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Genetics

Friedreich ataxia (FA) is a rare neurodegenerative condition that is inherited in an autosomal-recessive pattern. The disease is characterized by progressive loss of muscle coordination and strength, spasticity, and increasing sensory dysfunction,¹ especially of proprioception and vibration sense in the lower extremities.² Other prominent clinical features of FA include dysarthria, dysphagia, scoliosis, pes cavus, hypertrophic cardiomyopathy, cardiac arrhythmias, diabetes, and loss of vision and hearing.²

Options for Genetic Testing in FA

A definitive diagnosis of FA is established by the detection of biallelic pathogenic variations in the FXN gene, which codes for the mitochondrial protein frataxin. Frataxin is responsible for iron homeostasis within the mitochondria. Deficiency leads to the increased deposition and accumulation of iron in the mitochondria and various organ systems throughout the body, as well as increased oxidative stress.^2,3

Read more about FA etiology

Genetic testing may be done via molecular approaches such as single-gene testing and the use of a multigene panel.²

Single-Gene Testing

A single-gene test result that is positive for FA confirms the presence of an abnormal repeat expansion of the guanine-adenine-adenine (GAA) trinucleotide on intron 1 of FXN. In approximately 96% of cases, this GAA repeat expansion is observed on both alleles.²

If only one abnormal allele with a GAA repeat expansion is detected, the next step in genetic testing is a sequence analysis of FXN to detect any pathogenic inactivating variants that might affect the other allele. In most of the remaining 4% of cases, FA can be detected with this type of genetic analysis.²

If sequence analysis does not identify any inactivating variants, subsequent analysis is undertaken to identify intragenic deletions or duplications. This can be accomplished with quantitative polymerase chain reaction (PCR) testing, long-range PCR testing, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray to identify single-exon deletions or duplications. Individuals with FA very rarely may have one allele with either a large intragenic deletion or a deletion of the entire FXN gene and a second affected allele with a full-penetrance GAA repeat expansion.²

Read more about FA testing

Multigene Panel

This method evaluates the FXN gene as well as other genes of interest that may be contributing to ataxia so that other neurological conditions can be ruled out. A multigene panel is generally recommended later in the diagnostic process to exclude other neurodegenerative conditions and identify individuals who have an atypical presentation of FA. Next-generation sequencing has limitations in identifying expanded repeats and cannot diagnose the majority of individuals with FA. Also, some multigene panels may include genes that are not associated with the condition, hence some laboratories may use custom-designed panel options that include sequence and duplication analysis, deletion, or other non-sequence-based tests.²

Affected genes associated with other conditions causing peripheral neuropathy and ataxia include^2,4:

TDP1, causing spinocerebellar ataxia with axonal neuropathy;
GDAP1, GJB1, HINT1, MFN2, MPZ, PMP22, SH3TC2, and SORD plus 70 other genes that contribute to the development of Charcot-Marie Tooth Syndrome;
TTPA, causing ataxia with vitamin E deficiency;
APTX, causing ataxia with oculomotor apraxia type 1; and
SETX, causing ataxia with oculomotor apraxia type 2.

Read more about FA differential diagnosis

GAA Repeat Expansion Size

Researchers have identified 4 classes of alleles, each with a differently sized GAA repeat expansion in intron 1 of the FXN gene: normal-size alleles, mutable normal (premutation) alleles, full-penetrance alleles, and borderline alleles.²

Normal Alleles

Normal FXN alleles on intron 1 contain between 5 and 33 GAA repeats. Short normal alleles present fewer than 12 repeats, and long normal alleles have between 12 and 33 repeats.

Short normal alleles account for 80% to 85% of these alleles, and the remaining 15% are long normal. The presence of more than 27 repeats is rare in this category.²

Mutable Normal (Premutation) Alleles

These alleles contain between 34 and 65 GAA trinucleotide repeats. They present in fewer than 1% of all FXN alleles.²

Full-Penetrance Alleles

These pathogenic alleles cause FA and contain between 66 and 1300 GAA repeats; most include between 600 and 1200 GAA repeats.²

Read more about FA diagnosis

Borderline Alleles

These alleles contain between 44 and 66 GAA repeats, including the separation between normal and full-penetrance alleles. They contain the shortest GAA repeats associated with disease manifestation. An affected individual with a 56-repeat allele has been reported.^2,5

It is possible that a patient with FA who has borderline alleles will demonstrate incomplete penetrance. This may affect the phenotypic presentation as well as age at onset of the disorder. Borderline alleles account for fewer than 1% of all FXN alleles.²

Molecular genetic testing cannot determine absence or presence of nucleotide interruptions of the GAA tract as the exact line between normal and full-penetrance alleles remains poorly defined. According to clinical studies conducted, borderline alleles cause increased risk for phenotypic expression, although the amount of risk is yet defined.²

Rare Allelic Structures

Rarely, FXN alleles may exhibit an interrupted pattern in which the GAA trinucleotide repeats do not occur in tandem but rather are interrupted by other nucleotides. These alleles are of varying lengths, and different types of nucleotides interrupt the sequence, usually at the 3’ end of the GAA repeat. Interrupted alleles may contribute to a later onset of FA in the atypical subtypes of the condition (late-onset FA and very late-onset FA).²

Read more about FA types

Pattern of Inheritance

FA is genetically inherited in an autosomal-recessive pattern, in which both parents must be carriers of an affected FXN gene.¹ In this case, each child has a 25% chance of inheriting FA, a 25% chance of not being affected, and a 50% chance of becoming an asymptomatic carrier.²

Genetic testing is recommended for all at-risk relatives — including siblings — of individuals with a diagnosis of FA. A known carrier may request prenatal testing, particularly if the partner is also a carrier. Preimplantation genetic testing is also possible.²

Carrier Frequency and Epidemiology

Carrier frequency is 1 in every 60 to 100 people.² FA is the most common inherited ataxia throughout Europe, the United States, the Middle East, North Africa, and the Indian subcontinent. It is most frequently inherited by individuals of Western European descent.^2,6

Read more about FA epidemiology

References

Friedreich ataxia. MedlinePlus. Accessed January 20, 2023.
Bidichandani SI, Delatycki MB. Friedreich ataxia. GeneReviews® [Internet]. Posted December 18, 1998. Updated June 1, 2017. Accessed January 20, 2023.
Delatycki MB, Bidichandani SI. Friedreich ataxia–pathogenesis and implications for therapies. Neurobiol Dis. 2019;132:104606. doi:10.1016/j.nbd.2019.104606
Bird TD. Charcot-Marie-Tooth hereditary neuropathy overview. GeneReviews® [Internet]. Posted September 28, 1998. Revised September 29, 2022. Accessed January 20, 2023.
Tai G, Yiu EM, Corben LA, Delatycki MB. A longitudinal study of the Friedreich Ataxia Impact Scale. J Neurol Sci. 2015;352(1):53-57. doi:10.1016/j.jns.2015.03.024
Friedreich ataxia fact sheet. NIH. National Institute of Neurological Disorders and Stroke. Accessed January 20, 2023.

Reviewed by Debjyoti Talukdar, MD, on 1/30/2023.

Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT

Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT is a freelance medical writer and Doctor of Physical Therapy from Maryland. She has expertise in the therapeutic areas of orthopedics, neurology, chronic pain, gastrointestinal dysfunctions, and rare diseases especially Ehlers Danlos Syndrome.

Friedreich Ataxia (FA)