Sabrina Sacconi1, Audrey Briand-Suleau2, Marilyn Gros2, Christian Baudoin2, Richard J L F Lemmers2, Sophie Rondeau2, Nadira Lagha2, Pilvi Nigumann2, Chiara Cambieri2, Angela Puma2, Françoise Chapon2, Tanya Stojkovic2, Christophe Vial2, Françoise Bouhour2, Michelangelo Cao2, Elena Pegoraro2, Philippe Petiot2, Anthony Behin2, Bras Marc2, Bruno Eymard2, Andoni Echaniz-Laguna2, Pascal Laforet2, Leonardo Salviati2, Marc Jeanpierre2, Gaël Cristofari2, Silvère M van der Maarel2. 1. From the Peripheral Nervous System (S.S., M.G., C.C., A.P.), Muscle & ALS Department, Pasteur 2 Hospital, Centre Hospitalier Universitaire de Nice, and Institute for Research on Cancer and Aging of Nice (S.S., C.B., N.L., P.N., G.C.), CNRS, INSERM, Université Côte d'Azur; Department of Genetics and Molecular Biology (A.B.-S., S.R., M.J.), Cochin Hospital, Paris, France; Department of Human Genetics (R.J.L.F.L., S.M.v.d.M.), Leiden University Medical Center, the Netherlands; Rare Neuromuscular Diseases Centre (C.C.), Department of Human Neuroscience, Sapienza University of Rome, Italy; Pathology Department (F.C.), CHRU of Caen, INSERM U1075, University of Caen, Normandy; Myology Institute (T.S., A.B., B.E.), Center of Research in Myology, APHP, Sorbonne Université, UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Paris; Electromyography and Neuromuscular Department (C.V., F.B., P.P.), Neurologic Hospital, Lyon East Hospital Group, Lyon-Bron, France; Neuromuscular Center, Department of Neuroscience (M.C., E.P.), and Clinical Genetics Unit, Department of Women's and Children's Health (L.S.), University of Padova, Italy; Institut Imagine, Imagine Bioinfomatics Platform (M.B.), Paris Descartes University; Département de Neurologie (A.E.-L.), Hôpitaux Universitaires, Strasbourg; Nord/Est/Ile de France Neuromuscular Center (P.L.), Neurology Department, Raymond Poincaré Teaching Hospital, Garches; INSERM U1179 (P.L.), END-ICAP, Versailles Saint-Quentin-en-Yvelines University, Montigny-le-Bretonneux, France; and IRP Città della Speranza (L.S.), Padova, Italy. sacconi.s@chu-nice.fr. 2. From the Peripheral Nervous System (S.S., M.G., C.C., A.P.), Muscle & ALS Department, Pasteur 2 Hospital, Centre Hospitalier Universitaire de Nice, and Institute for Research on Cancer and Aging of Nice (S.S., C.B., N.L., P.N., G.C.), CNRS, INSERM, Université Côte d'Azur; Department of Genetics and Molecular Biology (A.B.-S., S.R., M.J.), Cochin Hospital, Paris, France; Department of Human Genetics (R.J.L.F.L., S.M.v.d.M.), Leiden University Medical Center, the Netherlands; Rare Neuromuscular Diseases Centre (C.C.), Department of Human Neuroscience, Sapienza University of Rome, Italy; Pathology Department (F.C.), CHRU of Caen, INSERM U1075, University of Caen, Normandy; Myology Institute (T.S., A.B., B.E.), Center of Research in Myology, APHP, Sorbonne Université, UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Paris; Electromyography and Neuromuscular Department (C.V., F.B., P.P.), Neurologic Hospital, Lyon East Hospital Group, Lyon-Bron, France; Neuromuscular Center, Department of Neuroscience (M.C., E.P.), and Clinical Genetics Unit, Department of Women's and Children's Health (L.S.), University of Padova, Italy; Institut Imagine, Imagine Bioinfomatics Platform (M.B.), Paris Descartes University; Département de Neurologie (A.E.-L.), Hôpitaux Universitaires, Strasbourg; Nord/Est/Ile de France Neuromuscular Center (P.L.), Neurology Department, Raymond Poincaré Teaching Hospital, Garches; INSERM U1179 (P.L.), END-ICAP, Versailles Saint-Quentin-en-Yvelines University, Montigny-le-Bretonneux, France; and IRP Città della Speranza (L.S.), Padova, Italy.
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. CLINICALTRIALSGOV IDENTIFIER: NCT01970735.
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. CLINICALTRIALSGOV IDENTIFIER: NCT01970735.
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