Friedreich's ataxia

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. ==Genetics==

FRDA is an autosomal-recessive disorder that affects a gene (FXN) on chromosome 9, which produces an important protein called frataxin. 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. 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 Achilles tendon can improve independence and mobility to alleviate equinus deformity. An automated implantable cardioverter-defibrillator can be implanted after a severe heart failure. ==Prognosis==

The disease evolves differently in different people. but people with fewer symptoms can live into their 60s or older. ==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. 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==

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 ==

|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 ==