Topic 11.1 Genetics of Friedreichs 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
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.
11.1 Genetics of Friedreich ataxia
Martin B. Delatycki, Alexandra Durr, Paola Giunti, Grace Yoon and Susan E. Walther
As described in Chapter 1: section 1.2, Friedreich ataxia (FRDA) is an autosomal recessive condition caused by biallelic pathogenic variants in the FXN gene. Approximately 96% of affected individuals are homozygous for an expansion of a GAA trinucleotide repeat in intron 1 of this gene and about 4% are compound heterozygous, with a triplet repeat expansion in one allele and another pathogenic variant in the other (1). Only one family with a homozygous point mutation has been reported (2). In those homozygous for the GAA repeat expansion, there is an inverse correlation between the size of the smaller repeat (GAA1) and disease severity, including age at symptom onset (3-5).
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
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.