Friedreich's ataxia

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Friedreich's ataxia
SynonymsSpinocerebellar ataxia, Friedreich, FDRA, FA
Protein FXN PDB 1ekg.png
Frataxin
SpecialtyNeurology Edit this on Wikidata
Symptomslack of coordination, balance issues, gait abnormality
Complicationscardiomyopathy, scoliosis, diabetes
Usual onset5-15 years
Durationlong term
Causesgenetic
Treatmentphysical therapy

Friedreich's ataxia, or FDRA, is an autosomal recessive inherited disease that causes progressive damage to the nervous system. It is the most common inherited ataxia, affecting approximately 1 in 29,000 individuals.[1] FDRA 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 in most cases a wheelchair is required for mobility.

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.[2]

Signs and symptoms[edit]

Symptoms 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:

It presents before 22 years of age with progressive staggering or stumbling gait and frequent falling. Lower extremities are more severely involved. The symptoms are slowly progressing. Long-term observation shows that many patients reach a plateau in symptoms in the patient's early adulthood. On average, after 10–15 years with the disease, patients lose the ability to stand or walk without assistance. However, disease progression is variable, and some patients may still be ambulatory decades after onset, while others require the use of a wheelchair within a few years.[4]

The following physical signs may be detected on physical examination:

Genetics[edit]

Friedreich's ataxia has an autosomal recessive pattern of inheritance.

Friedreich's ataxia is an autosomal recessive disorder that occurs when the FXN gene on chromosome 9 contains amplified intronic GAA repeats (an example of Trinucleotide repeat expansion). The FXN gene encodes the protein frataxin.[5] GAA repeat expansion causes frataxin levels to be reduced and long tracts of GAA repeats induce chromosome breaks in (in vivo yeast studies). 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.[5] The exact role of frataxin in normal physiology remains unclear.[6]

The mutant gene contains expanded GAA triplet repeats in the first intron;[7] 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.[8]

Pathology[edit]

The primary site of pathology is in the spinal cord and peripheral nerves. Sclerosis and degeneration of dorsal root ganglion, spinocerebellar tracts, lateral corticospinal tracts, and posterior columns.[9] 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.[citation needed]

Pathogenesis[edit]

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. 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.[10] 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 molecule necessary to carry out metabolic functions in cells. Frataxin also regulates iron transfer in the mitochondria for providing a proper amount of reactive oxygen species (ROS) to maintain normal processes.[11] Without frataxin, the energy in the mitochondria falls, and excess iron causes extra ROS to be created, leading to further cell damage.[10][11]

DNA damage[edit]

Mitochondrial DNA (mtDNA) is especially exposed to attack by ROS since it is located within the mitochondria. Because several enzymes of the electron transport chain are encoded in mtDNA, ROS-induced damage to mtDNA may cause further increases in ROS production and oxidative stress. Elevated levels of DNA double-strand breaks have been reported in Friedreich’s ataxia patient fibroblasts and fibroblasts from a mouse model of Friedreich’s ataxia.[12] Using a lentivirus gene delivery system to deliver the frataxin gene to Friedreich’s ataxia patient and mouse model cells, it was possible to obtain long-term over-expression of frataxin mRNA and frataxin protein levels. This over-expression was associated with a substantially reduced level of DNA double-strand breaks.[12] It appears that frataxin is normally involved in the repair of DNA damage, which may be important for preventing neurodegeneration.[12]

Diagnosis[edit]

A diagnosis of Friedreich's ataxia requires investigation of the medical history and a thorough physical examination, in particular looking for balance difficulty, loss of proprioception, an absence of reflexes, and signs of other neurological problems. Genetic testing provides a conclusive diagnosis.[13] Other tests that may aid in the diagnosis or management of the disorder include:

Treatment[edit]

Therapeutic strategies and disease insight have expanded rapidly over recent years, providing new opportunities for disease relief.[14]

Rehabilitation[edit]

Rehabilitation therapy is a cornerstone of present-day ataxia therapy and there is evidence that this therapy improves symptoms in the short-term and that, with continued exercise, benefits can be maintained long-term.[14]

Physical therapy should consist of intensive motor coordination, balance, and stabilization training. 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.[15] Frenkel exercises and PNF techniques were developed to improve proprioception and have been shown to be effective in ataxic patients.[14] Low intensity strengthening exercises should also be incorporated to maintain functional use of the upper and lower extremities.[16] Stabilization exercises of the trunk and low back can help with postural control and the management of scoliosis,[15] especially if the person is non-ambulatory and requires the use of a wheelchair. Stretching and muscle relaxation exercises can be prescribed to help manage spasticity and prevent deformities.[16] 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.[17]

Outside of therapy, patients should be encouraged to keep up continuous coordination and balance training to preserve gains.[17] Balance and coordination training using visual feedback can be incorporated into activities of daily living. Exercises should reflect functional tasks such as cooking, transfers and self-care.[15] The focus is to preserve the patient's level of functioning: if a person is able to walk, they should do it as much as possible.[17]

Video game therapy, or exergaming, is a promising new tool for the treatment of FDRA. Physiotherapy exercises complemented by whole-body and coordinative training on commercially available video game technology have been found to be beneficial for both early onset and advanced, multisystem degenerative ataxia patients. Video game-based training involves motivational reward incentives and stimulating exercise environments that can stimulate and train patients’ real-world activities and anticipatory coordination capacities. Many patients find video games to be a convenient, cost-effective, and motivational way to engage in rehabilitation exercises.[14]

Speech therapy[edit]

Patients 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.[18] 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.[19]

Devices[edit]

Good quality, well-fitted orthoses can support normal joint alignment, promote correct posture, stabilize joints during walking, and improve range of motion. This is important to help manage spasticity, and to prevent foot deformities and scoliosis.[1]

There is some evidence that devices for electrical stimulation, such as functional electrical stimulation or transcutaneous nerve stimulation, may help alleviate symptoms associated with FDRA.[1]

Wearable proprioceptive stabilizers like the Equistasi are neurological rehabilitation devices meant to exert focal mechanical vibration on muscles and joints. Research indicates that this may improve limb and gait ataxia in patients affected by FDRA and similar conditions.[20]

Orthopedic shoes have been shown to improve gait in ambulatory individuals.[1] In severe cases in which the rehabilitation treatment applications are insufficient, use of supportive devices enables the patient to function more easily within the present functional level.[21] As progression of ataxia occurs, assistive devices such as a cane, walker, or wheelchair may be 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.

Medication[edit]

Although there are not yet any curative pharmacological therapies for Friedreich's Ataxia, many of its side effects respond well to medication. In particular, the cardiac abnormalities associated with Friedreich's Ataxia can often be controlled with ACE inhibitors such as enalapril, ramipril, lisinopril or trandolapril, sometimes used in conjunction with beta blockers. Patients who have already developed symptomatic heart failure might be prescribed eplerenone or digoxin to keep it under control.[1]

Surgery[edit]

Patients with Friedreich's Ataxia may require some surgical interventions with the aim to help the patient maintain functional independence for as long as possible.

If physical and pharmacological interventions have proven ineffective, surgical solutions may be considered to correct deformities caused by abnormal muscle tone. Titanium screws and rods inserted in the spine help prevent or slow the progression of scoliosis. In patients suffering from the equinus deformity, surgically lengthening the Achilles tendon has been shown to improve independence and mobility.[1]

Patients experiencing severe heart failure that does not respond to maximal medical management may be considered for implantation of an automated implantable cardioverter-defibrillator or, in some cases, a cardiac transplant.[1]

Prognosis[edit]

Every patient has a particular form of evolution of the disease.[21] In general, patients who were younger at diagnosis, and those who have longer GAA triplet expansions, tend to have more severe symptoms.[1] Studies investigating FRDA have often provided inconclusive and contradicting results arising from inhomogeneity in trial populations, nonvalidated measures used in older studies,[14] and low availability of study participants[22] It is hoped that the use and development of model clinical instruments and technologies such as computerized gait monitoring, speech evaluation, and imaging along with molecular indices will add precision and new avenues for capturing ataxic symptoms and physiologic functions, thereby resulting in more precise and extended measurement of disease progression.[14]

A further confounding factor is that treatments that affect the course of the disease are continuously being developed. Where decline to complete disability was once thought to be inevitable, recent research proves that a period of inpatient rehabilitation may reverse or halt the downward decline in function seen in most patients[1] and that, with continued exercise, benefits can be maintained indefinitely.[14]

The estimated life expectancy has been found to be about 40-50 years. Congestive heart failure and cardiac arrhythmia are the leading cause of death.[23]However, some people with less severe features of FDRA live into their sixties or older.[13]

Clinical research[edit]

There is currently no FDA-approved disease-modifying agent to correct Friedreich's Ataxia at the genetic or cellular level[14], and much research has been focused on discovering such an agent.

RG2833, a histone deacetylase inhibitor developed by Repligen, was acquired by BioMarin Pharmaceutical in January 2014.[24] A phase Ib clinical trial with RG2833 has been successfully completed in 2014 and research continues.[25]

Workload test

Protection of cells from damage with the use of deuterated compounds has been attempted by Retrotope. Its first drug RT001 is a deuterated synthetic homologue of ethyl linoleate, a polyunsaturated fatty acid (11,11-D2-ethyl linoleate). Polyunsaturated fatty acids (PUFAs)are essential nutrients which are the major component of lipid membranes, particularly in mitochondria. Their high susceptibility to oxidation by reactive oxygen species through the chain reaction can be substantially reduced by the replacement of hydrogen (H) atoms with the isotope deuterium (D), yielding D-PUFAs. RT001 has been compared with non-deuterated linoleic acid ethyl ester in a randomized, double-blind, controlled trial in 18 FRDA patients for 4 weeks.[26] Primary endpoints were safety, tolerability, and pharmacokinetics. Secondary endpoints included the FARS, a timed foot-walk test and cardiopulmonary exercise testing. The study met its primary safety and tolerability endpoints.[27] An improvement in peak workload and VO2 max in the RT001 group compared to placebo, as well as a positive trend in the neurological scales in the drug group were detected, thus further development is planned.

Research in gene therapy is another treatment under development. One study in mouse models showed that gene replacement therapy completely reversed the cardiac symptoms of Friedreich's Ataxia at the functional, cellular, and molecular levels.[14] This provides a promising outlook in the future treatment of Friedreich's ataxia.

Treatment strategies proven to be inefficient[edit]

Nicotinamide (vitamin B3) represents was found effective in preclinical FA models and well-tolerated by FA patients. An open-label, dose-escalation study demonstrated that higher doses boosted frataxin expression and attenuated abnormal heterochromatin, but failed to establish any clinical benefit in a study of 12 months. The trial is being extended.[25]

A Cochrane review on treatment of patients with Friedreich ataxia with antioxidants concluded that there is limited but not persuasive evidence of efficacy.[28] An antioxidant Idebenone was removed from the Canadian market in 2013 due to lack of effectiveness.[29]

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.[30] However, in the Phase 3 trial released in December 2016, the results did not meet primary endpoints. [31] The trial is to be repeated with new endpoints.

Epidemiology[edit]

Friedreich's ataxia is the most prevalent inherited ataxia,[32] affecting about 1 in 50,000 people in the United States. Males and females are affected equally. The estimated carrier prevalence is 1:110.[citation needed]

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.[33]

Epidemiological data shows that prevalence of Friedriech's ataxia follows patterns in the prevalence of haplogroup R1b. Both are more common in northern Spain, Ireland and France, rare in Russia and Scandinavia, and both follow a gradient through central and eastern Europe. This data provides an image of the prehistory of Friedreich's ataxia; a population carrying the disease went through a population bottleneck in the Franco-Cantabrian region during the last ice age. The correlation also provides a useful tool for predicting the prevalence of Friedreich's ataxia.[34]

History[edit]

Friedreich, 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.[35][36][37] Further observations appeared in a subsequent paper in 1876.[38]

Friedreich's ataxia was first linked to a GAA repeat expansion on chromosome 9 in 1996.[39]

Frantz Fanon wrote his medical thesis on Friedreich's ataxia, in 1951.[40]

References[edit]

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External links[edit]

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