Friedreich Ataxia

Updated: Jul 14, 2016
  • Author: Jasvinder Chawla, MD, MBA; Chief Editor: Selim R Benbadis, MD  more...
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Overview

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. 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.

 

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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.

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Epidemiology

Frequency

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]

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