Topic 1.2. Genetics and pathophysiology of 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

1.2 Genetics and pathophysiology of Friedreich ataxia
1.2.1 Genetics, incidence and carrier frequency
1.2.2 Pathophysiology

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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.

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.

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.

1.2 Genetics and pathophysiology of Friedreich ataxia

Sanjay I. Bidichandani, Hélène Puccio and Robert B. Wilson

1.2.1 Genetics, incidence and carrier frequency

FRDA is caused by loss-of-function variants in the FXN gene (7). As an autosomal recessive condition, individuals with FRDA inherit disease-causing variants from both parents, each of whom is an asymptomatic carrier. By far, the most prevalent disease-causing variant in FRDA is an expanded GAA triplet-repeat sequence in intron 1 of the FXN gene. Indeed, about 96% of individuals with FRDA are homozygous for this mutation, which ranges in size from 100 to 1500 GAA triplets. Whereas rare alleles may fall outside of these bounds, the most common allele sizes encountered in practice range from 600 to 1200 triplets. Normal, non-FRDA alleles contain less than 36 GAA triplets, the majority of which are 8 to 12 triplets in length. The remaining 4% of individuals with FRDA are compound heterozygous with an expanded GAA triplet-repeat sequence in one of the FXN alleles, and another deleterious mutation in the other allele (26). The latter class of disease-causing variants include a variety of inactivating FXN mutations. These mutations, which are individually rare, include missense, nonsense, splice, and small insertion/deletion variants that span the entire length of the gene. Rare instances of large deletions have also been seen that involve an entire exon or multiple contiguous exons.

All individuals with FRDA genotyped to date have at least one expanded GAA triplet-repeat. Strong linkage disequilibrium indicates that the expanded GAA triplet-repeat arose from a relatively recent common founder (27). As a result, the expanded GAA triplet-repeat is seen predominantly in the Indo-European population, and in populations with whom they have admixed. The carrier frequency in Indo-Europeans is estimated to be about 1%, which supports an incidence rate of about 1 in 40,000.

1.2.2 Pathophysiology

The FXN gene encodes a mitochondrial protein called frataxin (28). The expanded GAA triplet-repeat results in FXN transcriptional deficiency, which is inversely correlated with the length of the repeat (29). Most individuals with FRDA are homozygous for expanded alleles containing more than 500 triplets, and typically express 5% to 10% frataxin transcript compared to non-FRDA levels. However, a subset (about 20%) of individuals have at least one expanded allele containing less than 500 triplets, which leads to a higher (10% to 20%) residual frataxin transcript level (30). Heterozygous carriers, such as parents of affected individuals, remain asymptomatic despite expressing about 50% of normal, non-FRDA levels of FXN transcript. Expanded GAA repeats cause FXN transcriptional deficiency via epigenetic silencing, and/or by the formation of an abnormal RNA-DNA hybrid structure called an R-loop, both of which are bona fide therapeutic targets in FRDA (31, 32).

Frataxin functions in the biogenesis of iron-sulfur (Fe-S) clusters (33), which are essential cofactors that participate in a number of cellular pathways including mitochondrial respiration, iron metabolism and DNA metabolism. In FRDA, deficiency of frataxin results in decreased mitochondrial ATP production, perturbed iron metabolism and dysregulated oxidative stress response (34). Tissues that are pathologically involved in FRDA tend to be highly dependent on mitochondrial oxidative phosphorylation (34-36). These include the nervous system (large sensory neurons of the dorsal root ganglia; spinocerebellar and corticospinal tracts as well as the posterior columns of the spinal cord; cerebellar dentate nuclei), the heart, and pancreatic β-cells. Tissue vulnerability and pathological involvement likely begin during embryonic development (37, 38) and continue throughout life to the later stages of disease; however, the precise pathophysiological determinants of disease progression in FRDA are not well understood.

Sanjay I. Bidichandani, MBBS, PhD
Professor of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

Hélène Puccio, PhD
Research Director Inserm, Institut Neuromyogène – Pathophysiology and Genetics of Neuron and Muscle, Lyon, France

Robert B. Wilson, MD, PhD
Professor of Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA

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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.