Friedreich’s ataxia prognosis

Last updated Nov. 6, 2024, by Lindsey Shapiro, PhD
Medically reviewed by David Lynch, MD, PhD

In its typical course, Friedreich’s ataxia (FA) emerges in childhood or adolescence, slowly progresses to wheelchair dependency in the next 10-20 years, and is associated with early mortality, usually in the fourth or fifth decade of life. Still, the rate of progression is variable and depends on several factors.

Advances in FA management have improved the long-term outlook for FA patients. Prompt genetic testing and initiation of appropriate treatments to manage FA and its comorbidities can help to slow disease progression and improve prognosis.

Factors influencing disease progression

FA is a slowly progressing disease, with most patients losing ambulation around 15 years after symptom onset, but how quickly disability accumulates depends largely on genetic factors. An earlier diagnosis and proper management after symptom onset can also influence outcomes.

GAA repeat size and age at onset

About 96% of FA patients are homozygous for GAA repeat expansions in exon 1 of the FXN gene. GAA repeat length in the smaller allele (GAA1) is a major determinant of FA disease progression.

A greater number of GAA repeats is associated with earlier age of neurological symptom onset and faster progression to wheelchair dependency. Smaller repeat sizes are associated with late-onset disease (after age 25) or very late-onset disease (after age 40), as well as with a milder disease progression.

GAA1 repeat size may account for about 40% of variability in these two factors — age at onset and age at wheelchair dependency — while the size of the larger allele (GAA2) may account for up to 10%.

Some non-neurological features of FA, including cardiomyopathy, left ventricular hypertrophy, and orthopedic problems, such as scoliosis and pes cavus, are more common in patients with longer GAA1 expansions. These can contribute to a more severe disease course.

Disease progression is variable in compound heterozygous patients with a GAA repeat expansion in one FXN allele and another deleterious mutation in the other, and may be influenced by both the length of the GAA repeat and the type of pathogenic variant on the other allele.

Null mutations are more severe with an earlier age at disease onset and faster progression, whereas others are associated with an atypical and milder disease. Cardiomyopathy is less common in compound heterozygotes.

Early diagnosis and treatment

Reaching the right diagnosis sooner can enable the start of disease-modifying therapies with the capability of slowing disease progression and potentially extending survival. This will become even more critical as additional FA therapies emerge.

A prompt diagnosis also enables the identification and management of non-neurological manifestations that contribute to a more severe disease course, including cardiac issues, diabetes, or orthopedic problems.

Long-term outlook and prognostic indicators

Most FA patients become wheelchair-bound by the age of 45, and life expectancy is shortened to an average of 40-50 years, with cardiac disease being the leading cause of premature death. However, some patients may live into their 70s and beyond, with prognosis varying substantially depending on age at disease onset and disease severity.

Factors usually associated with worse survival in FA include:

• longer GAA repeats
• younger age at onset
• diabetes
• cardiac disease — the leading cause of mortality in FA, estimated to account for roughly 60% of premature deaths.

As disease-modifying therapies and better management of FA comorbidities emerge, outcomes for FA patients may improve. Reaching a prompt and accurate diagnosis can enable earlier initiation of necessary treatments, possibly slowing the loss of ambulation, minimizing the impact of comorbidities, and prolonging survival.