Friedreich’s ataxia genetics and inheritance patterns

Last updated Aug. 8, 2024, by Lindsey Shapiro, PhD
Medically reviewed by David Lynch, MD, PhD

Friedreich’s ataxia (FA) is the most common hereditary cause of ataxia, resulting from autosomal recessive mutations in the FXN gene. Genetic testing to uncover FXN mutations is the gold standard for distinguishing FA from differential diagnoses and definitively establishing its presence.

Genetics and inheritance patterns

FA is caused by biallelic pathogenic variants in the FXN gene on chromosome 9 that result in substantially reduced expression of the mitochondrial protein frataxin and subsequent disruptions in cellular energy production, particularly in cells such as neurons and cardiomyocytes that have high energetic demands.

The rare condition is inherited in an autosomal recessive manner. Heterozygous FXN mutation carriers are asymptomatic despite having about 50% of normal FXN expression. It is uncommon for FA patients to present with a family history of the disease, as both parents are asymptomatic carriers in the majority of cases. A family history is more likely with large sibships or in consanguineous populations.

Linkage disequilibrium analyses indicate that GAA trinucleotide repeat expansions in FXN — found in at least one allele of essentially all affected patients — arose from a recent common founder. As such, FA is almost exclusively seen in people of Indo-European descent, with a carrier frequency of about 1%.

Types of mutations

To date, virtually all genotyped FA patients exhibit a GAA trinucleotide repeat expansion in at least one FXN allele, with the vast majority having these expansions in both alleles. A minority of patients are compound heterozygous, with a GAA repeat expansion in one allele and another deleterious mutation in the other.

GAA trinucleotide repeat expansions

GAA trinucleotide repeat expansions in intron 1 of FXN result in transcriptional silencing of FXN and reduced expression of frataxin. Homozygous GAA repeat expansions are the cause of FA for more than 95% of patients.

FXN alleles in the general population contain fewer than 36 GAA repeats, with most being 8-12 triplets in length. In FA alleles, repeats range from 100 to 1,500 triplets, with most patients in the 600-1,200 range.

GAA repeats are somatically and intergenerationally unstable, with expansions or contractions possible and with variation in different tissues. Alleles with more than 36 but fewer than 100 triplets rarely cause clinical manifestations of FA, but could theoretically expand somatically and cause mild or later-onset disease. Repeat expansions are usually found in tandem, but may more rarely be interrupted by other nucleotide sequences.

Compound heterozygotes

A minority of FA patients (around 4%) are compound heterozygotes, carrying an expanded GAA repeat sequence in one FXN allele and another deleterious mutation on the other.

These mutations may include missense, nonsense, insertions, deletions, or splice site variants. They are found throughout the FXN gene and have varying effects on frataxin production and stability.

• Null mutations, including nonsense variants, affect FXN transcription similarly to homozygous repeat expansions. Little to no frataxin is produced.
• Frameshift or missense variants may affect FXN transcription and cause frataxin deficiency or result in dysfunctional or unstable frataxin.

Bi-allelic point mutations without GAA repeat expansion have been described in a case report.

Influence of genetics on clinical presentation

For patients with homozygous GAA repeat expansions, there is an inverse correlation between GAA repeat size, particularly on the smaller allele, and disease severity. Patients with more than 500 GAA repeats on both alleles typically have around 5%-10% residual frataxin transcript, while patients with at least one expanded allele containing fewer than 500 triplets have higher residual frataxin transcript levels (10%-20%).

Longer GAA repeats and lower frataxin expression is associated with an earlier age of disease onset, faster progressing neurological disability, and a greater burden of non-neurological comorbidities such as cardiomyopathy, orthopedic issues, and diabetes. Interrupted GAA repeat expansions or somatically unstable borderline alleles may be associated with late-onset or more slowly progressing FA.

The phenotype of compound heterozygotes is variable and may depend on how the mutation influences FXN transcription, as well as the size of the expanded GAA repeat on the other allele.

Null mutations are associated with a similar or more severe disease course as homozygous repeat expansions, whereas mutations that allow some residual frataxin function have been linked to a later disease onset and relative preservation of neurological functions. Compound heterozygotes in general are found to be at a lower risk of cardiomyopathy.

Genetic testing and counseling for family members

Genetic testing for FXN mutations is the definitive way to reach a diagnosis in a patient suspected for FA. Commercial testing panels are available for sizing GAA repeat expansions. Point mutations present in a second allele can be identified through sequencing after an expansion is found on the first allele.

At the time of conception, siblings of an FA patient have a 25% chance of also being affected and a 50% chance of being an asymptomatic carrier. As a person ages and becomes older than their FA-affected sibling was at the time of symptom onset and is still asymptomatic, the risk of having FA decreases.

Families should be advised of these risks. Genetic testing or other physical evaluations for FA or carrier status in siblings of an affected patient may be indicated depending on the family’s preference. If a sibling is identified as having FA presymptomatically, they should be referred to a clinical geneticist.

FA patients and known carriers should also be advised of the risks that their future offspring will carry a pathogenic mutation. Family planning options including prenatal diagnosis, preimplantation genetic testing, adoption, or use of donor gametes/embryos may be discussed.
 

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