Topic 12.2. Management for individuals with compound heterozygosity

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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.

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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.

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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.
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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.


12.2 Management for individuals with compound heterozygosity

Martin B. Delatycki

For individuals with FXN compound heterozygosity where the phenotype is the same as typical FRDA due to homozygosity for intron 1 GAA repeat expansions, the management guidelines in this document should be followed. The main atypical phenotype seen in FXN compound heterozygosity is “spastic ataxia” where there is marked lower limb spasticity. Here the management is directed at treatment of spasticity (see Chapter 3.4). It cannot be assumed that other features of typical FRDA are not present and therefore monitoring for other features should be done, such as regular monitoring for cardiomyopathy (see Chapter 4.2) and diabetes mellitus (see Chapter 10.1).

 
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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.
If a person compound heterozygous for a FXN GAA expansion and a point mutation/deletion has a similar phenotype to those with Friedreich ataxia due to homozygosity for GAA expansions, they should be managed as per the guidelines in this document.


If spastic ataxia is the predominant phenotype, then the main management issue is that of spasticity and the guidelines for management of spasticity should be followed.


It should never be assumed that other features of typical Friedreich ataxia (e.g., cardiomyopathy, diabetes) will not be present in individuals with compound heterozygosity; therefore, monitoring for these should take place.

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
1. Campuzano V, Montermini L, Molto MD, Pianese L, Cossee M, Cavalcanti F, et al. Friedreich’s ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science. 1996;271(5254):1423-7.

2. Cossée M, Dürr A, Schmitt M, Dahl N, Trouillas P, Allinson P, et al. Friedreich’s ataxia: point mutations and clinical presentation of compound heterozygotes. Annals of Neurology. 1999;45(2):200-6.

3. 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.

4. 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.

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.