Friedreich's ataxia is an autosomal recessive inherited disease that causes progressive damage to the nervous system. It manifests in initial symptoms of poor coordination such as gait disturbance; it can also lead to scoliosis, heart disease and diabetes, but does not affect cognitive function. The disease is progressive, and ultimately a wheelchair is required for mobility. Its incidence in the general population is roughly 1 in 50,000. The particular genetic mutation (expansion of an intronic GAA triplet repeat in the FXN gene) leads to reduced expression of the mitochondrial protein frataxin. Over time this deficiency causes the aforementioned damage, as well as frequent fatigue due to effects on cellular metabolism. The ataxia of Friedreich's ataxia results from the degeneration of nervous tissue in the spinal cord, in particular sensory neurons essential (through connections with the cerebellum) for directing muscle movement of the arms and legs. The spinal cord becomes thinner and nerve cells lose some of their myelin sheath (the insulating covering on some nerve cells that helps conduct nerve impulses). The condition is named after the German physician Nikolaus Friedreich, who first described it in the 1860s.
Signs and symptomsSymptoms typically begin sometime between the ages of 5 to 15 years, but in Late Onset FA may occur in the 20s or 30s. Symptoms include any combination, but not necessarily all, of the following:
- Muscle weakness in the arms and legs
- Loss of coordination
- Vision impairment
- Hearing impairment
- Slurred speech
- Curvature of the spine ( scoliosis)
- High plantar arches ( pes cavus deformity of the foot)
- Diabetes (about 20% of people with Friedreich's ataxia develop carbohydrate intolerance and 10% develop diabetes mellitus)
- Heart disorders (e.g., atrial fibrillation, and resultant tachycardia (fast heart rate) and hypertrophic cardiomyopathy)
- Cerebellar: nystagmus, fast saccadic eye movements, truncal ataxia, dysarthria, dysmetria.
- Lower motor neuron lesion: absent deep tendon reflexes.
- Pyramidal: extensor plantar responses, and distal weakness are commonly found.
- Dorsal column: Loss of vibratory and proprioceptive sensation occurs.
- Cardiac involvement occurs in 91% of patients, including cardiomegaly (up to dilated cardiomyopathy), symmetrical hypertrophy, heart murmurs, and conduction defects. Median age of death is 35 years, while females have better prognosis with a 20-year survival of 100% as compared to 63% in men.
GeneticsFriedreich's ataxia is an autosomal recessive disorder that occurs when the FXN gene contains amplified intronic GAA repeats (an example of Trinucleotide repeat expansion). The FXN gene encodes the protein frataxin. GAA repeat expansion causes frataxin levels to be reduced. Frataxin is an iron-binding protein responsible for forming iron–sulphur clusters. One result of frataxin deficiency is mitochondrial iron overload which can cause damage to many proteins. The exact role of frataxin in normal physiology remains unclear. The gene is located on chromosome 9. The mutant gene contains expanded GAA triplet repeats in the first intron; in a few pedigrees, point mutations have been detected. Because the defect is located in an intron (which is removed from the mRNA transcript between transcription and translation), this mutation does not result in the production of abnormal frataxin proteins. Instead, the mutation causes gene silencing (i.e., the mutation decreases the transcription of the gene) through induction of a heterochromatin structure in a manner similar to position-effect variegation. Besides reducing expression of frataxin, long tracts of GAA repeats induce chromosome breaks in in vivo yeast studies.
PathologyThe primary site of pathology is spinal cord and peripheral nerves. Sclerosis and degeneration of dorsal root ganglion, spinocerebellar tracts, lateral corticospinal tracts, and posterior columns. The motor neurons of the spinal cord are spared. In peripheral nerves there is a loss of large myelinated fibres. Progressive destruction of dorsal root ganglia accounts for thinning of dorsal roots, degeneration of dorsal columns, transsynaptic atrophy of nerve cells in Clarke's column and dorsal spinocerebellar fibers, atrophy of gracile and cuneate nuclei and neuropathy of sensory nerves. The lesion of the dentate nucleus consists of progressive and selective atrophy of large glutamatergic neurons and grumose degeneration of corticonuclear synaptic terminals that contain gamma-aminobutyric acid (GABA). Small GABA-ergic neurons and their projection fibers in the dentato-olivary tract survive. Atrophy of Betz cells and corticospinal tracts constitute a second lesion.
PathogenesisLow 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. In normal individuals, the FXN gene encodes frataxin, a mitochondrial matrix protein. This globular protein consists of two α helices and seven β strands and is highly conserved, occurring in all eukaryotes and some prokaryotes. Frataxin has a variety of known functions. Frataxin assists iron-sulfur protein synthesis in the electron transport chain to ultimately generate adenosine triphosphate (ATP), the energy currency necessary to carry out metabolic functions in cells. Frataxin also regulates iron transfer in the mitochondria in order provide a proper amount of reactive oxygen species (ROS) to maintain normal processes. Without frataxin, the energy in the mitochondria fails, and excess iron causes extra ROS to be created, leading to further cell damage.
DiagnosisA diagnosis of Friedreich's ataxia requires a careful clinical examination, which includes a medical history and a thorough physical exam, in particular looking for balance difficulty, loss of proprioception, absence of reflexes, and signs of neurological problems. Genetic testing now provides a conclusive diagnosis. Other tests that may aid in the diagnosis or management of the disorder include:
- Electromyogram (EMG), which measures the electrical activity of muscle cells,
- Electrocardiogram (ECG), which gives a graphic presentation of the electrical activity or beat pattern of the heart
- Echocardiogram, which records the position and motion of the heart muscle
- Blood tests to check for elevated glucose levels and vitamin E levels
- Magnetic resonance imaging (MRI) or computed tomography (CT) scans, tests which provide brain and spinal cord images that are useful for ruling out other neurological conditions
TreatmentA person suffering from Friedreich's Ataxia may require some surgical interventions (mainly for the spine and heart). Often, titanium screws and rods are inserted in the spine to help prevent or slow the progression of scoliosis. As progression of ataxia occurs, assistive devices such as a cane, walker, or wheelchair are required for mobility and independence. Other assistive technology, such as a standing frame, can help reduce the secondary complications of prolonged use of a wheelchair. The goal of surgery is to keep the patient ambulatory as long as possible. In many cases, patients experience significant heart conditions as well. These conditions are much more treatable, and are often countered with ACE inhibitors such as enalapril or lisinopril and other heart medications such as digoxin. Persons with Friedreich’s ataxia may benefit from a conservative treatment approach for the management of symptoms. Health professionals educated in neurological conditions, such as physical therapists and occupational therapists, can prescribe an exercise program tailored to maximize function and independence. To address the ataxic gait pattern and loss of proprioception typically seen in persons with Friedreich’s ataxia, physical therapists can use visual cueing during gait training to help facilitate a more efficient gait pattern. The prescription of an assistive device along with gait training can also prolong independent ambulation. Low intensity strengthening exercises should also be incorporated to maintain functional use of the upper and lower extremities. Fatigability should be monitored closely. Stabilization exercises of the trunk and low back can help with postural control and the management of scoliosis. This is especially indicative if the person is non-ambulatory and requires the use of a wheelchair. Balance and coordination training using visual feedback can also be incorporated into activities of daily living. Exercises should reflect functional tasks such as cooking, transfers and self-care. Along with gait training, balance and coordination training should be developed to help minimize the risk of falls. Stretching exercises can be prescribed to help relieve tight musculature due to scoliosis and pes cavus deformities.
IdebenoneIdebenone, an antioxidant, was recently removed from the Canadian market in 2013 due to lack of effectiveness. A Cochrane review on antioxidants and other pharmacological treatment of patients with Friedreich ataxia concluded that there is limited but not persuasive evidence of efficacy.
NicotinamideNicotinamide administration on patients was associated with a sustained improvement in frataxin concentrations towards those seen in asymptomatic carriers during 8 weeks of daily dosing. The daily oral administration of 3.8 g nicotinamide resulted in a 1.5-times increase, whereas 7.5 g resulted in a doubling of frataxin protein concentration.
Speech therapyPatients also often undertake speech therapy since dysarthria (a motor speech disorder) occurs in almost all Friedreich's ataxia patients. However, the dysarthria is not always ataxic and the dysarthria can be mixed. The speech intelligibility in speakers with dysarthria and Friedreich's Ataxia can be mild to severely reduced. Speech therapy seeks to improve speech outcomes and/or compensate for communication deficits. Dysphagia (difficulty swallowing) is also a common symptom of Friedreich's ataxia, and speech therapy can support patients to eat and drink in a safer way.
Clinical researchRG2833, a histone deacetylase inhibitor developed by Repligen, was acquired by BioMarin Pharmaceutical in January 2014. The first human trials with this compound began in 2012. Horizon Pharma's development plan of interferon gamma-1B for treatment of FA was given fast track designation by the Food and Drug Administration in 2015. In its trials released in December 2016, however, the results showed no improvements over placebo in patients.http://www.fiercebiotech.com/biotech/horizon-slumps-after-phase-3-friedreich-s-ataxia-trial-flops
EpidemiologyFriedreich's ataxia 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 1:110. A 1984 Canadian study was able to trace 40 cases of classical Friedreich's disease from 14 French-Canadian kindreds previously thought to be unrelated to one common ancestral couple arriving in New France in 1634: Jean Guyon and Mathurine Robin.
HistoryFriedreich, working as a professor of pathology at the University of Heidelberg, reported five patients with the condition in a series of three papers in 1863. Further observations appeared in a subsequent paper in 1876. Frantz Fanon wrote his medical thesis on Friedreich's ataxia, in 1951.Adam Shatz, "Where Life Is Seized", London Review of Books, 19 January 2017
- European Friedreich's Ataxia Consortium for Translational Studies
- FARA The Friedreich's Ataxia Research Alliance at www.cureFA.org
- Asks the Experts - Responses: Friedreich's Ataxia at Muscular Dystrophy Association
- NCBI Genes and Disease: Friedreich's ataxia at National Center for Biotechnology Information
- Canadian Association for Familial Ataxias - Claude St-Jean Foundation
- British Columbia (BC) Ataxia Society