Friedreich Ataxia

What is Friedreich Ataxia?

Friedreich ataxia (FA) is a genetic disorder that accounts for about half of all ataxia cases, a condition that affects movement and coordination. This condition was first noted in 1863 by a German doctor named Nikolaus Friedreich, and it’s characterized by damage to the nervous system resulting in problems with walking, muscle weakness, loss of sensation, distorted sense of body position (proprioception), and slurred speech. The disease is usually inherited from both parents (autosomal recessive inheritance), with symptoms typically showing up during childhood. As time goes on, the symptoms of this disease become more severe, leading to further health complications. Some individuals may require the assistance of wheelchairs, lose their sight and hearing, and may also develop other health problems like diabetes and an abnormal curve in the spine (scoliosis).

The most common cause of death for those with Friedreich ataxia is due to a heart condition known as hypertrophic cardiomyopathy. Individuals with FA have an unusual amount of repeating patterns of three DNA bases (trinucleotide repeats) on a gene located on chromosome 9 called the frataxin (FXN) gene. This gene is responsible for making the frataxin protein, an important substance that helps produce enzymes necessary for the production of energy in our cells (adenosine triphosphate or ATP) and the management of iron stores. In those with FA, these abnormal repeats cause the gene to be silenced, leading to a decrease in frataxin. Cells that are particularly active and depend on ATP production, like nerve cells (neurons), heart muscle cells (cardiomyocytes), and insulin-producing cells in the pancreas (pancreatic beta cells), are negatively affected.

What Causes Friedreich Ataxia?

Friedreich’s ataxia (FA) is caused by a problem in the frataxin gene, which is located on chromosome 9q, the 9th chromosome in the centromeric region (9q13-21.1). This gene makes the protein frataxin. Frataxin is important because it helps regulate iron and energy production in cellular powerhouses called mitochondria. Frataxin is found in all tissues of the body, but particularly in the nervous system, heart, and in insulin-producing cells of the pancreas.

Without frataxin, iron starts to gather in the mitochondria, and this iron reacts with oxygen to create harmful molecules known as free radicals. At the same time, the ability of the mitochondria to defend against these free radicals decreases. This is particularly harmful to cells that make a lot of frataxin, and the lack of this protein leads to the death of certain cells, specifically nerve cells, heart cells, and insulin-producing cells.

Friedreich’s ataxia is mainly caused by a repeat of three nucleotides (the building blocks of DNA), GAA (guanine-adenine-adenine) in specific areas of the frataxin gene. While in a healthy gene there would be 7-34 repeats, in someone with FA, there can be 66-1700. This repeat causes the frataxin gene to be less active in making the frataxin protein.

Repeats of GAA can affect when the disease starts and how quickly it progresses. Larger repeats cause the disease to start earlier, progress faster, and be more severe. The repeats are generally stable if they’re interrupted by other sequences. However, if the repeats are not interrupted, they can expand dramatically and cause disease.

People with FA usually have these GAA repeat expansions in both copies of their frataxin genes. However, about 4% of people with FA have these repeats in one gene and another type of genetic change, called a point mutation, in the other. The severity of the disease depends on where the mutation is located within the gene. Mutations that affect certain parts of the frataxin gene cause less severe symptoms than those that affect other parts.

There are several common mutations in the frataxin gene. Three of the most common are the II54F mutation mostly found in Southern Italians, the ATG>ATT mutation at the start of gene, and the G130V mutation, which is known to cause a less severe form of the disease. The symptoms can vary in those who carry these mutations, such as onset of symptoms after the age of 25, normal or increased reflexes, and muscle weakness without balance issues.

There have been a few documented cases of Friedreich’s ataxia in families where the specifics of the gene mutations differ, but these cases are rare.

Risk Factors and Frequency for Friedreich Ataxia

Friedreich’s ataxia (FA) is a common inherited condition that disrupts coordination, making up about half of all cases of this kind, and three-quarters of cases in people under 25. It affects 1 in every 50,000 people in the United States, and is more common in people from Western Europe. The disease is found everywhere in the world, but it’s seen a lot in Europe, the Middle East, South Asia, and North Africa.

FA is particularly common in people of European descent, likely because the genetic mutation that causes it can be traced back to a common European ancestor. It’s estimated that 1 in 75 people carry this mutation. It’s also worth mentioning that FA affects men and women equally. Typically, the condition starts showing up in early adolescence, most commonly when a person is between 8 and 15 years old.

Signs and Symptoms of Friedreich Ataxia

Ataxia typically shows up in a young patient as having trouble with coordinated movements, especially when walking. Symptoms start off gradually, often with difficulty standing or running. This can happen in kids or teenagers who previously had normal physical development. Some patients might initially experience these coordination issues on one side of their body, but this usually spreads to affect all parts of their body. A fever can sometimes lead to these symptoms.

Those with ataxia often walk with a wide stance and have to keep shifting to stay balanced. When they try to correct their balance, it may result in uncontrolled movements. Patients might also display a walking pattern where the soles of their feet irregularly hit the floor. This is due to the loss of sensation. The condition gradually affects the upper body, leading to irregular movements while sitting and standing, affecting the arms and resulting in involuntary trembling or jerky movements. There may also be uncontrolled facial movements. Over time, the patients may lose their ability to move around without help, progressing from using a walker to a wheelchair, until they are confined to their bed.

Other symptoms may include:

• Feeling weak, tired, or sleepy during the day
• Slurred and slow speech, which may eventually become hard to understand
• Difficulty swallowing, which when combined with problems with speech and coordination, may result in choking
• Loss of vision due to damage to the nerves responsible for sight
• Impaired mental functions, especially in planning or organizing tasks

A family history of FA could be important for diagnosis.

• Musculoskeletal Exam:
• Progressive difficulty with movement and coordination, typically starting in adolescence
• Incoordination of the upper body
• Muscle weakness and reduced muscle tone
• Shrinking muscles
• Foot deformities, high arch, foot inversion, bent toes
• Kyphoscoliosis, an abnormal curve of the spine

• Neurological Exam:
• Diminished or absent reflexes
• Abnormal muscle responses
• Muscle spasms
• Nerve issues that affect the senses
• Loss of touch and pressure sensation
• Loss of awareness of body position and vibration
• Loss of sensitivity to pain and temperature
• Difficulty speaking
• Impaired coordination
• Issues with bladder control
• Decline in vision
• Jerky eye movements
• Difficulty moving the eyes
• Abnormalities in eye reflexes, deafness, and a sense of spinning

• Psychological Exam:
• Minor difficulties in executive functioning
• Rapid shifts in emotion

• Cardiovascular Exam:
• Bluish color in extremities due to reduced blood flow
• Enlarged heart
• Rapid heartbeat
• Irregular heartbeat
• Additional or abnormal heart sounds

Testing for Friedreich Ataxia

Diagnosing Friedreich’s Ataxia (FA), a genetic disease that affects nerves in the arms and legs, is largely based on your medical history and a physical examination. The tests conducted aren’t so much to confirm FA, but to eliminate other possible conditions and to check for serious complications of the disease.

To rule out other causes, your doctor might ask for several tests. They may include:

– Blood sugar test: This measures the level of glucose in your blood. A high blood glucose level may indicate diabetes.

– Vitamin E level: Deficiency of this vitamin can affect the nervous system and it’s important to rule out.

– Electromyography: This is a diagnostic test that evaluates the health of muscles and the nerve cells that control them.

– Nerve conduction studies: This involves attaching small patches (electrodes) on your skin to measure how fast nerves are transmitting signals. If this test shows absent or very weak nerve signals, it’s a significant clue.

If these tests suggest you could have FA, then there are further tests your doctor will consider:

– Genetic Testing: The key test for FA is genetic testing. This involves a blood test that looks for an abnormality in the gene linked to FA. This particular test is the only one capable of detecting the specific type of genetic abnormality (known as GAA repeats) that cause the disease. There is also a prenatal version of this test for expecting parents who want to check if their unborn child has FA.

– Imaging: The preferred type of scan for FA is Magnetic Resonance Imaging (MRI), which enables a detailed view of different parts of your body. People suspected of having FA should have an MRI of the brain and spinal cord, as the disease specifically causes atrophy (shrinking of muscle mass) in these areas.

Depending on your symptoms, your doctor might also ask for other tests. These could include:

– An electrocardiogram: This test measures your heart’s rhythm to detect irregularities. In the case of FA, it can show fast heart rate or a heart condition known as atrial fibrillation.

– An echocardiogram: This ultrasound test of the heart can show if your heart’s muscle has thickened. In some FA patients, it can also show if the wall separating the left and right sides of the heart (septum) has thickened unevenly.

– Auditory testing: Your hearing might be checked to see if specific sound waves, known as waves III and IV, are missing. But wave I is typically still present in FA patients.

– Vision testing: This can detect delays in the time it takes for visual information to go from your eyes to your brain, as well as issues with the intensity of certain types of visual information (for example, the p100 wave).

Treatment Options for Friedreich Ataxia

Despite being identified more than 150 years ago, there isn’t currently a cure for Friedreich’s ataxia (FA) – a rare genetic disease that affects the nervous system causing problems like balance and coordination difficulties, heart disease, and diabetes.

The main emphasis in treatment is managing symptoms and dealing with complications like diabetes and heart failure.

Physical therapy (PT) plays a critical role in slowing down disease progression and maintaining function. PT aims to strengthen body posture and promote muscle use through exercises designed to improve coordination, balance, strength, and stabilization. These exercises help patients maintain Practical use of their limbs, manage scoliosis (a condition that causes a sideways curvature of the spine), and improve ataxia (a lack of muscle control). Exercises known as Frenkel exercises and something called proprioceptive neuromuscular facilitation stretching are used to try to improve body position sense. Additionally, physical therapists also use muscle relaxation and stretching exercises to manage muscle spasticity (a condition where muscles are continuously contracted) and prevent deformities in the back and foot. Breathing exercises are also fundamental.

Occupational therapy focuses on helping patients maintain independence by teaching them techniques such as safely transferring from a chair to a bed, mobilizing independently, falling safely, and utilizing mobility aids like wheelchairs.

Assistive devices, such as orthopedic shoes, canes, wheelchairs, and braces, can significantly help with movement, muscle spasms, and the prevention of scoliosis and other deformities. Other methods such as functional electrical stimulation and transcutaneous nerve stimulation can help alleviate walking difficulties caused by the disease.

Medications are also vital in managing the disease. Their primary function is to manage pain, treat heart failure, and prevent infections.

In certain cases, surgery might be necessary. This could be for conditions like kyphoscoliosis – an extreme curvature of the back in both the sideways and front to back planes. Surgeries can also be performed to correct foot deformities. In exceptional cases, devices like automated implantable cardioverter-defibrillators may be implanted, or heart transplants performed, particularly for patients who have severe heart disease due to FA.

What else can Friedreich Ataxia be?

When examining someone with Ataxia symptoms, several conditions can be considered, aside from Friedreich’s ataxia (FA). All these conditions will need different ways to distinguish from FA:

• Spinocerebellar ataxia (types 1, 2, 3) or pure cerebellar ataxia – this is a disease that starts early in life and causes poor coordination, eye problems, hearing loss, nerve issues, epilepsy, unusual movement, muscle disorders, nerve damage, brain shrinkage, and cognitive challenges. Imaging can show specific signs of brain shrinkage that is different from FA.
• Dentatorubro-pallidoluysian atrophy – this condition causes muscle spasms, epilepsy, unusual movement, behavioral changes, intellectual disability, and coordination problems. To differentiate it from FA, the patient’s behavior, psychiatric symptoms, and intellectual capabilities are considered.
• Demyelinating peripheral neuropathy or chronic inflammatory demyelinating polyneuropathy – this is an autoimmune disorder that causes muscle weakness and peripheral neuropathy. The presence of inflammation in the spinal fluid distinguishes it from FA.
• Roussy-Levy variant of Charcot-Marie-Tooth disease – this is a disease that leads to areflexia (absence of neurologic reflexes) and coordination problems. It separates from FA through the pattern of inheritance and the presence of dysmyelination (a process that damages the protective covering of nerve fibers).
• Cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss syndrome – This disorder is caused by a single mutation of a specific gene. Genetic testing distinguishes it from FA.
• Episodic ataxia – This is differentiated from FA through patient history.
• Autosomal recessive spastic ataxia of Charlevoix-Saguenay – A disease caused by a gene mutation, characterized by early muscle stiffness, poor coordination, and peripheral neuropathy. Brain MRI, showing involvement of the pons, distinguishes it from FA.
• Abetalipoproteinemia (Bassen-Kornzweig disease) – This disease is caused by a gene mutation that affects fat absorption, cholesterol/triglyceride levels, eye health, peripheral neuropathy, and coordination. The condition is differentiated from FA by checking lipid levels and improvement with fat-soluble vitamin supplementation.
• Drug-induced ataxia – This can be differentiated from FA by patient history and the resolution of symptoms when the drug causing symptoms is removed.
• Ataxia with vitamin E deficiency – This disease is caused by a mutation in a specific gene leading to coordination issues, nerve problems, and retinitis pigmentosa (an eye disorder that affects the retina). It is differentiated from FA by checking vitamin E levels and an improvement in symptoms with vitamin E supplementation.
• Ataxia-telangiectasia – A disease caused by a gene mutation that leads to poor coordination, abnormal eye movements, other neurological disorders, immune deficiency, and skin and eye telangiectasias. It is distinguished from FA by checking the alpha-fetoprotein levels.
• Refsum disease – A disease caused by a gene mutation leading to increased phytanic acid levels, retinitis pigmentosa, dry and rough skin, peripheral neuropathy, poor coordination, and hearing loss. The condition is differentiated from FA by checking phytanic acid levels and improvement with dietary restriction.

What to expect with Friedreich Ataxia

In general, Friedreich’s ataxia (FA) has a challenging prognosis. Most people with this condition end up needing a wheelchair by age 45, and the average duration of the disease is between 15 to 20 years. The main cause of death for these patients is due to heart issues, specifically problems like heart failure or abnormal heart rhythms.

Heart issues are the most common cause of death in these patients. On average, people with this condition pass away at 36.5 years old, although ages can range from as young as 12 to as old as 87. Two out of three patients sadly succumb to heart failure or abnormal heart rhythms.

Possible Complications When Diagnosed with Friedreich Ataxia

Cardiac conditions:

• Inflammation of heart muscle (Myocarditis)
• Scarring in the heart muscle (Myocardial fibrosis)
• Abnormally large heart (Cardiomegaly)
• Equal enlargement of heart muscles (Symmetrical hypertrophy)
• Heart failure due to an enlarged or thickened heart muscle (Congestive heart failure caused by dilated or hypertrophic cardiomyopathy)
• Fast heart rate (Tachycardia)
• Irregular and rapid heartbeat (Atrial fibrillation)
• Slowed down electrical signals in the heart (Heart block)

Muscle and skeleton related conditions:

• A severe spinal curvature that can cause heart and breathing problems (Kyphoscoliosis)
• High-arched foot (Pes cavus)

Endocrine conditions:

• Blood sugar disease (Diabetes mellitus)

Preventing Friedreich Ataxia

Friedreich’s ataxia (FA) is a genetic disease, which means you can’t prevent it because it’s inherited. This disease usually starts to show signs while a person is still a child or in their early teenage years, especially between the ages of 8 and 15. If a family has one kid with this disease, there is a one in four chance that any of their other children could also inherit it. If the parents are closely related (a consanguineous union), the likelihood of their child having FA increases.

Before deciding to have children, genetic testing and advice (genetic counseling) is important because it can help figure out whether one or both parents carry the gene that causes this disease and how likely it is that their child could have FA. Even if only one parent passes on the defective gene, the child will be a carrier of it.

Unfortunately, there isn’t a cure for this disease, so the symptoms tend to get worse over time. Eventually, most people with FA end up needing things like wheelchairs to help them move around because their muscle coordination gets worse. They may also lose their sight and hearing, and develop additional health problems like diabetes and an abnormal curvature of the spine (scoliosis). However, those people with milder symptoms can often live longer, sometimes even into their sixties. The most common cause of death among people with FA is a disease called hypertrophic cardiomyopathy, which makes the heart muscle abnormally thick.

It’s very important for anyone with this disease to see a heart specialist (cardiologist), as this disease can also affect the heart. They will need to have their heart closely checked throughout their whole life.