Friedreich ataxia (FRDA) is characterized by progressive ataxia with onset from early childhood to early adulthood with mean age at onset from 10 to 15 years (range: age two years to the eighth decade) [Delatycki et al 1999b]. Ataxia manifests initially as poor balance when walking, followed by slurred speech and upper-limb ataxia.
Among individuals with FRDA, about 75% have "typical Friedreich ataxia" and about 25% of individuals with biallelic FXN full-penetrance GAA repeat expansions have "atypical Friedreich ataxia" [Dürr et al 1996] including late-onset FRDA (LOFA) (i.e., onset after age 25 years), very late-onset FRDA (VLOFA) (i.e., onset after age 40 years), and FRDA with retained reflexes (FARR).
Typical Friedreich Ataxia
Gait ataxia, present in all individuals with FRDA [Delatycki et al 1999b], is caused by a combination of spinocerebellar degeneration and loss of joint position sense (proprioception). It is the earliest manifestation in most affected individuals. Poor balance is accentuated when visual input is eliminated, such as in darkness or when the eyes are closed (Romberg sign).
Within five years of onset of manifestations, most individuals exhibit "scanning" dysarthria, lower-extremity weakness, and diminished or absent joint position and vibration sense distally. These neurologic manifestations result from progressive degeneration of the dorsal root ganglia, posterior columns, corticospinal tracts, dorsal spinocerebellar tracts of the spinal cord, and cerebellum. Ankle and knee jerks are generally absent, and plantar responses are usually upgoing.
Dysarthria, present in 95% of individuals [Delatycki et al 1999b], is generally of three types: mild dysarthria, increased velopharyngeal involvement manifesting as hypernasality, and increased laryngeal dysfunction manifesting as increased strained-strangled vocal quality [Folker et al 2010]. Over time, dysarthria becomes worse with changes in speaking rate and utterance duration [Rosen et al 2012].
Mild dysphonia characterized by hoarseness (combined roughness and breathiness), increased strain, and altered pitch variability is also seen [Vogel et al 2017].
Dysphagia, manifesting as oropharyngeal incoordination, weakness, and spasticity, has been reported in 92% of individuals [Vogel et al 2014]. In one study, significant airway compromise was observed in 34% of individuals and silent aspiration in 26%. Severity of dysphagia correlates with disease duration and severity [Keage et al 2017].
Peripheral motor and sensory involvement results from a mixed axonal peripheral neuropathy. Nerve conduction studies generally show a motor nerve conduction velocity of greater than 40 m/s with reduced or absent sensory nerve action potentials with an absent H reflex. Central motor conduction time is abnormal after transcranial magnetic stimulation [Brighina et al 2005].
Muscle weakness, often present, is most prominent early in the disease course in the hip extensors and abductors. As disease advances, distal limb muscle weakness and wasting become evident. Although pes cavus is common (55%), it generally causes little problem.
Restless leg syndrome, an uncontrollable urge to move the legs usually because of an uncomfortable sensation, affected 32%-50% of individuals in two studies [Frauscher et al 2011, Synofzik et al 2011].
Spasticity was reported in 21% of individuals [Ribaï et al 2007]. Spasticity in the lower limbs can significantly affect foot plantar flexors and inverters more than dorsiflexors and everters, commonly resulting in equinovarus deformity late in the disease [Delatycki et al 2005].
Likewise, spasticity may result in contractures and significant morbidity, particularly in individuals who are non-ambulatory [Milne et al 2016]. Scoliosis, present in approximately two thirds of individuals when assessed clinically, is identified in 100% of individuals assessed radiographically. Milbrandt et al [2008] found that 49 of 77 individuals had scoliosis; ten were treated with a brace and 16 required spinal surgery.
Spastic bladder, reported in 41% of individuals, manifests as urinary frequency and urgency [Delatycki et al 1999a]. In 158 individuals with FRDA, 82% had lower urinary tract involvement that affected quality of life in 22% [Musegante et al 2013]; of the 28 who underwent urodynamic studies, all had normal serum creatinine concentration and four had upper urinary tract dilatation.
Autonomic disturbance becomes more common with disease progression. It is thought that the loss of unmyelinated fibers results in autonomic clinical features such as cold cyanosed feet. Formal cardiovascular autonomic function testing, however, has not shown involvement of the sudomotor and cardiovascular autonomic functions [Indelicato et al 2018].
Sleep-disordered breathing and sleep
apnea are more prevalent in individuals with FRDA (21%) than in the general population (5%) [Corben et al 2013].
Ophthalmologic manifestations. Abnormal eye movements, the most frequent non-ataxia clinical features in FRDA, affect 91% of individuals [Reetz et al 2018]. 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]. Generally, horizontal and vertical gaze palsy does not occur.
Optic nerve atrophy, often asymptomatic, occurs in approximately 25% of individuals. Dürr et al [1996] found reduced visual acuity in 13% of individuals studied. Although study of the anterior and posterior visual pathways by visual field testing and optical coherence tomography (OCT), pattern visual evoked potentials, and diffusion-weighted imaging revealed that all individuals studied had optic nerve abnormalities, only five of 26 (19%) had related symptoms [Fortuna et al 2009]. With disease progression, diminution of contrast acuity is typical [Seyer et al 2013].
Cardiomyopathy. Hypertrophic cardiomyopathy, defined as increased thickness of the interventricular septum, is present in about two thirds of individuals [Delatycki et al 1999a]. While manifestations of cardiomyopathy usually occur later in the disease course [Dutka et al 1999], in rare instances cardiomyopathy may precede the onset of ataxia [Alikaşifoglu et al 1999, Leonard & Forsyth 2001]. For example, Quercia et al [2010] reported sudden death in a young child with FRDA.
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]. Electrocardiography, which is abnormal in the vast majority, most commonly shows T wave inversion, left axis deviation, and repolarization abnormalities [Dutka et al 1999].
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]. Two studies found that in 12% and 20% of individuals ejection fraction was reduced [Regner et al 2012a, Weidemann et al 2012]; longitudinal strain is commonly reduced [St John Sutton et al 2014].
Later in the disease course, the cardiomyopathy may become dilated with reduction in left ventricular wall thickness [Rajagopalan et al 2010] and progressive systolic dysfunction [Kipps et al 2009]. Symptoms often present when disease is moderately advanced include exertional dyspnea (40%), palpitations (11%), and anginal pain. Coronary artery disease should be considered when there is angina and/or sudden deterioration in cardiac function [Giugliano & Sethi 2007].
Although supraventricular ectopy is observed with disease duration, associated diminished cardiac function or cardiac hypertrophy are uncommon [Mejia et al 2021].
Arrhythmias (especially atrial fibrillation) and congestive heart failure, which are prevalent in later stages of the disease, are the most common cause of death [Tsou et al 2011]. Of note, the degree of neurologic impairment did not predict whether an affected individual would have stable or rapid progression of cardiomyopathy. However, in their longitudinal study, Pousset et al [2015] identified genotypes associated with a "low-risk group" (approximately 80% of individuals) in whom ejection fraction declined slowly and remained in the normal range and a "high-risk group" (approximately 20% of individuals) in whom decline of the ejection fraction declined into the abnormal range and was associated with high mortality (see Genotype-Phenotype Correlations).
Diabetes mellitus occurs in up to 30% of individuals [Cnop et al 2013]; 65% of diabetic individuals use insulin [McCormick et al 2017a].
Impaired glucose tolerance is seen in up to an additional 49% of individuals with FRDA [Ristow 2004, Cnop et al 2012].
Individuals who are not diabetic demonstrate high insulin responsiveness to oral glucose testing and low insulin sensitivity [Isaacs et al 2016].
Diabetes is an independent predictor of reduced survival in FRDA [Indelicato et al 2024]. In one study, multivariable analysis identified diabetes, disability stage, and history of arrhythmogenic disorder as independent predictors of survival. Combining these predictors with left ventricular systolic dysfunction, the authors created a sum score of four points. In the absence of all predictors, 10-year survival in FRDA is 96.4%, which approaches that of the general European population. However, these rates progressively decrease until they reach 42.4% when three or four predictors are present [Indelicato et al 2024].
Hearing loss includes sensorineural hearing loss in 13% of individuals with FRDA [Dürr et al 1996] and/or auditory neuropathy causing difficulty hearing in the presence of background noise (even in the absence of electrophysiologic evidence of auditory pathway disorder) [Rance et al 2008].
Cognition. While cognition is generally not impaired in FRDA, motor and mental reaction times can be significantly slowed [Botez-Marquard & Botez 1993, Wollmann et al 2002, Corben et al 2006].
Motor planning is markedly impaired [Corben et al 2010, Corben et al 2011]. Motor overflow is also more prevalent in people with FRDA than in controls [Low et al 2013].
The intelligence profile of individuals with FRDA is characterized by concrete thinking, poor capacity in concept formation and visuospatial reasoning, and reduced speed of information processing [Mantovan et al 2006]. Additional issues include problems with attention and working memory [Klopper et al 2011] and impaired inhibition and cognitive flexibility based on the Haylings Sentence Completion Task [Corben et al 2017].
In a meta-analysis of 18 studies reporting neuropsychological test results, individuals with FRDA exhibited reduced performance in cognitive domains including attention, executive functions, language, memory, and visuospatial functions [Naeije et al 2022].
Neurobehavioral/psychiatric manifestations. Personality in individuals with FRDA is characterized by high persistence and low self-transcendence (defined as an individual's ability to look beyond the self to adopt a larger perspective that includes concern for others) when assessed by the Temperament and Character Inventory [Sayah et al 2018].
Bone mineral density. In at least one site assessed, six of 28 individuals had reduced bone mineral density for age [Eigentler et al 2014]. There was a negative correlation between disease severity and femoral neck bone density. Although females were more likely to have clinical fractures than males, no association was found between bone mineral density and fracture occurrence. In fact, all fractures occurred in those with a z score greater than -2.
Other. Inflammatory bowel disease and growth hormone deficiency are more common in individuals with FRDA than in the general population [Shinnick et al 2016].
Neuroimaging. Cerebral, cerebellar, and spinal cord involvement is seen on different MRI-based techniques. Volumetric MRI studies have shown widespread involvement of white and gray matter. A voxel-based morphometry study showed symmetric volume loss in the dorsal medulla, infer-medial portions of the cerebellar hemispheres, rostral vermis, and dentate region [Della Nave et al 2008]. No volume loss in cerebral hemispheres was observed. Lower fractional anisotropy, higher mean diffusivity, and increased radial diffusivity compared to controls have been found in the dentatorubral, dentatothalamic, and thalamocortical tracts [Akhlaghi et al 2014].
Reduced N-acetylaspartate in the cerebellum has been demonstrated by 1H-MRS [Iltis et al 2010] and increased diffusion-weighted imaging may be present in some brain white matter tracts [Rizzo et al 2011].
Volume loss in the dentate nucleus region, brain stem, and superior and inferior cerebellar penduncles appear to be early features in FRDA [Harding et al 2021]. White matter abnormalities, especially in the corticospinal tracts, are intermediate features, whereas cerebellar and cerebral gray matter loss appear at a later stage.
Progression and prognosis. The rate of progression of FRDA is variable. The average time from onset of manifestations to wheelchair dependence is ten years [Dürr et al 1996, Delatycki et al 1999a]. Several studies found that progression is more rapid in those with earlier disease onset [Reetz et al 2015, Tai et al 2015, Patel et al 2016, Rummey et al 2022].
In a large study, Harding [1981] reported an average age at death of 37 years. Tsou et al [2011] reported, in a study of 61 individuals, mean age of death of 36.5 years and median age of 30 years. The most common causes of death were cardiac (38 individuals), non-cardiac (most commonly pneumonia) (17), and unknown cause (6). More recently, in a study in which individuals were followed between 2010 and 2022, death occurred on average at age 39 years. Deaths due to cardiovascular events, responsible for 29.5% of deaths, occurred earlier than deaths due to non-cardiac deaths [Indelicato et al 2024].
Survival into the sixth and seventh decades has been documented.
Atypical Friedreich Ataxia
Late-onset FRDA (LOFA) and very late-onset FRDA (VLOFA). In approximately 15% of individuals with FRDA, onset is later than age 25 years.
LOFA onset is defined as onset between age 26 and 39 years. VLOFA onset is defined as onset at age 40 years and older [Bidichandani et al 2000, Bhidayasiri et al 2005]. The oldest reported age of onset among individuals with biallelic full-penetrance GAA expansions is 80 years [Alvarez et al 2013].
It typically takes five years to make a diagnosis in LOFA, compared to the three years described for typical FRDA [Indelicato et al 2020].
In 44 individuals with LOFA and 30 individuals with VLOFA, milder clinical findings than those in typical FRDA included dysarthria, absent tendon reflexes, extensor plantar reflexes, weakness, amyotrophy, loss of proprioception, cerebellar atrophy, scoliosis, cardiomyopathy, and functional disability.
When compared to individuals with onset between ages zero and seven years, eight to 14 years, and 15 to 24 years, difficulties with upright stability progress much more slowly in individuals with onset after age 24 years [Rummey et al 2022].
When compared to typical FRDA, secondary skeletal involvement (e.g., scoliosis and pes cavus) is less frequent in LOFA [Martinez et al 2017].
FRDA with retained reflexes (FARR) accounts for approximately 12% of individuals who have biallelic full-penetrance GAA expansions [Coppola et al 1999].
Tendon reflexes may be retained for more than ten years after disease onset. Some individuals with FARR have brisk tendon reflexes that can be accompanied by clonus. Other typical manifestations are later age of onset and lower incidence of secondary skeletal involvement and cardiomyopathy.
Spastic paraparesis without ataxia. Individuals who have biallelic full-penetrance GAA repeats may on rare occasion present with spastic gait without gait or limb ataxia; they usually have hyperreflexia. Age of onset is on average 5.8 years later than those with typical FRDA. Ataxia develops with time [Montermini et al 1997c, Gates et al 1998, Castelnovo et al 2000, Lhatoo et al 2001, Badhwar et al 2004].
In Acadians (eastern Canada) with FRDA, age at disease onset and wheelchair dependence are on average 3.0 years later than that of individuals with typical FRDA; likewise, the incidence of cardiomyopathy is lower (48% vs 82%) [Montermini et al 1997b].
Other rare presentations of FRDA
Visual deficit with episodic blindness, optic atrophy, spastic paraparesis, and sensory neuropathy without ataxia [
Diehl et al 2010]
