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Despite significant progress in the search for disease modifying agents, the chronic, progressive nature of Friedreich ataxia (FRDA) continues to have a profound impact on the health and well-being of affected individuals. As for those living with other rare diseases, individuals with FRDA often find it difficult to access expert specialist multi-disciplinary care for long-term, evidence-based management. In response to this need, the Consensus Clinical Management Guidelines for Friedreich Ataxia were developed and published in 20141. Since this time, some new evidence in managing FRDA has emerged warranting an update of the Clinical Management Guidelines (CMGs), but the challenges of developing guidelines for rare diseases remain. In particular, the lack of adequately powered studies means that many management recommendations are based on low-certainty evidence. Deciding to update the guidelines provided an opportunity to consider alternative methods of grading the evidence and establishing the strength of the recommendations, to help overcome some of these challenges.
In 2019, the RARE-Bestpractices Working Group published a framework for developing guidelines in rare diseases using the robust Grading of Recommendations Assessment and Evaluation (GRADE) system2, which was adopted for this iteration of the Friedreich ataxia CMGs. In this approach, the GRADE system is supplemented with three strategies specific to rare diseases: a) reviewing and including literature in like conditions, thus providing “Indirect evidence”, b) the systematic collection of expert clinical observations and/or patient perceptions via bespoke “structured observation forms” and, c) the use of available clinical registry data. Moreover, the GRADE framework ensures a transparent and dynamic process of continual updating of the recommendations as new evidence emerges.
Methodology
In 2020, an executive guidelines panel comprising seven international clinicians was commissioned to provide oversight of the guidelines development process and endorse the final recommendations. The guidelines panel invited international expert clinicians and researchers (the authors) to write background chapter content and develop recommendations for topics that were assigned according to their particular expertise. Individuals with FRDA and/or their families were included throughout the development of the guidelines to provide a lived perspective of FRDA, specifically contributing to the development of the topics and the lay summaries of the clinical recommendations.
Using the GRADE methodology, the authors developed clinical questions pertinent to their particular topics in the Patient, Intervention, Comparison, Outcome (PICO) format, which guided the literature search (from 2014 to June 2020). The search was completed by two methodological experts who then summarized and synthesized the evidence using the GRADE structure. Evidence profiles, natural history registry data, expert clinical observations and feedback from individuals living with FRDA were used by the authors in a structured, transparent process (using evidence to recommendation tables) to develop the final clinical recommendations.
Based on the evidence and other information, the authors graded the strength of the recommendation and the level of evidence for each recommendation. For the rating of the strength of the recommendation, in addition to evidence from studies in FRDA, evidence from like conditions, clinical experience and expert consensus was taken into account when published evidence was not available. The level of evidence was based on published evidence from studies in FRDA. If there was no published evidence in FRDA, evidence from other like conditions or clinical expertise may have been used to make the recommendation – this was graded as ‘very low’ or in some cases ‘low’ level evidence. See the table below for an explanation of the symbols used to grade recommendations.
| Strength of recommendation | Symbol | Level of evidence | Symbol |
| Strong for intervention | ↑↑ | High | ⨁⨁⨁⨁ |
| Conditional for intervention | ↑ | Moderate | ⨁⨁⨁◯ |
| Neither intervention nor comparison | — | Low | ⨁⨁◯◯ |
| Conditional against intervention | ↓ | Very low | ⨁◯◯◯ |
| Strong against intervention | ↓↓ |
The authors also developed best practice statements for clinical care points that were considered self-evident or were not amenable to the GRADE process. The process was overseen by a project coordinator (see {publication} for details).
The opinions of clinicians and individuals with a lived experience of FRDA were sought in deciding the best repository and process of dissemination of the CMGs.
Outcome
Seventy clinical expert authors representing 13 countries contributed to two overview chapters and to 15 topic-specific chapters containing clinical recommendations and/or best practice statements. New topics to emerge since 2014 included emergency medicine, digital and assistive technologies and a stand-alone section on mental health. Evidence evaluated according to the GRADE criteria generated 130 new recommendations and 95 best practice statements. The authors were able to achieve consensus on the recommendations and all recommendations and best practice statements were endorsed by the executive guidelines panel. Eleven individuals with a lived experience of FRDA provided feedback on the development of topics, the lay summaries of the recommendations and the process of dissemination of the CMGs.
Feedback from authors and those with a lived experience of FRDA indicated the best repository and process of dissemination of the CMGs was through a dedicated website designed to house the CMGs, comprising topic chapters, lay summaries, recommendations, best practice statements and links to the evidence to recommendation tables completed by the authors. It was deemed crucial that a dedicated website could accommodate the ongoing process of review and update of the CMGs.
We encourage you to read the publication associated with the development of the guidelines and welcome you to this website. Please note we welcome feedback from users of the CMGs that can be considered by the authors when a chapter is updated.
References
1Corben, L.A., Lynch, D., Pandolfo, M. et al. Consensus clinical management guidelines for Friedreich ataxia. Orphanet J Rare Dis 9, 184 (2014).
2Pai M, Yeung CHT, Akl EA, Darzi A, Hillis C, Legault K, et al. Strategies for eliciting and synthesizing evidence for guidelines in rare diseases. BMC Med Res Methodol. 2019;19(1):67.
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’s 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.
2022 Guidelines Update Steering Committee
Louise A. Corben, PhD (Project Lead)
Associate Professor, Murdoch Children’s Research Institute, Melbourne, Victoria, Australia
louise.corben@mcri.edu.au
Sarah C. Milne, B.Physio, PhD (Methods Lead)
Physiotherapist, Murdoch Children’s Research Institute, Melbourne, Victoria, Australia
sarah.milne@mcri.edu.au
Veronica Collins, PhD (Editorial Lead)
Scientific Editor, Bruce Lefroy Centre, Murdoch Children’s Research Institute, Melbourne, Victoria, Australia
vcollins@espero.net.au
Ann Musheno
Administrative Support, Friedreich’s Ataxia Research Alliance (FARA), Downingtown, Pennsylvania, USA
Geneieve Tai
Research Assistant, Murdoch Children’s Research Institute, Melbourne, Victoria, Australia
Executive Guidelines Panel (listed alphabetically)
Martin B. Delatycki, MBBS, FRACP, PhD
Co-Director, Bruce Lefroy Centre, Murdoch Children’s Research Institute, Parkville, Victoria, Australia
martin.delatycki@vcgs.org.au
Jennifer Farmer, MS
Chief Executive Officer, Friedreich’s Ataxia Research Alliance (FARA), Downingtown, PA, USA
jen.farmer@curefa.org
Kimberly Y. Lin, MD
Associate Professor, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
David Lynch, MD, PhD
Professor of Neurology and Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
lynchd@mail.med.upenn.edu
Massimo Pandolfo, MD
Professor (Clinical), McGill University, Montreal, Quebec, Canada
massimo.pandolfo@mcgill.ca
Jörg B. Schulz, MD
Chair of Neurology, Department of Neurology, RWTH Aachen University, Aachen, NRW, Germany
Sub H. Subramony, MD
Professor of Neurology and Pediatrics, University of Florida College of Medicine, Gainesville, Florida, USA
s.subramony@neurology.ufl.edu
2022 Guidelines Authors
Hamed Akhlaghi, MD, PhD, FACEM, GradDipClinUSS
Head of Emergency Medicine Research, St Vincent’s Hospital (Melbourne), Melbourne, Victoria, Australia
hamed.akhlaghi@svha.org.au
Sanjay I. Bidichandani, MBBS, PhD
Professor of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahama, USA
sanjay-bidichandani@ouhsc.edu
Sylvia Boesch, MD, MSc
Head, Center for Rare Movement Disorders Innsbruck, Department of Neurology, Medical University Innsbruck, Innsbruck, Austria
sylvia.boesch@i-med.ac.at
Miriam Cnop, MD, PhD
Professor, Universite Libre de Bruxelles, Brussels, Belgium
miriam.cnop@ulb.be
Louise Corben, PhD
Principal Research Fellow, Murdoch Children’s Research Institute, Melbourne, Victoria, Australia
louise.corben@mcri.edu.au
Manuela Corti, P.T., PhD
Assistant Professor, University of Florida, Gainesville, Florida, USA
m.corti@peds.ufl.edu
Martin B. Delatycki, MBBS, FRACP, PhD
Co-Director, Bruce Lefroy Centre, Murdoch Children’s Research Institute, Parkville, Victoria, Australia
martin.delatycki@vcgs.org.au
Antoine Duquette, MD, MSc, FRCPI
Associate Clinical Professor, Centre hospitalier de l’Université de Montréal, Montréal, Québec, Canada
antoine.duquette@umontreal.ca
Alexandra Durr, MD, PhD
Professor of Neurogenetics, Sorbonne université, Paris, France
alexandra.durr@icm-institute.org
Andreas Eigentler, MD, PhD
Resident of Neurology, Department of Neurology, Medical University Innsbruck, Innsbruck, Austria
andreas.eigentler@i-med.ac.at
Anton Emmanuel, MD, FRCP
Consultant NeuroGastroenterologist, National Hospital Neurology & Neurosurgery, London, UK
Jennifer Farmer, MS
Chief Executive Officer, Friedreich’s Ataxia Research Alliance (FARA), Downingtown, Pennsylvania, USA
jen.farmer@curefa.org
John M. (Jack) Flynn, MD
Richard M. Armstrong Jr. Endowed Chair, Chief of Orthopaedic Surgery, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
Noushin Chini Foroush, MD
Neurology Registrar, Monash Medical Centre, Melbourne, Victoria, Australia
noushin.chiniforoush@gmail.com
Anne Fournier, MD, FRCPC
Professor of Pediatrics, University of Montreal, Montreal, Québec, Canada
anne.fournier@umontreal.ca
Marcondes C. França Jr, MD, PhD
Associate Professor, Department of Neurology, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
mcfjr@unicamp.br
Paola Giunti, MD, PhD
Professor, Queen Square Institute of Neurology, UCL, London, UK
p.giunti@ucl.ac.uk
Ellen W. Goh, BAppSc(OccTherapy)
Neurosciences Clinical Lead Occupational Therapist, Monash Health, Melbourne, Victoria, Australia
ellen.goh@monashhealth.org
Lisa Graf, MSc
University Hospital of Tübingen, Tübingen, Germany
Marios Hadjivassiliou, MD
Professor of Neurology, Sheffield Teaching Hospitals NHS Trust and University of Sheffield, Sheffield, South Yorkshire, UK
Maggie-Lee Huckabee, PhD
Distinguished Professor, University of Canterbury, Christchurch, Canterbury, NZ
maggie-lee.huckabee@canterbury.ac.nz
Mary G. Kearney, MD
Neurology Research Fellow, Tallaght University Hospital, Tallaght, Dublin, Ireland and European Patient Advocate at the European Reference Network for Rare Neurological Diseases
marykearney@gmail.com
Arnulf H. Koeppen, MD
Research Physician, Veterans Affairs Medical Center, Albany, New York, USA
arnulf.koeppen@med.va.gov
Yenni Lie, MBBS, FRACP
Neurologist, Monash Health, Melbourne, Victoria, Australia
yenni.lie@monashhealth.org
Kimberly Y. Lin, MD
Associate Professor, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
Anja Lowit, PhD
Professor, Strathclyde University, Glasgow, UK
a.lowit@strath.ac.uk
David Lynch, MD, PhD
Professor of Neurology and Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
lynchd@mail.med.upenn.edu
Caterina Mariotti, MD
Neurologist, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
caterina.mariotti@istituto-besta.it
Katherine Mathews, MD
Professor, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA
katherine-mathews@uiowa.edu
Shana E. McCormack, MD, MTR
Assistant Professor of Pediatrics, Attending Physician, Perelman School of Medicine at the University of Pennsylvania, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
mccormacks1@chop.edu
Sarah C. Milne, BPhysio, PhD
Physiotherapist, Murdoch Children’s Research Institute, Melbourne, Victoria, Australia
sarah.milne@mcri.edu.au
Lisa Montenegro, MD
Assistant Professor/Anesthesia, Perelman School of Medicine, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
lisa.montenegro@gmail.com
Thierry Morlet, PhD
Senior research scientist, Nemours Children’s Health, Wilmington, Delaware, USA
thierry.morlet@nemours.org
Gilles Naeije, MD, PhD
Assistant Professor, Neurology Department, CUB-Hôpital Erasme, Brussels, Belgium
gilles.naeije@erasme.ulb.ac.be
Massimo Pandolfo, MD
Professor (Clinical), McGill University, Montreal, Quebec, Canada
massimo.pandolfo@mcgill.ca
Jalesh N. Panicker, MD, DM, FRCP
Associate Professor and Consultant Neurologist in Uro-Neurology, The National Hospital for Neurology and Neurosurgery and UCL Queen Square Institute of Neurology, London, UK
Michael H. Parkinson, MBBS, PhD
Consultant Neurologist, National Hospital for Neurology & Neurosurgery, London, UK
Aarti Patel, MD
Associate Professor of Medicine, University of South Florida, Tampa, Florida, USA
apatel15@usf.edu
Ronald Mark Payne, MD
Professor of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, USA
rpayne@iu.edu
Susan Perlman, MD
Clinical Professor of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
sperlman@ucla.edu
Roger E. Peverill, MBBS, PhD
Cardiologist, MonashHeart, Monash Health, Clayton, Victoria, Australia
roger.peverill@monash.edu
Francoise Pousset, MD
Sorbonne Université, Cardiology Department, AP-HP, Pitié-Salpêtrière University Hospital, Paris, France
f.pousset@aphp.fr
Hélène Puccio, PhD
Research Director Inserm, Institut Neuromyogène – Pathophysiology and Genetics of Neuron and Muscle, Lyon, France
helene.puccio@inserm.fr
Myriam Rai, PhD
Director of Global Relations & Initiatives, Friedreich’s Ataxia Research Alliance (FARA), Brussels, Belgium
myriam.rai@curefa.org
Gary Rance, BEd, Dip Aud, MSc, PhD
Head of Department, Audiology & Speech Pathology, The University of Melbourne, Parkville, Victoria, Australia
grance@unimelb.edu.au
Kathrin Reetz, MD
Professor for Translational Neurodegeneration, Department of Neurology, RWTH Aachen University, Aachen, NRW, Germany
kreetz@ukaachen.de
Tennille J. Rowland, MPhil, Grad Cert OT (Neuro Rehab), BOccThy
Advanced Occupational Therapist, Royal Brisbane & Women’s Hospital, Brisbane, Queensland, Australia
Tennille.Rowland@health.qld.gov.au
Phoebe Sansom, BPhysio(Hons), PGCertRehab
Physiotherapist, Monash Health, Melbourne, Victoria, Australia
Phoebe.sansom@monashhealth.org
Konstantinos Savvatis, MD, PhD
Consultant Cardiologist, St. Bartholomew’s Hospital, Barts Health NHS Trust, London, UK
k.savvatis@ucl.ac.uk
Ellika T. Schalling, PhD, SLP
Professor, Uppsala University, Uppsala, Sweden
ellika.schalling@neuro.uu.se
Ludger Schöls, MD
Professor of Neurology, Eberhard-Karls University, Tübingen, Germany
Ludger.Schoels@uni-tuebingen.de
Jörg B. Schulz, MD
Chair of Neurology, Department of Neurology, RWTH Aachen University, Aachen, NRW, Germany
Barbara Smith, PhD, PT
Assistant Professor, University of Florida, Gainesville, Florida, USA
Elisabetta Soragni, PhD
Director of Research, The Friedreich’s Ataxia Research Alliance, Downingtown, Pennsylvania, USA
liz.soragni@curefa.org
Caroline Spencer, PhD
Postdoctoral Fellow, Boston University, Boston, Massachusetts, USA
cspencer@bu.edu
Sub H. Subramony, MD
Professor of Neurology and Pediatrics, University of Florida College of Medicine, Gainesville, Florida, USA
s.subramony@neurology.ufl.edu
Matthis Synofzik, MD
Professor, Hertie-Institute for Clinical Brain Research & Center for Neurology, Tübingen, Germany
matthis.synofzik@uni-tuebingen.de
David J. Szmulewicz, MBBS, PhD, FRACP
Neurologist, The Florey Institute of Neuroscience and Mental Health, Melbourne, Victoria, Australia
dsz@me.com
Geneieve Tai, BBiomedSc(Hons)
Research Assistant, Murdoch Children’s Research Institute, Parkville, Victoria, Australia
geneieve.tai@mcri.edu.au
Jaclyn Tamaroff, MD
Instructor in Pediatrics, Division of Pediatric Endocrinology and Diabetes, Vanderbilt University Medical Center, Nasvhille, Tennessee, USA
jaclyn.tamaroff@vumc.org
Lauren Treat, MD
Assistant Professor of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA
lauren.treat@childrenscolorado.org
Ariane Veilleux Carpentier, MD
Neurology Resident, Université de Montréal, Montréal, Québec, Canada
Adam P. Vogel, PhD
Professorial Fellow, The University of Melbourne, Melbourne, Victoria, Australia
vogela@unimelb.edu.au
Susan E. Walther, MS, CGC
Genetic Counselor, Clinic for Special Children, Strasburg, Pennsylvania, USA
David R. Weber, MD, MSCE
Assistant Professor of Pediatrics – Endocrinology, The Children’s Hospital of Philadelphia and The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
weberd@chop.edu
Neal J. Weisbrod, MD
Assistant Professor of Neurology, University of Florida, University of Florida, Florida, USA
George Wilmot, MD, PhD
Associate Professor, Department of Neurology, Emory University, Atlanta, Georgia, USA
gwilmot@emory.edu
Robert B. Wilson, MD, PhD
Professor of Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
wilsonr@pennmedicine.upenn.edu
Grace Yoon, MD
Clinical Geneticist, The Hospital for Sick Children, Toronto, Ontario, Canada
grace.yoon@utoronto.ca
Theresa Zesiewicz, MD
Professor, University of South Florida, Tampa, Florida, USA
tzesiewi@usf.edu
2014 authors acknowledgements
These authors are acknowledged for previous content used in 2022 guidelines but not listed in the author list at the end of the specific chapter, although they may be listed at the end of another chapter on which they are an author.
Roger Peverill, David Lynch and Ronald Mark Payne; Kelly Sullivan and Theresa Zesiewicz (Chapter 5)
Kelly Sullivan; Marios Hadjivassiliou (Chapter 8)
Lisa Friedman, Kimberly Schadt and David Lynch (Chapter 13)
2022 Guidelines Patient & Caregiver Panel
Anonymous
A person living with Friedreich ataxia
New Zealand
Anonymous
A person living with Friedreich ataxia
USA
Mark Barling
A person living with Friedreich ataxia
Australia
Raychel Furr Bartek
A family member of a person who lived with Friedreich ataxia
USA
Mary Caruso
A family member of a person living with Friedreich ataxia
USA
Ashlee Dolby
A person living with Friedreich ataxia
Australia
Alex Fielding
A person living with Friedreich ataxia
Ambassador & Director, Friedreich’s Ataxia Research Alliance (FARA)
USA
Marianne Hakim
A person living with Friedreich ataxia
President, Friedreich Ataxia Lebanese Association (FALA)
Lebanon
Elizabeth Hamilton
The caregiver of a person living with Friedreich ataxia
USA
Mary Kearney
A family member of a person living with Friedreich ataxia
Patient Advocate, European Reference Network for Rare Neurological Disease
Secretary, Friedreich’s Ataxia Research Alliance Ireland
Member, Irish College of General Practitioners
Ireland
Fabrice LECORNU
A person living with Friedreich ataxia
Member, Association Française de l’Ataxie de Friedreich (AFAF)
France
Steve Sommerville
The caregiver of a person living with Friedreich ataxia
USA
Publication of Manuscript & Publications Arising from the 2022 Guidelines Development
Manuscript Publication
Corben LA, Collins V, Milne S, Farmer J, Musheno A, Lynch D, Subramony S, Pandolfo M, Schulz JB, Lin K, Delatycki MB; Clinical Management Guidelines Writing Group. Clinical management guidelines for Friedreich ataxia: best practice in rare diseases. Orphanet J Rare Dis. 2022 Nov 12;17(1):415. doi: 10.1186/s13023-022-02568-3. PMID: 36371255; PMCID: PMC9652828.
Additional Publications Arising from 2022 Guidelines Development
Naeije, G., Schulz, J.B. & Corben, L.A. The cognitive profile of Friedreich ataxia: a systematic review and meta-analysis. BMC Neurol 22, 97 (2022). https://doi.org/10.1186/s12883-022-02615-3
Tamaroff, J., DeDio, A., Wade, K., Wells, M., Park, C., Leavens, K., Rummey, C., Kelly, A., Lynch, D. R., & McCormack, S. E. (2022). Friedreich’s Ataxia related Diabetes: Epidemiology and management practices. Diabetes Research and Clinical Practice, 186, 109828. Advance online publication. https://doi.org/10.1016/j.diabres.2022.109828
2014 Guidelines
Corben, L.A., Lynch, D., Pandolfo, M. et al. Consensus clinical management guidelines for Friedreich ataxia. Orphanet J Rare Dis 9, 184 (2014). https://doi.org/10.1186/s13023-014-0184-7
Dedication
The Clinical Management Guidelines for Friedreich ataxia in its entirety is the collective work of many authors including practitioners, researchers, patients and caregivers. Though it is grounded in research, we also acknowledge the importance of honoring the real life experiences of those who have been impacted by this disease and are grateful for their contribution.
We dedicate this document to all those who have given of themselves to this work, knowing that it is in our collective contributions that we will slow disease progression, find treatments and ultimately a cure.
“Alone, there is only so much we can do but together there is nothing that we cannot do.”
-Ronald Bartek, President & Co-Founder, Friedreich’s Ataxia Research Alliance (FARA)