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. 2025 Sep 23;27(12):101588.
doi: 10.1016/j.gim.2025.101588. Online ahead of print.

Type and position of repeat interruptions as determinants of disease severity and expansion size in Friedreich ataxia

Mehdi Benkirane  1 , Cecilia Marelli  2 , Ariane Choumert  3 , Cyril Goizet  4 , Olivier Patat  5 , Claire Ewenczyk  6 , Mathieu Anheim  7 , André Mégarbané  8 , Lise Larrieu  9 , Cyril Charlin  3 , Fabienne Ory-Magne  10 , Annabelle Chaussenot  11 , Mélanie Fradin  12 , Claire Guissart  9 , Morgane Pointaux  9 , Mireille Cossée  13 , Marie-Claire Vincent  13 , Anne Bergougnoux  13 , Clément Hersent  13 , Corinne Bareil  9 , Agathe Roubertie  14 , Frédérique Fluchère  15 , Mathilde Renaud  16 , Laurent Kremer  7 , Christine Tranchant  7 , Shahram Attarian  15 , Sylvie Odent  12 , Vincent Laugel  17 , Ulrike Walther-Louvier  18 , Beatrice Desnous  19 , Eric Bieth  5 , Isabelle Husson  20 , Jean Phillipe Azulay  15 ; INTREP-AF consortium; François Rivier  21 , Bérénice Doray  22 , Alexandra Durr  6 , Safa Aouinti  23 , Nicolas Molinari  23 , Michel Koenig  24
Collaborators, Affiliations

Type and position of repeat interruptions as determinants of disease severity and expansion size in Friedreich ataxia

Mehdi Benkirane et al. Genet Med. .

Abstract

Purpose: In Friedreich ataxia (FRDA) the size of the smaller GAA expansion is a major determinant of disease severity; interruption motifs were identified after the discovery of the pathogenic expansions; however, their impact is only recently investigated.

Methods: 164 patients with FRDA with biallelic expansions and 15 patients without FRDA were analyzed for interruption(s) number, position, and motif. Expansion size and age at onset of ataxia (AAO) were determined for patients with FRDA.

Results: Three groups of patients with FRDA were identified by the simultaneous analysis of the precise distance ("depth") between the interruptions (mostly nontriplet) and the 3' end of the expansion (P < .001), the smaller expansion size (P < .001), and AAO (P < .001). Classical FRDA corresponds to absence of interruption or interruption depth < 8 repeats, with AAO often <15 years (area under the curve [AUC] = 0.90; 95% CI, 0.84-0.96); LOFA to interruption depth of 8 to 18 repeats (AUC = 0.97; 95% CI, 0.94-1), with AAO 15 to 34 years (AUC = 1; 95% CI, 1-1); and vLOFA to interruption depth > 18 (AUC = 0.97; 95% CI, 0.92-1), with AAO > 34 years. Multiple (>5) triplet interruptions hamper further expansion.

Conclusion: This study provides the molecular basis for a novel classification of FRDA that should be recommended for correct diagnosis.

Keywords: Ataxia; FXN; Interruption depth; Nontriplet interruption; Triplet interruption.

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Conflict of interest statement

Conflict of Interest Michel Koenig and Claire Ewenczyk are supported by Biogen for participation at an international congress. Cecilia Marelli received travel grants from Nutricia, Biogen, and Vitaflo for participation to national and international congress and is member of a BIOGEN Board. Cyril Goizet received consulting fees and honoraria for lectures from BIOGEN. Alexandra Durr serves as an advisor at Critical Path Ataxia Therapeutics Consortium, and her Institution (Paris Brain Institute) receives consulting fees on her behalf from Biogen, Huntix, UCB, as well as research grants from the NIH, ANR and holds partly a Patent B 06291873.5 on “Anaplerotic therapy of Huntington’s disease and other polyglutamine diseases.” Mathieu Anheim declares honoraria and travel grant from Biogen.

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