This term does not characterize a disease but a group of diseases. Annotations can be found at a more specific level.
Friedreich ataxia comprises the following Phenodis entries:
Phenodis:9953 Friedreich ataxia 1, OMIM:229300;
Phenodis:10825 Friedreich ataxia 2, OMIM:601992;
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]....
Diagnosis
Clinical DiagnosisBefore 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].Individuals with FRDA typically exhibit a combination of the following findings:Progressive ataxia of gait and limbsAbsent 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 weaknessAutosomal recessive inheritanceOther signs:Usually present. Pyramidal weakness of the legs, extensor plantar responsesFrequent. Scoliosis, pes cavus, hypertrophic non-obstructive cardiomyopathyPresent in 10%-25%. Optic atrophy, deafness, glucose intolerance, or diabetes mellitusThe diagnosis is confirmed in those with biallelic mutation of FXN.Molecular Genetic TestingGene. FXN (previously known as FRDA, X25) is the only gene in which mutations are known to cause FRDA.Evidence for locus heterogeneity. 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 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. Allele sizes. Four classes of alleles are recognized for the GAA triplet repeat sequence in intron 1 of FXN [Cossee et al 1997, Montermini et al 1997a, Sharma et al 2004]:Normal alleles. 5-33 GAA triplet 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 triplet 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.Premutation length alleles 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. Note: Expanded alleles may also show non-GAA interruptions (typically close to the 3’ end of the repeat tract) as described above for premutation 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 testingTable 1. Summary of Molecular Genetic Testing Used in Friedreich Ataxia (FRDA)View in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityHomozygotes 2Compound Heterozygotes 3FXNTargeted mutation analysis 4GAA triplet repeat expansion
98% 52% 6ClinicalSequence analysisSequence variants 7, 8NA 9Deletion / duplication analysis 10Partial- or whole-gene deletion NAUnknown 111. The ability of the test method used to detect a mutation that is present in the indicated gene2. If both FXN alleles have expanded GAA triplet 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 triplet repeat and the other has an inactivating intragenic point mutation or deletion. 4. 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]. Sequence analysis of the amplicon of the GAA repeat region can determine the number of GAA repeats and presence of interrupts of premutation alleles. 5. Approximately 98% of individuals with FRDA have expanded GAA triplet repeat mutations in intron 1 of FXN on both alleles. 6. Approximately 2% of individuals with FRDA have an expanded GAA triplet repeat mutation in the disease-causing range in one FXN allele and an intragenic inactivating FXN mutation (e.g., point mutation or exon deletion) in the other allele. 7. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. 8. Sequence analysis of exons and flanking regions will identify FXN intragenic inactivating mutations 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 mutations in both FXN alleles have been reported. 10. Testing that identifies deletions/duplications not readily 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 expanded GAA repeat mutation [Zühlke et al 2004]. See Molecular Genetics. Interpretation of test resultsThe 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 one allele having a large GAA expanded allele of full penetrance and a second allele having fewer than 100 GAA triplet repeats may be difficult. Note: Interpretation is further complicated by the possibility that the size of the expanded GAA triplet 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]. Detection of intragenic inactivating FXN mutations outside of the GAA repeat region 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 at between 1:60 and 1:100 in Indo-Europeans, the possibility of another etiology should be considered in symptomatic heterozygous individuals if sequence analysis fails to detect a second inactivating FXN mutation (see Differential Diagnosis).For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing StrategyTo confirm/establish the diagnosis in a proband. Molecular genetic testing for the expanded GAA triplet repeat in intron 1 of FXN should be conducted on any individual whose clinical presentation and family history suggest Friedreich ataxia. Because the diagnostic test is relatively specific and inexpensive and the phenotypic spectrum is broad (see Natural History), clinicians should have a low threshold for such testing. If a full penetrance expanded GAA triplet repeat is identified on both alleles, the diagnosis of Friedreich ataxia is confirmed. If only one expanded allele is identified, sequencing of FXN is required. If a second inactivating mutation is identified, the diagnosis of Friedreich ataxia is confirmed. If a second inactivating mutation is not found, the two possibilities are: The diagnosis is Friedreich ataxia and the second mutation has not been identified (e.g., because the second mutation is in an intron or in the promoter); or The individual is heterozygous for one expanded allele and has another disorder (see Differential Diagnosis). If no expansion is found, the diagnosis of Friedreich ataxia is very unlikely and no further testing in relation to this specific diagnosis is indicated. Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) DisordersNo phenotypes other than the typical and atypical clinical presentations of FRDA discussed in this GeneReview 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]; 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....
Natural History
Classic Friedreich AtaxiaNeurologic 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]; 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 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].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 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 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].Bladder symptoms including urinary frequency and urgency were reported by 41% of individuals in one study [Delatycki et al 1999a].Dysarthria, present in the majority of individuals with FRDA, is generally of three types: mild dysarthria, increased velopharyngeal involvement, and increased laryngeal dysfunction. Dysarthria becomes worse as the disease progresses [Folker et al 2010].Autonomic disturbance becomes more common with disease progression. The most common manifestations are 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]. 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].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]. 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. 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].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].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]. 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. 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 findingsMotor nerve conduction velocity of greater than 40 m/s with reduced or absent sensory nerve action potentialAbsent H reflexAbnormal central motor conduction time after transcranial magnetic stimulation [Brighina et al 2005]Atypical FRDAApproximately 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 FRDAChorea 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]
Peripheral neuropathyFriedreich ataxia (FRDA) may be confused with Charcot-Marie-Tooth type 1 (CMT1) and Charcot-Marie-Tooth type 2 (CMT2), also known as hereditary motor and sensory neuropathy type 1 and 2 (HMSN1 and HMSN2), respectively. 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.AtaxiaAtaxia 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 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 mutations in APTX [Moreira et al 2001]. Inheritance is autosomal recessive. 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 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):Ataxia-telangiectasiaAtaxias associated with mitochondrial DNA mutationsBehr syndrome (spasticity, ataxia, optic atrophy, and intellectual disability)X-linked sideroblastic anemia and ataxiaMarinesco-Sjögren syndrome (cerebellar ataxia, cataracts, intellectual disability, short stature, and delayed sexual development)Deafness-dystonia-optic neuropathy syndromeLate-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).Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease in an individual diagnosed Friedreich ataxia (FRDA), the following evaluations are recommended:...
Management
Evaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed Friedreich ataxia (FRDA), the following evaluations are recommended:Neurologic assessmentPhysical therapy and occupational therapy assessment of strength and balance, need for adaptive aids, and the home and work environmentSpeech and swallowing assessmentECG and echocardiogram for evidence of cardiomyopathy; assessment by a cardiologist if abnormalAssessment of significant scoliosis by an orthopedic surgeonAssessment for obstructive sleep apneaBladder function with referral to a urologist if severe symptoms are presentHearing assessmentRandom blood glucose concentration for evidence of diabetes mellitusPsychological assessmentGenetics consultationTreatment of ManifestationsThere 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 lifestyleOccupational therapy assessment to ensure a safe home and work environmentTo 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 skillsManagement of dysphagia that may include dietary modification and, in the late stages of disease, use of nasogastric or gastrostomy feedingTreatment of cardiac disease to reduce morbidity and mortality, including anti-arrhythmic agents, anti-cardiac failure medication, anti-coagulants, and pacemaker/ implantable cardioverter defibrillator insertion. Cardiac transplantation is more controversial [Sedlak et al 2004].Treatment of diabetes mellitus with diet and, if necessary, oral hypoglycemic agents or insulinHearing aids, microphone and receiver as needed [Rance et al 2010]Antispasmodic agents for bladder dysfunctionTreatment of sleep apnea by continuous positive airway pressurePsychological (counseling and/or pharmacologic) support for affected individuals and familyPrevention of Primary ManifestationsNo existing treatment is proven to delay onset of FRDA or to slow disease progression.Prevention of Secondary ComplicationsThe measures outlined in Evaluations Following Initial Diagnosis can reduce the impact of some complications including joint contractures.SurveillanceThe following are appropriate.If ECG and echocardiogram performed at the time of initial diagnosis are normal, repeat annual ECG and echocardiogramHearing 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] Annual fasting blood sugar to monitor for diabetes mellitusAgents/Circumstances to AvoidAgents that can exacerbate ataxia (e.g., alcohol) should be consumed in moderation.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposesPregnancy ManagementA 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. Close cardiac monitoring is recommended in any woman with FRDA during pregnancy.Therapies Under InvestigationDeficiency 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 age eight to 18 years [Lynch et al 2010]. The results of another Phase III study from Europe are expected to be published shortly. 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 20mg/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]. 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]. 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 has been completed; results are yet to be published. Specific histone deacetylase inhibitors show much promise as treatment for 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]. 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. 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.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDFXN9q21.11
Frataxin, mitochondrialFXN homepage - Mendelian genesFXNData 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) View in own window 229300FRIEDREICH ATAXIA 1; FRDA 606829FRATAXIN; FXNNormal allelic variants. FXN, the only gene linked to FRDA, encodes frataxin via a major transcript 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. The most relevant variability in normal FXN alleles is the length of the GAA triplet repeat sequence in intron 1 (see Molecular Genetic Testing).Pathologic allelic variants. Inactivating mutations in FXN are essentially of three types: the GAA triplet repeat expansion, nonsense or frameshift mutations resulting in aberrant or premature termination of translation, and loss-of-function missense mutations. All result in loss of frataxin function. The latter two classes of mutation result either in deficiency of frataxin levels, or in its functional deficiency despite normal levels of frataxin. The expanded GAA triplet repeat results in transcriptional silencing of FXN via at least two mechanisms: Epigenetic silencing via repressive chromatin formation in the sequence flanking the repeat and near the transcription start site [Herman et al 2006, De Biase et al 2007, Greene et al 2007, Al-Mahdawi et al 2008]; or Formation of 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 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 molecular basis of the correlation of repeat length with disease severity and rate of progression. Partial-gene deletion of FXN, leading to loss of function of frataxin, has been reported [Zühlke et al 2004] but is exceedingly rare.Normal gene product. FXN encodes frataxin, a 210-amino acid protein that is predominantly located in the mitochondria. The carboxy-terminal region of frataxin is highly conserved in evolution and is a target for inactivating 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. FRDA is caused by loss of function of frataxin. 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 increase in oxidative stress.