Friedreich's ataxia


Friedreich's ataxia is an autosomal recessive genetic disease that causes difficulty walking, a loss of sensation in the arms and legs and impaired speech that worsens over time. Symptoms generally start between 5 and 20 years of age. Many develop hypertrophic cardiomyopathy and will require a mobility aid such as a cane, walker or wheelchair in their teens. As the disease progresses, people lose their sight and hearing. Other complications include scoliosis and diabetes mellitus.
The condition is caused by mutations in the FXN gene on chromosome 9. The FXN gene makes a protein called frataxin. In FRDA, the patient produces less frataxin. Degeneration of nerve tissue in the spinal cord causes the ataxia; particularly affected are the sensory neurons essential for directing muscle movement of the arms and legs through connections with the cerebellum. The spinal cord becomes thinner and nerve cells lose some myelin sheath.
No effective treatment exists, but there are several therapies in trials. FRDA shortens life expectancy due to heart disease and some people can live into their sixties or older.
FRDA affects 1 in 50,000 people in the United States and is the most common inherited ataxia. Rates are highest in people of Western European descent. The condition is named after the German physician Nikolaus Friedreich, who first described it in the 1860s.

Signs and symptoms

Symptoms typically start between the ages of 5 and 15, but in Late Onset FRDA they may occur after age 25 years. The progressive loss of coordination and muscle strength leads to loss of ambulation and the full-time use of a wheelchair. Most young people diagnosed with FRDA require mobility aids such as a cane, walker, or wheelchair by their childhood or early 20s.
The disease is progressive with increasing staggering or stumbling gait and frequent falling. Lower extremities are more severely involved. On average, after 10–15 years, people lose the ability to stand or walk without assistance. However, disease progression is variable, and people may be able to walk decades after onset, while others require a wheelchair within a few years.
Symptoms may include the following:
FRDA is an autosomal recessive disorder that affects a gene on chromosome 9 which produces an important protein called frataxin.
In 96% of cases the mutant FXN gene has 90–1,300 GAA trinucleotide repeat expansions in intron 1 of both alleles. This expansion causes epigenetic changes and formation of heterochromatin near the repeat. The length of the shorter GAA repeat is correlated with the age of onset and disease severity. The formation of heterochromatin results in reduced transcription of the gene and low levels of frataxin. People with FDRA might have 5-35% of the frataxin protein compared to healthy individuals. Heterozygous carriers of the mutant FXN gene have 50% lower frataxin levels but this decrease is not enough to cause symptoms.
In about 4% of cases the disease is caused by a point mutation, where the patient has an expansion in one allele and a point mutation in the other. A missense point mutation can have milder symptoms.
Depending on the point mutation a patient may end up with no frataxin, nonfunctional frataxin or frataxin that is not properly localized to the mitochondria.

Pathophysiology

FRDA affects the nervous system, heart and pancreas and other systems. Degeneration of nerve tissue in the spinal cord causes ataxia. The sensory neurons essential for directing muscle movement of the arms and legs through connections with the cerebellum are particularly affected. The disease primarily affects the spinal cord and peripheral nerves. The spinal cord becomes thinner and nerve cells lose some myelin sheath. The diameter of the spinal cord is smaller than that of unaffected individuals mainly due to smaller dorsal root ganglia. The motor neurons of the spinal cord are affected to a lesser extent than sensory neurons. In peripheral nerves there is a loss of large myelinated sensory fibers.
Structures in the brain are also affected by FRDA, notably the dentate nucleus of the cerebellum. In the heart, FRDA patients often develop some fibrosis, and over time many patients develop left ventricle hypertrophy and dilatation of the left ventricle.

Frataxin

The exact role of frataxin remains unclear. Frataxin assists iron-sulfur protein synthesis in the electron transport chain to generate adenosine triphosphate, the energy molecule necessary to carry out metabolic functions in cells. Frataxin also regulates iron transfer in the mitochondria by providing a proper amount of reactive oxygen species to maintain normal processes. One result of frataxin deficiency is mitochondrial iron overload, which damages many proteins due to effects on cellular metabolism.
Without frataxin, the energy in the mitochondria falls, and excess iron creates extra ROS, leading to further cell damage. Low frataxin levels lead to insufficient biosynthesis of iron–sulfur clusters that are required for mitochondrial electron transport and assembly of functional aconitase and iron dysmetabolism of the entire cell.

Diagnosis

Balance difficulty, loss of proprioception, an absence of reflexes, and signs of other neurological problems are common signs from a physical examination.
Diagnostic tests to support a physical examination include
Other diagnoses include Charcot-Marie-Tooth type 1 and 2, ataxia with vitamin E deficiency, ataxia-oculomotor apraxia type 1 and 2 and other early-onset ataxias.

Management

As there is no cure, physical therapy is ‘a way of life’ for the patient. Physical therapists have a critical role to play in educating patients and caregivers as to correct posture, muscle use and the identification and avoidance of features which aggravate spasticity such as tight clothing, poorly adjusted wheelchairs, pain and infection.
Because there is no cure, it is important that all FA patients engage with key community resources to contribute to the research process:
- : a database of all FA patients which can be used for accelerating research
- : an ongoing study charting FA over time which can be used for understanding the condition better.
- : an ongoing study charting FA over time which can be used for understanding the condition better.
- : the global patient alliance for FA; coordinates and funds research, is a center of news and information regarding FA

Rehabilitation

Physical therapy should consist of intensive motor coordination, balance, and stabilization training to preserve gains.
To address the ataxic gait pattern and loss of proprioception, physical therapists can use visual cueing during gait training to help facilitate a more efficient gait pattern. Frenkel exercises and Proprioceptive Neuromuscular Facilitation stretching might help improve proprioception. Low intensity strengthening exercises should be incorporated to maintain functional use of the upper and lower extremities. Stabilization exercises of the trunk and lower back can help with postural control and the management of scoliosis, especially if the patient requires a wheelchair. Stretching and muscle relaxation exercises can be prescribed to help manage spasticity and prevent deformities. Other goals can be set according to the needs and wishes of the patient, including increased transfer and locomotion independence; muscle strengthening; increased physical resilience; “safe fall” strategy; learning to use mobility aids; learning how to reduce the body's energy expenditure; and developing specific breathing patterns.
Speech therapy is recommended.

Devices

Well-fitted orthoses can promote correct posture, support normal joint alignment, stabilize joints during walking, improve range of motion and gait, reduce spasticity and prevent foot deformities and scoliosis.
Functional electrical stimulation or transcutaneous nerve stimulation devices may alleviate symptoms.
As progression of ataxia continues, assistive devices such as a cane, walker, or wheelchair may be required for mobility and independence. A standing frame can help reduce the secondary complications of prolonged use of a wheelchair.

Medication and surgery

Cardiac abnormalities can be controlled with ACE inhibitors such as enalapril, ramipril, lisinopril or trandolapril, sometimes used in conjunction with beta blockers. Patients with symptomatic heart failure might be prescribed eplerenone or digoxin to keep cardiac abnormalities under control.
Surgery may correct deformities caused by abnormal muscle tone. Titanium screws and rods inserted in the spine help prevent or slow the progression of scoliosis. Surgery to lengthen the Achilles tendon can improve independence and mobility in patients suffering from equinus deformity. Patients experiencing severe heart failure can have an automated implantable cardioverter-defibrillator implanted or a cardiac transplant.

Prognosis

Every patient has a particular form of evolution of the disease. In general, patients who were younger at diagnosis, and those with longer GAA triplet expansions, tend to have more severe symptoms.
Congestive heart failure and cardiac arrhythmia are the leading cause of death. However, patients with less severe symptoms can live into their sixties or older.

Epidemiology

FRDA affects Indo-European populations. It is rare in East Asians, Sub-Saharan Africans, and Native Americans.
FRDA is the most prevalent inherited ataxia, affecting about 1 in 50,000 people in the United States. Males and females are affected equally. The estimated carrier prevalence is 1:100.
A 1990-1996 study of Europeans calculated the incidence rate was 2.8:100,000. A later study estimated prevalence of 3-4 cases per 100,000 individuals.
FRDA follows the same pattern as haplogroup R1b. Haplogroup R1b is the most frequently occurring paternal lineage in western Europe. FRDA and Haplogroup R1b are more common in northern Spain, Ireland and France, rare in Russia and Scandinavia, and follow a gradient through central and eastern Europe. A population carrying the disease went through a population bottleneck in the Franco-Cantabrian region during the last ice age.
A study of Japanese patients with spinocerebellar degeneration found a rate of 2.4% making the prevalence rate of FRDA much rarer at 1:1,000,000.

History

The condition is named after the 1860s German pathologist and neurologist, Nikolaus Friedreich. Friedreich reported five patients in three papers in 1863 at the University of Heidelberg. Further observations appeared in a paper in 1876.
Frantz Fanon wrote his medical thesis on FRDA, in 1951.
A 1984 Canadian study traced 40 cases to one common ancestral couple arriving in New France in 1634.
FRDA was first linked to a GAA repeat expansion on chromosome 9 in 1996.

Research

Modulation of transcriptional factor Nrf2

The Cake Eaters is a 2007 independent drama film that stars Kristen Stewart as a young woman with FRDA.
The Ataxian is a documentary that tells the story of Kyle Bryant, an athlete with FRDA who completes a long-distance bike race in an adaptive "trike" to raise money for research.
Dynah Haubert is a lawyer with FRDA who works for Disability Rights Pennsylvania. She spoke at the 2016 Democratic National Convention about her support for Hillary Clinton and her work supporting Americans with disabilities.
Geraint Williams in an athlete affected by FRDA who is known for scaling Mount Kilimanjaro in an adaptive wheelchair.
Shobhika Kalra is an activist with FRDA who helped build over 1000 wheelchair ramps across the UAE, with the goal to make Dubai fully wheelchair-friendly by 2020.