Topic 11.5. Management of questions related to GAA repeat size in Friedreich ataxia

Return to Chapter Overview Page

Full Chapter PDF

Full TextRecommendationsLay SummaryAuthorsReferencesMethodology & Date

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

11.5 Management of questions related to GAA repeat size in Friedreich ataxia

Disclaimer / Intended Use / Funding

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.


11.5 Management of questions related to GAA repeat size in Friedreich ataxia

Martin B. Delatycki, Alexandra Durr, Paola Giunti, Grace Yoon and Susan E. Walther

Clinicians are often asked by affected individuals and/or parents for the size of GAA repeats that have been identified as the cause of that person’s FRDA. This information should be supplied, but an explanation of the significance of the repeat sizes should be provided. An important point that should be discussed is that whilst larger GAA1 repeat sizes are, on average, associated with a more severe phenotype, at an individual level this information cannot be used to accurately predict phenotype or prognosis.


Jump to Recommendations

Jump to Lay summary

Please note: Recommendations 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. Best Practice Statements are commonly accepted practices, as such formal rating of the quality of evidence by the GRADE process is not indicated. In addition if recommendations from the 2014 guidelines were deemed still relevant, although unable to undergo the scrutiny from a GRADE framework, they were also included as best practice statements.
Using GAA repeat size for counseling

QUESTION: Should (where available) GAA repeat size used for counseling versus not using GAA repeat size for counseling be used for pre-symptomatic testing of individuals at risk of Friedreich ataxia?
[sg_popup id=”587″ event=”click”][/sg_popup]STRENGTH OF RECOMMENDATION:
[sg_popup id=”658″ event=”click”][/sg_popup]LEVEL OF EVIDENCE: ⨁◯◯◯

RECOMMENDATION: Although not all testing laboratories report FXN GAA repeat sizes, we suggest that when repeat sizes are reported for pre-symptomatic testing for Friedreich ataxia and the individual is homozygous for FXN GAA expansions, this information is provided to the tested individual upon request. Where GAA repeat sizes are provided to the tested individual we suggest that the individual is informed that there is a negative correlation between GAA1 size and age at onset, but the range of age of onset for any GAA1 size is broad and the age of onset for that person cannot be predicted with certainty.

JUSTIFICATION: There are data that clearly demonstrate an inverse correlation between the smaller GAA repeat size (GAA1) and age of symptom onset in Friedreich ataxia, explaining approximately 40% of the variation in age of onset (3-5). General advice can be given based on these data, but a making a precise estimate of age of onset based on GAA1 repeat size is not possible.

SUBGROUP CONSIDERATION: This recommendation is for at-risk individuals undergoing pre-symptomatic genetic testing for Friedreich ataxia.

Evidence to Recommendation Table PDF

Lay summary of clinical recommendation for managing questions related to GAA repeat size in Friedreich ataxia


Why this recommendation?

Looking at the averages over a large number of people with Friedreich ataxia, there is a relationship between the number of repeats on the smaller of the two FXN genes (GAA1) and the age at which a person first shows symptoms of Friedreich ataxia, as well as the occurrence of some features of the condition including cardiomyopathy and diabetes. That is, the bigger GAA1 is (the larger the number of repeats), the earlier symptoms will occur, on average.

We suggest that, when requested, individuals with Friedreich ataxia are provided with information about their repeat sizes. They should also be informed that it is not possible to make a precise estimate about when symptoms will appear and what other features will be present based on the GAA1 repeat size.

What does this mean for you as a person living with Friedreich ataxia or caring for someone living with Friedreich ataxia?

It might be important for you to speak with your healthcare professional about obtaining information about GAA repeat sizes and what it means for you or your child.

Who is this recommendation specifically for?

This recommendation is specifically for individuals with Friedreich ataxia and parents or guardians of children with Friedreich ataxia.

Martin B. Delatycki, MBBS, FRACP, PhD
Co-Director, Bruce Lefroy Centre, Murdoch Children’s Research Institute, Parkville, Victoria, Australia Email: martin.delatycki@vcgs.org.au

Alexandra Durr, MD, PhD
Professor of Neurogenetics, Sorbonne Université, Paris, France
Email:  alexandra.durr@icm-institute.org

Paola Giunti, MD, PhD
Professor, Queen Square Institute of Neurology, UCL, London, UK
Email: p.giunti@ucl.ac.uk

Susan E. Walther, MS, CGC
Genetic Counselor, Clinic for Special Children, Strasburg, Pennsylvania, USA

Grace Yoon, MD
Clinical Geneticist, The Hospital for Sick Children, Toronto, Ontario, Canada
Email: grace.yoon@utoronto.ca

1. 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.

2. 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.

3. Delatycki MB, Paris DB, Gardner RJ, Nicholson GA, Nassif N, Storey E, et al. Clinical and genetic study of Friedreich ataxia in an Australian population. Am J Med Genet. 1999;87(2):168-74.

4. Dürr A, Cossee M, Agid Y, Campuzano V, Mignard C, Penet C, et al. Clinical and genetic abnormalities in patients with Friedreich’s ataxia. N Engl J Med. 1996;335(16):1169-75.

5. Filla A, De Michele G, Cavalcanti F, Pianese L, Monticelli A, Campanella G, et al. The relationship between trinucleotide (GAA) repeat length and clinical features in Friedreich ataxia. Am J Hum Genet. 1996;59(3):554-60.

6. Tsou AY, Paulsen EK, Lagedrost SJ, Perlman SL, Mathews KD, Wilmot GR, et al. Mortality in Friedreich ataxia. J Neurol Sci. 2011;307:46-9.

7. Arbour L, Canadian Paediatric Society, Bioethics Committee. Guidelines for genetic testing of healthy children. Paediatr Child Health. 2003;8(1):42-52.

8. Borry P, Evers-Kiebooms G, Cornel MC, Clarke A, Dierickx K, Public, et al. Genetic testing in asymptomatic minors: background considerations towards ESHG Recommendations. Eur J Hum Genet. 2009;17(6):711-9.

9. Borry P, Fryns JP, Schotsmans P, Dierickx K. Carrier testing in minors: a systematic review of guidelines and position papers. Eur J Hum Genet. 2006;14(2):133-8.

10. Botkin JR, Belmont JW, Berg JS, Berkman BE, Bombard Y, Holm IA, et al. Points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents. Am J Hum Genet. 2015;97(1):6-21.

11. Vears DF, Ayres S, Boyle J, Mansour J, Newson AJ, Education E, et al. Human Genetics Society of Australasia position statement: Predictive and presymptomatic genetic testing in adults and children. Twin Res Hum Genet. 2020;23(3):184-9.

12. Borry P, Stultiens L, Goffin T, Nys H, Dierickx K. Minors and informed consent in carrier testing: a survey of European clinical geneticists. J Med Ethics. 2008;34(5):370-4.

13. Ross LF. Carrier detection in childhood: a need for policy reform. Genome Med. 2010;2(4):25.

14. Borry P, Goffin T, Nys H, Dierickx K. Attitudes regarding predictive genetic testing in minors: a survey of European clinical geneticists. Am J Med Genet C Semin Med Genet. 2008;148C(1):78-83.

15. Mand C, Gillam L, Duncan RE, Delatycki MB. “It was the missing piece”: adolescent experiences of predictive genetic testing for adult-onset conditions. Genet Med. 2013;15(8):643-9.

16. Ackerman MJ, Priori SG, Willems S, Berul C, Brugada R, Calkins H, et al. HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies this document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA). Heart Rhythm. 2011;8(8):1308-39.

17. Hershberger RE, Lindenfeld J, Mestroni L, Seidman CE, Taylor MR, Towbin JA, et al. Genetic evaluation of cardiomyopathy–a Heart Failure Society of America practice guideline. J Card Fail. 2009;15(2):83-97.

18. Lowe GC, Corben LA, Duncan RE, Yoon G, Delatycki MB. “Both sides of the wheelchair”: The views of individuals with, and parents of individuals with Friedreich ataxia regarding pre-symptomatic testing of minors. J Genet Couns. 2015;24(5):732-43.

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.