eMedicine Specialties > Neurology > Movement and Neurodegenerative Diseases

Friedreich Ataxia

Author: Jasvinder Chawla, MBBS, MD, MBA, Associate Professor of Neurology, Director of Neurology Residency Training Program, Director of Clinical Neurophysiology Laboratory, Assistant Director of Neurology Clerkship Program, Department of Neurology, Loyola University Medical Center
Contributor Information and Disclosures

Updated: Nov 6, 2008

Introduction

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.

For related information see eMedicine articles Neuropathy of Friedreich Ataxia in Neurology and Friedreich Ataxia in Orthopedic Surgery.

Pathophysiology

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.

Frequency

International

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

Clinical

History

• 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.
• 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 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.
• 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 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.²

• 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.³
• 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.

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