Friedreich's ataxia

Friedreich's ataxia (FRDA) is a rare, inherited, autosomal recessive neurodegenerative disorder that primarily affects the nervous system, causing progressive damage to the spinal cord, peripheral nerves, and cerebellum, leading to impaired muscle coordination (ataxia). The condition typically manifests in childhood or adolescence, with initial symptoms including difficulty walking, loss of balance, and poor coordination. As the disease progresses, it can also impact speech, vision, and hearing. Many individuals with Friedreich's ataxia develop scoliosis, diabetes, and hypertrophic cardiomyopathy, a serious heart condition that is a leading cause of mortality in patients.

Friedreich's ataxia is caused by mutations in the FXN gene, which result in reduced production of frataxin, a protein essential for mitochondrial function, particularly in iron-sulfur cluster biogenesis. The deficiency of frataxin disrupts cellular energy production and leads to oxidative stress, contributing to the neurological and systemic symptoms associated with the disorder. 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.

There is currently no cure for Friedreich's ataxia, but treatment focuses on symptom management and slowing disease progression. In 2023, the US Food and Drug Administration (FDA) approved omaveloxolone as the first treatment for Friedreich's ataxia. This medication works by reducing oxidative stress and inflammation in neurons, which helps improve motor function in some patients. Ongoing research continues to explore potential therapies aimed at increasing frataxin levels, protecting mitochondria, and addressing the genetic cause of the disease. Although life expectancy may be reduced, particularly due to cardiac complications, advancements in care and treatment have improved outcomes for many individuals with Friedreich's ataxia.

FRDA is the most common inherited ataxia (1 in 40,000 of those of European descent). Rates of FRDA are highest in people of Western European descent; it is comparatively rare in other ethnic groups. The condition is named after 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 the age of 25 years. The symptoms are broad, but consistently involve gait and limb ataxia, dysarthria and loss of lower limb reflexes.

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. Advanced stages of disease are associated with supraventricular tachyarrhythmias, most commonly atrial fibrillation.

Early-onset cases

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

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 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 (missense, nonsense, or intronic) point mutation, with an expansion in one allele and a point mutation in the other. A missense point mutation can have milder symptoms.

Pathophysiology

FRDA affects the nervous system, heart, pancreas, and other systems.

Degeneration of nerve tissue in the spinal cord causes ataxia. 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. One result of frataxin deficiency is mitochondrial iron overload, which damages many proteins due to effects on cellular metabolism.

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 are made to confirm a physical examination such as electromyogram, nerve conduction studies, electrocardiogram, echocardiogram, blood tests for elevated glucose levels and vitamin E levels, and scans such as X-ray radiograph for scoliosis. MRI and CT scans of brain and spinal cord are done to rule out other neurological conditions. Finally, a genetic test is conducted to confirm.

Management

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

Therapeutics

Omaveloxolone

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.

Physical therapy typically includes intensive motor coordination, balance, and stabilization training to preserve gains. Low-intensity strengthening exercises are incorporated to maintain functional use of the upper and lower extremities.

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.

Managing cardiac involvement

Cardiac abnormalities can be controlled with ACE inhibitors such as enalapril, ramipril, lisinopril, or trandolapril, sometimes used in conjunction with beta blockers. Affected people who also have symptomatic congestive heart failure may be prescribed eplerenone or digoxin to keep cardiac abnormalities under control. but people with fewer symptoms can live into their 60s or older. FRDA is the most prevalent inherited ataxia, affecting approximately 1 in 40,000 with European descent. The prevalence rate of FRDA in Japan is 1:1,000,000.

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.

History

thumb|Nikolaus Friedreich|alt=Photo of Nikolaus Friedreich

The condition is named after the nineteenth century German pathologist and neurologist, Nikolaus Friedreich. Friedreich reported the disease 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.

Society and culture

thumb|300 px| Kyle Bryant training on his [[recumbent bicycle|alt=Photo of 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.

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 spoke at the 2016 Democratic National Convention about supporting Americans with disabilities.

Geraint Williams is 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 United Arab Emirates in 2018 to try to make Dubai fully wheelchair-friendly by 2020.

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 Giorgia, a young woman with Friedreich's ataxia, who will change his life.

Comedian Fiona Cauley has Friedrich's ataxia and often talks about her disability and wheelchair in her comedy.

Research

There is no cure for Friedreich's ataxia, and treatment development is directed toward slowing, stopping, or reversing disease progression.

In 2019, Reata Pharmaceuticals reported positive results in a phase 2 trial of RTA 408 (Omaveloxolone or Omav) to target activation of a transcriptional factor, Nrf2. Nrf2 is decreased in FRDA cells.

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. The Friedreich's Ataxia App is the only global community app which enables novel forms of research.

The Friedreich's Ataxia Research Alliance (FARA) is the global patient advocacy research organization coordinating the community, funding critical research, and maintaining the definitive pipeline, which describes all drug development programs currently underway.

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

Improve mitochondrial function and reduce oxidative stress

Vatiquinone is being developed by PTC Therapeutics. Vatiquinone is a para-benzoquinone and targets the NAD(P)H dehydrogenase (quinone 1) (NQO1) enzyme to increase the biosynthesis of glutathione.
Retrotope is advancing RT001. RT001 is a deuterated synthetic homologue of ethyl linoleate, an essential omega-6 polyunsaturated fatty acid which is one of the major components of lipid membranes, particularly in mitochondria. Oxidation damage might be reduced if the polyunsaturated fatty acids in the lipids were made more rigid and less susceptible to oxidation by the replacement of hydrogen atoms with the heavy hydrogen isotope deuterium.

Modulation of frataxin-controlled metabolic pathways

Dimethyl fumarate has been shown to increase frataxin levels in FRDA cells, mouse models, and humans. DMF showed an 85% increase in frataxin expression over 3 months in multiple sclerosis .

Frataxin replacements or stabilizers

Erythropoietin mimetics are orally available peptide imitations of erythropoietin. They are small molecules, erythropoietin receptor agonists designed to activate the tissue-protective erythropoietin receptor.
Etravirine, an antiviral drug used to treat HIV, was found in a drug repositioning screening to increase frataxin levels in peripheral cells. Fratagene Therapeutics is developing a small molecule called RNF126 to inhibit an enzyme which degrades frataxin.
Nomlabofusp (CTI-1601) is recombinant fusion protein designed to deliver frataxin to mitochondria. It is being developed by Larimar Therapeutics and is in a Phase 2 trial.
Nicotinamide (vitamin B3) was found effective in preclinical FRDA models and well tolerated.
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.

References

External links

Friedreich's Ataxia Global Patient Registry
NIH's FRDA information page