Topic 11.2. Management of testing for adult siblings of a person with Friedreich ataxia

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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

11.2 Management of testing for adult siblings of a person with Friedreich ataxia
11.2.1 Carrier testing for adult siblings
11.2.2 Other examinations for at-risk adult 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.


11.2 Management of testing for adult siblings of a person with Friedreich ataxia

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

At the time of conception, the siblings of a person with FRDA have a 1-in-4 risk of having two FXN pathogenic variants and being affected by FRDA. The risk for an individual sibling, however, depends on their age. If they are younger than the proband was at the onset of symptoms, their risk of having FRDA is essentially 1 in 4. If they are older and asymptomatic the risk can be lower, since the probability of having FRDA decreases as an individual becomes older and doesn’t have symptoms. However, even if the sibling is many years older than the age at which the proband developed symptoms, there still remains a risk of disease given the possibility of marked differences in age of onset within the same family. This relates largely to when siblings inherit different size expanded FXN GAA repeats.

11.2.1 Carrier testing for adult siblings

The goal of carrier testing for adult siblings of a person with FRDA is to allow for reproductive planning. The decision to undergo carrier testing should be voluntary and made after appropriate genetic counseling, which should include a review of the autosomal recessive inheritance pattern and natural history of FRDA. Carrier status for FRDA does not in itself confer any medical risk. It should be emphasized to the person undergoing testing that while a carrier for FRDA is healthy, they are at risk of transmitting the FXN pathogenic variant to offspring.

When an adult sibling requests carrier testing, a clinician should:

● inform the person that their risk of being a carrier at conception was 1 in 2, but if they are much older than their sibling was at symptom onset, the chances of being a carrier is about 2 in 3 (since the 1-in-4 chance of being affected is by then close to zero).

● warn that there is a small chance that testing will identify that they have two FXN pathogenic variants and will at some point develop symptoms of the condition. There should be a thorough discussion about the pros and cons of such testing.

● offer a neurological examination as this may identify subtle features of the condition such as mild ataxia, absent lower limb reflexes, altered vibration sense and/or altered proprioception.

● offer to arrange psychological support if signs of FRDA are identified. The absence of any clinical signs of FRDA means the risk of that person being diagnosed with the condition through genetic testing is low. If subtle symptoms are identified then the individual should be forewarned about the possibility that FRDA may be diagnosed and provided with appropriate psychological support.

● arrange follow-up genetic counseling to discuss testing of their current/future partner (if the sibling is heterozygous for a FXN pathogenic variant), risks to future pregnancies as well as options for prenatal diagnosis and preimplantation genetic testing (if that is available).

11.2.2 Other examinations for at-risk adult siblings

If siblings do not wish to undergo genetic testing, or may do so at some time in the future, 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 but cannot exclude the possibility of biallelic FXN pathogenic variants being present.

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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 adults

QUESTION: Should offering echocardiograms versus no echocardiograms be used for untested adult siblings of people with Friedreich ataxia?
[sg_popup id=”587″ event=”click”][/sg_popup]STRENGTH OF RECOMMENDATION:
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RECOMMENDATION: We suggest that adult siblings of a person with Friedreich ataxia, who do not wish to have genetic testing to confirm whether or not they have Friedreich ataxia, be offered echocardiography to see if they have any cardiac signs that may require treatment.

JUSTIFICATION: Cardiac involvement is the main cause of mortality in Friedreich ataxia (6) and can be treated to reduce the chance of cardiac morbidity and mortality. Offering echocardiography can enable a person who does not wish to have genetic testing to avoid possible definitive diagnosis of Friedreich ataxia, while at the same time maintaining safety. Identification of cardiac abnormality by echocardiography may lead to treatment that can reduce morbidity and mortality. Normal echocardiography may result in reduced anxiety for the individual.

SUBGROUP CONSIDERATION: This recommendation is for untested adult siblings of individuals with Friedreich ataxia.

Evidence to Recommendation Table PDF
Physical examination for at-risk adults

QUESTION: Should offering a physical examination versus no physical examination be used for adult siblings of people with Friedreich ataxia?
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RECOMMENDATION: We suggest that adult siblings of people with Friedreich ataxia should be offered a physical examination. They should be made aware that this could identify signs of Friedreich ataxia. Absence of signs of Friedreich ataxia does not mean that they will not be found to have biallelic pathogenic variants in FXN. The older the individual with a normal examination, the less likely they are to have biallelic pathogenic variants in FXN.

JUSTIFICATION: Although there is no published evidence, clinical experience indicates that siblings of people with Friedreich ataxia often value the outcome of a physical examination. The key here is that it should be offered as an option and not be made mandatory. In offering the option, the possibility of identifying signs of Friedreich ataxia should be made known to the individual before the examination.

SUBGROUP CONSIDERATION: This recommendation is for adult siblings of individuals with Friedreich ataxia.

Evidence to Recommendation Table PDF
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.
Requests for carrier testing by at-risk adult siblings are best managed on a case-by-case basis; there is no evidence to support the routine provision or refusal of carrier testing for Friedreich ataxia.


All at-risk siblings identified as having Friedreich ataxia pre-symptomatically and their families would benefit from immediate post-test counseling and psychosocial support and referral for appropriate neurological and cardiac surveillance.

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


Why these recommendations?

When they are conceived, the brothers and sisters (siblings) of a person with Friedreich ataxia have a 1-in-4 chance of having two faulty FXN genes and therefore having Friedreich ataxia. As a sibling becomes older and does not have symptoms, the more likely it is that they don’t have the condition.

Testing for Friedreich ataxia is different depending on whether the sibling is an adult or a child. Adult siblings who do not show symptoms of Friedreich ataxia may want to be tested for Friedreich ataxia to see if they are a carrier of the condition, particularly if they are thinking about starting a family. Testing an adult sibling who has no symptoms is unlikely to show that they have Friedreich ataxia, but occasionally it can do so.

Some adult siblings prefer not to have testing for Friedreich ataxia, but they can have other tests in case they have any symptoms that can be treated.

We suggest that adult individuals who choose not to be tested can have heart ultrasound and electrocardiogram (also called an ECG or EKG) to see if they have any symptoms that may need treatment. Offering heart screening can enable a person who does not wish to have genetic testing to avoid possibly knowing they have Friedreich ataxia, while at the same time maintaining their safety.

For those adults who request testing for Friedreich ataxia, we suggest in the first instance they are offered a physical examination to check for features of the condition.

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.

Who are these recommendations specifically for? 

These recommendations are specifically for adult brothers or sisters of individuals 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

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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.

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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.

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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.