AUTHOR INFORMATION

Section 1 of 9

Authored by Jasvinder Chawla, MD, Director, Neurology Residency Training Program, Assistant Professor of Neurology, Department of Neurology, Loyola University of Chicago Medical Center

Jasvinder Chawla, MD, is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and American Clinical Neurophysiology Society

Edited by Dianna Quan, MD, Director, Electromyography Laboratory, Assistant Professor, Department of Neurology, University of Colorado Health Sciences Center; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Florian P Thomas, MD, MA, PhD, DrMed, Associate Chief of Staff, St Louis VA Medical Center; Associate Director, Neurology Residency Program; Professor, Departments of Neurology, Molecular Virology, and Molecular Microbiology and Immunology, Saint Louis University School of Medicine; Matthew J Baker, MD, Consulting Staff, Collier Neurologic Specialists, Naples Community Hospital; and Nicholas Lorenzo, MD, Chief Editor, eMedicine Neurology; Consulting Staff, Neurology Specialists and Consultants

Author's Email:	Jasvinder Chawla, MD
Editor's Email:	Dianna Quan, MD

eMedicine Journal, May 1 2006, VOLUME 7, Number 5

INTRODUCTION

Section 2 of 9

Background: 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. It 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.

Pathophysiology: The major pathophysiologic finding in FA 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 VIII, 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.

Frequency:

• Internationally: FA 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: FA 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).

Race: FA 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 FA 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).

CLINICAL

Section 3 of 9

History:

• Onset of 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.
  
  
  
• 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.



• 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.
  
  
  

Physical: See Staging for a scale used to rate functional disability in patients with FA.

• 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.



• Mental retardation, 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.

Causes: Classic FA 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.

• 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 recent 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.



• 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.



• 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.

DIFFERENTIALS

Section 4 of 9

Other Problems to be Considered:

Refsum disease
Abetalipoproteinemia
Ataxia with isolated vitamin E deficiency
Spinocerebellar ataxia (SCA) types 1, 2, 3
Dentatorubropallidoluysian atrophy
Hereditary motor and sensory neuropathies

WORKUP

Section 5 of 9

Lab Studies:

• Genetic counseling is available for prenatal diagnosis 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.



• No evidence of CSF abnormality exists in patients with FA.

Imaging Studies:

• Magnetic resonance imaging (MRI) is the study of choice in the evaluation of the atrophic changes seen in FA. 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.

Other Tests:

• 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.

Staging:

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

    • Score ___

  • Oculomotor movement score ___/6
  
  
  
• Total ataxia score ___/100

TREATMENT

Section 6 of 9

Medical Care: The results of treating ataxia in 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.

Recently high-dose propanolol 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.

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. 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.
  
  
  
  • 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.
  
  
  

Surgical Care: Apart from surgery for scoliosis and foot deformities that may be helpful in selected cases, no significant surgical treatment is available for FA. Recently, heart transplantation for FA dilated cardiomyopathy has been performed.

Diet: No data exist to suggest that any alteration of diet would affect the onset, progression, or outcome of this disease.

Activity: 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.

FOLLOW-UP

Section 7 of 9

Prognosis:

• The prognosis of FA is poor.



• The disorder is progressive, with a mean duration of 15-20 years.



• Over 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.

TEST QUESTIONS

Section 8 of 9

CME Question 1: Which of the following does not represent a possible complication of Friedreich ataxia?

A: Cardiac arrhythmia
B: Diabetes mellitus
C: Optic atrophy
D: Hypertension
E: Kyphoscoliosis

The correct answer is D: Hypertension is not associated with Friedreich ataxia.

CME Question 2: Which of the following is not a cardinal feature of Friedreich ataxia?

A: Dysarthria
B: Limb ataxia
C: Dementia
D: Extensor plantar responses
E: Gait ataxia

The correct answer is C: Mental retardation, dementia, and psychosis are uncommon, although some degree of cognitive dysfunction may occur.

Pearl Question 1 (T/F): Tendon reflexes are preserved in almost all cases of Friedreich ataxia.

The correct answer is False: Tendon reflexes are absent in almost all cases.

Pearl Question 2 (T/F): The gait ataxia that develops in Friedreich ataxia is both sensory and cerebellar and often is referred to as tabetocerebellar.

The correct answer is True: The ataxia has both sensory and cerebellar components.

Pearl Question 3 (T/F): The major pathophysiologic finding in Friedreich ataxia is a peripheral "dying back process" primarily affecting unmyelinated axons.

The correct answer is False: The “dying back process” affects only large myelinated axons.

Pearl Question 4 (T/F): Onset of Friedreich ataxia is characterized by gait ataxia, typically affecting both lower extremities equally.

The correct answer is True: Occasionally, one arm and leg become ataxic before those of the other side; however, this is not typical.

BIBLIOGRAPHY

Section 9 of 9

• Beltinger A, Riffel B, Stohr M: Somatosensory evoked potentials following median and tibial nerve stimulation in patients with Friedreich's ataxia. Eur Arch Psychiatry Neurol Sci 1987; 236(6): 358-63[Medline].
• Chamberlain S, Koenig M, Richter A: Molecular analysis of the Friedreich's ataxia locus. Adv Neurol 1993; 61: 193-204[Medline].
• Currier RD: A treatment for ataxia [editorial]. Arch Neurol 1995 May; 52(5): 449[Medline].
• Delatycki MB, Williamson R, Forrest SM: Friedreich ataxia: an overview. J Med Genet 2000 Jan; 37(1): 1-8[Medline].
• Durr A, Cossee M, Agid Y, et al: Clinical and genetic abnormalities in patients with Friedreich's ataxia. N Engl J Med 1996 Oct 17; 335(16): 1169-75[Medline].
• Forrest SM, Knight M, Delatycki MB, et al: The correlation of clinical phenotype in Friedreich ataxia with the site of point mutations in the FRDA gene. Neurogenetics 1998 Aug; 1(4): 253-7[Medline].
• Friedman JH: Machado-Joseph disease/spinocerebellar ataxia 3 responsive to buspirone. Mov Disord 1997 Jul; 12(4): 613-4[Medline].
• Harding AE, Zilkha KJ: 'Pseudo-dominant' inheritance in Friedreich's ataxia. J Med Genet 1981; 18: 285-7.
• Hart PE, Lodi R, Rajagopalan B: Antioxidant treatment of patients with Friedreich ataxia: four-year follow-up. Arch Neurol 2005 Apr; 62(4): 621-6[Medline].
• Jitpimolmard S, Small J, King RH: The sensory neuropathy of Friedreich's ataxia: an autopsy study of a case with prolonged survival. Acta Neuropathol (Berl) 1993; 86(1): 29-35[Medline].
• Johnson WG: Friedreich ataxia. Clin Neurosci 1995; 3(1): 33-8[Medline].
• Koeppen AH: The hereditary ataxias. J Neuropathol Exp Neurol 1998 Jun; 57(6): 531-43[Medline].
• Kosutic J, Zamurovic D: High-dose beta-blocker hypertrophic cardiomyopathy therapy in a patient with Friedreich ataxia. Pediatr Cardiol 2005 Sep-Oct; 26(5): 727-30[Medline].
• Lynch DR, Lech G, Farmer JM: Near infrared muscle spectroscopy in patients with Friedreich's ataxia. Muscle Nerve 2002 May; 25(5): 664-73[Medline].
• Mello KA, Abbott BP: Effect of sulfamethoxazole and trimethoprim on neurologic dysfunction in a patient with Joseph's disease . Arch Neurol 1988 Feb; 45(2): 210-3[Medline].
• Pandolfo M: Friedreich's ataxia: new development and perspectives. Generations: The Official Publication of the National Ataxia Foundation 1999; 27(1): 6-9.
• Sedlak TL, Chandavimol M, Straatman L: Cardiac transplantation: a temporary solution for Friedreich's ataxia-induced dilated cardiomyopathy. J Heart Lung Transplant 2004 Nov; 23(11): 1304-6[Medline].
• Subramony SH, McDaniel O, Vedanarayanan VV: Very late-onset Friedreich's ataxia. Mov Disord 1999; 14(5): 904.
• Trouillas P, Takayanagi T, Hallett M: International Cooperative Ataxia Rating Scale for pharmacological assessment of the cerebellar syndrome. The Ataxia Neuropharmacology Committee of the World Federation of Neurology. J Neurol Sci 1997 Feb 12; 145(2): 205-11[Medline].
• Trouillas P, Serratrice G, Laplane D: Levorotatory form of 5-hydroxytryptophan in Friedreich's ataxia. Results of a double-blind drug-placebo cooperative study. Arch Neurol 1995 May; 52(5): 456-60[Medline].
• Voncken M, Ioannou P, Delatycki MB: Friedreich ataxia-update on pathogenesis and possible therapies. Neurogenetics 2004 Feb; 5(1): 1-8[Medline].
• Wills AJ, Marsden CD: Fifty Neurologic Cases from the National Hospital. 1999.
• Zouari M, Feki M, Ben Hamida C: Electrophysiology and nerve biopsy: comparative study in Friedreich's ataxia and Friedreich's ataxia phenotype with vitamin E deficiency. Neuromuscul Disord 1998 Aug; 8(6): 416-25[Medline].

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