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FSHD1 and FSHD2 form a disease continuum

Sabrina Sacconi 1 Audrey Briand-Suleau 2 Marilyn Gros 3 Christian Baudoin 4 Richard J.L.F. Lemmers 5 Sophie Rondeau 6 Nadira Lagha 7 Pilvi Nigumann 4 Chiara Cambieri 8 Angela Puma 9 Françoise Chapon 10, 11 Tanya Stojkovic 12 Christophe Vial 13 Françoise Bouhour 14 Michelangelo Cao 15 Elena Pegoraro 16 Philippe Petiot 17 Anthony Béhin 18 Bras Marc 19 Bruno Eymard 20 Andoni Echaniz-Laguna 21 Pascal Laforet 18 Leonardo Salviati 22 Marc Jeanpierre 23 Gael Cristofari 4 Silvere van Der Maarel 24 
Abstract : Objective To compare the clinical features of patients showing a classical phenotype of facioscapulohumeral muscular dystrophy (FSHD) with genetic and epigenetic characteristics of the FSHD1 and FSHD2 loci D4Z4 and SMCHD1. Methods This is a national multicenter cohort study. We measured motor strength, motor function, and disease severity by manual muscle testing sumscore, Brooke and Vignos scores, clinical severity score (CSS), and age-corrected CSS, respectively. We correlated these scores with genetic (D4Z4 repeat size and haplotype; SMCHD1 variant status) and epigenetic (D4Z4 methylation) parameters. Results We included 103 patients: 54 men and 49 women. Among them, we identified 64 patients with FSHD1 and 20 patients with FSHD2. Seven patients had genetic and epigenetic characteristics of FSHD1 and FSHD2, all carrying repeats of 9–10 D4Z4 repeat units (RU) and a pathogenic SMCHD1 variant. In the remaining patients, FSHD was genetically excluded or remained unconfirmed. All clinically affected SMCHD1 mutation carriers had a D4Z4 repeat of 9–16 RU on a disease permissive 4qA haplotype. These patients are significantly more severely affected by all clinical scales when compared to patients with FSHD1 with upper-sized FSHD1 alleles (8–10 RU). Conclusion The overlap between FSHD1 and FSHD2 patients in the 9–10 D4Z4 RU range suggests that FSHD1 and FSHD2 form a disease continuum. The previously established repeat size threshold for FSHD1 (1–10 RU) and FSHD2 (11–20 RU) needs to be reconsidered.
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Submitted on : Friday, October 4, 2019 - 10:34:04 AM
Last modification on : Friday, June 17, 2022 - 2:18:20 PM

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Sabrina Sacconi, Audrey Briand-Suleau, Marilyn Gros, Christian Baudoin, Richard J.L.F. Lemmers, et al.. FSHD1 and FSHD2 form a disease continuum. Neurology, American Academy of Neurology, 2019, 92 (19), pp.e2273-e2285. ⟨10.1212/WNL.0000000000007456⟩. ⟨hal-02305410⟩

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