, ultrasounds, gene guns, or liposomes (Inacio,

2017). Though nonviral techniques are more cost effective and easier to produce, they can be less effective in the DNA transfer (Inacio, 2017).

While gene therapy techniques are promising for the future, researchers have faced obstacles in gene delivery and activation (Inacio, 2017). Treatments are also expensive and quite risky due to the complications that have yet to be resolved (Inacio, 2017). Still, studies have shown that it could be the missing puzzle piece to cure Friedreich’s ataxia. One heavily researched gene therapy technique that has been used in FA trials is an RNA-based therapy strategy where functional frataxin mRNA is delivered to ribosomes via lipid nanoparticles

(Inacio, 2017). Researchers are also looking at utilizing synthetic RNA-based molecules to halt the excessive GAA trinucleotide expansion that occurs on chromosome 9 for FA patients (Inacio,

2017). This would reactivate regular transcription in the FXN gene (Inacio, 2017). Although they are facing various obstacles, many researchers believe that gene therapy research will ultimately be the cure for Friedreich’s ataxia. Closing

As a progressive neuromuscular disease, Friedreich’s ataxia is a rare autosomal disorder that affects thousands of people throughout the United States. Though FA was originally identified in nineteenth century, researchers only gained a better understanding of the genetics being the disease in the 1990s. Since Friedreich’s ataxia is a result of a recessive genetic defect, it can only be inherited when an individual receives two copies of the mutated genes. This is what leads to neurodegeneration, loss of balance, impaired coordination, scoliosis, cardiac problems, and diabetes. Since carriers remain unaffected, researchers believe that a future cure for Friedreich’s ataxia only needs to heighten defective frataxin levels to 50% of what is normal.

There has been a multitude of research about Friedreich’s ataxia that has sparked hope in the

Fredrich’s ataxia community. Treatments have included physical therapy, occupational therapy, pharmaceutical trials, and gene therapy research. Through this aggressive research, a cure for

Friedreich’s ataxia may be just around the corner. References

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