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Friedreich Ataxia

Synonym: FRDA

, MBBS, PhD and , MBBS, FRACP, PhD.

Author Information
, MBBS, PhD
Professor of Pediatrics and Head of Pediatric Genetics
University of Oklahoma Health Sciences Center
Oklahoma City, Oklahoma
, MBBS, FRACP, PhD
Professor and Director, Clinical Genetics, Austin Health and Bruce Lefroy Centre for Genetic Health Research
Murdoch Childrens Research Institute
Victoria, Australia

Initial Posting: ; Last Update: July 24, 2014.

Summary

Disease characteristics. Friedreich ataxia (FRDA) is characterized by slowly progressive ataxia with mean onset between age ten and 15 years and usually before age 25 years. FRDA is typically associated with dysarthria, muscle weakness, spasticity in the lower limbs, scoliosis, bladder dysfunction, absent lower limb reflexes, and loss of position and vibration sense. Approximately two thirds of individuals with FRDA have cardiomyopathy; up to 30% have diabetes mellitus; and approximately 25% have an "atypical" presentation with later onset or retained tendon reflexes.

Diagnosis/testing. The diagnosis of FRDA is suspected based on clinical findings and confirmed by detection of biallelic pathogenic variants in FXN. The most common type of mutation, which is observed on both alleles in more than 90% of individuals with FRDA, is an abnormally expanded GAA repeat in intron 1 of FXN. The remaining individuals with FRDA are compound heterozygotes for an abnormally expanded GAA repeat in the disease-causing range in one allele and another intragenic pathogenic variant in the other allele.

Management. Treatment of manifestations: Prostheses; walking aids and wheelchairs for mobility; speech, occupational, and physical therapy; pharmacologic agents for spasticity; orthopedic interventions for scoliosis and foot deformities; hearing devices for auditory involvement; dietary modifications and placement of a nasogastric tube or gastrostomy for dysphagia; antiarrhythmic agents, anti-cardiac failure medications, anticoagulants, and pacemaker insertion for cardiac disease; dietary modification, oral hypoglycemic agents or insulin for diabetes mellitus; antispasmodics for bladder dysfunction; psychological support, both pharmacologic and counseling.

Surveillance: At least annual assessment of overall status; examination for complications including spasticity, scoliosis, and foot deformity; annual ECG, echocardiogram, and fasting blood sugar to monitor for diabetes mellitus; hearing assessment every two to three years; a low threshold for sleep study to investigate for obstructive sleep apnea.

Agents/circumstances to avoid: Environments that place an individual at risk for falls such as rough surfaces for ambulant individuals; excessive use of alcohol, which can increase ataxia.

Therapies under investigation: Idebenone, deferiprone, erythropoietin, histone deacetylase inhibitors, EPI-743, PPAR gamma agonists, nicotinamide, resveratrol.

Genetic counseling. FRDA is inherited in an autosomal recessive manner. Each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of having no pathogenic variant. Carrier testing of at-risk relatives, prenatal testing for pregnancies at increased risk, and preimplantation genetic diagnosis are possible if both FXN pathogenic variants have been identified in an affected family member.

Diagnosis

Suggestive Findings

Diagnosis of Friedrich ataxia (FRDA) should be suspected in individuals with a combination of the following findings:

  • Progressive ataxia of gait and limbs
  • Dysarthria; decrease in/loss of position sense and/or vibration sense in lower limbs; muscle weakness
  • Absent muscle stretch reflexes in the legs (in atypical cases, reflexes may be preserved; see FRDA with retained reflexes)
  • Onset before age 25 years (in atypical cases, onset may be delayed; see late-onset FRDA and very late-onset FRDA)
  • Family history consistent with autosomal recessive inheritance

Especially if these additional findings are present:

  • Pyramidal weakness of the legs, extensor plantar responses
  • Scoliosis, pes cavus, hypertrophic non-obstructive cardiomyopathy
  • Glucose intolerance, diabetes mellitus, optic atrophy, or deafness

Note: Before the identification of FXN, clinical diagnostic criteria for Friedreich ataxia (FRDA) were established by Geoffroy et al [1976] and refined by Harding [1981]. Following identification of FXN, studies have shown that up to 25% of individuals with GAA expansion mutations in both FXN alleles exhibit clinical findings that differ from the previously established clinical diagnostic criteria [Filla et al 2000].

Establishing the Diagnosis

The diagnosis of Friedreich ataxia is established in a proband by detection of biallelic pathogenic variants in FXN, the only known gene to be associated with FRDA. (See Table 1).

Allele sizes. Four classes of alleles are recognized for the GAA repeat sequence in intron 1 of FXN [Cossee et al 1997, Montermini et al 1997a, Sharma et al 2004]:

  • Normal alleles. 5-33 GAA repeats. More than 80%-85% of alleles contain fewer than 12 repeats (short normal; SN) and approximately 15% have 12-33 repeats (long normal; LN). Normal alleles with more than 27 GAA repeats are rare.
  • Mutable normal (premutation) alleles. 34-65 GAA repeats. Although the exact frequency of these alleles has not been formally determined, they likely account for fewer than 1% of FXN alleles.
  • Full-penetrance (disease-causing expanded) alleles. 66 to approximately 1700 GAA repeats. The majority of expanded alleles contain between 600 and 1200 GAA repeats [Campuzano et al 1996, Durr et al 1996, Filla et al 1996, Epplen et al 1997].
  • Borderline alleles. 44-66 GAA repeats. The shortest repeat length associated with disease (i.e., the exact demarcation between normal and full-penetrance alleles) has not been clearly determined (see Penetrance).
  • Rare alleles of variant structure. In contrast to the alleles discussed above in which the GAA trinucleotides are perfect repeats, in rare pathogenic alleles the GAA repeats are not in perfect tandem order but rather are interrupted by other nucleotides. Such “interrupted FXN alleles” differ in length and types of nucleotides in the interruption, but they are typically close to the 3’ end of the GAA repeat tract (see Molecular Genetics).
    Note: (1) Molecular genetic testing does not determine presence or absence of nucleotide interruptions of the GAA tract. (2) These rare interrupted alleles may be associated with LOFA or VLOFA [Stolle et al 2008] (see Genotype-Phenotype Correlations).

Interpretation of test results. The exact demarcation between normal and full-penetrance alleles remains poorly defined. While the risk for phenotypic expression with borderline alleles is increased, it is not possible to offer precise risks. Therefore, the interpretation of test results in an individual with a large GAA expanded allele of full penetrance and a second allele of fewer than 100 GAA trepeats may be difficult.

One genetic testing strategy is molecular genetic testing of FXN.

An alternative genetic testing strategy is use of a multi-gene panel that includes FXN and other genes of interest (see Differential Diagnosis). While this is not recommended as a first-line strategy in typical cases, it may help identify some patients with atypical presentations. Note: The genes included and the methods used in multi-gene panels vary by laboratory and over time.

Table 1. Summary of Molecular Genetic Testing Used in Friedreich Ataxia (FRDA)

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by This Method
Homozygotes 2Compound Heterozygotes 3
FXNTargeted mutation analysis 490%-94% 56%-10% 6
Sequence analysis 7, 8NA 9
Deletion/duplication analysis 10NASee footnote 11
Unknown 12NA

1. See Table A. Genes and Databases for chromosome locus and protein name. See Molecular Genetics for information on allelic variants detected in this gene.

2. If both FXN alleles have expanded GAA repeats the individuals are designated homozygotes, whether the alleles have the same or different numbers of repeats.

3. Individuals are designated compound heterozygotes if one allele has an expanded GAA repeat and the other allele has an inactivating intragenic pathogenic variant or deletion.

4. GAA repeat expansion detected

5. More than 90% of individuals with FRDA have an abnormally expanded GAA repeat in intron 1 of FXN on both alleles [Campuzano et al 1996, Monros et al 1997].

6. The remainder of individuals with FRDA have an abnormally expanded GAA repeat in the disease-causing range in one FXN allele and another intragenic pathogenic variant in the other allele.

7. Sequence analysis detects variants that are benign, likely benign, of unknown significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

8. Sequence analysis of exons and flanking regions will identify FXN pathogenic variants located outside of the GAA repeat region. Nonsense, missense, frameshift, and splicing defect mutations have been identified (see Molecular Genetics).

9. To date, no affected individuals with inactivating intragenic variants in both FXN alleles have been reported.

10. Testing that identifies exonic or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

11. One intragenic deletion of FXN (deleting ~2.8 kb at the 3’ end of FXN, including exon 5a) has been identified in an affected individual whose other allele had an abnormally expanded GAA repeat [Zühlke et al 2004, Anheim et al 2012]. See Molecular Genetics.

12. Among individuals who satisfy the clinical diagnostic criteria for FRDA and who have normal vitamin E levels, fewer than 1% have no GAA expansion in either allele of FXN. It is possible that these individuals have pathogenic variants at a locus distinct from FXN [Durr et al 1996, McCabe et al 2000, Christodoulou et al 2001, Marzouki et al 2001]. However, no other loci have been convincingly linked to the FRDA phenotype.

Clinical Description

Natural History

Typical Friedreich ataxia is observed in about 75% of affected individuals and atypical presentations (with later onset or retained tendon reflexes) are observed in about 25%.

Typical Friedreich Ataxia

Neurologic manifestations. Individuals with typical Friedreich ataxia (FRDA) develop progressive ataxia with onset from early childhood through to early adulthood, starting with poor balance when walking, followed by slurred speech and upper-limb ataxia. The mean age of onset of symptoms is ten to 15 years [Delatycki et al 1999b]; onset can be as early as age two years and as late as the eighth decade. Gait ataxia, caused by a combination of spinocerebellar degeneration and loss of joint-position sense (proprioception), is the earliest symptom in the vast majority. The poor balance is accentuated when visual input is eliminated, such as in darkness or when the eyes are closed (Romberg sign). Ankle and knee jerks are generally absent, and plantar responses are up-going.

Within five years of symptom onset, most individuals with FRDA exhibit "scanning" dysarthria, lower extremity weakness, and diminished or absent joint-position and vibration sense distally — neurologic manifestations that result from progressive degeneration of the dorsal root ganglia, posterior columns, corticospinal tracts, the dorsal spinocerebellar tracts of the spinal cord, and the cerebellum. Involvement of peripheral sensory and motor neurons results in a mixed axonal peripheral neuropathy.

Muscle weakness is often present and is most prominent in hip extensors and abductors; as disease advances, distal limb muscle weakness and wasting become evident.

Spasticity in the lower limbs is common and can be significant, affecting foot plantar flexors and inverters to a greater extent than dorsiflexors and everters. Thus, in the late stages of disease, equinovarus deformity is commonly seen [Delatycki et al 2005] and may result in contractures and significant morbidity. Pes cavus is common (55%) but generally causes little problem for affected individuals. Restless leg syndrome is common in individuals with Friedreich ataxia, affecting 32%-50% of individuals in two studies [Frauscher et al 2011].

Scoliosis is present in approximately two thirds of individuals with FRDA when assessed clinically and 100% when assessed radiographically. A study found that 49 of 77 individuals with FRDA had scoliosis; ten were treated with a brace and 16 required spinal surgery [Milbrandt et al 2008].

Autonomic disturbance becomes more common with disease progression. The most common manifestations are cold, cyanosed feet; bradycardia is less common.

Speech. Dysarthria, present in the majority of individuals with FRDA, is generally of three types: mild dysarthria, increased velopharyngeal involvement manifest as hypernasality, and increased laryngeal dysfunction manifest as increased strained-strangled vocal quality [Folker et al 2010]. Dysarthria becomes worse as the disease progresses with the main changes seen over time being in speaking rate and utterance duration [Rosen et al 2012].

Swallowing. Dysphagia is common in FRDA with 92% of individuals reporting issues with swallowing [Vogel et al 2014]. Dysphagia in FRDA relates to oropharyngeal incoordination, weakness, and spasticity.

Hypertrophic cardiomyopathy, defined as increased thickness of the interventricular septum, is present in about two thirds of individuals with FRDA [Delatycki et al 1999a]. Echocardiographic evaluation may reveal left ventricular hypertrophy that is more commonly asymmetric than concentric [Dutka et al 2000, Bit-Avragim et al 2001, Koc et al 2005]. When more subtle cardiac involvement is sought by methods such as tissue Doppler echocardiography, an even larger percentage of individuals have detectable abnormalities [Dutka et al 2000, Mottram et al 2011]. Between 12% and 20% of individuals have reduced ejection fraction [Regner et al 2012, Weidemann et al 2012] and longitudinal strain is commonly reduced [St John Sutton et al 2014].

Later in the disease course, the cardiomyopathy may become dilated. Progressive systolic dysfunction is common [Kipps et al 2009] and reduction in left ventricular wall thickness is often seen as disease progresses [Rajagopalan et al 2010].

Electrocardiography (ECG) is abnormal in the vast majority, with T wave inversion, left axis deviation, and repolarization abnormalities being most commonly seen [Dutka et al 1999].

Symptoms related to cardiomyopathy usually occur in the later stages of the disease [Dutka et al 1999] but in rare instances may precede ataxia [Alikasifoglu et al 1999, Leonard & Forsyth 2001]. Quercia et al [2010] established the diagnosis of FRDA in a young child evaluated for sudden death. Subjective symptoms of exertional dyspnea (40%), palpitations (11%), and anginal pain may be present in moderately advanced disease. Arrhythmias (especially atrial fibrillation) and congestive heart failure frequently occur in the later stages of the disease and are the most common cause of mortality [Tsou et al 2011]. Coronary artery disease may occur and should be considered if there is angina and/ or sudden deterioration in cardiac function [Giugliano & Sethi 2007].

Urinary issues. Bladder symptoms including urinary frequency and urgency were reported by 41% of individuals in one study [Delatycki et al 1999a].

Sleep disordered breathing. Sleep disordered breathing and sleep apnea are more prevalent in those with FRDA than in the healthy population. There is a minimum prevalence of 21% of obstructive sleep apnea compared to an incidence of about 5% in the general population [Corben et al 2013].

Diabetes mellitus occurs in up to 30% of individuals with FRDA [Cnop et al 2013]. Impaired glucose tolerance is seen in up to an additional 49% [Ristow 2004, Cnop et al 2012].

Ophthalmic manifestations. Optic nerve atrophy, often asymptomatic, occurs in approximately 25% of individuals with FRDA. Reduced visual acuity was found in 13% in one study [Durr et al 1996]. Study of the anterior and posterior visual pathways in FRDA by visual field testing and optical coherence tomography, pattern visual evoked potentials, and diffusion-weighted imaging revealed that all individuals studied had optic nerve abnormalities, but only 5/26 (19%) had related symptoms [Fortuna et al 2009]. Progressive diminution of contrast acuity is typical with disease progression [Seyer et al 2013].

Abnormal extraocular movements include irregular ocular pursuit, dysmetric saccades, saccadic latency, square wave jerks, ocular flutter, and marked reduction in vestibulo-ocular reflex gain and increased latency [Fahey et al 2008]. Horizontal and vertical gaze palsy does not occur.

Hearing loss. Sensorineural hearing loss occurs in 13% of individuals with FRDA [Durr et al 1996]. Auditory neuropathy may occur and difficulty hearing in background noise is common [Rance et al 2008].

Cognitive skills. While cognition is generally not impaired in FRDA, motor and mental reaction times can be significantly slowed [Wollmann et al 2002, Corben et al 2006]. Motor planning is markedly impaired [Corben et al 2010, Corben et al 2011]. The intelligence profile of individuals with FRDA is characterized by concrete thinking and poor capacity in concept formation and visuospatial reasoning with reduced speed of information processing [Mantovan et al 2006]. Problems with attention and working memory have also been demonstrated [Klopper et al 2011]. Motor overflow is also more prevalent in FRDA than in controls [Low et al 2013]. Those with earlier onset and larger FXN intron 1 GAA repeats tend to have more severe cognitive difficulties than those with later onset and smaller GAA repeats [Nachbauer et al 2014].

Progression. The rate of progression of FRDA is variable. The average time from symptom onset to wheelchair dependence is ten years [Durr et al 1996, Delatycki et al 1999a].

In a large study conducted in the early 1980s, the average age at death was 37 years [Harding 1981]. In a more recent study, the mean and median age of death was 36.5 years and 30 years, respectively [Tsou et al 2011]. Survival into the sixth and seventh decades has been documented. The most common cause of death was cardiac (38/61), with the remainder (17/61) being non-cardiac (most commonly pneumonia) or unknown cause (6/61) [Tsou et al 2011].

A study of 65 pregnancies in 31 women with FRDA found no increase in the rate of spontaneous miscarriage, preeclampsia, prematurity, or cesarean section [Friedman et al 2010]. Approximately one third of the women each reported that the symptoms of FRDA worsened, improved, or were unchanged during pregnancy.

Neuroimaging. MRI is often normal in the early stages of FRDA. With advanced disease, atrophy of the cervical spinal cord and cerebellum may be observed [Bhidayasiri et al 2005]. Atrophy of the superior cerebellar peduncle, the main outflow tract of the dentate nucleus, may also be seen [Akhlaghi et al 2011]. Cervical spinal cord size correlates with disease severity as measured by the Friedreich Ataxia Rating Scale [Chevis et al 2013].

A voxel-based morphometry study showed a symmetric volume loss in the dorsal medulla, infero-medial portions of the cerebellar hemispheres, rostral vermis, and dentate region [Della Nave et al 2008]. No volume loss in cerebral hemispheres was observed. Lower fractional anisotropy, higher mean diffusivity and increased radial diffusivity have been found in the dentato-rubral, dentato-thalamic and thalamo-cortical tracts in individuals with FRDA compared to controls [Akhlaghi et al 2014].

Reduced N-acetylaspartate in the cerebellum has been demonstrated by 1H-MRS [Iltis et al 2010] and increased diffusion weighted imaging may be present in a number of brain white matter tracts [Rizzo et al 2011].

Electrodiagnostic findings

  • Nerve conduction studies generally show a motor nerve conduction velocity of greater than 40 m/s with reduced or absent sensory nerve action potential with an absent H reflex.
  • Central motor conduction time is abnormal after transcranial magnetic stimulation [Brighina et al 2005].

Atypical Presentations

Approximately 25% of individuals homozygous for full-penetrance GAA expansion mutations in FXN have atypical findings [Durr et al 1996] that include the following:

  • Late-onset FRDA (LOFA) and very late-onset FRDA (VLOFA). In approximately 15% of individuals with FRDA, onset is later than age 25 years. In individuals with LOFA, the age of onset is 26-39 years; and, in VLOFA, the age of onset is over 40 years [Bidichandani et al 2000, Bhidayasiri et al 2005]. The oldest reported age of onset among individuals homozygous for the GAA expansion is 80 years [Alvarez et al 2013].

    Disease progression is usually slower in LOFA than in typical FRDA, including a later age of confinement to a wheelchair and lower incidence of secondary skeletal abnormalities (e.g., scoliosis, pes cavus, pes equinovarus) [Lynch et al 2006].
  • FRDA with retained reflexes (FARR) accounts for approximately 12% of individuals who are homozygous for the GAA expansion [Coppola et al 1999]. Some individuals with FARR show brisk tendon reflexes that can be accompanied by clonus. Tendon reflexes may be retained for more than ten years after the onset of the disease. FARR usually has a later age of onset and lower incidence of secondary skeletal involvement and cardiomyopathy [Coppola et al 1999].
  • FRDA in Acadians. Montermini et al [1997b] showed that Acadians with FRDA have a later age of onset (on average 3.0 years later than those with typical FRDA) and of wheelchair confinement, and a much lower incidence of cardiomyopathy (48% vs 82%).

Spastic paraparesis without ataxia. Individuals who are homozygous for full-penetrance GAA expansions may rarely present with spastic gait disturbance without gait or limb ataxia. These individuals usually have hyperreflexia and a later age of onset (on average 5.8 years later than those with typical FRDA); they develop ataxia with time [Montermini et al 1997b, Gates et al 1998, Castelnovo et al 2000, Lhatoo et al 2001, Badhwar et al 2004].

Other rare presentations of FRDA

Genotype-Phenotype Correlations

Despite the general genotype-phenotype correlations described below, it is not possible to precisely predict the specific clinical outcome in any individual based on genotype. The remaining variability in individuals with FRDA may be caused by genetic background (e.g., Acadian individuals, the presence of the p.Cys282Tyr mutation in HFE [Delatycki et al 2014]), somatic heterogeneity of the expanded GAA repeat [Montermini et al 1997b, Sharma et al 2004, De Biase et al 2007], and other unidentified factors.

Homozygotes for Pathogenic GAA Repeat Expansions

GAA repeat size. The age of onset, presence of leg muscle weakness/wasting, duration until wheelchair use, and prevalence of cardiomyopathy, pes cavus, and scoliosis have all shown statistically significant inverse correlations with the size of the expanded GAA repeat [Durr et al 1996, Filla et al 1996, Monros et al 1997, Montermini et al 1997b]. The size of the shorter of the two expanded pathogenic GAA repeat alleles shows better correlation than the larger repeat allele and accounts for approximately 50% of the variation in age of onset [Filla et al 1996].

La Pean et al [2008] found that age at diagnosis is a better predictor of disease severity, including disease progression, and association with scoliosis and cardiomyopathy. This suggests that factors other than the repeat length (e.g., other genetic, epigenetic, and environmental variables) play a role in determining the severity of disease.

Late-onset FRDA (LOFA) and very late-onset FRDA (VLOFA)

  • Individuals with LOFA (i.e., age of onset >25 years) frequently exhibit fewer than 500 GAA repeats in at least one of the expanded alleles [Bhidayasiri et al 2005].
  • Individuals with VLOFA (i.e., age of onset >40 years) usually have fewer than 300 GAA repeats in at least one of the expanded alleles [Bidichandani et al 2000, Berciano et al 2005]. However, Bidichandani et al [2000] reported an individual with VLOFA who was homozygous for expansions with greater than 800 GAA repeats, underscoring the inability to predict the clinical outcome in each individual.

    In the full penetrance range, there are uncommon FXN alleles that are interrupted by other nucleotides thereby disrupting a section of the long tract of tandem GAA repeats (see Molecular Genetics). Counting only the number of GAA repeats in the uninterrupted section, such alleles tend to be shorter in length (equivalent in length to alleles of 100-300 GAA repeats), and are often associated with LOFA/VLOFA. Stolle et al [2008] reported six people with such interrupted alleles (with a conventional expanded GAA repeat mutation containing more than 600 repeats in the other FXN allele) whose onset ranged from age 34 to 75 years. It is not clear if the milder FRDA phenotype results from the interruptions per se, or the fact that interrupted alleles are often short, or both.

FRDA in Acadians. Despite the milder phenotype in this population, no significant differences were found either in the size of the GAA expansions or in the pathogenic sequence variants of FXN compared to individuals with typical FRDA [Montermini et al 1997b]. This finding supports the existence of other genetic modifiers of disease severity.

Spastic paraparesis without ataxia may be seen in those with smaller expanded alleles [Berciano et al 2002], or in association with the p.Gly130Val missense mutation [McCabe et al 2002].

Cardiomyopathy is more frequently seen in individuals with a higher number of GAA repeats [Durr et al 1996, Filla et al 1996, Monros et al 1997]:

  • Isnard et al [1997] found echocardiographic evidence of left ventricular hypertrophy in 81% of those with FRDA with GAA repeat lengths greater than 770 repeats and in only 14% of those with repeat lengths of fewer than 770 repeats.
  • Significant correlation is seen between the size of the GAA expansion and various diastolic parameters [Mottram et al 2011] as well as the thickness of the interventricular septum and left ventricular wall [Isnard et al 1997, Dutka et al 1999, Bit-Avragim et al 2001].
  • Montermini et al [1997b] and Delatycki et al [1999b] showed that the presence of cardiomyopathy correlated with disease severity as defined by age of onset.
  • Cuda et al [2002] described an individual with particularly severe early childhood-onset cardiac hypertrophy that preceded the onset of ataxia; the individual was homozygous for large GAA expansions and additionally had a pathogenic variant in TNNT2, the gene encoding cardiac troponin T.

Diabetes mellitus or abnormal glucose tolerance does not show a clear-cut correlation with the size of the GAA expansion. Filla et al [1996] found that individuals with diabetes mellitus tend to have larger repeat lengths; in a larger cohort, however, Durr et al [1996] did not find significant correlation either with the size of the GAA expansion or with disease duration. Despite the lack of correlation with the GAA expansion size, Delatycki et al [1999b] found a correlation between the incidence of diabetes mellitus and earlier age at onset.

Compound Heterozygotes for a GAA Expansion and an Intragenic Inactivating Pathogenic Variant or Deletion

Although the phenotype in most compound heterozygotes for a full-penetrance GAA expansion and another intragenic pathogenic variant is clinically indistinguishable from the typical FRDA phenotype seen in homozygotes for expanded GAA repeats [Campuzano et al 1996, Filla et al 1996, Cossee et al 1999, Zühlke et al 2004], exceptions have been observed:

  • Compound heterozygosity for the p.Gly130Val or p.Asp122Tyr missense variants, each located near the amino end of the highly conserved carboxy-terminal domain of frataxin, results in an atypically mild FRDA phenotype [Bidichandani et al 1997, Cossee et al 1999]. Affected individuals have slowly progressive disease, absence of dysarthria, retention of reflexes, and mild or absent gait/limb ataxia.
  • Two individuals who were compound heterozygous for the c.2delT pathogenic variant presented with chorea [Zhu et al 2002, Spacey et al 2004].

Compound Heterozygotes for a Full-Penetrance GAA Expansion and a Borderline "Mutable" Allele

Individuals with somatically unstable, borderline alleles have LOFA/VLOFA, mild and gradually progressive disease, and normal reflexes/hyperreflexia [Sharma et al 2004].

Penetrance

Penetrance is complete in homozygotes with both alleles having full-penetrance GAA repeat expansions and in compound heterozygotes for a full-penetrance GAA expansion in one allele and a FXN pathogenic variant in the other allele. However, because of wide variability in the size of pathogenic expanded alleles, and for other unknown reasons, onset can range from before age five years to older than age 50 years. This variability in age-dependent penetrance can occasionally occur within the same sibship.

The allele size at the lower end of the pathogenic allele range has not been clearly defined in FRDA. It is possible that incomplete penetrance is associated with borderline alleles and expanded alleles containing fewer than 100 GAA repeats. Individuals with a borderline allele and a full-penetrance allele may develop LOFA/VLOFA. Sharma et al [2004] showed that somatic instability of the borderline allele was required for clinical expression of the FRDA phenotype; and, therefore, alleles with fewer than 37 GAA repeats are unlikely to cause disease. Although the exact frequency of borderline alleles has not been formally determined, they account for fewer than 1% of FXN alleles.

Anticipation

Friedreich ataxia (FRDA) is inherited in an autosomal recessive manner; therefore, anticipation is not observed because the disease is typically not observed in more than one generation.

Prevalence

The prevalence of FRDA is 2:100,000-4:100,000. The carrier frequency is 1:60-1:100.

FRDA is the most common inherited ataxia in Europe, the Middle East, South Asia (Indian subcontinent), and North Africa.

FRDA has not been documented in Southeast Asians, in sub-Saharan Africans, or among Native Americans. A lower than average prevalence of FRDA is noted in Mexico.

Differential Diagnosis

Peripheral neuropathy

  • Friedreich ataxia (FRDA) may be confused with Charcot-Marie-Tooth type 1 (CMT1) and Charcot-Marie-Tooth type 2 (CMT2). CMT1 is caused by axonal demyelination and CMT2 by axonal degeneration. Some individuals with CMT present in childhood with clumsiness, areflexia, and minimal distal muscle weakness. In children with FRDA who have not developed dysarthria or extensor plantar responses, the diagnosis of CMT may be difficult to exclude solely on clinical findings. Inheritance of CMT is generally autosomal dominant; however, autosomal recessive and X-linked forms exist (see CMT Overview).
  • Spinocerebellar ataxia with axonal neuropathy (SCAN1) is characterized by ataxia, axonal sensorimotor polyneuropathy, distal muscular atrophy, pes cavus, and steppage gait — signs that may collectively mimic FRDA. SCAN1 is caused by mutation of TDP1, the gene encoding tyrosyl-DNA phosphodiesterase 1, a topoisomerase I-dependent DNA damage repair enzyme [El-Khamisy et al 2005]. Inheritance is autosomal recessive.

Ataxia

  • Ataxia with vitamin E deficiency (AVED) (caused by mutation of TTPA, encoding α-tocopherol transfer protein), abetalipoproteinemia, or other fat malabsorptive conditions should be considered in individuals with the FRDA phenotype without GAA expansions [Cavalier et al 1998, Hammans & Kennedy 1998]. Most individuals with AVED fulfill the diagnostic criteria for FRDA, although titubation and hyperkinesia are more frequently seen in AVED than in FRDA [Cavalier et al 1998]. Although less frequent than in FRDA, cardiomyopathy is seen in 19% of those with AVED [Cavalier et al 1998]. It is important to differentiate FRDA from AVED because, unlike FRDA, AVED can be effectively treated with continuous lifelong vitamin E supplementation. Serum concentration of vitamin E and lipid-adjusted vitamin E may also be used to differentiate AVED from FRDA [Feki et al 2002]. Inheritance of AVED is autosomal recessive.
  • Ataxia with oculomotor apraxia type 1 (AOA1) (oculomotor apraxia and hypoalbuminemia; early-onset cerebellar ataxia with hypoalbuminemia) is characterized by childhood onset of slowly progressive cerebellar ataxia followed by oculomotor apraxia and a severe axonal sensorimotor peripheral neuropathy. The initial manifestation is progressive gait imbalance in childhood (age 2-18 years) that may be associated with chorea. All affected individuals initially have generalized areflexia that is followed later by a peripheral neuropathy. Cognitive impairment may be noted. The clinical phenotype of AOA1 may be highly variable; however, the presence of chorea, severe sensorimotor neuropathy, oculomotor anomalies, cerebellar atrophy on MRI, and absence of the Babinski sign can help to distinguish AOA1 from FRDA [Le Ber et al 2003]. AOA1 is associated with pathogenic variants in APTX [Moreira et al 2001]. Inheritance is autosomal recessive. Due to its phenotypic similarities, this condition was initially called FRDA2 when the locus was mapped and before the gene was known [Christodoulou et al 2001].

    AOA1 is the most common recessively inherited ataxia in Japan; in Portugal, it is second to FRDA. AOA1 has also been reported with variable frequencies in France, Germany, Italy, Taiwan, Tunisia, and Australia [Le Ber et al 2005].
  • Ataxia with oculomotor apraxia type 2 (AOA2) is characterized by ataxia with onset between age ten and 22 years, cerebellar atrophy, axonal sensorimotor neuropathy, oculomotor apraxia, choreiform or dystonic movement, and elevated alpha-fetoprotein (AFP) levels [Le Ber et al 2004]. It is caused by mutation of SETX, the gene encoding senataxin [Moreira et al 2004]. Inheritance is autosomal recessive. Among Europeans, AOA2 is the most common non-FRDA autosomal recessive cerebellar ataxia.

Other early-onset ataxias may be distinguishable by virtue of their characteristic clinical features (see also Ataxia Overview):

Spasticity. Friedreich ataxia (FRDA) is rare among individuals with uncomplicated (isolated) autosomal recessive spastic paraparesis [Wilkinson et al 2001, Badhwar et al 2004] (see also Hereditary Spastic Paraplegia Overview). However, autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) may present with early-onset ataxia and areflexia, Babinski sign, loss of vibratory sensation, and pes cavus without spasticity [Shimazaki et al 2005].

Multisystem atrophy. VLOFA caused by a shorter GAA expansion allele may mimic multiple system atrophy of the cerebellar type [Berciano et al 2005].

Huntington disease. Rarely, FRDA can present as a phenocopy of Huntington disease [Wild et al 2008].

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed Friedreich ataxia (FRDA), the following evaluations are recommended:

  • Neurologic assessment
  • Physical therapy and occupational therapy assessment of strength and balance, need for adaptive aids, and the home and work environment
  • Speech and swallowing assessment
  • Assessment of significant scoliosis by an orthopedic surgeon
  • ECG and echocardiogram for evidence of cardiomyopathy; assessment by a cardiologist if abnormal
  • Bladder function with referral to a urologist if severe symptoms are present
  • Assessment for obstructive sleep apnea
  • Random blood glucose concentration for evidence of diabetes mellitus
  • Ophthalmologic assessment if any ophthalmologic symptoms are present
  • Hearing assessment
  • Psychological assessment
  • Medical genetics consultation

Treatment of Manifestations

There is little objective evidence regarding management of FRDA. A multidisciplinary approach is essential for maximal benefit because FRDA affects multiple organ systems:

  • Prostheses, walking aids, wheelchairs, and physical therapy as prescribed by a physiatrist (rehabilitation medicine specialist) to maintain an active lifestyle
  • Inpatient rehabilitation, which has been shown to improve physical function as measured by the Functional Independence Measure [Milne et al 2012].
  • Occupational therapy assessment to ensure a safe home and work environment
  • To manage spasticity: physical therapy including stretching programs, standing frame and splints, pharmacologic agents such as baclofen and botulinum toxin. Intrathecal baclofen can be beneficial where oral administration is unsuccessful or side effects are excessive [Berntsson et al 2013]. Orthopedic interventions, both operative and non-operative, for scoliosis and foot deformities [Delatycki et al 2005] may be necessary.
  • Speech therapy to maximize communication skills
  • Management of dysphagia that may include dietary modification and, in the late stages of disease, use of nasogastric or gastrostomy feeding
  • Treatment of cardiac disease to reduce morbidity and mortality, including anti-arrhythmic agents, anti-cardiac failure medication, anti-coagulants, and pacemaker/ implantable cardioverter defibrillator insertion [Lynch et al 2012a]. Cardiac transplantation is more controversial [Sedlak et al 2004, Yoon et al 2012].
  • Antispasmodic agents for bladder dysfunction
  • Treatment of sleep apnea by continuous positive airway pressure
  • Treatment of diabetes mellitus with diet and, if necessary, oral hypoglycemic agents or insulin
  • Hearing aids, microphone, and receiver as needed [Rance et al 2010] (see also Hereditary Hearing Loss and Deafness Overview)
  • Psychological (counseling and/or pharmacologic) support for affected individuals and family

Surveillance

The following are appropriate.

  • If ECG and echocardiogram performed at the time of initial diagnosis are normal, repeat testing annually
  • Annual fasting blood sugar to monitor for diabetes mellitus
  • Hearing assessment every two to three years or more often if symptoms are present. This should include testing of hearing in background noise, as it is more often abnormal than the common audiogram assessed in a quiet environment [Rance et al 2008]
  • Sleep study to investigate for obstructive sleep apnea if concerns are raised by clinical history or a screening test such as the Epworth Sleepiness Scale

Agents/Circumstances to Avoid

Alcohol can exacerbate ataxia and should be consumed in moderation. Illicit drugs may well affect neuronal well-being and may exacerbate FRDA and thus should be avoided. Environments that place an ambulant individual at risk for falls (e.g., rough surfaces) should be avoided.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes

Pregnancy Management

Close cardiac monitoring is recommended in any woman with FRDA during pregnancy.

Therapies Under Investigation

A summary of therapies under investigation can be found online.

Deficiency of frataxin results in abnormal accumulation of intramitochondrial iron, defective mitochondrial respiration, and overproduction of oxygen free radicals with evidence of oxidant-induced intracellular damage (see Molecular Genetics).

Antioxidant therapy by free radical scavengers including coenzyme Q10, vitamin E, and idebenone (a short-chain analog of coenzyme Q10), and chelation therapy have been considered potential treatments for slowing the progression of FRDA:

  • Coenzyme Q10 and vitamin E. Following three to six months' antioxidant treatment with coenzyme Q10 and vitamin E, Lodi et al [2001] showed improved ATP production in the heart and skeletal muscle of individuals with FRDA. An open label trial of these agents in ten individuals for 47 months resulted in sustained improvement in bioenergetics and improved cardiac function, as assessed by increased fractional shortening [Hart et al 2005].

    A study that compared low-dose coenzyme Q10 (30 mg/day) to high-dose coenzyme Q10 (600 mg/day) and vitamin E (2100 IU/day) over two years found no difference in the change in International Cooperative Ataxia Rating Scale (ICARS) score between the two groups [Cooper et al 2008]. A significant proportion of individuals with FRDA had low serum coenzyme Q10 levels.
  • Idebenone has shown promise as a treatment for FRDA.

    A reduction in left ventricular hypertrophy has been found in some studies [Hausse et al 2002, Buyse et al 2003, Mariotti et al 2003] but not in others [Lagedrost et al 2011].

    A Phase II clinical trial of three doses of idebenone (5, 15, and 45 mg/kg) compared to placebo suggested a dose-related neurologic benefit as measured by the ICARS [Di Prospero et al 2007]. However, no significant neurologic benefit was shown in a Phase III study of idebenone conducted on 70 individuals with FRDA aged eight to 18 years [Lynch et al 2010].

    The results of another Phase III study from Europe are expected to be published shortly.
  • A0001 (α-tocopheryl quinone) is an antioxidant with superior bioavailability to idebenone. It showed promise in a small one-month placebo controlled study [Lynch et al 2012b]. A0001 is no longer being developed but a related compound, EPI-743, is being evaluated in placebo-controlled studies in adults and children with FRDA.
  • Iron chelators have been proposed as a possible therapy for lowering the intramitochondrial iron overload. Nonspecific iron chelators (e.g., desferrioxamine) for the specific reduction of mitochondrial iron overload may not be effective; a clinical trial was terminated for lack of efficacy.

    The oral iron chelator, deferiprone, has shown promise as a treatment for FRDA in an open label study [Boddaert et al 2007]. Iron in the cerebellar dentate nucleus was reduced as measured by MRI; neurologic benefit was suggested.

    The results of a Phase II placebo-controlled study of deferiprone are expected shortly.
  • An 11-month open-labeled study of combined low-dose deferiprone and low-dose idebenone (both given at 20 mg/kg/day) found a significant reduction in intraventricular septum thickness and left ventricular mass index over the course of the study [Velasco-Sánchez et al 2011]. Although there was no significant change in the International Cooperative Ataxia Rating Scale score, some subscale scores showed significant increases and others showed significant decreases over the course of the study.

    Desferrioxamine along with pyridoxal isonicotinoyl hydrazone, a mitochondrial permeable ligand, limited cardiac hypertrophy in a conditional Fxn knockout mouse model [Whitnall et al 2008].

Increasing frataxin levels. Because the abnormal GAA repeat expansion results in reduced quantities of normal FXN transcript and frataxin protein, a number of studies have been conducted to identify compounds that increase their levels. This is achieved mainly by increasing FXN expression and stabilizing the FXN transcript and frataxin protein. In some cases the exact mechanism underlying the increase in frataxin levels is not yet understood. Agents that have been found to increase frataxin levels in cellular models include hemin, butyric acid [Sarsero et al 2003], and erythropoietin [Sturm et al 2005].

  • An open label study of erythropoietin resulted in increased frataxin levels and significant decrease in the levels of urinary 8-hydroxydeoxyguanosine and serum peroxides, which are markers of oxidative stress [Boesch et al 2007].
  • An in vitro study showed that carbamylated erythropoietin, which does not bind to the erythropoietin receptor and therefore is non-erythropoietic, increased frataxin to similar levels as native erythropoietin [Sturm et al 2010]. A Phase II study of carbamylated erythropoietin did not identify any clinical benefit nor evidence of increase in frataxin levels after 43 days treatment [Boesch et al 2014].
  • A small six-month placebo-controlled study of erythropoietin did not identify any biochemical or clinical benefit of treatment [Mariotti et al 2012].

Specific histone deacetylase (HDAC) inhibitors show much promise as treatments for FRDA through upregulation of FXN expression [Herman et al 2006, Libri et al 2014]. In a mouse model of FRDA, frataxin levels were restored to normal levels in the heart and central nervous system by a novel HDAC inhibitor, compound 106 [Rai et al 2008]. A Phase I human trial of RG2833, a closely related HDAC inhibitor molecule, was recently completed [Gottesfeld et al 2013]. Nicotinamide (vitamin B3), a class III HDAC inhibitor, was shown to increase frataxin expression in FRDA cell and mouse models [Chan et al 2013]. An open label, dose escalation study of nicotinimide in FRDA showed a dose-dependent increase in FXN transcript and protein, achieving levels seen in asymptomatic carriers [Libri et al 2014]. However, no changes were observed in clinical measures in this short eight-week trial.

Interferon gamma has been found to upregulate frataxin in cell and mouse models of FRDA [Tomassini et al 2012]. It also prevents pathologic changes in dorsal root ganglia and improves motor performance in a FRDA mouse model. A Phase I human trial is underway.

Resveratrol has also been shown to upregulate frataxin expression in vitro and in vivo [Li et al 2013]. A proof of principle study is soon to be published.

Other therapies. Varenicline, an agent used to assist with smoking cessation, was identified as a possible therapy for ataxia [Zesiewicz et al 2009]; however, a Phase II study was prematurely terminated due to concerns about safety and tolerability of the drug.

PPAR gamma agonists have been suggested as therapies for FRDA because they increase frataxin levels in vitro [Marmolino et al 2009] and improve antioxidant responses [Marmolino et al 2010]. A Phase II study of one PPAR gamma agonist, pioglitazone, is underway.

Gene therapy to supplement the loss of function of frataxin is also under consideration. The cardiomyopathy of a conditional cardiac FXN deletion mouse model was both prevented and reversed by intravenous FXN delivered by an adeno-associated virus vector [Perdomini et al 2014].

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Friedreich ataxia (FRDA) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents are obligate carriers of an FXN pathogenic variant.
  • Depending on the mutations present in the proband, each parent may have one of the following:
    • A pathogenic expanded allele (i.e., a GAA trinucleotide repeat allele that is in the disease-causing range)
    • Another deleterious FXN pathogenic variant
    • A premutation allele (i.e., a GAA trinucleotide repeat allele that is predisposed to expand into the abnormal range)
  • Carriers (heterozygotes) of one FXN pathogenic variant are asymptomatic.

Note: Carriers of premutation alleles are rare, and although their exact prevalence is unknown, they are far less common than carriers of pathogenic expanded alleles. Consequently, expansion of premutation alleles as a means of transmitting FRDA is very unusual.

Sibs of a proband

  • When both parents carry a full-penetrance allele, or one parent carries a full-penetrance allele and the other parent carries another pathogenic FXN variant:
    • At conception, each sib has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
    • If an adult at-risk sib is unaffected , the statistical risk of his/her being a carrier is 2/3. However, the wide range in age of onset and variable intergenerational instability of the GAA expansion dictate the use of caution in diagnosing an at-risk sib as unaffected based on clinical findings alone (i.e., without using molecular genetic testing).
  • When one parent carries a full-penetrance allele or another pathogenic FXN variant, and the other parent carries a premutation allele, sibs have a less than 25% chance of being affected.

Offspring of a proband

  • All offspring inherit one pathogenic FXN allele from the affected parent.
  • Offspring have a 50% chance of being affected only if the reproductive partner of the proband is a carrier of a full-penetrance allele or another pathogenic FXN variant.
  • If the reproductive partner of the proband carries a premutation allele, the risk to each offspring of developing FRDA is less than 50%.
  • If the reproductive partner of the proband does not carry an expanded FXN allele, the risk to each offspring of developing FRDA is very low but not zero because of the possibility of the presence of another FXN pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the FXN pathogenic variants in the family.

Carrier testing is possible for individuals whose reproductive partner is a known carrier of a FXN pathogenic variant.

Note: Carriers of one FXN mutant allele for this autosomal recessive disorder are not at risk of developing FRDA.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the FXN pathogenic variants have been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing of this gene or custom prenatal testing.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the FXN pathogenic variants have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • FARA (Friedreich's Ataxia Research Alliance)
    533 West Uwchlan Avenue
    Downingtown PA 19335
    Phone: 484-879-6160
    Fax: 484-872-1402
    Email: info@CureFA.org
  • Friedreich Ataxia Research Association (Australasia)
    179 Queen Street
    Level 6
    Melbourne Victoria 3000
    Australia
    Phone: 03 9867 1910
    Email: varlli@fara.org.au
  • Medline Plus
  • National Library of Medicine Genetics Home Reference
  • NCBI Genes and Disease
  • Ataxia UK
    Lincoln House
    1-3 Brixton Road
    London SW9 6DE
    United Kingdom
    Phone: 0845 644 0606 (helpline); 020 7582 1444 (office); +44 (0) 20 7582 1444 (from abroad)
    Email: helpline@ataxia.org.uk; office@ataxia.org.uk
  • euro-ATAXIA (European Federation of Hereditary Ataxias)
    Ataxia UK
    9 Winchester House
    Kennington Park
    London SW9 6EJ
    United Kingdom
    Phone: +44 (0) 207 582 1444
    Email: marco.meinders@euro-ataxia.eu
  • International Network of Ataxia Friends (INTERNAF)
    Email: internaf-owner@yahoogroups.com
  • Muscular Dystrophy Association - USA (MDA)
    3300 East Sunrise Drive
    Tucson AZ 85718
    Phone: 800-572-1717
    Email: mda@mdausa.org
  • National Ataxia Foundation
    2600 Fernbrook Lane
    Suite 119
    Minneapolis MN 55447
    Phone: 763-553-0020
    Email: naf@ataxia.org
  • Spanish Ataxia Federation (FEDAES)
    Spain
    Phone: 34 983 278 029; 34 985 097 152; 34 634 597 503
    Email: sede.valladolid@fedaes.org; sede.gijon@fedaes.org; sede.bilbao@fedaes.org
  • CoRDS Registry for the National Ataxia Foundation
    Sanford Research
    2301 East 60th Street North
    Sioux Falls SD 57104
    Phone: 605-312-6423
    Email: Cords@sanfordhealth.org
  • European Friedreich's Ataxia Consortium for Translation Studies (EFACTS) Patient Registry
    Germany
  • Friedreich's Ataxia Research Alliance Patient Registry
    Friedreich's Ataxia Research Alliance
    533 West Uwchlan Avenue
    Downingtown PA 19335
    Phone: 484-879-6160
    Fax: 484-872-1402
    Email: info@CureFA.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Friedreich Ataxia: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
FXN9q21​.11Frataxin, mitochondrialFXN homepage - Mendelian genesFXN

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Friedreich Ataxia (View All in OMIM)

229300FRIEDREICH ATAXIA 1; FRDA
606829FRATAXIN; FXN

Gene structure. FXN encodes frataxin via a major transcript (NM_000144.4) composed of five coding exons (1-5a) [Campuzano et al 1996]. Minor transcripts, produced via alternate splicing with two other exons (5b and 6) have been detected, but their role(s) remain unknown. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Benign allelic variants. The most relevant variability in normal FXN alleles is the length of the GAA repeat sequence in intron 1 (see Establishing the Diagnosis, Allele sizes).

Pathogenic allelic variants. Inactivating mutations in FXN are essentially of three types: the GAA repeat expansion, nonsense or frameshift mutations resulting in aberrant or premature termination of translation, and loss-of-function missense and splicing mutations. A 2776-bp deletion including exon 5a has been reported [Zuhlke et al 2004]. See Diagnosis for explanation of the four classes of GAA repeats.

Note that interpretation of the pathogenicity of expanded alleles may be complicated by the possibility that the size of the expanded GAA trinucleotide repeat in leukocytes may not necessarily be the same as that in pathologically relevant tissues such as the dorsal root ganglia and heart. Some differences in allele lengths were noted between different tissues in a study involving six autopsies; however, larger studies will be needed to uncover any consistent correlation between GAA repeat sizes in blood versus pathologically affected tissues [De Biase et al 2007].

Normal gene product. FXN encodes frataxin, a 210-amino acid protein (NP_000135.2) that is predominantly located in the mitochondria. The carboxy-terminal region of frataxin is highly conserved in evolution and is a target for pathogenic missense mutations. The tissues primarily affected in FRDA are known to express high levels of frataxin. Frataxin binds iron and is required for the synthesis of iron-sulfur clusters and, thereby, for the synthesis of enzymes in the respiratory chain complexes I – III and aconitase.

Abnormal gene product. All pathogenic mutations (i.e., GAA repeat expansion, nonsense or frameshift mutations resulting in aberrant or premature termination of translation, and loss-of-function missense mutations) result in loss of frataxin function. The latter two classes of mutation result either in deficiency of frataxin levels or in functional deficiency of frataxin despite normal levels. The expanded GAA repeat results in transcriptional silencing of FXN via at least two mechanisms:

These pathogenic mechanisms result in deficiency of FXN transcript levels and ultimately in deficiency of frataxin protein. Frataxin deficiency results in secondary deficiency of iron-sulfur cluster containing enzymes, mislocalization of cellular iron, and increased sensitivity to oxidative stress. Together these result in impaired mitochondrial respiratory function and increased oxidative stress. Indeed, the deficiency of frataxin is directly proportional to the length of the expanded GAA repeat [Pianese et al 2004], which is the molecular basis for the correlation of repeat length with disease severity and rate of progression.

References

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Suggested Reading

  1. Koenig M. Friedreich ataxia and AVED. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill. Chap 232. Available online. 2014. Accessed 7-22-14.

Chapter Notes

Acknowledgments

SI Bidichandani's work is supported by the National Institutes of Health. MB Delatycki is an NHMRC Practitioner Fellow.

Author History

Tetsuo Ashizawa, MD; University of Texas Medical Branch (1998-2009)
Sanjay I Bidichandani, MBBS, PhD (1998-present)
Martin Delatycki, MBBS, FRACP, PhD (2006-present)
Pragna I Patel, PhD; Baylor College of Medicine (1998-2002)

Revision History

  • 24 July 2014 (me) Comprehensive update posted live
  • 2 February 2012 (me) Comprehensive update posted live
  • 25 June 2009 (me) Comprehensive update posted live
  • 25 August 2006 (me) Comprehensive update posted to live Web site
  • 30 August 2004 (cd) Revision: addition of sequence analysis
  • 22 June 2004 (me) Comprehensive update posted to live Web site
  • 9 December 2002 (sb) Revisions
  • 3 April 2002 (me) Comprehensive update posted to live Web site
  • 18 December 1998 (pb) Review posted to live Web site
  • 20 September 1998 (sb) Original submission
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