TY - JOUR

T1 - New genotype-phenotype correlations in a large European cohort of patients with sarcoglycanopathy

AU - Alonso-Pérez, Jorge

AU - González-Quereda, Lidia

AU - Bello, Luca

AU - Guglieri, Michela

AU - Straub, Volker

AU - Gallano, Pia

AU - Semplicini, Claudio

AU - Pegoraro, Elena

AU - Zangaro, Vittoria

AU - Nascimento, Andrés

AU - Ortez, Carlos

AU - Comi, Giacomo Pietro

AU - Dam, Leroy Ten

AU - De Visser, Marianne

AU - van der Kooi, A J

AU - Garrido, Cristina

AU - Santos, Manuela

AU - Schara, Ulrike

AU - Gangfuß, Andrea

AU - Løkken, Nicoline

AU - Storgaard, Jesper Helbo

AU - Vissing, John

AU - Schoser, Benedikt

AU - Dekomien, Gabriele

AU - Udd, Bjarne

AU - Palmio, Johanna

AU - D'Amico, Adele

AU - Politano, Luisa

AU - Nigro, Vincenzo

AU - Bruno, Claudio

AU - Panicucci, Chiara

AU - Sarkozy, Anna

AU - Abdel-Mannan, Omar

AU - Alonso-Jimenez, Alicia

AU - Claeys, Kristl G

AU - Gomez-Andrés, David

AU - Munell, Francina

AU - Costa-Comellas, Laura

AU - Haberlová, Jana

AU - Rohlenová, Marie

AU - Elke, De Vos

AU - De Bleecker, Jan L

AU - Dominguez-González, Cristina

AU - Tasca, Giorgio

AU - Weiss, Claudia

AU - Deconinck, Nicolas

AU - Fernández-Torrón, Roberto

AU - López de Munain, Adolfo

AU - Camacho-Salas, Ana

AU - Melegh, Béla

AU - Hadzsiev, Kinga

AU - Leonardis, Lea

AU - Koritnik, Blaz

AU - Garibaldi, Matteo

AU - de Leon-Hernández, Juan Carlos

AU - Malfatti, Edoardo

AU - Fraga-Bau, Arturo

AU - Richard, Isabelle

AU - Illa, Isabel

AU - Díaz-Manera, Jordi

N1 - © The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.

PY - 2020/9/1

Y1 - 2020/9/1

N2 - Sarcoglycanopathies comprise four subtypes of autosomal recessive limb-girdle muscular dystrophies (LGMDR3, LGMDR4, LGMDR5 and LGMDR6) that are caused, respectively, by mutations in the SGCA, SGCB, SGCG and SGCD genes. In 2016, several clinicians involved in the diagnosis, management and care of patients with LGMDR3-6 created a European Sarcoglycanopathy Consortium. The aim of the present study was to determine the clinical and genetic spectrum of a large cohort of patients with sarcoglycanopathy in Europe. This was an observational retrospective study. A total of 33 neuromuscular centres from 13 different European countries collected data of the genetically confirmed patients with sarcoglycanopathy followed-up at their centres. Demographic, genetic and clinical data were collected for this study. Data from 439 patients from 13 different countries were collected. Forty-three patients were not included in the analysis because of insufficient clinical information available. A total of 159 patients had a confirmed diagnosis of LGMDR3, 73 of LGMDR4, 157 of LGMDR5 and seven of LGMDR6. Patients with LGMDR3 had a later onset and slower progression of the disease. Cardiac involvement was most frequent in LGMDR4. Sixty per cent of LGMDR3 patients carried one of the following mutations, either in a homozygous or heterozygous state: c.229C>T, c.739G>A or c.850C>T. Similarly, the most common mutations in LMGDR5 patients were c.525delT or c.848G>A. In LGMDR4 patients the most frequent mutation was c.341C>T. We identified onset of symptoms before 10 years of age and residual protein expression lower than 30% as independent risk factors for losing ambulation before 18 years of age, in LGMDR3, LGMDR4 and LGMDR5 patients. This study reports clinical, genetic and protein data of a large European cohort of patients with sarcoglycanopathy. Improving our knowledge about these extremely rare autosomal recessive forms of LGMD was helped by a collaborative effort of neuromuscular centres across Europe. Our study provides important data on the genotype-phenotype correlation that is relevant for the design of natural history studies and upcoming interventional trials in sarcoglycanopathies.

AB - Sarcoglycanopathies comprise four subtypes of autosomal recessive limb-girdle muscular dystrophies (LGMDR3, LGMDR4, LGMDR5 and LGMDR6) that are caused, respectively, by mutations in the SGCA, SGCB, SGCG and SGCD genes. In 2016, several clinicians involved in the diagnosis, management and care of patients with LGMDR3-6 created a European Sarcoglycanopathy Consortium. The aim of the present study was to determine the clinical and genetic spectrum of a large cohort of patients with sarcoglycanopathy in Europe. This was an observational retrospective study. A total of 33 neuromuscular centres from 13 different European countries collected data of the genetically confirmed patients with sarcoglycanopathy followed-up at their centres. Demographic, genetic and clinical data were collected for this study. Data from 439 patients from 13 different countries were collected. Forty-three patients were not included in the analysis because of insufficient clinical information available. A total of 159 patients had a confirmed diagnosis of LGMDR3, 73 of LGMDR4, 157 of LGMDR5 and seven of LGMDR6. Patients with LGMDR3 had a later onset and slower progression of the disease. Cardiac involvement was most frequent in LGMDR4. Sixty per cent of LGMDR3 patients carried one of the following mutations, either in a homozygous or heterozygous state: c.229C>T, c.739G>A or c.850C>T. Similarly, the most common mutations in LMGDR5 patients were c.525delT or c.848G>A. In LGMDR4 patients the most frequent mutation was c.341C>T. We identified onset of symptoms before 10 years of age and residual protein expression lower than 30% as independent risk factors for losing ambulation before 18 years of age, in LGMDR3, LGMDR4 and LGMDR5 patients. This study reports clinical, genetic and protein data of a large European cohort of patients with sarcoglycanopathy. Improving our knowledge about these extremely rare autosomal recessive forms of LGMD was helped by a collaborative effort of neuromuscular centres across Europe. Our study provides important data on the genotype-phenotype correlation that is relevant for the design of natural history studies and upcoming interventional trials in sarcoglycanopathies.

KW - Adolescent

KW - Adult

KW - Aged

KW - Child

KW - Child, Preschool

KW - Cohort Studies

KW - Europe/epidemiology

KW - Female

KW - Genetic Association Studies/methods

KW - Humans

KW - Male

KW - Middle Aged

KW - Muscular Dystrophies, Limb-Girdle/diagnosis

KW - Retrospective Studies

KW - Sarcoglycanopathies/diagnosis

KW - Young Adult

U2 - 10.1093/brain/awaa228

DO - 10.1093/brain/awaa228

M3 - Journal article

C2 - 32875335

VL - 143

SP - 2696

EP - 2708

JO - Brain

JF - Brain

SN - 0006-8950

IS - 9

ER -