INTRODUCTION — The hereditary ataxias are a genetically heterogeneous group of diseases characterized by motor incoordination resulting from dysfunction of the cerebellum and its connections. This topic will review the clinical aspects of Friedreich ataxia, a neurodegenerative disorder that is the most common of the hereditary ataxias.
Other hereditary ataxias are discussed separately. (See "Overview of the hereditary ataxias" and "Overview of cerebellar ataxia in adults", section on 'Chronic progressive ataxias'.)
GENETICS — Most cases of Friedreich ataxia are caused by loss-of-function mutations in the frataxin (FXN) gene located on chromosome 9q13 [1-3]. The great majority of patients have an expanded guanine-adenine-adenine (GAA) trinucleotide repeat in intron 1 of both alleles of the FXN gene. The repeat expansion results in reduced transcription of the gene (ie, silencing) and decreased expression of the gene product frataxin [4,5].
The number of GAA repeats can vary from 66 to 1700 [1,6], compared with 7 to 34 in normal alleles [2,7]. Most patients have repeats between 600 and 1200 triplets. Repeat numbers between 34 and 100 seldom result in disease, but their significance is mainly determined by whether or not they are interrupted by non-GAA repeats. Interruption stabilizes the repeat against expansions in subsequent generations. On the other hand, uninterrupted repeat tracts of this size are not stable; they are considered to be premutations because they can expand to over 300 repeats in just a single generation [7].
The manifestations of Friedreich ataxia vary in part with the number of GAA expansions. Larger GAA expansions, particularly on the smaller allele, correlate with earlier age at onset, shorter times to loss of ambulation, a greater frequency of cardiomyopathy, and loss of reflexes in the upper limbs [1,8]. Patients with late-onset cerebellar ataxia and retained reflexes tend to have smaller repeats [1]. True heterozygotes (eg, first-degree relatives) have no neurologic or cardiac abnormalities that can be ascribed to Friedreich ataxia [9].
Less than 5 percent of patients with Friedreich ataxia are compound heterozygotes with the GAA repeat containing 66 to 1700 triplets on one allele and a frataxin point mutation (missense, nonsense, intronic, or exonic) in the other allele [2,10-15]. Compound heterozygotes may exhibit phenotypic variability and atypical presentations such as delayed age of onset (older than 25 years), retained or exaggerated deep tendon reflexes, and isolated spastic paraparesis without ataxia. (See 'Clinical features' below.)
Genetic heterogeneity of Friedreich ataxia has been described but appears to be rare, as only a few families have been reported [16,17].
PATHOGENESIS — Frataxin is a mitochondrial protein whose normal role includes iron-sulfur cluster biogenesis, iron chaperoning, iron detoxification, antioxidation, and possibly the regulation of iron storage [18]. It is expressed at particularly high levels in the tissues involved in Friedreich ataxia, such as the brain, heart, and pancreas [19-21]. Compared with healthy controls, patients with Friedreich ataxia have impairment of enzymatic antioxidants [22].
A longstanding hypothesis is that Friedreich ataxia is a result of mitochondrial accumulation of iron, which may promote injury caused by oxidative stress [23-29]. In support of the oxidative stress hypothesis, it has been shown that mutated frataxin is associated with deficient activity of the iron-sulfur (Fe-S) respiratory enzymes, deficient production of aconitase (an iron-sulfur protein involved in iron homeostasis) [30], and failure of induction of superoxide dismutase and of the iron import machinery [31]. Furthermore, patients with Friedreich ataxia exhibit elevated levels of oxidative stress markers, including elevated urinary concentrations of 8-hydroxy-2'deoxyguanosine (8OH2'dG) [23] and elevated plasma concentrations of malondialdehyde (MDA) [32].
Homozygous deletions of frataxin in the mouse cause embryonic lethality a few days after implantation, demonstrating an important role for frataxin during early development [33]. One hypothesis is that the milder phenotype in humans may be caused by residual frataxin expression associated with the expansion mutations (see 'Genetics' above). Mutant mice with frataxin-deficient neurons, cardiac muscle, and striated muscle reproduce important features of the human disease, including cardiomyopathy, sensory neuropathy, deficient aconitase and respiratory chain complex activity, and intramitochondrial iron accumulation [34].
An alternate but less widely endorsed hypothesis holds that Friedreich ataxia is not associated with oxidative damage. In support of this hypothesis, there is evidence that iron accumulation occurs after the onset of pathology and late after the inactivation of the iron-sulfur (Fe-S) containing enzymes [35]. In addition, there is conflicting experimental evidence regarding the importance of oxidative stress in the pathophysiology of Friedreich ataxia [36].
EPIDEMIOLOGY — Friedreich ataxia is the most common hereditary ataxia; it accounts for up to one-half of hereditary ataxia cases overall, and up to three-quarters of cases among individuals <25 years of age [7,37]. It occurs with a frequency of approximately 1 in 30,000 to 1 in 50,000 in White individuals [7,38]. The GAA triplet repeat expansion that causes Friedreich ataxia is found only in individuals of European, North African, Middle Eastern, or Indian origin [39]. Thus, the prevalence of the disease is lowest in China, Japan, and sub-Saharan Africa.
Age of onset — The age of onset with Friedreich ataxia is usually in the adolescent years [38] but ranges from 2 to >70 years of age [1,40]. Age of onset is an important predictor of overall disease severity and speed of progression. Based on review of more than 1100 patients with Friedreich ataxia followed in a longitudinal natural history study, four categories have been proposed [41]:
●Early onset (0 to 7 years) – 324 patients (29 percent), median of 790 GAA repeats
●Typical onset (8 to 14 years) – 438 patients (39 percent), median of 704 GAA repeats
●Intermediate onset (15 to 24 years) – 234 patients (21 percent), median of 500 GAA repeats
●Late onset (≥25 years) – 119 patients (11 percent), median of 250 GAA repeats
Among these groups, the rate of disease progression varies inversely with the age of onset [41]. Age of onset also correlates with number of GAA repeats, with disease onset occurring 2.3 to 2.7 years earlier for every 100 repeats [41,42].
CLINICAL FEATURES — The major clinical manifestations of Friedreich ataxia are neurologic dysfunction, cardiomyopathy, and diabetes mellitus [38]. Because the disease is progressive, the full clinical picture may not be seen until several years after presentation.
Neurologic involvement
Typical phenotype — A variety of neurologic abnormalities are associated with Friedreich ataxia [40]. Almost all patients present with limb ataxia. Early loss of position and vibration sense occurs, reflecting posterior column spinal cord dysfunction, as well as dorsal root and peripheral, primarily sensory, axonal neuropathy. In turn, loss of position and vibration sense exacerbates the cerebellar ataxia. Involvement of the autonomic nervous system can cause bladder dysfunction.
●Progressive ataxia of all four limbs and gait is a nearly universal feature, usually presenting in adolescence [1,9,38,43-45].
●Deep tendon reflexes eventually are lost in approximately 90 percent of patients [1,44], but they may be retained for an extended period of time in younger children [46].
●Motor weakness involving the feet and legs occurs in up to 88 percent of patients, followed later in the course by weakness involving the hands and arms [1,9,44].
●Cerebellar dysarthria is a common feature [1,9,38,45].
●Sensory loss in the distal limbs affects 73 to 92 percent of patients [1,9,38,44,45] and predominately involves proprioception and vibration sense, reflecting posterior column spinal cord dysfunction, as well as dorsal root and a peripheral, primarily sensory, axonal neuropathy. Pain and temperature sensation are generally retained.
●Dysphagia occurs in 27 to 64 percent [9,38,44].
●Reduced visual acuity is observed in 13 to 27 percent [1,44], and optic atrophy affects up to 30 percent. Eye movement abnormalities may include horizontal nystagmus, saccadic smooth pursuit, and square wave jerks with fixation [1,9,38].
●Hearing loss eventually develops in 8 to 22 percent [1,9,44].
●Bladder dysfunction with urinary urgency and later onset of incontinence affects 23 to 53 percent [1,44,45].
●Kyphoscoliosis is common and can precede the neurologic symptoms [1,9,38,44,45]. Motor neuropathy can result in pes cavus, equinovarus deformities, hammer toes, and atrophy of the intrinsic small muscles of the hand.
●Daytime somnolence or fatigue related to sleep-disordered breathing may be more prevalent than in the general population [47].
●Cognition is usually preserved, though neuropsychologic testing may show evidence of mild executive dysfunction [38].
Atypical phenotypes — Atypical Friedreich ataxia phenotypes account for approximately 25 percent of cases and include patients with the following characteristics [1,48]:
●Late-onset (after age 25 years) disease, often with slower progression than typical Friedreich ataxia and absence of cardiomyopathy [1,49-51]
●Friedreich ataxia with retained reflexes [52]
●Leg spasticity with little or no gait and limb ataxia [53-58]
Rare cases of Friedreich ataxia can present as a Huntington disease phenocopy. (See "Huntington disease: Clinical features and diagnosis", section on 'Differential diagnosis'.)
Neuroimaging — Magnetic resonance imaging (MRI) in Friedreich ataxia typically reveals atrophy of the spinal cord and medulla [59,60]. Cerebellar atrophy on MRI is uncommon, particularly early in course of the disease [40].
When brain volumes are analyzed longitudinally and compared with healthy controls, a spatial pattern emerges that may not be apparent to the naked eye. Volume loss appears first in the dentate nuclei, brainstem, and superior and inferior cerebellar peduncles [61]. Cerebral white matter abnormalities follow, especially in the corticospinal pathways. Cerebellar atrophy and cerebral gray matter loss in sensorimotor areas become apparent later in the disease course.
Electrodiagnostic studies — Nerve conduction studies reflect an axonal sensory neuropathy with reduced or absent sensory nerve action potentials [62]. Motor conduction velocities are only mildly slowed, and somatosensory and auditory evoked potentials are abnormal. Optic nerve abnormalities are seen on visual-evoked responses in up to 64 percent of patients [9].
Neuropathology — A critical feature of Friedreich ataxia is the progressive loss of the sensory cells of the dorsal root ganglia, which accounts for the following changes [63]:
●Thinning of the dorsal nerve roots
●Degeneration of the posterior (dorsal) columns of the spinal cord
●Atrophy of neurons in Clarke column and dorsal spinocerebellar fibers
●Atrophy of gracile and cuneate nuclei
In the cerebellum, there is atrophy of the dentate nucleus and its efferent axons [63]. In the cortex, there is loss of Betz cells and corresponding corticospinal tract degeneration; the latter feature is also observed in the spinal cord.
Nerve biopsy reveals a loss of myelinated sensory nerve fibers [64], and secondary axonal degeneration is seen in the later stages of the disease.
Cardiomyopathy — Hypertrophic cardiomyopathy (HCM) is the most common cardiac complication of Friedreich ataxia, affecting up to 85 percent of patients by early adulthood [65-68]. The main clinical manifestations are atrial arrhythmias and heart failure, which is a frequent cause of death. (See 'Prognosis' below.)
Among patients identified with HCM during childhood (≤18 years), the mean age at diagnosis is 11 years, and approximately two-thirds of patients are asymptomatic at the time of diagnosis [68]. Rare patients present in early childhood, sometimes before the diagnosis of Friedreich ataxia has been made. Symptoms related to cardiac involvement include chest pain, palpitations from arrhythmias, and heart failure symptoms (eg, dyspnea, exercise intolerance) [38,40]. Echocardiography shows concentric left ventricular hypertrophy in nearly all cases [68-71].
The rate of progression and risk factors for early death from HCM are not well studied. In a retrospective multicenter cohort study of 75 children with Friedreich ataxia-associated HCM (median age at diagnosis, 10.8 years), 54 percent of patients were symptomatic over a median follow-up of five years [68]. Eight patients (16 percent) developed atrial arrhythmias (mostly atrial fibrillation/flutter), representing an annual rate during adolescence of 1.85 percent. Nonsustained ventricular tachycardia was uncommon (7.8 percent). Freedom from death or heart transplantation at 5 and 10 years was 97 and 81 percent, respectively. There were no clinical or radiographic predictors of outcome identified.
Other studies have indicated that affected patients tend to have longer GAA repeat alleles [1,72,73]. The severity of cardiomyopathy does not appear to correlate with neurologic function [71].
Skeletal deformities — As noted above, kyphoscoliosis may present early in the course of Friedrich ataxia and affects 60 to 80 percent of patients, while foot deformities (mainly pes cavus or talipes equinovarus) affect 52 to 74 percent [1,9,38,40,44,45].
Diabetes mellitus — Overt diabetes mellitus or impaired glucose tolerance occurs in 8 to 32 percent of patients with Friedreich ataxia [1,9,40,45], which is several times higher than in age-matched controls [74]. Diabetes appears to cluster within sibships, with a greater risk if an affected sibling is diabetic [9]. Insulin resistance and impaired insulin release due to pancreatic beta cell dysfunction account for the alteration in glucose metabolism [74,75]. Insulin usually is required, but some patients can be controlled with oral hypoglycemic drugs [9].
EVALUATION AND DIAGNOSIS — The diagnosis of Friedreich ataxia is based upon clinical findings but should be confirmed by genetic testing. Neuroimaging of the brain and spinal cord with MRI is recommended for all patients presenting with ataxia to exclude other causes (eg, tumor or other structural lesions, inflammation, infarction, hemorrhage) and to evaluate for cerebellar atrophy, which may suggest an alternative diagnosis.
●Genetic testing for the triplet repeat expansions in the first intron of the frataxin (FXN) gene that cause Friedreich ataxia should be performed in all patients with progressive cerebellar ataxia and autosomal recessive inheritance. In the case of sporadic ataxia, genetic workup should be performed if the clinical picture is consistent with a chronic and progressive ataxia and workup for other acquired ataxias is negative. Among patients with typical symptoms of Friedreich ataxia and normal vitamin E levels, the proportion who do not have a GAA expansion in either allele of the FXN gene is <1 percent [48]. (See "Overview of cerebellar ataxia in adults".)
●Frataxin levels from blood samples or buccal cells using immunoassay methods can identify individuals with Friedreich ataxia and presymptomatic carriers and may be useful in rare cases where genetic testing has not identified a pathogenic mutation [76-79]. Alternatively, some institutions measure the serum frataxin level in-house as a first-line test for most patients with cerebellar ataxia and either no family history or a history suggestive of recessive inheritance because it is faster and less expensive than gene testing. Depending upon those results and the patient's clinical phenotype, genetic testing may involve either specific gene sequencing, a panel, or, increasingly, whole-exome sequencing.
●When the diagnosis is uncertain, serum alpha-tocopherol (vitamin E) levels should be checked; levels are typically normal in patients with Friedreich ataxia, while very low levels are suggestive of ataxia with vitamin E deficiency. (See 'Differential diagnosis' below.)
●The absence of cerebellar atrophy on brain MRI is supportive of the diagnosis of Friedreich ataxia [40]. The presence of significant cerebellar atrophy does not exclude the diagnosis but suggests alternative forms of hereditary ataxia other than Friedreich ataxia [62].
●Electrocardiographic (ECG) or echocardiographic abnormalities indicative of cardiac involvement are supportive features.
●Evidence of a sensory axonal neuropathy on electrodiagnostic testing is a supportive feature for the diagnosis, while the absence of neuropathy does not exclude the diagnosis [40]. Electrodiagnostic testing is seldom useful for diagnosis in the modern era.
A 1981 report of 115 patients from 90 families established the main clinical criteria for Friedreich ataxia, which were autosomal recessive inheritance, onset before age 25 years, ataxia of all four limbs, absence of lower limb reflexes, and presence of pyramidal signs [9]. However, later studies showed that the disease presentation is more variable, as some individuals have later onset or retained tendon reflexes (see 'Atypical phenotypes' above). Therefore, these criteria are not useful because they exclude atypical phenotypes, which account for approximately 25 percent of cases [80].
Differential diagnosis — As noted above, the full clinical picture of Friedreich ataxia may not be seen until several years after presentation. As a result, early clinical diagnosis may be difficult, particularly in patients without a positive family history [1]. Two disorders may be confused with Friedreich ataxia in this setting:
●Ataxia-telangiectasia (AT), an autosomal recessive genetic disorder. Children with AT who are homozygotes have progressive cerebellar ataxia, abnormal eye movements, other neurologic abnormalities, oculocutaneous telangiectasias, and immune deficiency. Associated features include pulmonary disease, an increased incidence of malignancy, radiation sensitivity, and diabetes mellitus caused by insulin resistance. The most consistent laboratory abnormality is an elevation of serum alpha-fetoprotein (AFP) level. The diagnosis of AT is established by the presence of characteristic clinical findings (particularly progressive cerebellar ataxia) and identification of pathogenic variants in both alleles of the ataxia-telangiectasia mutated (ATM) gene. AT can be difficult to distinguish clinically from other chronic ataxic syndromes. If ataxia develops early, AT may be misdiagnosed as an ataxic variety of cerebral palsy. When the onset is delayed, AT most often is mistaken for Friedreich ataxia. (See "Ataxia-telangiectasia".)
●The Roussy-Levy variant of Charcot-Marie-Tooth disease, which is an autosomal dominant disorder that can present with areflexia and ataxia. The peripheral neuropathy is characterized by dysmyelination rather than the axonal neuropathy seen in Friedreich ataxia. (See "Charcot-Marie-Tooth disease: Genetics, clinical features, and diagnosis".)
Inherited ataxias that can resemble Friedreich ataxia with adolescent onset, decreased or absent reflexes, and absence of cerebellar atrophy on brain MRI include the following [40,81]:
●Ataxia with vitamin E deficiency, an autosomal recessive disease caused by mutations in the alpha tocopherol transfer protein gene. It can present as a slowly progressive gait-predominant ataxia syndrome with neuropathy. In addition, some patients develop retinitis pigmentosa. High doses of vitamin E typically lead to neurologic improvement, although recovery may be slow and incomplete. (See "Overview of the hereditary ataxias", section on 'Ataxia with vitamin E deficiency'.)
●Abetalipoproteinemia (Bassen-Kornzweig disease), an autosomal recessive disorder caused by mutations in the microsomal triglyceride transfer protein gene, which leads to impaired fat absorption, abnormally low serum concentrations of total cholesterol and triglyceride, and absent serum beta lipoprotein. The neurologic manifestations include progressive retinal degeneration, peripheral neuropathy, and ataxia. Supplementation with vitamin E and the other fat-soluble vitamins early in the clinical course may improve the neuropathy and retinopathy. (See "Neuroacanthocytosis", section on 'Abetalipoproteinemia'.)
●Refsum disease, a rare autosomal recessive peroxisomal disorder characterized by retinitis pigmentosa, ichthyosis, sensorimotor polyneuropathy, and cerebellar ataxia. In addition, ECG changes and sensorineural hearing loss are also seen. The disease usually presents in adolescence but can present in early adulthood. Patients with classic Refsum disease are unable to degrade phytanic acid due to deficient activity of phytanoyl-CoA hydroxylase (PhyH) caused by mutations in the PHYH gene. Strict reduction in dietary phytanic acid intake may be associated with improvement in the peripheral neuropathy and ataxia. (See "Peroxisomal disorders", section on 'Refsum disease'.)
Certain rare autosomal recessive ataxias can occur at higher rates in specific areas because of consanguineous marriages. Included in this group are the following:
●Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), a rare, early-onset disorder with a classic triad of early spasticity, cerebellar ataxia, and sensorimotor peripheral neuropathy that is caused by mutations in the sacsin molecular chaperone (SACS) gene. This disorder was initially described in families from Quebec, but pathogenic mutations in SACS have now been identified around the world. Affected children are usually symptomatic by one year of age. Brain MRI characteristically shows abnormalities involving the pons. (See "Overview of cerebellar ataxia in adults", section on 'Autosomal recessive ataxias'.)
●Mitochondrial DNA (deoxyribonucleic acid) depletion syndrome 7, the second most common inherited ataxia in Finland [82], originally classified as infantile-onset spinocerebellar ataxia [83]. It is characterized by early-onset ataxia with ophthalmoplegia, hearing loss, sensory axonal neuropathy, and epilepsy.
Other ataxic conditions resembling Friedreich ataxia may be distinguished on the basis of characteristic clinical features such as cerebellar atrophy [48]. As examples, ataxia with oculomotor apraxia (AOA) types 1 and 2 are disorders that present as early-onset autosomal recessive or sporadic cerebellar ataxias with oculomotor apraxia, chorea, facial and limb dystonias, sensorimotor polyneuropathy, cerebellar atrophy, and cognitive impairment. They represent up to 20 percent of cases of autosomal recessive cerebellar ataxia.
●AOA type 1, also known as early-onset AOA, usually presents in the first decade of life, although onset has been reported as late as age 25 years. It is associated with hypercholesterolemia and hypoalbuminemia. The cause is a mutation in the APTX gene that encodes aprataxin, a protein that may be involved in repair of single-stranded DNA breaks. (See "Ataxia-telangiectasia", section on 'Differential diagnosis'.)
●AOA type 2 is more common than type 1 and has a later onset, from the third to the sixth decade. It is less frequently associated with cognitive impairment, and oculomotor apraxia is a feature in only approximately 50 percent of cases. It is associated with elevated levels of AFP. AOA type 2 results from mutations in the SETX gene, which encodes senataxin, a DNA and RNA (ribonucleic acid) helicase. (See "Ataxia-telangiectasia", section on 'Differential diagnosis'.)
MANAGEMENT — Friedreich ataxia is a multisystem disorder, and management often requires a team of special services that includes neurology, physical medicine, cardiology, orthopedics, endocrinology, and speech therapy.
Anticipatory care
●An occupational and physical therapy program should be initiated early and modified over time to address the progressive loss of balance and fine motor control; adaptive devices to assist in ambulation and activities of daily living eventually will be needed.
●Yearly cardiac evaluation for evidence of arrhythmia and cardiomyopathy is required. Some experts suggest that the initial evaluation include both echocardiography and cardiac MRI, followed by annual echocardiography during follow-up [71]. Consensus guidelines recommend cardiology evaluation at the time of Friedreich ataxia diagnosis with examination, ECG, echocardiography, and ambulatory ECG monitoring, followed by annual follow-up to include examination, ECG, and echocardiography for asymptomatic patients and more frequent follow-up for symptomatic patients [84]. The guidelines also state that it is reasonable to do ambulatory ECG monitoring or monitoring with an event recorder for patients with symptoms of palpitations and those without symptoms every one to four years, increasing in frequency with increasing age.
Of course, patients who develop new cardiac symptoms should be seen promptly. Although there is no specific treatment for Friedreich ataxia-related cardiomyopathy, conventional drugs and device implantation can be used to manage heart failure and arrhythmia [85]. (See "Hypertrophic cardiomyopathy: Management of patients without outflow tract obstruction".)
●Swallowing should be evaluated at baseline and as needed thereafter depending upon symptoms, with speech and swallowing therapy for patients with dysphagia or aspiration [40].
●Scoliosis screening is recommended annually for children who present with Friedreich ataxia and at baseline for those who present as adults, followed by orthopedic referral for those with musculoskeletal abnormalities [40].
●Ophthalmology and audiology evaluations are recommended at baseline and every two to three years thereafter, with appropriate referrals for patients with impairment of vision or hearing [40].
●Patients should be screened annually for the development of diabetes.
●Urodynamic studies should be obtained if bladder dysfunction is suspected [40].
●A sleep study is indicated if there is suspicion for sleep disorder [48].
●Genetic and psychological counseling are important to aid in coping with a chronic progressive disorder.
Omaveloxolone — Omaveloxolone was approved by the US Food and Drug Administration (FDA) in February 2023 for patients 16 years of age and older as the first therapy for Friedreich ataxia [86]. It is believed to act primarily as an antioxidant via activation of nuclear factor erythroid 2-related factor 2 (Nrf2), which is implicated in cellular response to oxidative injury, and inhibition of nuclear factor kappa B (NF-kB), which is a proinflammatory transcription factor [87]. Based on evidence of efficacy reviewed below and the progressive nature of the disorder, we suggest omaveloxolone in all patients with Friedreich ataxia who are 16 years of age and older. However, given the modest benefits and potential burdens of treatment, including side effects, monitoring, and cost, some patients and families may reasonably choose not to start omaveloxolone until more experience with the drug accumulates.
FDA approval was based on results of an international randomized trial (MOXIe), in which 103 patients 16 to 40 years of age with Friedreich ataxia (median age, 21 to 22 years; mean disease duration, approximately 4.5 years) were randomly assigned to oral omaveloxolone 150 mg daily or placebo for 48 weeks [88]. Patients with uncontrolled diabetes or clinically significant heart disease were excluded. The primary outcome was based on the prespecified group of 87 patients without pes cavus; of these, 82 evaluable patients received 48 weeks of treatment and had completed primary outcome measurements on the modified Friedreich Ataxia Rating Scale (mFARS; scores range from 0 to 99, with lower scores indicating better neurologic function). Among these patients, mFARS scores improved by 1.55 points in the omaveloxolone group and worsened by 0.85 points in the placebo group (mean difference between groups -2.4 points, 95% CI -4.3 to -0.5). The full study population of 103 patients showed a similar effect, with a slightly lower magnitude of benefit (mean difference between groups -1.93, 95% CI -3.71 to -0.16). Secondary efficacy measures numerically favored omaveloxolone but were not statistically significant.
Although this was a single trial with limitations and the effect size was relatively modest, Friedreich ataxia is a slowly progressive disease, and it has been proposed that small differences in functional progression over one to two years could translate to meaningful differences over the course of the disease. In a natural history study that included over 800 patients with Friedreich ataxia, the mean progression in mFARS scores from baseline was 1.9 points by year 1, 4.2 points by year 2, and 9.6 points by year 5 [89]. An ongoing open-label extension study is following 149 patients who took part in either the initial placebo-controlled dose-finding study [90] or the multicenter trial [88,91]. An analysis of mFARS scores over time in the delayed-start group (initially randomized to placebo) and the early-start group found that the difference in mFARS scores between groups that existed at the end of the placebo-controlled trial period was preserved after 24 weeks of open-label omaveloxolone, suggesting a disease-modifying rather than symptomatic effect of the therapy [91]. However, more studies are needed to explore potential disease-modifying effects, to better understand whether modest short-term gains in mFARS scores translate to patient-important benefits on function and quality of life, and to examine effects in younger patients with the disease.
Adverse effects that occurred more commonly with omaveloxolone than placebo in the 48-week trial included elevated aminotransferase levels (37 versus 2 percent; no cases of clinical liver injury), headache (37 versus 25 percent), nausea (33 versus 14 percent), and diarrhea (20 versus 10 percent) [88]. Maximum elevations of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) occurred within 12 weeks of starting omaveloxolone (>3 times the upper limit of normal [ULN] in 31 percent and >5 times the ULN in 16 percent) and were generally asymptomatic and reversible with drug hold [86,88]. Brain natriuretic peptide (BNP) levels increased from baseline in 14 percent of patients but only exceeded 200 picograms/mL in 4 percent of patients, and there were no clinical cardiac adverse events. Low density lipoprotein (LDL) levels rose by a mean of 23.5 mg/dL over the 48 weeks of the study. No new safety signals emerged in the open-label extension study with up to 144 weeks of omaveloxolone therapy [91].
The recommended dose of omaveloxolone is 150 mg orally once daily on an empty stomach (at least one hour before eating). Testing required in the package insert for safety monitoring includes ALT, AST, bilirubin, BNP, and lipid profile. Liver function tests (LFTs) are recommended monthly for the first three months and then periodically as clinically indicated. Precautions and dose adjustments are recommended for concomitant use of strong or moderate cytochrome P450 (CYP) 3A4 inhibitors or inducers and for patients with hepatic impairment.
Pregnancy implications — Although data are limited, the available evidence suggests that patients with Friedreich ataxia are not at high risk for complications of pregnancy or worsening of disease symptoms during pregnancy [92,93]. One of the largest studies retrospectively reviewed 31 patients with Friedreich ataxia from the United States who had 65 pregnancies [93]. Spontaneous abortion occurred in 14 percent, a rate lower than the estimated national incidence. Rates of preterm birth (13 percent) and preeclampsia (4 percent) were similar to the incidence of these conditions in the general population. Delivery was vaginal in 78 percent of cases. Newborns were discharged to home in 95 percent of cases. The percentage of patients reporting that pregnancy made the symptoms of Friedreich ataxia worse, unchanged, or improved (36, 36, and 29 percent, respectively) was similar.
Investigational therapies — Investigational therapies for Friedreich ataxia have focused on improving mitochondrial function and increasing frataxin expression [94]. Noninvasive devices to help symptoms are also being studied.
Gene therapy — Research efforts to elucidate the mechanism of gene silencing of the expanded frataxin (FXN) gene may lead to therapeutic targets [37]. There is evidence that the expansion causes the gene to become transcriptionally silent because of changes in histones, around which DNA is coiled into chromatin. These changes include decreases in acetylation. Thus, histone deacetylase inhibitors are a promising avenue of future therapy [95-98].
Idebenone — One theory holds that Friedreich ataxia may be the result of mitochondrial accumulation of iron, which promotes injury caused by oxidative stress (see 'Pathogenesis' above). The administration of antioxidants such as idebenone (a free radical scavenger), coenzyme Q10, or vitamin E can decrease markers of oxidative injury [23,99,100].
Clinical data are limited. A 2016 systematic review identified only two small randomized controlled trials with a treatment duration of at least 12 months that evaluated idebenone for patients with Friedreich ataxia [101-103]. In these trials, idebenone was not effective for improving ataxia, and results were inconsistent for change in interventricular septal thickness [101].
Deferiprone — Iron chelation with deferiprone is another possible treatment approach but has generally been avoided because Friedreich ataxia is associated with normal or mildly reduced levels of plasma iron, despite iron accumulation in mitochondria and specific brain regions. In addition, there is a risk of neutropenia and agranulocytosis with this agent. (See "Iron chelators: Choice of agent, dosing, and adverse effects", section on 'Deferiprone'.)
One six-month controlled trial evaluated 72 patients (ages 7 to 35 years) with Friedreich ataxia and randomly assigned them to treatment with deferiprone 20, 40, or 60 mg/kg per day or placebo [104]. Compared with the placebo group, which did not show deterioration in clinical scores, there was no significant change in ataxia scores for patients in the deferiprone 20 mg/kg group, but those in the 40 mg/kg group had significant worsening of ataxia. The 60 mg/kg per day dose was discontinued because of increased ataxia. One patient assigned to deferiprone developed reversible neutropenia, though none developed agranulocytosis. The short duration and small size of this trial are major limitations. Nevertheless, given these data, deferiprone is not recommended for the treatment of Friedreich ataxia outside of clinical trials.
Others — Studies are investigating the potential symptomatic benefits of cerebellar transcranial direct current stimulation (tDCS) on ataxia and cognition in patients with Friedreich ataxia and other ataxias [105]. tDCS is a noninvasive technique by which continuous low-voltage current is applied to the scalp to modulate neuronal excitability. In cerebellar disorders, tDCS is thought to increase inhibition from Purkinje cells to the dentate nuclei and achieve an overall effect of increased cerebellar inhibition [106]. In a short-term randomized trial of 24 patient with Friedreich ataxia, cerebellar tDCS (20 minutes per day, five days per week for one week) led to modest improvements in ataxia and cognitive rating scales compared with sham tDCS [107]. Further studies are needed to optimize treatment parameters and determine whether effects are sustained and clinically meaningful.
PROGNOSIS — As noted above, severity of disease and rate of progression are variable, with more severe disease being associated with a higher number of GAA repeats [1,108]. The mean time from symptom onset to use of a wheelchair ranges from 11 to 25 years [1,9,43,109]. Most patients die between the ages of 30 and 40, with a mean age of 37 years in some studies, though some patients survive until the eighth decade [109-111]. With late-onset Friedreich ataxia, disease progression is generally slower [1,112].
The major cause of death is cardiac dysfunction, typically congestive heart failure or arrhythmia [73,111]. Less often, death occurs from noncardiac causes, such as pneumonia due to bulbar dysfunction with inability to protect the airway.
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●Basics topic (see "Patient education: Friedreich ataxia (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Etiology – Friedreich ataxia is an autosomal recessive degenerative disorder leading to progressive ataxia, neuropathy, and cardiomyopathy. Most cases are caused by biallelic loss-of-function expanded trinucleotide (GAA) repeat variants in intron 1 of the frataxin (FXN) gene, which encodes the mitochondrial protein, frataxin. (See 'Genetics' above.)
●Epidemiology – Friedreich ataxia is the most common hereditary ataxia; it accounts for up to one-half of hereditary ataxia cases overall. The onset of symptoms is usually in the adolescent years, although there is a wide range. Longer GAA repeats generally correlate with earlier age of onset and higher disease severity. (See 'Epidemiology' above.)
●Clinical features – The major clinical manifestations of Friedreich ataxia are neurologic dysfunction and cardiomyopathy. Almost all patients present with limb and gait ataxia. Deep tendon reflexes eventually are lost in most patients. Additional manifestations can include optic atrophy, dysphagia, dysarthria, motor weakness, distal loss of position and vibration sense, reduced visual acuity, hearing loss, bladder dysfunction, kyphoscoliosis, and diabetes mellitus. Atypical phenotypes include those with late-onset disease, preserved reflexes, lower limb spasticity, and/or absence of cardiomyopathy. (See 'Clinical features' above.)
●Diagnosis – The diagnosis of Friedreich ataxia is based upon clinical findings and should be confirmed by genetic testing for pathologic repeat expansion of the FXN gene. Neuroimaging of the brain and spinal cord with MRI is recommended for all patients presenting with ataxia to exclude other causes (eg, tumor or other structural lesions, inflammation, infarction, hemorrhage) and to evaluate for cerebellar atrophy. (See 'Evaluation and diagnosis' above.)
A variety of other genetic causes of ataxia and neuropathy have overlapping clinical features and are distinguished through genetic testing. (See 'Differential diagnosis' above.)
●Management – Friedreich ataxia is a multisystem disease, and management requires a multidisciplinary team of special services.
•An occupational and physical therapy program should be initiated early. Periodic evaluation of cardiac function is required. Similarly, patients should be monitored for the development of dysphagia, scoliosis, vision loss, hearing loss, bladder dysfunction, sleep apnea, and diabetes mellitus. Genetic and psychological counseling are also important. (See 'Anticipatory care' above.)
•For patients 16 years of age and older with Friedreich ataxia, we suggest treatment with omaveloxolone (Grade 2C). However, given the modest benefits and potential burdens of treatment, some patients and families may reasonably choose not to start omaveloxolone until more experience with the drug accumulates. Patients require monitoring of liver function tests, brain natriuretic peptide (BNP), and lipids during treatment. (See 'Omaveloxolone' above.)
●Prognosis – Disease severity and rate of progression are variable in Friedreich ataxia, with more severe disease being associated with a higher number of GAA repeats. The mean time to wheelchair dependence ranges from 11 to 25 years in different studies. Death is usually related to the cardiomyopathy and occurs at a mean age of 37 years, though some patients survive until the eighth decade. (See 'Prognosis' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Robert Cruse, DO, who contributed to an earlier version of this topic review.
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