Topic 11.3. Management of testing for minor siblings of a person with 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

11.3 Management of testing for minor siblings of a person with Friedreich ataxia
11.3.1 Carrier testing for minor siblings
11.3.2 Pre-symptomatic testing for minor siblings
11.3.3 Other examinations for at-risk minor siblings

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.


11.3 Management of testing for minor siblings of a person with Friedreich ataxia

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

The issues related to testing minor siblings of a person with FRDA differ depending on whether the sibling is a mature or immature minor. A mature minor is defined as a person younger than 18 years of age who has the capacity to make healthcare decisions whilst an immature minor does not. There is no specific age at which an immature minor becomes a mature minor. The process of becoming a mature minor is a gradual one. Assessment of whether a minor can make a particular healthcare decision needs to be judged on a case-by-case basis.

11.3.1 Carrier testing for minor siblings

Carrier testing of children for autosomal recessive conditions for the purpose of reproductive planning is not generally recommended (7-11). As discussed below, because of the variable age of onset of FRDA, there is always a possibility that genetic testing of the FXN gene will identify that the person will go on to develop FRDA (in this case it would be considered pre-symptomatic genetic testing). The basic principle which guides this general approach to carrier testing in minors is the child’s right to self-determination, autonomy, and privacy, and concerns regarding a child’s ability to provide voluntary informed consent to genetic testing. A systematic review of 14 guidelines/practice statements from 24 different groups concluded that carrier testing should not be performed in children, and that testing should be deferred until the child is able to provide informed consent (9). There are cases where exceptions to this general rule may be in the best interest of the minor and his or her family (12, 13), as in the case of an emancipated minor (a minor who is legally independent of their parents) or adolescent. A large survey of clinical geneticists identified cognitive, emotional and sexual maturity of the minor and parental support as crucial factors in deciding whether to disclose genetic risk to children or to allow adolescents to request carrier testing (14).

In general, carrier testing in children for FRDA for the sole purpose of reproductive planning should be deferred until the child is able to fully participate in the decision to undergo genetic testing. In the case of an emancipated minor or mature, well-informed adolescent, the decision to undergo genetic testing should always be preceded by appropriate genetic counseling with the decision to test or not being made on a case-by-case basis. The potential psychological and social risks should be discussed, particularly the potential to identify future risk of FRDA for the adolescent, and they should be encouraged to involve their parents in the decision process. There is little data to show the extent of benefits and harms associated with pre-symptomatic testing in minors, but a study of nine individuals who underwent pre-symptomatic testing for adult-onset disorders (six gene positive) did not identify adverse outcomes from knowing their genetic status (15).

11.3.2 Pre-symptomatic testing for minor siblings

Genetic testing of an at-risk individual who has no clinical symptoms of the disease is considered pre-symptomatic testing. As FRDA is characterized by a wide range in age of onset and variable intergenerational instability of the GAA expansion, a sibling of an individual with FRDA may have inherited two FXN pathogenic variants but not yet developed symptoms at the time of clinical evaluation. There is considerable difference of opinion within the genetics community regarding if or when to offer pre-symptomatic genetic testing for childhood or adolescent-onset disorders that do not have definitive medical therapies or preventive measures, as is the case for FRDA. A survey of 177 clinical geneticists revealed the majority was unwilling to provide a pre-symptomatic genetic test for children in this specific situation, although for adolescents they were significantly more willing to do so if the request was made together with the adolescent’s parents (14).

A review of current guidelines on pre-symptomatic testing from four major genetics societies revealed general consensus and acknowledgement that each situation is unique and should be managed on a case-by-case basis (7, 8, 10, 11). All four societies maintain that the primary justification for pre-symptomatic genetic testing in children and adolescents should be timely medical benefit or substantial psychosocial benefit in the absence of definitive medical benefit. Other general recommendations include the need for detailed and careful genetic counseling for the parents and child, commensurate on maturity, prior to the initiation of any pre-symptomatic genetic testing. The genetic counseling session should include exploration of the psychological and social risks and benefits of early genetic diagnosis from both the parents’ and child’s perspectives. When possible, the child should be involved in the decision-making process and documentation of their assent should take place.

There are currently no published guidelines or studies which specifically address the issue of pre-symptomatic genetic testing for FRDA. The subcommittee that produced these current guidelines did not reach consensus on the issue of pre-symptomatic testing of minors. Reasons for not offering pre-symptomatic genetic testing for FRDA included the need to respect the minor’s autonomy and freedom to choose whether or not to undergo genetic testing when they reach adulthood, and the lack of effective treatments to slow progression of FRDA at this time. Reasons for offering pre-symptomatic genetic testing for FRDA included the potential benefit of surveillance for cardiac manifestations of FRDA (i.e., cardiomyopathy), the potential for the family to plan for the future needs of their child, and the potential for the affected minor to participate in clinical trials of therapeutic agents at an early stage of the disease course. There are currently no studies which specifically address early treatment of cardiac manifestations in pre-symptomatic FRDA. However, clinical screening protocols and genetic testing (with appropriate genetic counseling) for family members at risk of inherited forms of cardiomyopathy, which include FRDA, is standard of care (16, 17). Given the difficulty in reaching consensus, the subcommittee recommends a multidisciplinary approach to pre-symptomatic genetic testing in children for FRDA.

A qualitative study aimed to ascertain the opinions of individuals with FRDA (n=10) and parents (n=10) regarding pre-symptomatic testing of minors via semi-structured interview (18). Four findings emerged. First, a number of arguments for and against testing minors were identified. Second, strong support existed from parents about the parental right to test their at-risk immature children, but individuals with FRDA were of mixed opinions. Third, both individuals with FRDA and parents felt it was not the clinician’s role to make the final decision about whether testing occurs. Finally, a specific issue of concern was what and when to tell at-risk children about the test result.

11.3.3 Other examinations for at-risk minor siblings

If siblings do not undergo genetic testing other tests may be offered to ensure that if symptoms develop, they are recognized and treated. Siblings can be offered a physical examination, but they need to be informed that signs of FRDA may be found. Cardiac disease is common in FRDA and echocardiography and electrocardiogram can be offered to look for cardiac signs while the sibling can avoid a definitive diagnosis of FRDA. If no signs of FRDA are identified through physical examination or cardiac testing, this can provide reassurance to the at-risk sibling and parents but cannot exclude the possibility of biallelic FXN pathogenic variants being present.


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.
Echocardiography for at-risk minors

QUESTION: Should offering echocardiograms versus not offering echocardiograms be used for untested siblings (minors) of a person with 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: If an asymptomatic at-risk minor sibling of a person with Friedreich ataxia has not had genetic testing to confirm whether or not they have the genetic predisposition to Friedreich ataxia, we suggest they should be offered echocardiography to assess if they have cardiac morbidity that may require treatment. The minor (when of maturity to understand) and their parents should be made aware that echocardiography can identify that the child has Friedreich ataxia on the basis of the presence of typical cardiac findings. They should also be made aware that a normal echocardiogram does not exclude the diagnosis of Friedreich ataxia.

JUSTIFICATION: Treatment of cardiac morbidity may reduce symptoms and risk of mortality.

SUBGROUP CONSIDERATION: This recommendation is for untested siblings (minors) of people with Friedreich ataxia.

Evidence to Recommendation Table PDF
Additional psychological support for at-risk minors

QUESTION: Should additional support services, such as psychologist, ethicist, versus no additional support services be used for minors 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: We suggest minors at risk of Friedreich ataxia (siblings of people with Friedreich ataxia) should be offered psychological support to assist with dealing with anxiety that may arise from being at risk of developing the condition.

JUSTIFICATION: Being at risk of Friedreich ataxia may result in considerable psychological distress for the individual.

SUBGROUP CONSIDERATION: This recommendation is for siblings (minors) of people with Friedreich ataxia. The need for psychological support may vary with the age of the sibling and their testing status, particularly as the sibling moves from being an immature to a mature minor. Need should be assessed on an individual basis.

Evidence to Recommendation Table PDF
Testing for immature minors

QUESTION: Should offering testing versus not offering testing be used for immature minors 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: We cannot recommend the routine offer of pre-symptomatic genetic testing over refusal to offer testing for immature minors at risk of Friedreich ataxia. Each situation is unique and should be managed on a case-by-case basis with referral to a team with expertise in pre-symptomatic genetic testing and the related issues.

JUSTIFICATION: As there is no evidence to support the routine provision or refusal of pre-symptomatic genetic testing for Friedreich ataxia to immature minors at this time, each situation should be managed on a case-by-case basis. However, clinical experience suggests the following considerations:
(i) The family should be referred to a team with expertise in this field for discussion about testing.
(ii) The risks and benefits of pre-symptomatic genetic diagnosis from both the child’s and parents’ perspectives should be carefully reviewed during the pre-test assessment.
(iii) Minors who have the maturity to do so, should be involved in the decision as to whether or not they are tested.
(iv) A multidisciplinary approach to the pre-symptomatic testing process, with the additional involvement of a psychologist or psychiatrist with expertise in pediatric and adolescent issues should be employed in the process.
(v) All minors identified pre-symptomatically with the genetic predisposition to Friedreich ataxia and their families should receive immediate post-test counseling and psychosocial support.
(vi) All minors identified pre-symptomatically should be referred for appropriate neurological and cardiac surveillance.

If a therapy emerges that is proven to delay the onset and slow progression of Friedreich ataxia then proactive testing of unaffected siblings of individuals with Friedreich ataxia will be recommended.

SUBGROUP CONSIDERATION: This recommendation is for immature minors at risk of Friedreich ataxia. National regulations need to be taken into account as in some jurisdictions, pre-symptomatic testing of minors is not permitted.

Evidence to Recommendation Table PDF
Testing for mature minors

QUESTION: Should offering testing versus not offering testing be used for mature minors 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: We conditionally recommend testing over refusal of testing for an asymptomatic mature at-risk minor who requests genetic testing for Friedreich ataxia. When a mature minor requests testing, a referral should be made to a team with expertise in pre-symptomatic genetic testing for Friedreich ataxia and the related issues.

JUSTIFICATION: A ‘mature’ minor is defined as a person younger than 18 years who is deemed to have the capacity to make healthcare decisions on their own behalf and as such can weigh up the benefits and risks of testing for themselves. However, support for the decision-making process is integral to offering testing, with the following considerations:
(i) The views of the mature minor in relation to testing should be central to the decision as to whether testing takes place or not. Where the parents/guardians wish testing to take place but the mature minor does not, testing should not proceed.
(ii) The mature minor +/- their parents/guardians should be referred to a team with expertise in this field for discussion about the request.
(iii) The risks and benefits of pre-symptomatic genetic diagnosis from the perspectives of both the mature minor and their parents/guardians should be carefully reviewed during the pre-test assessment.
(iv) A multidisciplinary approach to the pre-symptomatic testing process, with the additional involvement of a psychologist or psychiatrist with expertise in adolescent issues, should be considered.
(v) All patients identified pre-symptomatically and their families should receive immediate post-test counseling and psychosocial support.
(vi) All patients identified pre-symptomatically should be referred for appropriate neurological and cardiac surveillance.

If the mature minor does not have biallelic FXN pathogenic variants then they will not develop Friedreich ataxia and this will generally result in relief of anxiety for the individual and their family, although some individuals may have a negative response to this finding due to the phenomenon of “survivor guilt”. If they are found to have biallelic FXN pathogenic variants, this is very likely to result in anxiety for the individual and their family, but from a medical perspective there are benefits in that they can have surveillance for cardiac involvement and therapy for this can be instituted when indicated.

SUBGROUP CONSIDERATION: This recommendation is for mature minors at risk of Friedreich ataxia. National regulations need to be taken into account as in some jurisdictions, pre-symptomatic testing of minors is not permitted.

Evidence to Recommendation Table PDF

Lay summary of clinical recommendations for testing for minor siblings of a person with Friedreich ataxia


Why these recommendations?

Being unsure about whether or not they are going to develop symptoms of Friedreich ataxia may cause worry and distress for brothers and sisters (siblings) of a person with the condition. We suggest the siblings of individuals with Friedreich ataxia be offered support to help with managing any worry about the possibility of developing symptoms.

For children who are siblings of a person with Friedreich ataxia but do not have symptoms, we cannot say if having a test for Friedreich ataxia is better than not having a test, because it will be different for each person and family. It is important that the family of the person with Friedreich ataxia is referred to a multidisciplinary team (including doctors and counselors) with expertise in this situation who will be able to provide specific advice to each family. Discussion with the team should include the positive and negative aspects of testing from both the child’s and parents’ viewpoints. Where possible and if sufficiently mature, the child should be involved in making a decision about testing.

In the case of a request for testing for Friedreich ataxia from a “mature minor” (that is, someone who is under the age of 18 years, but is considered capable of making health-related decisions for themselves) who does not show symptoms, we suggest testing under the following conditions:

  • ● The views of the mature minor requesting testing should be central to the decision as to whether testing takes place or not. Where the parents/guardians wish testing to take place but the mature minor does not, testing should not proceed.
  • ● The mature minor, with or without their parents/guardians, should be referred to a multidisciplinary team (possibly including a psychologist or psychiatrist who works with adolescents) with expertise in this field for discussion about the request.
  • ● The risks and benefits of a genetic diagnosis of Friedreich ataxia before symptoms appear (pre-symptomatic) from the perspectives of both the mature minor and their parents/guardians should be carefully explained during the assessment before testing.
  • ● If a mature minor is identified as having Friedreich ataxia before the onset of symptoms, they and their family should receive immediate post-test counseling and psychosocial support and be the individual should be referred for neurological and heart care.

We also suggest that brothers and sisters of an affected person, who are under the age of 18 and do not have symptoms of Friedreich ataxia or have not undergone genetic testing, should have a heart ultrasound and electrocardiogram to look for heart problems that may require treatment. This is to ensure that any heart problems can be treated even though the child has not undergone genetic testing.

If in the future, a therapy is found that delays or slows symptoms of Friedreich ataxia, the brothers and sisters of the person with Friedreich ataxia should be tested regardless of whether they have symptoms, so that the therapy can be started as soon as possible.

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 testing for Friedreich ataxia and what it means for you and your child. In some places, national regulations do not allow pre-symptomatic testing of minors. If that is the case, your healthcare professional will be able to advise you and your children.

Who is this recommendation specifically for?

These recommendations are specifically for brothers or sisters aged under 18 years of 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.