Topic 12.1. Overview of mutations other than the FXN intron 1 GAA expansion
This chapter of the Clinical Management Guidelines for Friedreich Ataxia and the recommendations and best practice statements contained herein were endorsed by the authors and the Friedreich Ataxia Guidelines Panel in 2022.
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12.1 Overview of mutations other than the FXN intron 1 GAA expansion
Martin B. Delatycki
While approximately 96% of Friedreich ataxia (FRDA) is due to homozygosity for FXN intron 1 GAA expansions, about 4% is due to compound heterozygosity for a GAA expansion on one FXN allele and a point mutation, small insertion and/or deletion or large deletion on the other (1, 2). Here, this latter group will be called “FXN compound heterozygosity”.
A large study compared the phenotype associated with compound heterozygosity in 111 individuals with FRDA with clinical features of 131 individuals with homozygous GAA repeat expansions (3). Mutations were examined using structural modelling, stability analyses and systematic literature review. Based on this, the FXN compound heterozygosity group was divided into three groups: (i) null mutation (no frataxin produced); (ii) moderate/strong impact on FXN function; (iii) minimal impact on FXN function. The group with a null mutation had a significantly earlier average age of onset and were more likely to have diabetes mellitus than people homozygous for a GAA expansion (3). However, individuals homozygous for a GAA expansion were more likely to have cardiomyopathy than those in the three compound heterozygosity groups (3).
The phenotype of individuals with FXN compound heterozygosity is very variable in part due to the non-GAA repeat mutation. For some, the phenotype is indistinguishable from “classical” FRDA due to homozygosity for GAA expansions and the management issues are identical. Other point mutations or deletions can lead to a milder, more severe or somewhat different phenotype to typical FRDA and this may mean that there are different management issues. Drawing conclusions about the impact of non-GAA repeat mutations is difficult because:
(i) only one or few individuals with the mutation are reported and where there is more than one individual reported with the mutation, they are often from the same family.
(ii) there is limited or no clinical data available for many of the mutations.
(iii) the size of the expanded FXN GAA repeat on the other allele is likely to be important in the phenotype.
The only mutation that is relatively common for which sufficient clinical data is available to make specific comment about phenotype is p.Gly130Val. The following characteristics are associated with p.Gly130Val:
(i) Lower limb spasticity is more prominent than in typical FRDA.
(ii) Upper limbs are affected to a far lesser extent than lower limbs.
(iii) Cardiomyopathy is less commonly seen than in typical FRDA.
(iv) Dysarthria is not reported.
Three siblings from a family where there is parental consanguinity have homozygosity for p.Arg165Cys, making them the first individuals to be reported with bi-allelic point mutations and no GAA expansion (4). They presented with a phenotype akin to Charcot Marie Tooth disease with optic atrophy resulting in diminished vision and dysarthria. One of the sibs was reported to have a normal echocardiogram.
Co-Director, Bruce Lefroy Centre, Murdoch Children’s Research Institute, Parkville, Victoria, Australia
Email: martin.delatycki@vcgs.org.au
2. Cossée M, Dürr A, Schmitt M, Dahl N, Trouillas P, Allinson P, et al. Friedreich’s ataxia: point mutations and clinical presentation of compound heterozygotes. Annals of Neurology. 1999;45(2):200-6.
3. Galea CA, Huq A, Lockhart PJ, Tai G, Corben LA, Yiu EM, et al. Compound heterozygous FXN mutations and clinical outcome in Friedreich ataxia. Ann Neurol. 2016;79(3):485-95.
4. Candayan A, Yunisova G, Cakar A, Durmus H, Basak AN, Parman Y, et al. The first biallelic missense mutation in the FXN gene in a consanguineous Turkish family with Charcot-Marie-Tooth-like phenotype. Neurogenetics. 2020;21(1):73-8.
These Guidelines are systematically developed evidence statements incorporating data from a comprehensive literature review of the most recent studies available (up to the Guidelines submission date) and reviewed according to the Grading of Recommendations, Assessment Development and Evaluations (GRADE) framework © The Grade Working Group.
This chapter of the Clinical Management Guidelines for Friedreich Ataxia and the recommendations and best practice statements contained herein were endorsed by the authors and the Friedreich Ataxia Guidelines Panel in 2022.
It is our expectation that going forward individual topics can be updated in real-time in response to new evidence versus a re-evaluation and update of all topics simultaneously.