Friedreich's ataxia

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Friedreich's ataxia
Other namesSpinocerebellar ataxia, FRDA, FA
diabetes mellitus
Usual onset5–20 years
DurationLong-term
CausesGenetic
Diagnostic methodMedical history and physical examination
TreatmentNone
PrognosisShortened life expectancy
Frequency1 in 50,000 (United States)

Friedreich's ataxia (FRDA or FA) is an

diabetes mellitus
.

The condition is caused by mutations in the FXN gene on

myelin sheath
.

In February 2023, the first approval of a treatment for FRDA was granted by the

U.S. Food and Drug Administration (FDA). Approval in the EU
is pending. There are several additional therapies in trial. FRDA shortens life expectancy due to heart disease, but some people can live into their 60s or older.

FRDA affects one 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 German physician Nikolaus Friedreich, who first described it in the 1860s.

Symptoms

Symptoms typically start between the ages of 5 and 15, but in late-onset FRDA, they may occur after age 25 years.[1] The symptoms are broad, but consistently involve gait and limb ataxia, dysarthria and loss of lower limb reflexes.[1]

Classical symptoms

There is some variability in symptom frequency, onset and progression. All individuals with FRDA develop

conduction defects. Scoliosis is present in about 60%. 7% of people with FRDA also have diabetes and having diabetes has an adverse impact on people with FA, especially those that show symptoms when young.[2][3]

Other symptoms

People who have been living with FRDA for a long time may develop other complications. 36.8% experience decreased visual acuity, which may be progressive and could lead to functional blindness.

tachyarrhythmias, most commonly atrial fibrillation.[1]

Other later stage symptoms can include,

saccadic eye movements, dysmetria and loss of coordination (truncal ataxia, and stomping gait).[1] Symptoms can involve the dorsal column such as the loss of vibratory sensation and proprioceptive sensation.[1]

The progressive loss of coordination and muscle strength leads to the full-time use of a wheelchair. Most young people diagnosed with FRDA require mobility aids such as a cane, walker, or wheelchair by early 20s.[5] The disease is progressive, with increasing staggering or stumbling gait and frequent falling. By the third decade, affected people lose the ability to stand or walk without assistance and require a wheelchair for mobility.[6]

Early-onset cases

Non-neurological symptoms such as scoliosis, pes cavus, cardiomyopathy and diabetes are more frequent amongst the early-onset cases.[1]

Genetics

image showing how two carriers can produce one in four offspring with FRDA. This is called an autosomal-recessive pattern of inheritance.
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.[7]

In 96% of cases, the mutant FXN gene has 90–1,300 GAA

carriers of the mutant FXN gene have 50% lower frataxin levels, but this decrease is not enough to cause symptoms.[11]

In about 4% of cases, the disease is caused by a (

point mutation, with an expansion in one allele and a point mutation in the other.[12] A missense point mutation can have milder symptoms.[12] Depending on the point mutation, cells can produce no frataxin, nonfunctional frataxin, or frataxin that is not properly localized to the mitochondria.[13][14]

Pathophysiology

FRDA affects the nervous system, heart, pancreas, and other systems.[15][16]

Degeneration of nerve tissue in the spinal cord causes ataxia.

peripheral nerves
.

The spinal cord becomes thinner and nerve cells lose some

myelin sheath.[15] The diameter of the spinal cord is smaller than that of unaffected individuals mainly due to smaller dorsal root ganglia.[16] The motor neurons of the spinal cord are affected to a lesser extent than sensory neurons.[15] In peripheral nerves, a loss of large myelinated sensory fibers occurs.[15]

Structures in the brain are also affected by FRDA, notably the dentate nucleus of the cerebellum.[16] The heart often develops some fibrosis, and over time, develops left-ventricle hypertrophy and dilatation of the left ventricle.[16]

Frataxin

The exact role of frataxin remains unclear.[17] 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. It also regulates iron transfer in the mitochondria by providing a proper amount of reactive oxygen species (ROS) to maintain normal processes.[18] One result of frataxin deficiency is mitochondrial iron overload, which damages many proteins due to effects on cellular metabolism.[19]

Without frataxin, the energy in the mitochondria falls, and excess iron creates extra ROS, leading to further cell damage.[18] 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.[19]

Diagnosis

Balance difficulty, loss of proprioception, an

CT scans of brain and spinal cord are done to rule out other neurological conditions.[22] Finally, a genetic test is conducted to confirm.[22]

Other diagnoses might include Charcot-Marie-Tooth types 1 and 2, ataxia with vitamin E deficiency, ataxia-oculomotor apraxia types 1 and 2, and other early-onset ataxias.[23]

Management of Symptoms

Physicians and patients can reference the clinical management guidelines for Friedreich ataxia.[24] These Guidelines are intended to assist qualified healthcare professionals in making informed treatment decisions about the care of individuals with Friedreich ataxia.[25]

Therapeutics

Omaveloxolone received FDA approval under the brand name Skyclarys for the treatment of Friedreich's ataxia in February 2023.[26] Approval in the EU is pending.[27]

Rehabilitation

Physical therapists play a critical role in educating on correct posture, muscle use, and the identification and avoidance of features that aggravate spasticities such as tight clothing, poorly adjusted wheelchairs, pain, and infection.[28]

Physical therapy typically includes intensive motor coordination, balance, and stabilization training to preserve gains.[29] Low-intensity strengthening exercises are incorporated to maintain functional use of the upper and lower extremities.[29] Stretching and muscle relaxation exercises can be prescribed to help manage spasticity and prevent deformities.[29] Other physical therapy goals include 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.[29] Speech therapy can improve voice quality.[30]

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.[5]

transcutaneous nerve stimulation devices may alleviate symptoms.[5]

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.[31][32]

Managing Cardiac Involvement

Cardiac abnormalities can be controlled with

congestive heart failure may be prescribed eplerenone or digoxin to keep cardiac abnormalities under control.[5]

Surgical Intervention

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

equinus deformity.[5] An automated implantable cardioverter-defibrillator can be implanted after a severe heart failure.[5]

Omaveloxolone was approved for medical use in the United States in February 2023.[33]

Prognosis

The disease evolves differently in different people.[31] In general, those diagnosed at a younger age or with longer GAA triplet expansions tend to have more severe symptoms.[5]

Congestive heart failure and

abnormal heart rhythms are the leading causes of death,[34] but people with fewer symptoms can live into their 60s or older.[22]

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 approximately 1 in 40,000 with European descent.[15] Males and females are affected equally. The estimated carrier prevalence is 1:100.[5] A 1990–1996 study of Europeans calculated the incidence rate was 2.8:100,000.[35] The prevalence rate of FRDA in Japan is 1:1,000,000.[36]

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.[37]

History

Photo of Nikolaus Friedreich
Nikolaus Friedreich

The condition is named after the 1860s German

University of Heidelberg.[39][40][41] Further observations appeared in a paper in 1876.[42]

Frantz Fanon wrote his medical thesis on FRDA, in 1951.[43]

A 1984 Canadian study traced 40 cases to one common ancestral couple arriving in New France in 1634.[44]

FRDA was first linked to a GAA repeat expansion on chromosome 9 in 1996.[45]

Research

Currently there is no cure for Friedreich's ataxia, and treatment development is currently directed toward slowing, stopping, or reversing disease progression. In 2019,

Nrf2.[46] Nrf2 is decreased in FRDA cells.[47][48][49][50] In May 2022, the FDA accepted a new drug application for omaveloxolone and granted it priority review.[51] Omaveloxolone received FDA approval under the brand name Skyclarys for the treatment of Friedreich's ataxia in February 2023.[26] Approval in the EU is pending.[27]

There are several additional therapies in trial. Patients can enroll in a registry to make clinical trial recruiting easier. The Friedreich's Ataxia Global Patient Registry is the only worldwide registry of Friedreich's ataxia patients to characterize the symptoms and establish the rate of disease progression.[52] The Friedreich's Ataxia App is the only global community app which enables novel forms of research.[53]

As of May 2021, research continues along the following paths.

Improve mitochondrial function and reduce oxidative stress

Modulation of frataxin controlled metabolic pathways

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.[57][58]
  • Etravirine, an antiviral drug used to treat HIV, was found in a drug repositioning screening to increase frataxin levels in peripheral cells.[59] Fratagene Therapeutics is developing a small molecule called RNF126 to inhibit an enzyme which degrades frataxin.[60]

Increase frataxin gene expression

Society and culture

Photo of Kyle Bryant training on his recumbent bicycle
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.[64]

romantic drama manga series written and illustrated by Naoshi Arakawa
. The story follows a young pianist named Kо̄sei Arima, who loses the ability to perform the piano after his mother's death, and his experiences after he meets violinist Kaori Miyazono who has an 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.[65]

Dynah Haubert spoke at the 2016 Democratic National Convention about supporting Americans with disabilities.[66]

Geraint Williams in an athlete affected by FRDA who is known for scaling Mount Kilimanjaro in an adaptive wheelchair.[67]

Shobhika Kalra is an activist with FRDA who helped build over 1000 wheelchair ramps across the United Arab Emirates in 2018 to try to make Dubai fully wheelchair-friendly by 2020.[68]

Butterflies Still Fly is a 2023 film, based on a true story, directed by Joseph Nenci. Italo is a light-hearted journalist, darkened by a personal drama that distracts him from work. He encounters with Giorgia, a young girl suffering from Friedreich's Ataxia, who will change his life.

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External links

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