Friedreich’s ataxia – symptoms and treatment

Definition of the disease. Causes of the illness

Friedreich’s ataxia is a rare genetic disorder that damages the cells of the cerebellum, spinal cord, medulla oblongata, pyramidal neurons, and nuclei of the cranial nerves.
The disease affects coordination of movements, weakens muscles, causes slurred speech, decreases tendon reflexes, and leads to foot deformities.

Friedreich’s ataxia is inherited in an autosomal recessive manner (i.e., when the mutant gene is inherited from both parents), but there are cases not linked to heredity. The onset of the disease usually occurs between 6 and 10 years of age, sometimes later, but cases have been described where the disease began in the first year of life. Friedreich’s ataxia affects 2 to 7 people per 100,000 population, affecting both human beings. The disease is not found in people of African descent.
Friedreich’s ataxia develops slowly but continuously, with rare minor remissions. During pregnancy, childbirth, any illnesses, and stresses, patients’ condition may worsen.

Symptoms of Friedreich’s ataxia

The clinical picture of Friedreich’s ataxia is characterized by damage to the central nervous, endocrine, and skeletal systems, cardiac muscle, and eyes.
The leading symptom of Friedreich’s ataxia is ataxia, or impaired coordination of movements. Until a certain age, children develop normally, walk well, run, and jump, but over time, parents notice that the child has developed a gait defect. Subsequently, there is uncertainty and swaying while walking, stumbling, and frequent falls. The patient walks with wide-set legs, makes abrupt, poorly controlled movements. It is difficult to stand steadily with the disease because weak muscles cannot bear the load. Running becomes easier than walking slowly. The disease also features a high and concave arch of the foot. Otherwise known as such deformation in the form of a strongly curved sole is called Friedreich’s foot, or ‘horse’ foot.

Friedreich’s ataxia usually begins with gait disturbance, then speech and hand function deteriorate. The change in gait is caused by degeneration of cerebellar and spinal cord cells, which is accompanied by impaired proprioceptive sensitivity — the sensation of the position of parts of one’s own body relative to each other and in space.
A characteristic and early symptom of Friedreich’s ataxia is a decrease and absence of tendon reflexes, primarily radial, ulnar, and knee reflexes, and the appearance of pathological signs, such as Rossolimo’s sign (toes or fingers quickly flex when lightly tapped on their pads) and Babinski’s sign (the big toe sharply extends when stroked on the outer edge of the sole).

Despite motor disturbances, muscle strength may remain normal for a long time. Sensitivity is mostly preserved, but in some cases, it may worsen due to nerve damage. There are burning, stabbing, and shooting pains in the arms and legs, and paresthesias resembling crawling ants.
Damage to the cerebellum not only leads to awkward movements but also impairs speech, vision, and hearing. Fine motor skills are also affected – the patient’s hands tremble, it is difficult for them to draw a straight line, and the child begins to write worse: the letters in height and width become different. In the later stages of the disease, the patient cannot articulate sounds normally, resulting in slurred speech. Eventually, it takes on the form of mumbling or disappears completely.”

Pathogenesis of Friedreich’s Disease

Friedreich’s disease is a genetic disorder with an autosomal recessive mode of inheritance, meaning the disease develops if the child has two copies of the defective gene (one from each parent). The parents may be healthy carriers.

In the disease, there is a mutation in the FXN gene, which encodes the frataxin protein. This protein regulates iron transport in mitochondria and participates in ATP production – the main source of energy in the body. When the FXN gene is damaged, the amount of normal frataxin protein decreases.

Without frataxin, iron accumulates in mitochondria and reacts with oxygen, leading to the formation of free radicals and a decrease in the antioxidant capacity of mitochondria. Due to frataxin deficiency, cells eventually die, especially neurons, cardiomyocytes, and pancreatic cells.

Damage to neurons leads to a reduction in the size of the spinal cord, medulla oblongata, pons, and cerebellum. The cerebellum may decrease in size while maintaining normal structure or with the development of various degenerative changes: cortical atrophy, loss of Purkinje cells, involvement of white matter, and cerebellar nuclei. These changes affect the course of the disease, leading to muscle weakness.

Classification and Stages of Friedreich’s Disease

In the International Classification of Diseases (ICD-10), Friedreich’s disease is coded as G11.1 – Early-onset cerebellar ataxia, and in ICD-11, it is coded as 8A03.10 – Friedreich’s ataxia.

Friedreich’s ataxia belongs to the group of autosomal recessive inherited ataxias. This group also includes:

• Pierre Marie syndrome;
• Ataxia with vitamin E deficiency;
• Betalipoproteinemia;
• Ataxia-telangiectasia;
• Ataxia with oculomotor apraxia;
• Congenital ataxia;
• Early-onset cerebellar ataxia.

In addition to autosomal recessive ataxias, hereditary ataxias also include:

• Autosomal dominant ataxias, such as spinocerebellar ataxia;
• Metabolic X-linked ataxias, such as adrenoleukodystrophy;
• Mitochondrial ataxias – mitochondrial encephalomyopathy with lactic acidosis.

There are no distinct stages of Friedreich’s disease.

Complications of Friedreich’s Disease

Friedreich’s disease can be complicated by scoliosis and dementia. Patients lose their ability to critically assess events and care for themselves. Other complications may arise, including heart failure, diabetes, loss of hearing and vision, and disability (the patient becomes a wheelchair user).

Diagnosis of Friedreich’s Disease

When diagnosing Friedreich’s disease, it is important to carefully collect medical history and identify characteristic symptoms. Severe cases of the disease do not pose diagnostic difficulties. The familial nature of the disease greatly facilitates diagnosis.

When there is suspicion of Friedreich’s disease, a clinical neurological examination is conducted: reflexes, balance, and nerve sensitivity are checked.

Neurophysiological examination data are very important for diagnosing the disease. Instrumental methods such as ECG, ultrasound of internal organs, spinal X-rays, EMG, and ENMG are used. Friedreich’s ataxia is characterized by pronounced and early impairment of somatosensory evoked potentials, i.e., the brain begins to respond less to electrical impulses during electromyography (EMG).

MRI performed in the early stage of the disease may reveal a decrease in the transverse size of the spinal cord, including atrophic changes in the posterior columns (bundles of nerve fibers in the white matter of the spinal cord). The cerebellum remains relatively preserved for a long time, but moderate atrophic changes in the cerebellar vermis and hemispheres are visible at a late stage.

A definitive diagnosis of Friedreich’s ataxia can only be made based on genetic testing. To confirm autosomal recessive inheritance of the defective gene, genetic testing of the patient and their close relatives – parents, siblings – is conducted.

The diagnosis of Friedreich’s disease is based on the following criteria:

• Autosomal recessive inheritance;
• Onset of the disease before the age of 25;
• Progressive ataxia mainly due to involvement of the posterior columns;
• Dysarthria;
• Absence of tendon reflexes;
• Loss of deep sensation in the hands and feet;
• Axonal sensory neuropathy;
• Changes in ECG;
• Development of Friedreich’s foot.

Differential Diagnosis

Friedreich’s ataxia should be distinguished from the following conditions:

• Multiple sclerosis: Both conditions involve weakened muscles, but multiple sclerosis is characterized by Charcot’s triad: intention tremor (trembling of the hands and legs during movement, especially at the end of an action, such as touching the nose with a finger), nystagmus, and scanning speech (slow speech with pauses at the beginning of a word or syllable). However, symptoms at the onset of the disease are not constant and typically manifest under stress. Additionally, multiple sclerosis is characterized by characteristic changes in the optic nerve during fundoscopic examination, which are not present in Friedreich’s disease.
• Cerebral palsy: This condition is easily distinguishable from Friedreich’s disease because only the cerebellar pathways are affected in cerebral palsy.
• Neurosyphilis: Diagnosis involves assessing symptoms and conducting serological blood analysis and examination of cerebrospinal fluid.
• Tumors or tuberculomas of the cerebellum: Friedreich’s disease can be confirmed with MRI of the brain and spinal cord (no tumor is visible on the images).
• Pierre Marie syndrome: This syndrome has a dominant inheritance mechanism, meaning that inheriting the defective gene from one parent is sufficient for its development. It typically manifests after 20-30 years of age and differs in degenerative changes of the nervous system.

Treatment of Friedreich’s Disease

There are currently no drugs specifically for Friedreich’s disease. Research is ongoing, but these are pilot projects.

To alleviate symptoms, the following approaches are used:

• Massage, therapeutic exercise, and kinesiology. Sometimes osteopathy is used, but its effectiveness has not been scientifically proven.
• Occupational therapy: Patients learn to perform daily tasks, such as gluing and assembling a box, and moving it to the desired location. Training is usually conducted in specialized educational institutions or psychiatric hospitals.
• Speech therapy methods if speech is affected.
• Conservative and surgical orthopedic treatment: Surgery temporarily improves gait and may help with spinal curvature and foot deformities. Conservative methods include orthopedic footwear.
• B vitamins, cofactors of energy enzymatic reactions, mitochondrial respiratory chain activators, antioxidants, and chelating agents, which help reduce iron accumulation in mitochondria (the effectiveness of these drugs is currently insufficiently proven).
• Succinic acid preparations stabilize energy metabolism and increase mitochondrial efficiency.
• Antiarrhythmic drugs and medications for heart failure may be used for treating cardiac conditions.
• Dietary changes, the use of hypoglycemic agents and/or insulin may be indicated for diabetes control.

In Friedreich’s ataxia, energy metabolism is disrupted, so patients need to consume less carbohydrate-rich foods: excess carbohydrates can exacerbate metabolic disorders.

The following three treatment methods are currently in the research stage and are not yet used:

1. Introduction of normal FXN genes, which should compensate for the work of damaged genes. Although there are currently few studies in this direction, there are promising results: trials on patient cells with Friedreich’s disease have shown increased levels of frataxin and decreased sensitivity of treated cells to oxidative stress.
2. In 2010, a large-scale study of Idebenone was conducted in several European centers in people with Friedreich’s ataxia, but the effectiveness of the drug was not confirmed. However, an earlier six-month study involving 48 individuals showed improvement in neurological functions in patients receiving high doses of Idebenone.
3. In 2010, an Austrian research group reported the results of a small study in which 12 individuals received erythropoietin injections three times a week for eight weeks. In 8 out of 10 participants, the level of frataxin increased by 15–63%, and the severity of the condition decreased by 6%.

Prognosis:

Many patients with Friedreich’s ataxia lose the ability to walk and require a wheelchair within 10-20 years of symptom onset. The condition can also lead to the development of heart disease, diabetes, and shorten life expectancy. However, some patients may live to be 60-70 years old and beyond.

Prevention:

Modern treatment methods, such as orthopedic surgery, medication therapy, and speech therapy, aim to control the disease as much as possible.

To avoid potential complications associated with changes in the musculoskeletal system and heart involvement, patients are recommended to remain under medical supervision. While the condition is typically treated by a neurologist, assistance from other specialists such as endocrinologists, ophthalmologists, orthopedists, cardiologists, and radiologists may also be required. Prosthetics, crutches, wheelchairs, and physical therapy help maintain an active lifestyle.

Parents of patients with Friedreich’s ataxia are advised to undergo testing since they may carry the pathogenic variant of the FXN gene. Prenatal diagnosis may be useful for families where both parents are carriers to identify the possibility of the condition in advance.

Creating a supportive environment around the patient, where they can feel confident, learn, work, engage in creative activities, and build relationships, is also important for maintaining their quality of life.