Friedreich ataxia (FA, FRDA, FRIEDREICH ATAXIA 1, OMIM# *229300) is an autosomal recessive ataxia resulting from a mutation of a gene locus on chromosome 9. The entity was first described in 1863 by Nikolaus Friedreich, a professor of medicine in Heidelberg, Germany.
FA was the earliest of the inherited ataxias to be distinguished from other locomotor ataxias and is the most common of the autosomal recessive ataxias. It accounts for at least 50% of cases of hereditary ataxias in most large series. Cardinal features include progressive limb and gait ataxia, dysarthria, loss of joint position and vibration senses, absent tendon reflexes in the legs, and extensor plantar responses.
The major pathophysiologic finding in Friedreich ataxia is a "dying back phenomena" of axons, beginning in the periphery with ultimate loss of neurons and a secondary gliosis. The primary sites of these changes are the spinal cord and spinal roots. This results in loss of large myelinated axons in peripheral nerves, which increases with age and disease duration. Unmyelinated fibers in sensory roots and peripheral sensory nerves are spared.
The posterior columns and corticospinal, ventral, and lateral spinocerebellar tracts all show demyelination and depletion of large myelinated nerve fibers to differing extents. This is accompanied by a fibrous gliosis that does not replace the bulk of the lost fibers. Overall, the spinal cord becomes thin and the anteroposterior (AP) and transverse diameters of the thoracic cord are reduced. The dorsal spinal ganglia show shrinkage and eventual disappearance of neurons associated with proliferation of capsular cells. The posterior column degeneration accounts for the loss of position and vibration senses and the sensory ataxia. The loss of large neurons in the sensory ganglia causes extinction of tendon reflexes.
Large neurons of the dorsal root ganglia, especially lumbosacral, and nerve cells in the Clarke column are reduced in number. The posterior roots become thin. The dentate nuclei exhibit mild to moderate neuronal loss and the middle and superior cerebellar peduncles are reduced in size. Patchy loss of Purkinje cells in the superior vermis of the cerebellum and of neurons in corresponding portions of the inferior olivary nuclei is typical. Mild degenerative changes occur in the pontine and medullary nuclei and optic tracts. The cerebellar ataxia is explained by loss of the lateral and ventral spinocerebellar tracts and involvement of the Clarke column, dentate nucleus, superior vermis, and dentatorubral pathways.
The corticospinal tracts are relatively spared down to the level of the cervicomedullary junction. Beyond this point, the corticospinal tracts are severely degenerated, which becomes progressively more severe moving down the spinal cord. This explains the common finding of bilateral extensor plantar responses and weakness late in the disease.
Loss of cells in the nuclei of cranial nerves VII, X, and XII results in facial weakness and speech and swallowing difficulties.
Myocardial muscle fibers also show degeneration and are replaced by macrophages and fibroblasts. Essentially, chronic interstitial myocarditis occurs with hypertrophy of cardiac muscle fibers; fibers become hypertrophied and lose their striations. This is followed by swelling and vacuolation and finally interstitial fibrosis. The nuclei appear hyperchromatic and occasionally vacuolated. The cytoplasm appears granular with frequent lipofuscin depositions.
Kyphoscoliosis is likely; it is secondary to spinal muscular imbalance.
Friedreich ataxia is a relatively common disorder. It is the most common autosomal recessive ataxia, accounting for approximately 50% of all cases of hereditary ataxia. Estimates of incidence range anywhere from 1 in 22,000 to 2 in 100,000, with most studies yielding an incidence among Europeans and North Americans of European descent of approximately 1.5 per 100,000 per year; a slightly higher incidence has been reported in Quebec.
Overall, the FA carrier rate has been estimated recently to be 1 in 60 to 1 in 90 with a disease prevalence of 1 per 29,000.
Mortality/Morbidity
Friedreich ataxia is a progressive disorder with significant morbidity. Loss of ambulation typically occurs 15 years after disease onset. More than 95% of patients are wheelchair bound by age 45 years.
In a series by Harding et al, the average age of death was 37.7 years±14.4 years (range, 21-69).[1]
Race
Friedreich ataxia is most prevalent in white populations. Most FA carriers and affected FA patients are believed to originate from a common European ancestor who lived more than 10,000 years ago. Frataxin gene expansions are therefore almost nonexistent among black African and Asian populations.
Age
The onset of Friedreich ataxia is early; it typically presents in children aged 8-15 years and almost always presents before age 20 years.
In a study by Harding et al, the mean onset of symptoms occurred at age 10.52±7.4 years (range, 1.5-27).[1]
Onset of Friedreich ataxia (FA) is early, with gait ataxia being the usual presenting symptom. Typically, both lower extremities are affected equally. Some patients may have hemiataxia initially before the symptoms become generalized. In some instances, the ataxia begins abruptly following a febrile illness in which ataxia of one lower extremity precedes that of the other.
Gait ataxia manifests as progressively slow and clumsy walking, which often begins after normal walking has developed. The ataxia may be associated with difficulty standing and running. The gait ataxia is both of a sensory and cerebellar type. This combination has been referred to as a tabetocerebellar gait. Opinions are conflicting as to whether the sensory or cerebellar features predominate. The cerebellar features of gait ataxia in FA include a wide-based gait with constant shifting of position to maintain balance. Sitting and standing are associated with titubation.
The sensory ataxia resulting from a loss of joint position sense contributes to the wide-based stance and gait but a steppage gait also is present, characterized by uneven and irregular striking of the floor by the bottom of the feet. Attempts to correct any imbalance typically result in abrupt and wild movements.
As the disease progresses, ataxia affects the trunk, legs, and arms. As the arms become grossly ataxic, both action and intention tremors may develop. Titubation of the trunk may appear. Facial, buccal, and arm muscles may become tremulous and occasionally display choreiform movements. The patient may experience easy fatigability.
Parkinson et al in their recent study revealed that early-onset cases deteriorate rapidly and are more frequently associated with non-neurological features such as diabetes, cardiomyopathy, scoliosis, and pes cavus. Late-onset cases have smaller GAA expansions and tend to have slower progression.[2]
Patients with advanced FA may have profound distal weakness of the legs and feet, although significant weakness of the arms is rare before the patient becomes bedridden. Eventually, the patient is unable to walk because of the progressive weakness and ataxia, becoming wheelchair bound and ultimately bedridden.
With disease progression, dysarthria and dysphagia appear. Speech becomes slurred, slow, and eventually incomprehensible. Patients may experience mild weakening of the facial muscles with associated weakness of swallowing. Incoordination of breathing, speaking, swallowing, and laughing may result in the patient nearly choking while speaking.
Nieto et al administered comprehensive neuropsychological testing measuring multiple domains in 36 FA patients.[3] The observed pattern of neuropsychological impairment is indicative of executive problems and parietotemporal dysfunction. Thus, cognitive impairment in FA is probably caused by the interruption of cerebrocerebellar circuits that have been proposed as the anatomical substrate of the cerebellar involvement in cognition.
Noval et al (2012) used optical coherence tomography to provide a better understanding of the ophthalmic features of FA.[4] The authors revealed that the visual pathway is affected in FA, but, in most patients, there is no significant visual impairment. In a small majority of patients, visual acuity declines with disease progression.
Family history
FA is characterized by autosomal recessive inheritance. In families with one affected child, the subsequent risk of another affected child is 25%. As in most recessive disorders, the risk of developing FA is highest following birth from a consanguineous union. In North America and Europe, however, most cases are sporadic and occur in nonconsanguineous families.
The overall risk of a patient with FA having a child with the condition is approximately 1 in 200, unless consanguinity is involved. If that same patient has a partner who is found to be a carrier of FA, then the risk becomes 1 in 2. Children descended from the unaffected sibling of a patient with FA and a nonconsanguineous spouse have a 1:1000 risk of developing FA.
Carrier testing is available for relatives of affected patients and their partners. However, the small risk of a point mutation also must be taken into account and incorporated into genetics counseling.
Prenatal diagnosis via direct mutation testing is also available.
See Staging for a scale used to rate functional disability in patients with Friedreich ataxia.
The cardinal features of FA are as follows:
Progressive limb and gait ataxia develops before the age of 30 years.
Lower extremity tendon reflexes are absent.
Evidence of axonal sensory neuropathy is noted.
Dysarthria, areflexia, motor weakness of the lower extremities, extensor plantar responses, and distal loss of joint position and vibration senses are not found in all patients within the first 5 years, but are eventually universal.
Foot deformity, scoliosis, diabetes mellitus, and cardiac involvement are other common characteristics. Clinical evidence of ventricular hypertrophy, systolic ejection murmurs, and third or fourth heart sounds may be noted.
Physical findings in patients with FA include gradual loss of vibratory and position senses from the onset, initially affecting the feet and hands. With progression, light touch, pain, and temperature sensation also may be diminished. Two-point discrimination may be affected in early cases.
Tendon reflexes are absent in almost all cases but may be weakly present if the patient is examined early in the course of the disease. Patellar and ankle jerks are affected most profoundly. Flexor spasms are common even in the absence of tendon reflexes, indicating that the areflexia is sensory in origin. Plantar reflexes are extensor in 90% of patients and absent in the rest. Abdominal reflexes usually are retained until late in the disease process.
Distal wasting, primarily of the upper extremities, is seen in 50% of patients. Muscle tone is usually normal or decreased. Sphincter control is usually intact but cases of urinary urgency and constipation, which are not usually severe, have occurred.
Kyphoscoliosis is a frequent but nonspecific finding that may be severe. With early onset, severe scoliosis can produce significant cardiopulmonary morbidity and death due to restricted respiratory function. Peripheral cyanosis of the lower limbs is common.
Foot deformities such as high plantar arches, foot inversion, and hammertoes may precede the gait ataxia. Typically, 50% of patients develop either pes cavus or varus deformities of one or both feet.
Visual acuity rarely is affected, but optic atrophy occurs in 25% of patients with FA and has resulted in occasional blindness. Visual evoked potentials (VEP) are abnormal in two thirds of patients, typically displaying reduced amplitude and delayed latency.
Nystagmus of various types may be found. Horizontal nystagmus, present in the primary position and increased on lateral gaze, occurs in 20% of patients with FA. Extraocular movements usually are affected and are characterized by abnormal square-wave jerks and saccadic pursuit, poor fixation, and impaired vestibulo-ocular reflexes. Pupillary reflexes are normal.
Deafness has been noted, in some cases in association with vertigo. Brain stem auditory evoked responses (BAER) are typically consistent with central auditory pathway pathology.
Hypertrophic cardiomyopathy develops in more than 50% of patients. Myocarditis, myocardial fibrosis, cardiac enlargement, progressive cardiac failure, tachycardias, and heart block also may be seen. Cardiac arrhythmia and congestive heart failure contribute to a significant number of deaths in patients with FA.
Approximately 10% of patients with FA develop diabetes mellitus. An even larger percentage demonstrate impaired glucose tolerance, which has been associated with an insulin receptor abnormality.
Intellectual disability, psychosis, and dementia are uncommon, but some degree of cognitive dysfunction may occur. Emotional lability, in the presence of normal cognitive function, is frequently present.
Classic Friedreich ataxia is the result of a gene mutation at the centromeric region of chromosome 9 (9q13-21.1) at the site of the gene encoding for the 210-amino-acid protein frataxin. This mutation is characterized by an excessive number of repeats of the GAA (guanine adenine adenine) trinucleotide DNA sequence in the first intron of the gene coding for frataxin. It is the only disease known to be the result of a GAA trinucleotide repeat. This expansion alters the expression of the gene, decreasing the synthesis of frataxin protein. The expanded GAA repeat is thought to result in frataxin deficiency by interfering with transcription of the gene by adopting an unstable helical structure. The larger the number of repeats, the more profound is the reduction in frataxin expression. A recent study from Stolle and colleagues have shown that interrupted GAA repeats do not clearly impact the age of onset in FA.[5]
In a normal chromosome, this trinucleotide sequence is repeated up to 50 times. In patients with FA, this sequence is repeated at least 200 times and often more than 1000 times.
Variability in the clinical presentation of FA may be explained by the extent of this trinucleotide repeat expansion. The age of disease onset, its severity, rate of progression, and extent of neurological involvement vary with the number of repetitive GAA sequences.
In addition, the frequency of extensor plantar responses, cardiomyopathy, leg weakness and wasting, sclerosis, and pes cavus increased with the size of the GAA expansion.
Larger GAA expansions correlated with earlier age of onset and shorter times to loss of ambulation.
In a study by Durr et al, the large majority of patients with FA (94%) were homozygous for the GAA trinucleotide (the GAA expansion was present on both alleles of the frataxin gene). The remaining 6% were compound heterozygotes for a GAA expansion and a frataxin point mutation (one allele had a GAA expansion, and the other had a point mutation with no expansion). No patients have been described who were homozygous for a point mutation.[6]
Point mutations not only reduce levels of the frataxin protein but are also responsible for the creation of abnormal protein. They also represent another source of variability in the clinical presentation of FA. Seventeen different point mutations have so far been described in FA.
Between 1% and 5% of the point mutations are single base changes in the sequence of the FA gene causing missense, nonsense, or splicing mutations. Patients with missense mutations displayed either mild or severe symptoms, whereas splicing, nonsense, and initiation codon mutations, associated with nonfunctional frataxin, result in a severe phenotype.
Point mutations of the frataxin gene involving the amino terminal typically present with a more benign course than those of the carboxy terminal.
The 3 most common point mutations are the Il54F mutation among southern Italians, the ATG>ATT mutation of the start codon, and the G130V mutation. Patients with the G130V mutation tend to have slower disease progression, brisk knee reflexes, and minimal dysarthria.
Cells and tissues of the body are differentially sensitive to frataxin deficiency. Cells normally requiring and producing greater amounts of frataxin tend to be most affected by FA. For example, sensory neurons in the dorsal root ganglion responsible for position sense highly express the frataxin gene and are affected greatly in FA. Myocardial muscle fiber also requires comparably larger amounts of frataxin than other tissues and is affected markedly in FA.
A number of experiments have confirmed the mitochondrial subcellular localization of frataxin in mammals. Frataxin has been shown to be essential for normal mitochondrial function, both for oxidative phosphorylation and iron homeostasis. Strong evidence exists that frataxin deficiency results in iron accumulation within mitochondria of affected cells in cell culture lines. Apparently, the rate of mitochondrial export is reduced. Hearts of patients with FA have revealed mitochondrial ironlike deposits that are not present in healthy hearts. Frataxin-deficient cells not only generate more free radicals, but also show a reduced capacity to mobilize antioxidant defenses. The search for experimental drugs increasing the amount of frataxin is a very active and timely area of investigation.[7]
The excessive mitochondrial accumulation of iron affects cytosolic iron levels. Excess intracellular iron stimulates the increased generation of free radicals and mitochondrial damage. Iron excess inactivates mitochondrial enzymes essential for the production of adenosine triphosphate (ATP). Cell death, particularly of neurons of the spinal cord and peripheral nervous system, ensues. A mouse model of FA is being developed to confirm evidence of this process in living animal models.
Genetic counseling is available for prenatal diagnosis of Friedreich ataxia for parents with one affected child. Population screening for carriers of the defective gene is not practical. A specific trinucleotide repeat expansion assay is available commercially in the United States and should be performed in all suspected cases of FA.
Total levels of Fe in bulk extracts were not significantly higher than normal, and the concentrations of Zn also remained in the normal range. Cu levels, however, were significantly lower in FA.
No evidence of CSF abnormality exists in patients with FA.
Magnetic resonance imaging (MRI) is the study of choice in the evaluation of the atrophic changes seen in Friedreich ataxia. MRI of the brain and spinal cord in patients with FA consistently shows atrophy of the cervical spinal cord with minimal evidence of cerebellar atrophy.
Transcranial sonography provides a quick-to-apply and inexpensive in vivo assessment of both cerebellar and noncerebellar abnormalities in FA, in particular highlighting dentate hyperechogenicity as a core feature.[8]
Echocardiography reveals symmetric, concentric ventricular hypertrophy, although some have asymmetric septal hypertrophy.
Approximately 65% of patients with FA have abnormal ECG findings. The most common findings are T-wave inversion, particularly in the inferior standard and lateral chest leads, and ventricular hypertrophy.
Nerve conduction velocity (NCV) study findings in FA usually are normal or display only mildly reduced velocities. Sensory nerve action potentials (SNAP) are absent in greater than 90% of patients with FA. The remaining 10% display reduced-amplitude SNAPs.
Brainstem auditory evoked responses are typically abnormal in FA, displaying absent waves III and IV with preservation of wave I. This is suggestive of involvement of central auditory pathways.
Visual evoked potentials are abnormal in two thirds of patients with FA. Absent or delayed latency and reduced amplitude of the p100 wave are seen.
Somatosensory evoked potentials (SSEP) reveal delayed central conduction time (N13a/N20, N13b/N20), dispersed potentials at the sensory cortex, as well as abnormal central motor conduction.
Borchers et al compared clinical tests for joint position sense (JPS) and vibration sense (VS) to a test of spatial position sense (SPS).[9] The SPS test was more sensitive than JPS and VS and revealed deficits potentially earlier than clinical screening tests. Only the SPS showed a positive correlation with ataxia severity. Their results indicate that proprioceptive deficits in Friedreich ataxia start earlier and are more severe than indicated by routine standard clinical testing.
A cross-section through the lower cervical cord clearly shows loss of myelinated fibers of the dorsal columns and the corticospinal tracts (Weil stain). Milder involvement of spinocerebellar tracts is also present. The affected tracts show compact fibrillary gliosis on hematoxylin and eosin (H&E) stain but no breakdown products or macrophages, reflecting the very slow rate of degeneration and death of fibers. The dorsal spinal ganglia show shrinkage and eventual disappearance of neurons associated with proliferation of capsular cells (H&E). The posterior roots are nearly devoid of large myelinated fibers. Within the thoracic spinal cord, degeneration and loss of cells of the Clarke column are apparent.
Currently, there are 3 different scales that are most frequently applied: The International Cooperative Ataxia Rating Scale (ICARS), the Friedreich Ataxia Rating Scale (FARS), and the Scale for the Assessment and Rating of Ataxia (SARA). All scales have been validated and compared with regard to their testing properties.[10] )
International Cooperative Ataxia Rating Scale (World Federation of Neurology)
Posture and gait disturbances
Walking capacities: The patient's gait is observed during a 10-meter walking test, including a half turn, near a wall at about 1.5 meters.
0 = Normal
1 = Almost normal naturally, but unable to walk with feet in tandem position
2 = Walking without support, but clearly abnormal and irregular
3 = Walking without support, but with considerable staggering; difficulties in half turn
4 = Walking with autonomous support no longer possible; the patient uses the episodic support of the wall for a 10-meter test
5 = Walking possible only with 1 stick
6 = Walking possible only with 2 special sticks or with a stroller
7 = Walking only with accompanying person
8 = Walking impossible, even with accompanying person (wheelchair)
Score ___
Gait speed: Patients who scored 1-3 on the preceding test are observed for gait speed; those who scored 4 and up on the preceding test automatically score 4 in this test.
0 = Normal
1 = Slightly reduced
2 = Markedly reduced
3 = Extremely slow
4 = Walking with autonomous support no longer possible
Score ___
Standing capacities, eyes open: The patient is asked first to try to stand on one foot; if impossible, to stand with feet in tandem position; if impossible, to stand with feet together; for the natural position, the patient is asked to find a comfortable standing position.
0 = Normal, able to stand on one foot for more than 10 seconds
1 = Able to stand with feet together, but no longer able to stand on one foot for more than 10 seconds
2 = Able to stand with feet together, but no longer able to stand with feet in tandem position
3 = No longer able to stand with feet together, but able to stand in natural position without support, with no or moderate sway
4 = Standing in a natural position without support, with considerable sway and considerable corrections
5 = Unable to stand in natural position without strong support of one arm
6 = Unable to stand at all, even with strong support of two arms
Score ___
Spread of feet in natural position without support, eyes open: The patient is asked to find a comfortable standing position, then the distance between medial malleoli is measured.
0 = Normal (spread < 10 cm)
1 = Slightly enlarged (spread 10-25 cm)
2 = Clearly enlarged (25 cm < spread < 35 cm)
3 = Severely enlarged (spread >35 cm)
4 = Standing in natural position impossible
Score ___
Body sways with feet together, eyes open
0 = Normal
1 = Slight oscillations
2 = Moderate oscillations (< 10 cm at the level of head)
3 = Severe oscillations (>10 cm at the level of head), threatening the upright position
4 = Immediate falling
Score ___
Body sways with feet together, eyes closed
0 = Normal
1 = Slight oscillations
2 = Moderate oscillations (< 10 cm at the level of head)
3 = Severe oscillations (>10 cm at the level of head), threatening the upright position
4 = Immediate falling
Score ___
Quality of sitting position (thighs together, on a hard surface, arms folded)
0 = Normal
1 = With slight oscillations of the trunk
2 = With moderate oscillations of the trunk and legs
3 = With severe dysequilibrium
4 = Impossible
Score ___
Posture and gait score (static score) ___/34
Kinetic functions
Knee-tibia test (decomposition of movement and intention tremor): The test is performed in the supine position so that visual control is possible; the patient is requested to raise one leg and place the heel on the opposite knee, and then slide the heel down the anterior tibial surface toward the ankle; on reaching the ankle joint, the leg is raised again in the air to a height of approximately 40 cm and the action is repeated; at least 3 movements of each limb must be performed for proper assessment.
0 = Normal
1 = Lowering of the heel in continuous axis but the movement is decomposed in several phases, without real jerks, or abnormally slow
2 = Lowering jerkily in the axis
3 = Lowering jerkily with lateral movements
4 = Lowering jerkily with extremely strong lateral movements or test impossible
Score right ___, Score left ___
Action tremor in the heel-to-knee test: During the same test as the preceding one, the action tremor of the heel on the knee is observed specifically while the patient holds the heel on the knee for a few seconds before sliding it down the anterior tibial surface; visual control is required.
0 = No trouble
1 = Tremor stopping immediately when the heel reaches the knee
2 = Tremor stopping in less than 10 seconds after reaching the knee
3 = Tremor continuing for more than 10 seconds after reaching the knee
4 = Uninterrupted tremor or test impossible
Score right ___, Score left ___
Finger-to-nose test (decomposition and dysmetria): The subject sits in a chair; the hand is resting on the knee before the beginning of the movement; visual control is required; 3 movements of each limb must be performed for proper assessment.
0 = No trouble
1 = Oscillating movement without decomposition of the movement
2 = Segmented movement in 2 phases and/or moderate dysmetria in reaching nose
3 = Segmented movement in more than 2 phases and/or considerate dysmetria in reaching nose
4 = Dysmetria preventing the patient from reaching nose
Score right ___, Score left ___
Finger-to-nose test (intention tremor of the finger): The studied tremor is that appearing during the ballistic phase of the movement; the patient is sitting comfortably with the hand resting on his/her thigh; visual control is required; 3 movements of each limb must be performed for proper assessment.
0 = No trouble
1 = Simple swerve of the movement
2 = Moderate tremor with estimated amplitude < 10 cm
3 = Tremor with estimated amplitude between 10 and 40 cm
4 = Severe tremor with estimated amplitude >40 cm
Score right ___, Score left ___
Finger-finger test (action tremor and/or instability): The sitting patient is asked to maintain his/her index fingers pointing at each other for about 10 seconds, at a distance of 1 cm, at the level of the thorax, under visual control.
0 = Normal
1 = Mild instability
2 = Moderate oscillations of the finger with estimated amplitude < 10 cm
3 = Considerable oscillations of the finger with estimated amplitude between 10 and 40 cm
4 = Jerky movements >40 cm of amplitude
Score right ___, Score left ___
Pronation-supination alternating movements: The subject, comfortably sitting on a chair, is asked to raise his/her forearm vertically and to make alternating pronating and supinating movements of the hand; each hand is moved and assessed separately.
0 = Normal
1 = Slightly irregular and slowed
2 = Clearly irregular and slowed, but without sway of the elbow
3 = Extremely irregular and slowed movements, with sway of the elbow
4 = Movement completely disorganized or impossible
Score right ___, Score left ___
Drawing of the Archimedes spiral on a predrawn pattern: The subject is comfortably settled in front of a table, sheet of paper being fixed to avoid artifacts; the subject is asked to perform the task without timing requirements; the same conditions of examination must be used at each examination (eg, same table, same pen); the dominant hand is examined.
0 = Normal
1 = Impairment and decomposition, the line quitting the pattern slightly but without hypermetric swerve
2 = Line completely out of the pattern with recrossing and/or hypermetric swerves
3 = Major disturbance due to hypermetria and decomposition
4 = Drawing completely disorganized or impossible
Score ___
Kinetic score (limb coordination) ___/52
Speech disorders
Dysarthria (fluency of speech): The patient is asked to repeat several times a standard sentence, always the same, for instance, "They heard him speak on the radio last night."
0 = Normal
1 = Mild modification of fluency
2 = Moderate modification of fluency
3 = Considerably slow and dysarthric speech
4 = No speech
Score ___
Dysarthria (clarity of speech)
0 = Normal
1 = Suggestion of slurring
2 = Definite slurring, most words understandable
3 = Severe slurring, speech not understandable
4 = No speech
Score ___
Dysarthria score ___/8
Oculomotor disorders
Gaze-evoked nystagmus: The subject is asked to look laterally at the finger of the examiner; the movements assessed are mainly horizontal, but they may be oblique, rotatory, or vertical.
0 = Normal
1 = Transient
2 = Persistent but moderate
3 = Persistent and severe
Score ___
Abnormalities of the ocular pursuit: The subject is asked to follow the slow lateral movement performed by the finger of the examiner.
0 = Normal
1 = Slightly saccadic
2 = Clearly saccadic
Score ___
Dysmetria of the saccade: Two index fingers of the examiner are placed in each temporal visual field of the patient, whose eyes are in the primary position; the patient is then asked to look laterally at the finger, on the right and on the left; the average overshoot or undershoot of the 2 sides is then estimated.
0 = Absent
1 = Bilateral clear overshoot or undershoot of the saccade
The results of treating ataxia in Friedreich ataxia (FA) have generally been disappointing. No therapeutic measures are known to alter the natural history of the neurological disease. Standard treatment is administered for heart failure, arrhythmias, and diabetes mellitus.
High-dose propranolol has been described in a case report by Kosutic with reduction in thickness of the septal and posterior left ventricular walls and with complete normalization of diffuse electrocardiographic repolarization abnormalities.[11]
Li and colleagues have shown that therapeutic efforts should focus on an approach that combines iron removal from mitochondria with a treatment that increases cytosolic iron levels to maximize residual frataxin expression in patients with FA.[12]
The other therapies that have been used are as follows:
5-Hydroxytryptophan
5-Hydroxytryptophan is a serotonin precursor that has been used for a decade or more by Trouillas et al to treat various forms of ataxia with mixed results.[13] This drug was known to suppress posthypoxic action myoclonus. The rationale for use of the drug in FA was that FA may in part be due to a cerebellar deficiency of serotonin.
The results of a double-blind, cross-over study by Trouillas et al demonstrated that the levorotatory form of 5-hydroxytryptophan was able to significantly modify the cerebellar symptoms in patients with FA; however, the effect was only partial and not clinically major.[13]
A study by Wessel demonstrated stabilization of posture in patients receiving long-term treatment with 5-hydroxytryptophan and a clear deterioration in patients who did not receive the treatment. This form of treatment requires further study.
Coenzyme Q
Coenzyme Q is an antioxidant that can buffer free radical formation that is induced by excess mitochondrial iron. A combined coenzyme Q (400 mg/d) and vitamin E (2100 IU/d) therapy has been used in a study of 10 patients with slowing of the progression of certain clinical features and a significant improvement in cardiac function.
Experimental studies are underway to evaluate the use of coenzyme Q derivatives in limiting the toxicity of iron to mitochondrial structures.
Idebenone
Idebenone has been used as therapy for Friedreich ataxia for more than a decade. At present, several studies have assessed the influence of therapy on neurologic or cardiac function.
The effect of intermediate-dose idebenone (20 mg/kg/d) on quality of life and neurologic function was assessed in a recent study by Brandsema et al.[14] The Pediatric Quality of Life Inventory, the International Cooperative Ataxia Rating Scale, and an Activities of Daily Living Scale before initiation of idebenone therapy and after 1 year of therapy were assessed.
The scores on the Pediatric Quality of Life Inventory were universally worse after 1 year and correlated with decreased activities of daily living scores. However, there was a trend toward improved total, emotional, social, and school components of quality of life scores after 1 year of idebenone therapy.
There was no statistically significant change in Pediatric Quality of Life Inventory scores between baseline and 1 year of idebenone therapy. Functional ability, as measured by activities of daily living scores, seems to have the most influence on the physical quality of life.
Co-enzyme Q10 and idebenone were recently reviewed once again by Parkinson et al in 2013.[15] Prior randomized, double-blind, placebo-controlled intervention trial by Lynch et al did not reveal any statistically significant difference between the placebo and idebenone on the International Cooperative Ataxia Rating Scale.[16]
Tomassini et al (2012) have revealed that in vivo treatment with interferon-gamma increases frataxin expression in dorsal root ganglia neurons, prevents their pathological changes, and ameliorates the sensorimotor performance in FA mice. These results disclose new roles for interferon-gamma in cellular metabolism and have direct implications for the treatment of FA.[17]
Pandolfo et al have recently reviewed the utility of deferiprone with specific regard to its iron chelating properties and clinical benefits.[18]
In a study done by Elincx-Benizri et al, the authors presented their experience of 5 FA patients treated with deferiprone (20 mg/kg/day), in addition to idebenone treatment, followed over a period of 10-24 months, under off-label authorization. The authors concluded that combination therapy of a low dose of deferiprone with idebenone is relatively safe and might improve neurological function and heart hypertrophy.[54] However, future studies are needed.
Apart from surgery for scoliosis and foot deformities that may be helpful in selected cases, no significant surgical treatment is available for Friedreich ataxia. A study from Milbrandt and colleagues emphasized that in scoliosis braces were seldom effective and that segmental constructs are effective in creating substantial intraoperative correction and maintaining correction postoperatively.[19]
In addition, heart transplantation for FA dilated cardiomyopathy has been performed.
Goulipian and colleagues have mentioned the role of orthopedic shoes combined with physical therapy. Their results demonstrated that orthopedic shoes improved gait disorders in a patient with Friedreich ataxia.[20]
No data exist to suggest that any alteration of activity level would affect the onset, progression, or outcome of this disease.
In regards to the delivery and utilization of oxygen in response to exercise, near infrared muscle spectroscopy may be an effective tool for monitoring the biochemical and functional features of FA.
A study by Milne, et al. concluded that management of spasticity and reduced muscle length should be considered in people with FA at disease onset to optimize function.[55]
Health related quality of life (QOL) measures are potentially useful as clinical markers of disease status in Friedreich ataxia (FA).
The prognosis of FA is poor.
Cardiac dysfunction is the most frequent cause of death in almost two thirds of the patients, most commonly from congestive heart failure or arrhythmia. More research is needed to establish the clinical significance of hypertrophy in FA.[21]
No distinct interrelations between FA cardiomyopathy and neurological status could be determined; therefore, regular follow-up of potential cardiac involvement in FA patients is essential in clinical practice.[22]
The decrease of Cu may be important in consideration of the potential benefit of Cu supplements in FA cardiomyopathy.
The disorder is progressive, with a mean duration of 15-20 years.
More than 95% of patients are wheelchair bound by age 45 years.
Commonly, patients survive to 25-30 years of age, although some patients have survived into the sixth and seventh decades, especially if they are free of heart disease and diabetes.
QOL is significantly worse in these individuals compared with population norms. Those with severe disease did not perceive a lower QOL than those with mild or moderate disease except in their physical functioning. A later age of onset and increased disease severity were negatively associated with physical QOL, while increased disease duration was positively associated with mental QOL.[23]
Paulsen et al have revealed a significant relationship between markers of disease status and health-related QOL. The authors found that the children with Friedreich ataxia have a lower health-related QOL than those without a chronic disease.[24]
Jasvinder Chawla, MD, MBA, Chief of Neurology, Hines Veterans Affairs Hospital; Professor of Neurology, Loyola University Medical Center
Disclosure: Nothing to disclose.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Florian P Thomas, MD, PhD, MA, MS, Chair, Neuroscience Institute and Department of Neurology, Director, National MS Society Multiple Sclerosis Center and Hereditary Neuropathy Foundation Center of Excellence, Hackensack University Medical Center; Founding Chair and Professor, Department of Neurology, Hackensack Meridian School of Medicine at Seton Hall University; Professor Emeritus, Department of Neurology, St Louis University School of Medicine; Editor-in-Chief, Journal of Spinal Cord Medicine
Disclosure: Nothing to disclose.
Chief Editor
Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, Tampa General Hospital, University of South Florida Morsani College of Medicine
Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Ceribell, Eisai, Greenwich, Growhealthy, LivaNova, Neuropace, SK biopharmaceuticals, Sunovion<br/>Serve(d) as a speaker or a member of a speakers bureau for: Eisai, Greenwich, LivaNova, Sunovion<br/>Received research grant from: Cavion, LivaNova, Greenwich, Sunovion, SK biopharmaceuticals, Takeda, UCB.
Additional Contributors
Dianna Quan, MD, Professor of Neurology, Director of Electromyography Laboratory, University of Colorado School of Medicine
Disclosure: Received research grant from: Alnylam; Pfizer; Cytokinetics; Momenta.
Pandolfo M. Friedreich's ataxia: new development and perspectives. Generations: The Official Publication of the National Ataxia Foundation. 1999. 27(1):6-9.
