Friedreich’s ataxia (FA or FRDA) is a rare autosomal recessive inherited condition that results in movement problems and progressive impairment of the nervous system.
It is caused by a mutation of a gene locus on chromosome 9. There is an expansion of an intronic GAA triplet repeat in the FXN gene. This genetic mutation can lead to reduced expression of frataxin, a protein in the mitochondria. This may cause frequent fatigue because of the effects on cellular metabolism.
A German doctor and professor of medicine named Nicholaus Friedreich was the first person to describe the disorder in that’s why the disorder was named after him.
The condition usually begins in childhood and results in ataxia that gets worse over time.
A lot of individuals have childhood onset of the symptoms of FA which occur between the ages 5 and 18 years. Adult onset is not that common for FA and it can occur anytime during adulthood but about 25% of individuals with FA manifest signs and symptoms of FA after age 25. Late-onset FA (LOFA between ages 26 and 39) and very late onset FA (VLOFA after age 40) normally progress more slowly compared to the ones that have early onset of the disorder. The first noticeable symptoms of FA are poor balance and coordination but some affected individuals may have a loss of muscle control affecting one side of the body (hemiataxia) initially before the other symptoms arise. In other cases, the ataxia starts immediately after a fever wherein ataxia of one lower extremity precedes that of the other.
Friedreich’s ataxia is also called spinocerebellar degeneration. It can cause impaired speech, hearing and vision, difficulty walking, poor balance and coordination like gait disturbance, gradual loss of sensation in the arms and legs, and muscle stiffness.
This disorder causes damage to the spinal cord and some parts of the brain. It can also cause heart diseases, diabetes, and scoliosis. The most frequent heart disease suffered by individuals with FA is hypertrophic cardiomyopathy which weakens and enlarges the heart muscle and can also be life-threatening. This condition does not affect cognitive functions such as reasoning and thinking abilities.
FA is a recessive disorder which only occurs in an individual who acquires two abnormal copies of the gene which is ideally one from each of his/her parent. This is a rare disorder but it is the most prevalent form of autosomal recessive ataxia accounting for at least 50% of the cases of hereditary ataxia. It is the earliest type of inherited ataxia to be distinguished among other locomotor ataxias. It affects approximately 1 in every 50,000 people. It can affect any person of any age and any gender.
Friedreich’s ataxia is a rare autosomal recessive disorder that can be inherited from recessive genes of the parents, one from the mother and another one from the father.
An individual who only has one defective copy of the gene is known as a carrier wherein he/she will not have FA but he/she could pass on the gene mutation to his/her kids.
If a couple is both carriers of FA, their kids will have 25% possibility of having the disorder and 50% possibility of inheriting one defective gene that they could pass on to their kids. The risk of developing FA is highest for those kids with both parents as carriers. In Europe and North America, most cases are sporadic and occur in nonconsanguineous families.
FA is caused by the FXN gene that contains amplified trinucleotide repeat expansion which is located on chromosome 9. The FXN gene encodes the protein frataxin. The FA gene mutation limits the production of frataxin, an important protein that functions in the mitochondria of the cell. A sequence of DNA called “GAA” is repeated between 7 to 22 times in the normal version of the FXN gene, but the repeat of the sequence occurs over a hundred up to a thousand times in the abnormal FXN gene. This defective pattern which is also known as a triple repeat expansion is the common cause of dominant genetic disorders and Friedreich’s ataxia is the only known recessive inherited disease that is a result of this kind of mutation.
Although almost all individuals who are affected by FA have two copies of the defective FXN gene, around 2% of affected people have other kinds of defects in the FXN gene that is liable for causing the condition.
The triple repeat expansion strongly interrupts the normal production of the protein frataxin which can be found in the mitochondria, the energy-producing area of the cell. Frataxin helps in moving iron and takes part in the formation of iron-sulfur clusters that are essential components in the energy production of the mitochondria. Without the normal production of frataxin, specific cells in the body such as the brain and heart muscle cells, spinal cord, and peripheral nerve, cannot adequately produce energy. Abnormal levels of frataxin are believed to allow a buildup of toxic byproducts resulting in oxidative stress and may also result in elevated levels of iron in the mitochondria. Free radicals are produced when the excess iron behaves with oxygen. These free radicals can harm the body and destroy cells even if they are essential molecules in the metabolism of the body.
The signs and symptoms of ataxia typically begin between age 5 to 15 years while in the late or adult onset, they may manifest in the 20s or 30s. In rare occasions, it may occur as late as the age of 75. The initial symptom that usually appears is a difficulty in walking or gait ataxia. The ataxia worsens little by little and it slowly spreads to the trunk and arms. The symptoms may vary depending on the individual and may include any combination of the following:
- Vision impairment
- Hearing impairment
- Muscle weakness in the legs and arms
- Slow and slurred speech
- Loss of coordination
- Loss of sensation in the extremities that can spread to other body parts
- Loss of tendon reflexes especially in the ankles and in the knees
- Chest pain
- Palpitations of the heart
- Shortness of breath
- Progressive staggering
- Frequent falling
- Stumbling gait
- Weak muscles
- Lack of reflexes in the legs
- Involuntary eye movements
- Difficulty sensing vibrations in the feet and legs
- Foot deformities
- Scoliosis that usually requires surgical intervention
- Carbohydrate intolerance
- Heart disorders such as hypertrophic cardiomyopathy, tachycardia, cardiac failure, heart block, and atrial fibrillation
- High plantar arches
Most FA patients get easily tired and require more rest. They also require longer periods of recovery for common illnesses like flu and colds.
FA is a progressive disease but the rate of progression varies per individual.
The symptoms are slow and progressive. A lot of patients reach a plateau in symptoms in their early adulthood. A patient with FA usually needs a wheelchair and requires assistance with all their daily activities within 10 to 20 years after the occurrence of the primary symptoms of FA. In later stages, they may become completely impaired.
FA can shorten an individual’s lifespan and the heart disease caused by FA is the usual cause of death. Some patients with less severe symptoms of FA can live up to their sixties, seventies, or even older.
Friedreich’s Ataxia is suspected in a person based on clinical examination but the conclusive diagnosis is verified by molecular genetic testing. Molecular genetic testing can show the mutations in the FXN gene that causes the disease.
To diagnose FA, the doctor checks the suspected patient’s medical history and performs a complete physical exam that includes a detailed neuromuscular exam. The exam focuses on detecting problems with the nervous system. The signs of damage include lack of sensation in the joints, loss of proprioception, lack of reflexes, signs of neurological problems, and poor balance.
There are other tests that can help in the diagnosis and management of the disease:
- Electrocardiogram (ECG) – gives a graphic presentation of the beat pattern of the heart or its electrical activity
- Electromyogram (EMG) – measures the electrical activity of muscle cells
- Echocardiogram – records the motion and position of the heart muscle
- Computed tomography (CT) or magnetic resonance imaging (MRI) scans – tests that provide images of the spinal cord and brain that are helpful in ruling out other neurological conditions
- Nerve conduction studies – measures the speed with which nerves transmit impulses
- Blood tests – used to determine vitamin E and heightened glucose levels
Prenatal diagnosis via direct mutation testing is also available.
There is currently no known cure or even effective treatment for Friedreich’s ataxia just like other forms of ataxia and other degenerative disorders of the nervous system.
However, treatment is available to ease the symptoms and the underlying conditions.
Non-surgical interventions like braces and other orthopedic devices or orthopedic surgery may be needed for treating scoliosis and deformation of the feet.
Medications are given to patients to treat diabetes and heart conditions that are affected by FA. Modification of diet, insulin, and/or oral hypoglycemic therapeutics may also be given to control diabetes mellitus.
Speech therapy is applied for those patients with impaired speech to help them in their verbal communication skills.
The use of assistive devices like walking aids, prostheses, and wheelchairs help a patient in doing his/her daily activities. Physical therapy helps strengthen the muscles and prolongs use of arms and legs.
Continuous medical supervision is recommended to a patient to prevent potential complications involving the spine, vision, hearing, muscles, feet, and the heart.
Genetic counseling is also advised for affected persons and their families because of the emotional strain that FA causes.
There are however treatment initiatives that are emerging.