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Last updated: 10/24/2023
Years published: 1984, 1987, 1988, 1989, 1992, 1993, 1996, 1997, 1998, 1999, 2000, 2003, 2007, 2015, 2018, 2023
NORD gratefully acknowledges Robert Power, NORD Editorial Intern from the University of Notre Dame, Sanjay I. Bidichandani, MBBS, PhD, CHF Claire Gordon Duncan Chair in Genetics, and David L. Boren Professor of Pediatrics, University of Oklahoma College of Medicine, for assistance in the preparation of this report.
Friedreichโs ataxia (FRDA) is a genetic, progressive, neurodegenerative movement disorder, with a typical age of onset between 10 and 15 years. Initial symptoms may include unsteady posture, frequent falling, fatigue and progressive difficulty walking due to impaired ability to coordinate voluntary movements (ataxia). Affected individuals often develop slurred speech (dysarthria), characteristic foot deformities and an irregular curvature of the spine (scoliosis). FRDA is often associated with cardiomyopathy, a disease of cardiac muscle that may lead to heart failure or irregularities in heart rhythm (cardiac arrhythmias). About a third of the people with FRDA develop diabetes mellitus. The symptoms and clinical findings associated with FRDA result from degenerative changes in sensory nerves, including the point where they enter the spinal cord in structures known as dorsal root ganglia, and in specific nerve tracts in the spinal cord, which leads to a deficiency of sensory signals to the cerebellum, the part of the brain that helps to coordinate voluntary movements. A specific region of the cerebellum called the dentate nucleus also degenerates in FRDA. FRDA is caused by abnormalities (variants) in the FXN gene and people with FRDA inherit a pathogenic variant from each parent, so both copies of their FXN gene do not function normally. This pattern, wherein parents who are clinically unaffected because they only carry a single variant FXN gene but can have a child who is affected because they inherit pathogenic variants from both carrier parents, is called autosomal recessive inheritance.
The primary symptom of FRDA is progressive ataxia of the limbs during walking. Ataxia involves inadequate muscle coordination that results in an unsteady gait and poor control of fine movements of the limbs. Involvement of muscles in the mouth and throat may lead to slurred speech and impaired swallowing. Intellect is unaffected. Sideways curvature of the spine (scoliosis) and foot abnormalities may develop. A form of heart disease (cardiomyopathy) may develop in over half of the people with FRDA. The clinical features are progressive and after initially making use of walking aids people with FRDA ultimately require the use of a wheelchair for mobility.
Atypical Presentations
Late-onset FRDA (LOFA)/Very late onset FRDA (VLOFA)
Most people with FRDA are diagnosed before age 25. LOFA and VLOFA are subtypes that affect approximately 15% of individuals with Friedreichโs ataxia. For LOFA the age of onset is between the ages of 26 and 39 years, and for VLOFA the age of onset is after the age of 40 years. Disease progression in these individuals is slower than that associated with typical FRDA.
FRDA is caused by pathogenic variants (mutations) in the FXN gene. The FXN gene codes for frataxin, a protein that is required for proper functioning of mitochondria, which are the energy producing parts of our cells. In people with FRDA, since both copies of the FXN gene are abnormal and they do not produce adequate amounts of frataxin, tissues that are especially dependent on mitochondrial energy production (e.g., nerve and heart cells) start to degenerate.
In most affected individuals, the FXN gene contains a very specific type of error called an expanded GAA trinucleotide repeat. Every gene consists of different arrangements of four chemical units (nucleotides) called adenine (A), cytosine (C), guanine (G), and thymine (T). In most people with FRDA, both copies of the FXN gene contain abnormally long tracts of repeating units consisting of guanine-adenine-adenine (GAA trinucleotide repeat). So, while people without FRDA have less than 30 GAA repeats, individuals with FRDA have expanded tracts ranging from 100 to 1300 repeats in both copies of the FXN gene, with the majority containing >500 repeats. Even though this expanded GAA repeat mutation is located within a โnon-codingโ region of the FXN gene (called intron 1) it results in gene silencing and reduction in capacity to produce frataxin protein. The severity of FXN gene silencing is proportional to the length of the expanded GAA repeat mutation. The variability of associated symptoms and findings is also correlated with the size of expanded GAA repeats. For example, shorter expansions (<500 GAA repeats) are often associated with later age of onset, slower progression of clinical features and absence of or mild cardiomyopathy. Parents of individuals with FRDA have one copy of the expanded GAA repeat mutation and one normal FXN gene, and they do not develop any signs of disease. While most people with FRDA have the expanded GAA repeat mutation in both copies of the FXN gene, a few (<5%) have the expanded GAA repeat mutation on one copy of the FXN gene and another pathogenic variant in the other FXN gene copy.
FRDA is inherited as an autosomal recessive condition. Recessive genetic disorders occur when an individual inherits a mutated gene from each parent. If an individual receives one normal gene and one mutated gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the mutated gene and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
The prevalence of FRDA is approximately 1 in 40,000 people. FRDA is the most common inherited ataxia in Europe, the Middle East, South Asia (Indian subcontinent) and North Africa. It is rarely identified in other populations.
FRDA is suspected in an individual based on characteristic symptoms and clinical examination. The diagnosis is confirmed by molecular genetic testing to look for pathogenic variants in the FXN gene. The most common type of variant โ which is observed in both the maternal and paternal copies of the FXN gene of more than 90% of individuals with FRDA โ is an abnormally expanded GAA repeat in intron 1 of the gene.
Treatment
Treatment of FRDA is largely symptomatic and supportive. A multidisciplinary treatment strategy is the most appropriate approach given that the condition affects multiple organ systems. Continuous medical supervision to avoid potential complications involving the heart, spine, feet, muscles, vision and hearing are recommended.
In 2023, the U.S. Food and Drug Administration (FDA) approved omavoloxolone (Skyclarys) as a therapy for individuals with FRDA who are at least 16 years of age. It was shown to reduce the speed of progression of the disease in clinical trials. This is not considered a disease-modifying therapy and the search for other therapies is ongoing (see Investigational Therapies below).
Prostheses, walking aids, wheelchairs and physical therapy help maintain an active lifestyle. Orthopedic surgery or non-surgical interventions may help curvature of the spine and abnormalities of the feet but should be carefully considered in consultation with a neurologist and orthopedic surgeon.
Heart problems and/or diabetes mellitus associated with FRDA may be treated with medication. Anti-arrhythmic agents and anti-cardiac failure medication may be used to treat heart disease. Dietary modification, oral hypoglycemic therapeutics and/or insulin may be considered for controlling diabetes mellitus. Vision and hearing problems may be treated with either corrective devices and/or drugs. Speech therapy helps maximize verbal communication skills.
Emotional strain can affect patients and their families, and psychological counseling may be helpful.
Genetic counseling is recommended for affected individuals and their families.
The Friedreichโs Ataxia Research Alliance (FARA) provides up-to-date information about therapies in development and current clinical trials on their website:
https://www.curefa.org/pipeline.html
Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/ .
All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/
For information about clinical trials sponsored by private sources, contact:
https://www.centerwatch.com/
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
INTERNET
Bidichandani SI, Delatycki MB. Friedreich Ataxia. 1998 Dec 18 [Updated 2017 Jun 1]. In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviewsยฎ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1281/ Accessed Oct 11, 2023.
Online Mendelian Inheritance in Man, OMIM (TM). John Hopkins University, Baltimore, MD. MIM Number 229300; Last Update: 04/12/2023. Available at: https://omim.org/entry/229300 Accessed Oct 11, 2023.
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Learn more https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/Ensuring that patients and caregivers are armed with the tools they need to live their best lives while managing their rare condition is a vital part of NORDโs mission.
Learn more https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder.
Learn more https://rarediseases.org/patient-assistance-programs/caregiver-respite/The information provided on this page is for informational purposes only. The National Organization for Rare Disorders (NORD) does not endorse the information presented. The content has been gathered in partnership with the MONDO Disease Ontology. Please consult with a healthcare professional for medical advice and treatment.
The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
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