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Friedreich ataxia (FRDA) is a rare inherited disorder that causes progressive damage to the nervous system resulting in symptoms ranging from gait disturbance and speech problems to heart disease. The disorder is named after the German neurologist Nikolaus Friedreich, who first described the condition in the 1860s. In individuals with FRDA, the spinal cord and peripheral nerves degenerate and become thinner. The cerebellum, which coordinates balance and movement, also degenerates to a lesser extent. (Figure 1) This damage results in awkward, unsteady movements and impaired sensory functions. The disorder also causes problems in the heart and spine, as well as other organs, and individuals may develop diabetes. FRDA does not affect thinking and reasoning abilities (cognitive functions). Neurological symptoms include muscle weakness and a loss of balance and coordination, or ataxia. Cardiac involvement can range from mild, asymptomatic abnormalities to severe, life-threatening problems with the musculature of the heart, leading to hypertrophic cardiomyopathy. Symptoms can also include progressive spasticity, dysarthria, absent lower limb reflexes, sensory loss, and scoliosis. Most individuals begin experiencing initial symptoms between 5 and 15 years of age, although there are atypical late-onset forms with initial symptoms presenting after age 25.1 Early symptom onset is usually associated with more severe disease progression. There is no cure for FRDA, but there are treatments for cardiac symptoms and ways to manage ataxia and muscle weakness. Since the disorder does not affect thinking and cognitive function, many individuals with FRDA lead active, rewarding lives.
FRDA is caused by mutations in the FXN (frataxin) gene located on the long arm of chromosome 9 that encodes for the mitochondrial protein frataxin. In the normal version of the gene, a GAA sequence of DNA in intron 1 is repeated between 7 and 22 times. In the defective FXN gene, the GAA repeat can expand over a thousand times, although the majority of individuals with FRDA have repeats ranging from 600 to 1,200. This abnormal pattern is called a trinucleotide repeat expansion. FRDA is the only known recessive genetic disorder caused by this abnormal GAA expansion. Approximately 98% of individuals with FRDA have a homozygous expansion of the GAA trinucleotide repeat in intron 1 of the FXN gene. The remaining 2% of FRDA patients have the trinucleotide expansion on 1 allele and a point mutation or deletion of the second allele.2
Although rare, FRDA is the most common form of hereditary ataxia, affecting about 1 person in 50,000 in the United States. An estimated 1 in 90 individuals of European ancestry carries an abnormal FXN gene.
FRDA is an autosomal recessive disease and males and females are equally affected. A carrier will not develop the disease but could pass the gene mutation on to his or her children. If both parents are carriers, their children have a 1 in 4 chance of having the disease and a 1 in 2 chance of inheriting 1 abnormal gene that they, in turn, could pass on to their children. (Figure 2)
The inability to properly express frataxin protein is the basic disorder in FRDA. The GAA trinucleotide repeat expansion greatly disrupts the normal production of frataxin found in the mitochondria, causing a deficiency of the protein. Frataxin protein is important for the incorporation of iron inside mitochondria. A prominent theory is that frataxin acts like a storage depot for iron, releasing it only where needed. (Figure 3) When frataxin is missing or defective, free iron may accumulate in mitochondria and cause oxidative stress—the buildup of harmful oxygen-based free radicals—that damages the cell.3 Mitochondria act as an essential energy producer for almost all cells in the body, which helps explain why FRDA affects multiple tissues. In addition, certain cells are particularly sensitive to frataxin deficiency. These include the heart, pancreas, and large nerve cells associated with the spinal cord. What is not well understood is why only certain cells are specifically sensitive to frataxin depletion, leading to profound clinical symptoms and eventually death.4
Symptoms of FRDA are caused by the erosion of structures in areas of the brain and spinal cord that control coordination, muscle movement, and some sensory functions. The symptoms typically begin between the ages of 5 and 15 years, although they can appear in adulthood, and on rare occasions as late as age 75. This situation, termed late-onset FRDA, can cause somewhat different symptoms and requires slightly different medical management.
The first symptom to appear is usually gait ataxia, or general unsteadiness when walking—with increased tripping. The ataxia gradually worsens and slowly spreads to the arms and the trunk. There is often loss of sensation in the extremities, which may spread to other parts of the body. Other features include loss of tendon reflexes, especially in the knees and ankles. Most people with FRDA develop scoliosis often requiring surgical intervention. Slowness and slurring of speech often develop and can progressively worsen. Also many individuals with later stages of FRDA develop hearing and vision loss. Other symptoms that may occur include chest pain, shortness of breath, and heart palpitations. These symptoms result from various forms of heart disease (hypertrophic cardiomyopathy, myocardial fibrosis, cardiac failure) that often accompany FRDA. Heart rhythm abnormalities such as tachycardia and heart block are also common.
About 20% of people with FRDA develop carbohydrate intolerance and 10% develop diabetes. Most affected individuals tire very easily and find that they require more rest and take a longer time to recover from colds and influenzalike illnesses.
The rate of progression varies from person to person. Generally, within 10 to 20 years after the appearance of the first symptoms, the person is confined to a wheelchair, and in later stages of the disease individuals may become completely incapacitated.
FRDA can shorten life expectancy and heart disease is the most common cause of death. However, some people with less severe features of FRDA live into their 60s, 70s, or older.
A diagnosis of FRDA includes a medical history and a thorough physical examination, with attention to balance difficulty, loss of joint sensation, absence of reflexes, and signs of neurological problems.
Historically, laboratory diagnosis of FRDA has been by detection of the GAA repeat expansions within intron 1 or other FXN gene mutations. Genetic testing can provide a conclusive diagnosis, can be used prenatally, and can be used to determine carrier status.
However, a molecular-based assay detecting mutations in the FXN gene is not able to effectively monitor treatment, is not amenable to multiplexing with other disease markers, and cannot be efficiently utilized for population screening. In contrast, a protein-based assay measuring concentration of frataxin is suitable for both diagnosis and treatment monitoring in individuals with FRDA. This assay is also useful when the clinical suspicion of the disease is present and a clinician wants to include or exclude its possibility in a cost-effective manner or to assist in the diagnosis of an atypical FRDA patient without a full complement of GAA-repeat expansion alleles.
The ability to measure frataxin in a high-throughput immunoassay provides not only the ability to perform population screening and presymptomatic diagnosis, but also serves as a biomarker used to measure disease progression or response to clinical trials. It also helps to distinguish patients who may have an expansion on a single allele from patients who are asymptomatic or exhibit late-onset presentation of disease.4,5 The discovery of this basic science technology shows the promise of a clinically relevant application and will no doubt be used as an outcome measure in future clinical trials of therapy for FRDA as well as implemented in newborn screening. The ability to measure and use frataxin concentrations as a biomarker gives hope that a treatment will be found for this progressive, neurodegenerative disease.
Mayo Medical Laboratories offers a quantitative immunoassay to measure frataxin levels in whole blood (FFRWB / Friedreich Ataxia, Frataxin, Quantitative, Whole Blood) and from dried blood spots (FFRBS / Friedreich Ataxia, Frataxin, Quantitative, Blood Spot).
Currently, there is no effective cure or treatment for FDRA. However, many of the symptoms and accompanying complications can be treated to help patients maintain optimal functioning as long as possible. Diabetes and heart problems can be treated with medications. Orthopedic problems such as foot deformities and scoliosis can be treated with braces or surgery. Physical therapy may prolong use of the arms and legs.
FRDA is typically silent for several years after birth until a pattern of symptoms begin to appear, although it is likely that damage begins long before. Once the symptoms begin to surface, treatment is primarily supportive, although several therapy clinical trials are in progress.6-8 It is generally accepted that treatment requires increasing frataxin protein concentrations and employing strategies to diagnose and treat patients as early as possible. Because early diagnosis will result in early initiation of treatment, an effort is underway working with the Discretionary Advisory Committee on Heritable Disorders in Newborns and Children to include FRDA in future considerations of newborn screening programs.9
Confirmatory patient testing currently relies on molecular-based testing of the FXN gene, but this type of testing is not amenable to high-throughput analysis. The Mayo Medical Laboratories assay uses frataxin as a potential FRDA biomarker and can utilize dried blood spots as a specimen type, facilitating diagnosis, newborn screening, and patient monitoring.
FRDA is an inherited disorder causing progressive damage to the nervous system due to a deficiency in frataxin, a critical protein for iron metabolism, antioxidant protection, and overall energy production. An immunoassay recently developed at Mayo Clinic and offered by Mayo Medical Laboratories for measuring frataxin concentration in whole blood and in dried blood spots is applicable to the diagnosis, population and newborn screening, and therapeutic monitoring of FRDA. Early diagnosis in the form of newborn screening appears promising for early intervention to reduce and prevent morbidity and mortality.
Mayo Clinic offers a comprehensive evaluation of adult and pediatric patients with FRDA by a multidisciplinary team including pediatric and adult neurology, cardiology, medical and biochemical genetics, endocrinology and physical medicine, among other specialties. Complete cardiology evaluation and treatment are included in the assessment. Visit http://www.mayoclinic.org/medical-genetics-rst/research.html for more information or contact the patient appointment coordinator at 507-774-8198.
Authored by Devin Oglesbee, PhD and Elizabeth Plumhoff