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 (16) , Marc Jeanpierre (22) , Gael Cristofari (4) , Silvere van Der Maarel (23)

1 CHU Nice - Centre Hospitalier Universitaire de Nice
2 IMRB - Institut Mondor de Recherche Biomédicale
3 AMU SMPM MED - Aix-Marseille Université - École de médecine
4 IRCAN - Institut de Recherche sur le Cancer et le Vieillissement
5 Leiden University Medical Center (LUMC)
6 CHU Necker - Enfants Malades [AP-HP]
7 UNS - Université Nice Sophia Antipolis (1965 - 2019)
8 UNIROMA - Università degli Studi di Roma "La Sapienza" = Sapienza University [Rome]
9 Service de Neurologie [CHU Nice]
10 Hôpital Côte de Nacre [CHU Caen]
11 COMETE - Mobilités : Vieillissement, Pathologie, Santé
12 Institut de Myologie
13 IP - Institut Pascal
14 HCL - Hospices Civils de Lyon
15 Nuffield Department of Clinical Neurosciences [Oxford]
16 Unipd - Università degli Studi di Padova = University of Padua
17 HCL - Hospices Civils de Lyon, Departement de Neurologie
18 CHU Pitié-Salpêtrière [AP-HP]
19 Polyclinique Saint Privat
20 ICM - Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute
21 AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre)
22 UPD5 - Université Paris Descartes - Paris 5
23 Center for Human and Clinical Genetics

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.

Domains: Life Sciences [q-bio]; Cognitive science; Neuroscience; Humanities and Social Sciences; Psychology

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