Background

Friedreich ataxia (FA) is the prototype of all forms of progressive ataxia, and it accounts for approximately one half of all cases of hereditary ataxia. FA is an autosomal recessive spinocerebellar disorder that has a slow but relentlessly degenerative course.^[1]

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Pathophysiology

FA is caused by mutations in the FXN gene, which provides instructions for making a protein called frataxin. Certain nerve and muscle cells cannot function properly with a shortage of frataxin, leading to the signs and symptoms of FA. Approximately 98% of mutant alleles have an expansion of a gossypol acetic acid (GAA) trinucleotide repeat in intron 1 of the gene, leading to reduced levels of frataxin.^{[2, 3, 4, 5, 6, 7, 8]}

The current hypothesis is that frataxin is a mitochondrial protein important for normal production of cellular energy. A defect in its action may result in abnormal accumulation of iron in mitochondria, leading to excess production of free radicals, which then results in cellular damage and death.^[9] The neural pathways affected in FA are those associated with large neuronal cell bodies and extensive axon elongations, which are the long tracts of the dorsal columns, pyramidal system, and peripheral nerves.

Epidemiology

Frequency

FA occurs in 1-2 per 100,000 of the US population. Its international prevalence is also 1-2 per 100,000; prevalence appears to be slightly higher in Quebec, Canada.

Symptoms may begin in infancy or in the third decade; however, symptoms usually begin when an individual is aged 8-15 years. Men and women are affected equally. All races are affected.

Mortality/Morbidity

The rate of progression of Friedreich ataxia (FA) is variable, but more than 95% of individuals with FA cannot ambulate by the time they are aged 45 years, and on average, patients lose the ability to walk 15 years following onset of symptoms. Age at death is rather variable. Reported mean ages have been in the mid fourth decade of life, although survival into the sixth and seventh decades of life has been documented. Death tends to be earlier if heart disease and diabetes are associated.

Clinical Presentation