Friedreich's ataxia

Friedreich's ataxia (FRDA or FA) 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. Many people also have a form of heart disease called hypertrophic cardiomyopathy. Symptoms typically start between 5 and 15 years of age. Most young people diagnosed with FRDA require a mobility aid such as a cane, walker or wheelchair by their teens. As the disease progresses, people lose their sight and hearing. Other complications include scoliosis and diabetes mellitus.

Friedreich's ataxia
Other namesSpinocerebellar ataxia, FRDA, FA
Frataxin
SpecialtyNeurology
SymptomsLack of coordination, balance issues, gait abnormality
ComplicationsCardiomyopathy, scoliosis, diabetes mellitus
Usual onset5–15 years
DurationLong-term
CausesGenetic
Diagnostic methodMedical history and physical examination
TreatmentPhysical therapy
PrognosisShortened life expectancy
Frequency1 in 50,000 (United States)

The condition is caused by mutations in the FXN gene on the chromosome 9, which produces a protein called 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. Physical symptoms, patient history and genetic testing confirms the diagnosis.

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 teens or early 20s.[1] The disease is progressive with increasing staggering or stumbling gait and frequent falling. Lower extremities are more severely involved. Long-term observation shows that many people reach a plateau in symptoms in the patient's early adulthood. 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 ambulatory decades after onset, while others require a wheelchair within a few years.[2]

Symptoms may include the following:

Genetics
FRDA has an autosomal recessive pattern of inheritance.

FRDA is an autosomal recessive disorder that affects a gene (FXN) on chromosome 9 which produces an important protein called frataxin.[5]

In 96% of cases the mutant FXN gene has 90-1,300 GAA trinucleotide repeat expansions in intron 1 of both alleles.[6] This expansion causes epigenetic changes and formation of heterochromatin near the repeat.[5] The length of the shorter GAA repeat is correlated with age of onset and disease severity.[7] The formation of heterochromatin results in reduced transcription of the gene and low levels of frataxin.[8] People with FDRA tend to have 5-35% of the frataxin expressed in healthy individuals. Heterozygous carriers of the mutant FXN gene have frataxin levels reduced by 50%; however, this decrease is not enough to cause symptoms.[9]

In about 4% of cases the disease is caused by a (missense, nonsense, or intronic) point mutation, where the patient is heterozygotes with an expansion in one allele and a point mutation in the other.[10] A missense point mutation can have milder symptoms.[10] A detailed genetic work up is needed to determine this diagnosis.[11]

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.[12][13]

Pathophysiology

FRDA affects the nervous system, heart and pancreas and other systems.[14] Degeneration of nerve tissue in the spinal cord causes ataxia.[14] The sensory neurons essential for directing muscle movement of the arms and legs through connections with the cerebellum are particularly affected.[14] The disease primarily affects the spinal cord and peripheral nerves.[14] The spinal cord becomes thinner and nerve cells lose some myelin sheath.[14] The diameter of the spinal cord is smaller than that of unaffected individuals mainly due to smaller dorsal root ganglia.[15] The motor neurons of the spinal cord are affected to a lesser extent than sensory neurons.[14] In peripheral nerves there is a loss of large myelinated sensory fibers.[14]

Structures in the brain are also affected by FRDA, notably the dentate nucleus of the cerebellum.[15] In the heart, FRDA patients often develop some fibrosis, and over time many patients develop left ventricle hypertrophy and dilatation of the left ventricle.[15]

Frataxin

The exact role of frataxin remains unclear.[16] 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 (ROS) to maintain normal processes.[17] One result of frataxin deficiency is mitochondrial iron overload, which damages many proteins due to effects on cellular metabolism.[5]

Without frataxin, the energy in the mitochondria falls, and excess iron creates extra ROS, leading to further cell damage.[18][17] 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.[18]

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.[20]

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.[21]

Rehabilitation

Physical therapy should consist of intensive motor coordination, balance, and stabilization training to preserve gains.[22][23]

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.[23] Frenkel exercises and Proprioceptive Neuromuscular Facilitation stretching might help improve proprioception.[21] Low intensity strengthening exercises should be incorporated to maintain functional use of the upper and lower extremities.[24] Stabilization exercises of the trunk and lower back can help with postural control and the management of scoliosis,[23] especially if the patient requires a wheelchair. Stretching and muscle relaxation exercises can be prescribed to help manage spasticity and prevent deformities.[24] 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.[22]

Speech therapy is recommended.[25][26]

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.[1]

Functional electrical stimulation or transcutaneous nerve stimulation devices may alleviate symptoms.[1]

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.[27][28]

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.[1]

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.[1] Patients experiencing severe heart failure can have an automated implantable cardioverter-defibrillator implanted or a cardiac transplant.[1]

Prognosis

Every patient has a particular form of evolution of the disease.[27] In general, patients who were younger at diagnosis, and those with longer GAA triplet expansions, tend to have more severe symptoms.[1]

Congestive heart failure and cardiac arrhythmia are the leading cause of death.[29] However, patients with less severe symptoms can live into their sixties or older.[19]

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,[30] affecting about 1 in 50,000 people in the United States. Males and females are affected equally. The estimated carrier prevalence is 1:100.[1]

A 1990-1996 study of Europeans calculated the incidence rate was 2.8:100,000.[31] A later study estimated prevalence of 3-4 cases per 100,000 individuals.[32]

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.[33]

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.[34]

History
Nikolaus Friedreich

The condition is named after the 1860's German pathologist and neurologist, Nikolaus Friedreich.[35] Friedreich reported five patients in three papers in 1863 at the University of Heidelberg.[36][37][38] Further observations appeared in a paper in 1876.[39]

Frantz Fanon wrote his medical thesis on FRDA, in 1951.[40]

A 1984 Canadian study traced 40 cases to one common ancestral couple arriving in New France in 1634.[41]

FRDA was first linked to a GAA repeat expansion on chromosome 9 in 1996.[42]

Research

As of October 2019 the most advanced candidate for a curative treatment is a small molecule Reata Pharmaceuticals developed to target activation of a transcriptional factor, Nrf2. [43] Nrf2 is decreased in FRDA cells.[44] This small molecule called RTA 408, Omaveloxolone or Omav increases the number and efficiency of mitochondria[45]

In October 2019, Reata announced the results of the second part of a Phase 2/3 clinical trial (MOXIe). The MOXIe trial met the goal of the Friedreich’s Ataxia Rating Scale (mFARS) after 48 weeks of treatment.[46] This randomized, placebo-controlled, double-blind study evaluated the safety and efficacy of 150 mg omaveloxone.[47][48][49]

  • Retrotope is advancing its first drug RT001 after releasing positive Phase 1b/2a results in 2018. RT001 is a deuterated synthetic homologue of ethyl linoleate, a polyunsaturated fatty acid (11,11-D2-ethyl linoleate) or PUFAs. PUFAs are the major component of lipid membranes, particularly in mitochondria. Their high susceptibility to oxidation by reactive oxygen species might be reduced by the replacement of hydrogen atoms with the isotope deuterium.[50] 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.[51] 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.[52]
  • EPI-743 (Vatiquinone) is a related compound to A0001 being developed by BioElectron which used to be known as Edison Pharmaceuticals.[53] Open label studies were completed in 2012.[54] EPI-743 is a para-benzoquinone and targets the NAD(P)H dehydrogenase (quinone 1) (NQO1) enzyme to increase the biosynthesis of glutathione. Glutathione controls oxidative stress.[55] It is being used in a number of related mitochondrial diseases clinical trials such as Leigh syndrome[56] and is planned for a clinical trial for FRDA in 2019.[57]
  • Epicatechin is a natural flavonoid being developed by Cardero Therapeutics. From safety studies and findings in Becker's muscular dystrophy Cardero is completing an open study in FRDA patients.[58]

Frataxin replacements or stabilizers
  • EPO mimetics are orally available peptide imitations of erythropoietin. They are small molecules erythropoietin receptor agonists designed to activate the tissue-protective erythropoietin receptor.[59] STATegics plans to start a preclinical PK-PD study with a lead compound.[60]
  • Ubiquitin competitors. Since carriers of FRDA are asymptomatic but have a reduced level of frataxin it might be enough to just prevent existing frataxin degradation and increase levels of frataxin.[61] Fratagene Therapeutics is developing a small molecule called RNF126 to inhibit an enzyme which degrades frataxin.[62][63]

FXN gene expression
  • BNM 290 is a second generation HDAC inhibitor which came from an acquisition by Biogen of Repligen's RG2833. HDAC inhibitors interfere with the histone deacetylase which functions to keep the DNA of a gene tightly coiled and silence protein expression. BioMarin planned to file an Investigational New Drug application in 2018.[64]
  • Jupiter Orphan Therapeutics is using resveratrol to improve mitochondrial function. In 2016, IND enabling studies were started in Australia for a modified compound normally found in the skins of red grapes.[65]
  • RNA-based approach to try to unsilence FXN gene and increase the expression of frataxin. This could be an effect of epigenetics and identifying novel non-coding RNA (ncRNA) responsible for directing the localized epigenetic silencing of the FXN gene.
  • Nicotinamide (vitamin B3) was found effective in preclinical FRDA models and well-tolerated by patients. An open-label, dose-escalation study demonstrated that higher doses boosted frataxin expression but failed to establish any clinical benefit in a 12 month study.[9]
  • Etravirine, an antiviral drug used to treat HIV, was found in a drug repositioning screening to increase frataxin levels in peripheral cells derived from Friedreich's ataxia patients.[66]
  • Dimethyl fumarate has been shown to increase frataxin levels in FA patient-derived cells, mouse models, and humans. Multiple sclerosis patients treated with DMF showed an 85% increase in frataxin expression over 3 months.[67]

Gene therapy
  • An adeno-associated virus vector was used to reduce mitochondrial cardiomyopathy in a mice model in 2014.[68]
  • Lentivirus-mediated delivery of the FXN gene has been shown to increase frataxin expression and prevent DNA damage in human and mouse fibroblasts.[69]
  • CRISPR Therapeutics received a grant from the Friedreich's Ataxia Research Alliance to investigate gene editing as a potential treatment for the disease in 2017.[70]

Society and culture
Kyle Bryant training on his recumbent bicycle

The Cake Eaters is a 2007 independent drama film that stars Kristen Stewart as a young woman with FRDA.[71]

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.[72]

Dynah Haubert is a lawyer with FRDA who works for Disability Rights Pennsylvania (DRP). She spoke at the 2016 Democratic National Convention about her support for Hillary Clinton and her work supporting Americans with disabilities.[73]

Geraint Williams in an athlete affected by FRDA who is known for scaling Mount Kilimanjaro in an adaptive wheelchair.[74]

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.[75]

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