Topic 1.3. Genotype phenotype correlations in Friedreich ataxia
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.
Topic Contents
1.3 Genotype phenotype correlations in Friedreich ataxia
1.3.1 Phenotype for individuals homozygous for GAA triplet repeat expansion
1.3.2 Compound heterozygous phenotype
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Disclaimer
The Clinical Management Guidelines for Friedreich ataxia (‘Guidelines’) are protected by copyright owned by the authors who contributed to their development or said authors’ assignees.
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.
Guidelines users must seek out the most recent information that might supersede the diagnostic and treatment recommendations contained within these Guidelines and consider local variations in clinical settings, funding and resources that may impact on the implementation of the recommendations set out in these Guidelines.
The authors of these Guidelines disclaim all liability for the accuracy or completeness of the Guidelines, and disclaim all warranties, express or implied to their incorrect use.
Intended Use
These Guidelines are made available as general information only and do not constitute medical advice. These Guidelines are intended to assist qualified healthcare professionals make informed treatment decisions about the care of individuals with Friedreich ataxia. They are not intended as a sole source of guidance in managing issues related to Friedreich ataxia. Rather, they are designed to assist clinicians by providing an evidence-based framework for decision-making.
These Guidelines are not intended to replace clinical judgment and other approaches to diagnosing and managing problems associated with Friedreich ataxia which may be appropriate in specific circumstances. Ultimately, healthcare professionals must make their own treatment decisions on a case-by-case basis, after consultation with their patients, using their clinical judgment, knowledge and expertise.
Guidelines users must not edit or modify the Guidelines in any way – including removing any branding, acknowledgement, authorship or copyright notice.
Funding
The authors of this document gratefully acknowledge the support of the Friedreich Ataxia Research Alliance (FARA). The views and opinions expressed in the Guidelines are solely those of the authors and do not necessarily reflect the official policy or position of FARA.
1.3 Genotype phenotype correlations in Friedreich ataxia
Ariane Veilleux Carpentier and Antoine Duquette
1.3.1 Phenotype for individuals homozygous for GAA triplet repeat expansion
In individuals with FRDA who are homozygous for a GAA triplet repeat expansion, the smaller allele size (GAA1) partially predicts disease evolution, phenotype, and prognosis, while the larger allele (GAA2) expansion is a weaker predictor of clinical variation (79).
Age at onset
Age at onset of symptom depends on the size of the expansions of both alleles but mainly correlates with the length of GAA1 (8, 11, 15, 53, 79, 80). Both GAA1 size and age at onset influence the rate of disease progression, the duration from onset to wheelchair dependency, and the age of loss of ambulation (11, 53, 79). Individuals with late-onset FRDA or very-late-onset FRDA have smaller GAA1 expansions than typical FRDA and a milder disease progression (73). Notably, smaller GAA1 expansion size may be associated with adult-onset spastic ataxia (81) or with spasticity and little ataxia (13). While GAA1 triplet expansions can account for 40% of the variability in age at onset and age at wheelchair dependency, GAA2 size is possibly responsible for 10% (53, 79).
No correlation has been found between GAA1 repeat length and age at onset of symptoms for individuals with non-neurological symptoms at onset (isolated cardiomyopathy or scoliosis) (51). The somatic instability of GAA repeats differs between tissues and may explain the lack of correlation between some symptoms, such as non-neurological symptoms, and GAA1 length (82).
Clinical features
Some clinical features of FRDA, such as dysarthria, sphincter disturbance, hearing loss, and decreased visual acuity appear to be linked mostly to disease duration (11, 79). GAA1 size correlates with the severity of proprioceptive impairment (23, 83-85) and pes cavus, scoliosis, and areflexia are more frequent with longer GAA1 expansions (11, 79). Both GAA1 and GAA2 repeat lengths correlate with dysphagia and lower-limb weakness (79).
Cardiomyopathy is the most frequent cause of mortality in FRDA. The increase in heart disease prevalence in association with higher repeat lengths became obvious when the first genotype-phenotype correlations were established (11, 53, 86). Evidence also suggests that left ventricular hypertrophy is significantly more prevalent in individuals with a GAA1 repeat size above 770 (84). More recently, another study showed that those with the worst cardiac evolution carry longer GAA repeats (23).
Diabetes mellitus is another important systemic non-neurological manifestation of FRDA, but the evidence regarding a correlation with repeat length is conflicting (11, 15, 53). Intriguingly, aberrant glucose metabolism has been shown to be associated with longer GAA1 repeat length (87).
1.3.2 Compound heterozygous phenotype
The phenotype of compound heterozygous individuals depends on the type of mutation on the non-expanded allele. Several mutations result in absent frataxin or loss of function and are associated with a typical FRDA phenotype (88). Individuals with missense mutations p.G130V and p.D122Y have an atypical phenotype with retained reflexes and without dysarthria (88). Null mutations result in an earlier age of onset and an increased risk of developing diabetes mellitus when compared to homozygous expansions (26). However, compound heterozygotes have a lower prevalence of cardiomyopathy (26).
Antoine Duquette, MD, MSc, FRCP(C)
Associate Clinical Professor, Centre hospitalier de l’Université de Montréal, Montréal, Québec, Canada
Email: antoine.duquette@umontreal.ca
Ariane Veilleux Carpentier, MD
Neurology Resident, Université de Montréal, Montréal, Québec, Canada
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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.