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GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Diagnosis/testing. Individuals with FRDA have identifiable mutations in the FXN gene. The most common type of mutation, which is observed on both alleles in more than 98% of individuals with FRDA, is a GAA triplet-repeat expansion in intron 1 of FXN. Approximately 2% of individuals with FRDA are compound heterozygotes for a GAA expansion in the disease-causing range in one FXN allele and another inactivating FXN mutation in the other allele. Molecular genetic testing is available on a clinical basis.
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; and psychological support, both pharmacologic and counseling. Prevention of secondary complications: exercise and physical therapy programs to maintain flexibility, optimize physical condition, and prevent contractures; maintenance of healthy body mass index; establishment of appropriate home and work environment to maximize independence and safety; management of dysphagia to prevent aspiration pneumonia. Surveillance: at least annual assessment of overall status, examination for complications including spasticity, scoliosis, 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 which place individual in danger of falls such as rough surfaces for ambulant individuals. Therapies under investigation: idebenone, deferiprone, erythropoietin, histone deacetylase inhibitors.
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 mutation. Carrier testing of at-risk relatives and prenatal testing for pregnancies at increased risk are possible if both FXN mutations have been identified in an affected family member.
Before the identification of the FXN gene, clinical diagnostic criteria for Friedreich ataxia (FRDA) were established by Geoffroy et al [1976] and refined by Harding [1981]. Following identification of the FXN gene, 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].
Individuals with FRDA typically exhibit a combination of the following findings:
Progressive ataxia of gait and limbs
Absent muscle stretch reflexes in the legs (in atypical cases, reflexes may be preserved; see FRDA with retained reflexes [FARR])
Onset before age 25 years (in atypical cases, onset may be delayed; see late-onset FRDA [LOFA] and very late-onset FRDA [VLOFA])
Dysarthria, decrease/loss in position sense and/or vibration sense in lower limbs, muscle weakness
Autosomal recessive inheritance
Other signs:
Usually present. Pyramidal weakness of the legs, extensor plantar responses
Frequent. Scoliosis, pes cavus, hypertrophic non-obstructive cardiomyopathy
Present in 10%-25%. Optic atrophy, deafness, glucose intolerance, or diabetes mellitus
The diagnosis is confirmed in those with two identifiable mutations in FXN.
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Gene. FXN (previously known as FRDA, X25) is the only gene directly implicated in the pathogenesis of FRDA:
Approximately 98% of individuals with FRDA have expanded GAA triplet-repeat mutations in intron 1 of FXN on both alleles. In an individual with FRDA, the GAA repeat expansion alleles may be the same length or different lengths.
Note: These individuals are designated homozygotes for an expanded GAA triplet-repeat mutation.
Approximately 2% of individuals with FRDA have an expanded GAA repeat mutation in the disease-causing range in one FXN allele and an intragenic inactivating FXN mutation (e.g., point mutation or exon deletion outside of the GAA repeat region) in the other allele.
Note: These individuals are designated compound heterozygotes.
To date, no affected individuals with inactivating intragenic mutations in both FXN alleles have been reported.
Other loci. 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 the FXN gene. It is possible that these individuals have mutations 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.
Christodoulou et al [2001] performed a genome-wide scan and identified genetic linkage to markers within 9p11-p23 in a large family with autosomal recessive ataxia similar to FRDA, designating the locus as FRDA2. However, they subsequently identified an inactivating mutation in the APTX gene (which maps within their interval at 9p13.3), and this family has since been reclassified as having ataxia with oculomotor apraxia type 1 (AOA1) [Christodoulou, personal communication].
Allele sizes. Four classes of alleles are recognized for the GAA triplet repeat sequence in intron 1 of the FXN gene [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 pure (uninterrupted) GAA repeats. Although the exact frequency of these alleles has not been formally determined, they likely account for fewer than 1% of FXN alleles.
Mutable normal alleles are not associated with FRDA but may expand during intergenerational transmission, resulting in disease-causing alleles in offspring.
Expansion of premutation alleles, sometimes more than tenfold the original size, has been observed in both paternal and maternal transmission.
It is not clear if every premutation allele is equally capable of expansion via intergenerational transmission or, indeed, if expansion is more likely in a premutation allele that is particularly unstable.
Alleles longer than 27 GAA triplet repeats are often interrupted by a (GAGGAA)n sequence. It has been postulated that (GAGGAA)n [Montermini et al 1997a] and perhaps also (GAAAGAA)n [Cossee et al 1997] interruptions of the GAA triplet repeat may stabilize premutation alleles and prevent their expansion into the abnormal range. However, clear guidelines regarding the implications of these interruptions and their clinical significance have not been established.
Full penetrance (disease-causing expanded) alleles. 66 to approximately 1700 pure (uninterrupted) 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]. The frequency of these alleles is estimated to be between 1/60 and 1/100 in Indo-Europeans. Expanded alleles may also show non-GAA interruptions (typically close to the 3’ end of the repeat tract) as described above for normal alleles. These alleles are often short (100 – 300 triplets) and are associated with LOFA or VLOFA [Stolle et al 2008] (see Genotype-Phenotype Correlations).
Borderline alleles. 44-66 pure (uninterrupted) 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). Using a sensitive assay to detect somatic instability, Sharma et al [2004] showed that individuals with a somatically unstable borderline allele and a full penetrance allele may develop LOFA/VLOFA. The shortest allele associated with FRDA is, therefore, 44 uninterrupted GAA triplets. Somatic instability was required for clinical expression of the FRDA phenotype; and, therefore, alleles with fewer than 37 GAA triplets are unlikely to cause disease. Although the exact frequency of these alleles has not been formally determined, they account for fewer than 1% of FXN alleles.
Note: Overlap exists between the sizes of premutation and borderline alleles; and, therefore, borderline alleles present a risk for intergenerational expansion. Borderline alleles may be associated with reduced penetrance (see Penetrance).
Clinical testing
The length of the GAA repeat is estimated by PCR and/or Southern blot assay [Campuzano et al 1996, Durr et al 1996, Montermini et al 1997a].
Direct sequencing is the most accurate method for analysis of the length and purity (i.e., interrupted vs uninterrupted) of premutation alleles.
Sequence analysis. PCR amplification of individual coding exons followed by sequencing is used to identify FXN intragenic inactivating mutations located outside of the GAA repeat region. Two types of mutations have been reported:
Nonsense, frameshift, and splicing defect mutations that cause or predict premature termination of translation. Mutations involving the translation initiation codon are predicted to result in aberrant initiation of translation.
Missense mutations, mainly involving the highly conserved, carboxy-terminal domain and thought to result in loss of frataxin protein function. See Table 2 (pdf) and Molecular Genetics.
Deletion/duplication analysis. One intragenic deletion of FXN (deleting ~2.8 kb at the 3’ end of the FXN gene, including exon 5a) has been identified in an affected individual whose other allele had an expanded GAA repeat mutation [Zühlke et al 2004]. See Molecular Genetics.
| Gene Symbol | Test Method | Mutations Detected | Mutation Detection Frequency by Test Method | Test Availability |
|---|---|---|---|---|
| FXN | Targeted mutation analysis | Homozygous GAA expansion | 98% | Clinical
 |
| Heterozygous GAA expansion | 2% | |||
| Sequence analysis | Heterozygous intragenic point mutation | |||
| Deletion/duplication analyses 1 | Heterozygous partial or whole gene deletion | Unknown |
1. Testing that identifies deletions/duplications not detectable by sequence analysis of individually amplified exons; a variety of methods including Southern blot analysis, quantitative real-time PCR, long-range PCR, multiplex ligation dependent probe amplification (MLPA), and array GH may be used.
Interpretation of test results
The exact demarcation between normal and full penetrance alleles remains poorly defined. While the risk of 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 one allele having a large GAA expanded allele of full penetrance and a second allele having fewer than 100 GAA repeats may be difficult.
Note: Interpretation is further complicated by the possibility that the size of the GAA expansion 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].
For issues to consider in interpretation of sequence analysis results, click here.
Detection of intragenic inactivating FXN mutations outside of the GAA repeat region (see Table 2) typically involves sequence analysis of all coding exons and flanking splice site regions. Potentially pathogenic mutations in other gene regions (e.g., gene promoter) may be missed. Furthermore, larger deletions/duplications involving multiple contiguous exons may also be missed by the strategy of sequencing individually amplified exons.
Because the heterozygote (carrier) frequency for full penetrance alleles is estimated to be between 1/60 and 1/100 in Indo-Europeans, the possibility of another etiology should be entertained in heterozygotes if sequence analysis fails to detect a second inactivating FXN mutation (see Differential Diagnosis).
Confirming the diagnosis in a proband
Perform targeted mutation analysis by PCR and/or Southern blot analysis of the GAA repeat.
Perform sequence analysis if the individual fulfills the clinical diagnostic criteria of FRDA and is heterozygous for an allele with an expanded GAA repeat mutation in the full penetrance range [Cossee et al 1999] .
Perform sequence analysis if the individual is heterozygous for an allele with an expanded GAA repeat mutation in the full penetrance range and clinical findings suggest an atypical FRDA presentation [Bidichandani et al 1997, Cossee et al 1999].
Consider another diagnosis if no GAA expansion alleles are detected; i.e., the individual has two normal-sized alleles. Sequence analysis is not recommended in these individuals (see Differential Diagnosis).
Carrier testing for:
At-risk relatives requires prior identification of the disease-causing mutations in the family;
The expanded GAA repeat mutation in the partner of a known heterozygous carrier or an individual with FRDA is appropriate if they are Indo-Europeans.
Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.
Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.
No phenotypes other than typical and atypical clinical presentations of FRDA are associated with mutations in FXN.
Neurologic manifestations. Individuals with typical Friedreich ataxia (FRDA) develop progressive ataxia in childhood or in the early teens, 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], but onset can be as early as age two years and as late as the sixth 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 the 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 causes little problem for affected individuals.
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]. More recently, 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 studied individuals had optic nerve abnormalities, but only 5/26 (19%) had related symptoms [Fortuna et al 2009].
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.
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 very common [Rance et al 2008].
Scoliosis is present in approximately two-thirds of individuals with FRDA when assessed clinically and 100% when assessed radiographically. A study of 77 individuals with FRDA found 49 (63%) had scoliosis of whom ten were treated with a brace and 16 required spinal surgery [Milbrandt et al 2008].
Bladder symptoms including urinary frequency and urgency were reported by 41% of individuals in one study [Delatycki et al 1999a].
Autonomic disturbance becomes more common with disease progression. The most common manifestation is cold, cyanosed feet; bradycardia is less common.
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]. The intelligence profile of individuals with FRDA is characterized by concrete thinking, poor capacity in concept formation and visuospatial reasoning with reduced speed of information processing [Mantovan et al 2006].
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]. Later in the disease course, the cardiomyopathy may become dilated. Progressive systolic dysfunction is common [Kipps et al 2009].
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]. 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. Coronary artery disease may occur especially if there is angina and/ or sudden deterioration in cardiac function [Giugliano & Sethi 2007].
Diabetes mellitus occurs in up to 30% of individuals with FRDA. Those without diabetes mellitus may have impaired glucose tolerance [Ristow 2004].
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].
The average age at death was age 37 years in a large study in the early 1980s [Harding 1981]. In a more recent study, the average interval from symptom onset to death was 36 years [De Michele et al 1996], perhaps suggesting increased longevity related to better management (particularly of cardiac complications) and recognition of milder phenotypes (See Compound Heterozygotes for an Expansion and a Point Mutation). Survival into the sixth and seventh decades has been documented. Death is often related to cardiomyopathy; aspiration pneumonia caused by dysphagia may also shorten the life span.
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]. A voxel-based morphometry study showed a symmetrical 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.
Electrodiagnostic findings
Motor nerve conduction velocity of greater than 40 m/s with reduced or absent sensory nerve action potential
Absent H reflex
Abnormal central motor conduction time after transcranial magnetic stimulation [Brighina et al 2005]
Approximately 25% of individuals homozygous for 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 who were homozygous for the GAA expansion is greater than 60 years [Galimanis et al 2008, Stolle et al 2008].
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). 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 [1997a] showed that Acadians with FRDA have a later age of onset and of wheelchair confinement, and a much lower incidence of cardiomyopathy.
Spastic paraparesis without ataxia. Individuals who are homozygous for 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; they develop ataxia with time [Gates et al 1998, Castelnovo et al 2000, Lhatoo et al 2001, Badhwar et al 2004].
Other rare presentations of FRDA
Chorea and pure sensory ataxia [Berciano et al 1997, Hanna et al 1998, Zhu et al 2002]
Apparently isolated cardiomyopathy with ataxia only becoming evident some time later [Leonard & Forsyth 2001]
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), somatic heterogeneity of the GAA expansion [Montermini et al 1997b, Sharma et al 2004, De Biase et al 2007], and other unidentified factors.
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 correlations with GAA expansion size [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, accounting 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 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 disease-causing range, interrupted alleles tend to be shorter in length (equivalent in length to alleles of 100-300 triplets), and are often associated with LOFA / VLOFA. Stolle et al [2008] reported six persons with such interrupted alleles (with a conventional expanded GAA repeat mutation containing >600 triplets in the other FXN gene) whose ages of onset ranged from 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 coding region of FXN compared to individuals with typical FRDA [Montermini et al 1997b]. This 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 with longer GAA repeat alleles [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 triplets and in only 14% of those with repeat lengths less than 770 triplets.
Significant correlation is seen between the length of the GAA expansion and 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 mutation in the cardiac troponin T gene.
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 an earlier age of onset.
Although most compound heterozygotes for a GAA expansion and a point mutation/deletion are clinically indistinguishable from typical individuals affected with FRDA who are homozygous for expanded GAA repeat mutations [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 mutations, 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 mutation presented with chorea [Zhu et al 2002, Spacey et al 2004].
Individuals with somatically unstable, borderline alleles present with LOFA/VLOFA, mild and gradually progressive disease, and normal reflexes/hyperreflexia [Sharma et al 2004].
Penetrance is complete in homozygotes with both alleles having GAA repeat expansions and in compound heterozygotes for a GAA expansion and a second deleterious FXN mutation 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.
Note: Because the allele size at the lower end of the mutant allele range has not been clearly defined, it is possible that incomplete penetrance is associated with borderline alleles and expanded alleles containing fewer than 100 GAA repeats. However, alleles of this size are rare.
Friedreich ataxia (FRDA) is inherited in an autosomal recessive manner; therefore, anticipation is not observed because the disease is almost never observed in more than one generation.
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 Asia, in sub-Saharan Africa, or among Native Americans. A lower than average prevalence of FRDA is noted in Mexico.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Peripheral neuropathy. Friedreich ataxia (FRDA) may be confused with Charcot-Marie-Tooth type 1 (CMT1) and Charcot-Marie-Tooth type 2 (CMT2), also known as the demyelinating form of hereditary motor and sensory neuropathy type 1 and 2 (HMSN1 and HMSN2). CMT1 is caused by 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.
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 a mutation in 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 mutations in 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 two to 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 mutations in the APTX gene [Moreira et al 2001]. Inheritance is autosomal recessive.
AOA1 is the most common recessively inherited ataxia in Japan; and, 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 mutations in 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):
Ataxias associated with mitochondrial DNA mutations
Behr syndrome (spasticity, ataxia, optic atrophy, and mental retardation)
Marinesco-Sjögren syndrome (cerebellar ataxia, cataracts, mental retardation, short stature, and delayed sexual development)
Late-onset hexosaminidase A deficiency (ataxia, upper and lower motor neuron disorders, dementia, and psychotic episodes) [Perlman 2002]
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].
Autosomal dominant ataxia with sensory neuropathy. Spinocerebellar ataxia type 4 (SCA4) [Flanigan et al 1996] and SCA25 [Stevanin et al 2004] may present with FRDA-like phenotypes (see Ataxia Overview).
To establish the extent of disease 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
ECG and echocardiogram for evidence of cardiomyopathy; assessment by a cardiologist if abnormal
Assessment of significant scoliosis by an orthopedic surgeon
Assessment for obstructive sleep apnea
Bladder function with referral to a urologist if severe symptoms are present
Hearing
Random blood glucose concentration for evidence of diabetes mellitus
Psychological assessment
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 physiatrist (rehabilitation medicine specialist) to maintain an active lifestyle
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. 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 insertion. Cardiac transplantation is more controversial [Sedlak et al 2004].
Treatment of diabetes mellitus with diet and, if necessary, oral hypoglycemic agents or insulin
Hearing aids, microphone and receiver as needed
Antispasmodic agents for bladder dysfunction
Treatment of sleep apnea by continuous positive airway pressure
Psychological (counseling and/or pharmacologic) support for affected individuals and family
The measures outlined in Evaluations Following Initial Diagnosis can reduce the impact of some complications such as joint contractures.
If ECG and echocardiogram performed at the time of initial diagnosis are normal, ECG and echocardiogram should be repeated annually.
Hearing assessment should be performed 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]
Fasting blood sugar should be performed yearly to monitor for diabetes mellitus.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes
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 Genetic Pathogenesis).
Antioxidant therapy by free radical scavengers such as coenzyme Q10, vitamin E and idebenone (a short-chain analog of coenzyme Q10) have been considered potential therapies 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. Idebenone is the most promising agent as a treatment of FRDA. There is good evidence that it reduces left ventricular hypertrophy [Hausse et al 2002, Buyse et al 2003, Mariotti et al 2003] and improves cardiac function [Buyse et al 2003]. A recent 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]. Phase III studies are underway in the US and Europe.
Iron chelators have been proposed as a possible therapy for lowering the intramitochondrial iron overload. Nonspecific iron chelators (such as 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; neurological benefit was suggested. A Phase II placebo-controlled trial is underway.
Pyridoxal isonicotinoyl hydrazone, a mitochondrial permeable ligand, along with desferrioxamine, limited cardiac hypertrophy in a conditional Fxn knockout mouse model [Whitnall et al 2008].
Upregulation of frataxin expression. Because the GAA repeat expansion results in reduced quantities of normal frataxin, a number of studies have been conducted to identify compounds that increase frataxin expression. Agents that have been found to increase frataxin expression in cellular models include hemin, butyric acid [Sarsero et al 2003], and erythropoietin [Sturm et al 2005]. Specific histone deacetylase inhibitors show much promise as treatments of FRDA through upregulation of frataxin expression [Herman et al 2006]. 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].
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]. A placebo-controlled trial is required to assess the clinical effects of erythropoietin in FRDA.
Gene therapy to supplement the loss of function of frataxin is also under consideration. However, a significant amount of basic research is needed before gene therapy can be feasible in a clinical setting.
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.
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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Friedreich ataxia (FRDA) is inherited in an autosomal recessive manner.
Parents of a proband
The parents are obligate carriers of an FXN gene mutation.
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 mutation
A premutation allele (i.e., a GAA trinucleotide repeat allele that is predisposed to expand into the abnormal range)
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, hyperexpansion 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 deleterious FXN gene mutation:
At conception, 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 being unaffected and not a carrier.
Once an at-risk sib is known to be clinically unaffected, the 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.
When one parent carries a full penetrance allele or another deleterious FXN gene mutation, and the other parent carries a premutation allele:
At conception, each sib of a proband whose parent is a carrier of a premutation allele has a 25% chance of inheriting both the full penetrance allele and the premutation allele. Because the premutation allele may remain unchanged or undergo minimal change (i.e., not expand to produce a full penetrance allele), the sibs have a less than 25% chance of being affected.
Each sib also has a 50% chance of being an asymptomatic carrier of either the full penetrance allele or the premutation allele and a 25% chance of being unaffected and having two normal alleles.
Offspring of a proband
All offspring inherit one mutant 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 deleterious FXN gene mutation.
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 expansion of the FXN GAA repeat (either premutation or full mutation), the risk to each offspring of developing FRDA is very low but not zero because of the possibility of the presence of a deleterious point mutation
Carrier testing of at-risk family members is possible if the mutations have been identified in the family.
Carrier testing for the GAA expansion is possible for individuals whose reproductive partner is a carrier of a FXN mutation. Testing for point mutations is not generally available, and may not be advisable given the rarity of FXN point mutations (assuming the reproductive partner is not related to someone with FRDA).
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. 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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant when the sensitivity of currently available testing is less than 100%. See
for a list of laboratories offering DNA banking.
Prenatal diagnosis for pregnancies at 25% risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately 10 to 12 weeks' gestation. Both disease-causing alleles of an affected family member must be identified before prenatal testing can be performed.
Note: Gestational age is expressed in weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see
.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.
| Gene Symbol | Chromosomal Locus | Protein Name | Locus Specific | HGMD |
|---|---|---|---|---|
| FXN | 9q13 | Frataxin, mitochondrial | Spinocerebellar Aaxia (FXN) | FXN |
FRDA results from a relative deficiency of the mitochondrial protein frataxin. Patients typically have 5%-30% of normal levels of FXN transcript and protein [Campuzano et al 1997]. Inactivating mutations in FXN are essentially of three types: the expanded GAA repeat mutation, aberrant or premature termination of translation, and loss-of-function missense mutations. All result in relative loss of frataxin function. The latter two classes of mutation result in either deficiency of frataxin levels, or in its functional deficiency despite normal levels of frataxin. The expanded GAA repeat results in transcriptional silencing of the FXN gene via at least two mechanisms: (a) the expanded GAA repeat induces heterochromatin formation in the flanking sequence resulting in silencing of the FXN gene [Herman et al 2006, Greene et al 2007, Al-Mahdawi et al 2008], and (b) the expanded GAA repeat adopts an abnormal DNA structure that interferes with transcription [Bidichandani et al 1998, Ohshima et al 1998, Grabczyk & Usdin 2000, Sakamoto et al 2001]. These mechanisms result in severe deficiency of FXN transcript levels and ultimately in deficiency of frataxin protein. Indeed, the deficiency of frataxin is directly proportional to the length of the expanded GAA repeat [Pianese et al 2004] and is the reason for the correlation of repeat length with disease severity a rate of progression.
The FXN gene encodes frataxin, a 210-amino acid protein that localizes to the inner mitochondrial membrane. The carboxy-terminal region of frataxin is highly conserved in evolution and is a target for inactivating missense mutations (Table 2). The tissues primarily affected in FRDA are known to express high levels of frataxin. Frataxin is required for the biogenesis of iron-sulfur clusters and, therefore, for the synthesis of enzymes in the respiratory chain complexes I – III and aconitase. Endocardial biopsies of individuals with FRDA showed a deficiency of iron-sulfur cluster containing proteins [Rotig et al 1997]. Frataxin deficiency results in misdistribution of mitochondrial iron, causing an increased labile iron pool in the mitochondria. Frataxin deficiency leads to reduced mitochondrial function and increased oxidative damage. As a result, affected individuals show deficient ATP production and cellular oxygenation in post-exercise skeletal muscle [Lodi et al 1999, Lynch et al 2002] and defective myocardial energy production [Lodi et al 2001, Bunse et al 2003].
The expanded GAA repeat mutation is inherently unstable, and shows progressive, postnatal instability in various tissues (somatic instability) throughout the life of patients. Strikingly, the expanded GAA repeat mutation continues to expand specifically in the dorsal root ganglia [De Biase et al 2007], the primary site of pathology in FRDA. This may be the reason for the progressive and tissue-specific pathology seen in FRDA and, perhaps, also the molecular basis for the pathogenicity of unstable borderline alleles [Sharma et al 2004].
Progress in the understanding of FRDA pathogenesis has resulted in the design of rational approaches to treat the disease. Indeed, several modalities are presently being tested in clinical trials (see Therapies Under Investigation). Strategies are either designed to reverse the cause(s) of frataxin deficiency or to counter the cellular consequence(s) of frataxin deficiency. Histone deacetylase inhibitors (HDACi) inhibit heterochromatin formation and reverse the FXN transcriptional silencing induced by the expanded GAA repeat mutation [Herman et al 2006]. Recombinant human erythropoietin (rhuEPO) increases frataxin protein levels by an unknown mechanism (without increasing FXN transcription) [Boesch et al 2007]. These two classes of drugs are presently being tested in patients to reverse the deficiency of frataxin. Given the increased oxidative stress and reduced antioxidant capacity in FRDA, various antioxidants are also being considered for the treatment of FRDA. Deferiprone, an iron chelator, corrects the mitochondrial iron misdistribution, makes chelated iron bioavailable, and restores mitochondrial ATP production [Kakhlon et al 2008]. Further elucidation of the mechanism(s) of disease pathogenesis may result in more specific strategies to reverse the disease process in FRDA.
Pathologic allelic variants. See Molecular Genetic Testing, Molecular Genetic Pathogenesis, and Table 2 (pdf).
See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals. GeneTests provides information about selected organizations and resources for the benefit of the reader; GeneTests is not responsible for information provided by other organizations.—ED.
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page
No specific guidelines regarding genetic testing for this disorder have been developed.
SI Bidichandani's work is supported by the National Institutes of Health, Muscular Dystrophy Association (MDA), Friedreich Ataxia Research Alliance (FARA), and Oklahoma Center for the Advancement of Science and Technology (OCAST). T Ashizawa's work is supported by the National Institutes of Health. MB Delatycki is an NHMRC Practitioner Fellow.
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)
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
