학술논문
Genotype-phenotype correlations in valosin-containing protein disease: a retrospective muticentre study.
Document Type
article
Author
Udd, Bjarne; Schoser, Benedikt; Zanoteli, Edmar; Souza, Paulo; Tasca, Giorgio; Lloyd, Thomas; Lopez-de Munain, Adolfo; Paradas, Carmen; Pegoraro, Elena; Nadaj-Pakleza, Aleksandra; De Bleecker, Jan; Badrising, Umesh; Alonso-Jiménez, Alicia; Kostera-Pruszczyk, Anna; Miralles, Francesc; Shin, Jin-Hong; Bevilacqua, Jorge; Olivé, Montse; Vorgerd, Matthias; Kley, Rudi; Brady, Stefen; Williams, Timothy; Domínguez-González, Cristina; Papadimas, George; Warman-Chardon, Jodi; Claeys, Kristl; de Visser, Marianne; Muelas, Nuria; LaForet, Pascal; Malfatti, Edoardo; Alfano, Lindsay; Nair, Sruthi; Manousakis, Georgios; Kushlaf, Hani; Harms, Matthew; Nance, Christopher; Ramos-Fransi, Alba; Rodolico, Carmelo; Hewamadduma, Channa; Cetin, Hakan; García-García, Jorge; Pál, Endre; Farrugia, Maria; Lamont, Phillipa; Quinn, Colin; Nedkova-Hristova, Velina; Peric, Stojan; Luo, Sushan; Oldfors, Anders; Taylor, Kate; Ralston, Stuart; Stojkovic, Tanya; Weihl, Conrad; Diaz-Manera, Jordi; Schiava, Marianela; Ikenaga, Chiseko; Villar-Quiles, Rocío; Caballero-Ávila, Marta; Topf, Ana; Nishino, Ichizo; Kimonis, Virginia
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Abstract
BACKGROUND: Valosin-containing protein (VCP) disease, caused by mutations in the VCP gene, results in myopathy, Pagets disease of bone (PBD) and frontotemporal dementia (FTD). Natural history and genotype-phenotype correlation data are limited. This study characterises patients with mutations in VCP gene and investigates genotype-phenotype correlations. METHODS: Descriptive retrospective international study collecting clinical and genetic data of patients with mutations in the VCP gene. RESULTS: Two hundred and fifty-five patients (70.0% males) were included in the study. Mean age was 56.8±9.6 years and mean age of onset 45.6±9.3 years. Mean diagnostic delay was 7.7±6 years. Symmetric lower limb weakness was reported in 50% at onset progressing to generalised muscle weakness. Other common symptoms were ventilatory insufficiency 40.3%, PDB 28.2%, dysautonomia 21.4% and FTD 14.3%. Fifty-seven genetic variants were identified, 18 of these no previously reported. c.464G>A (p.Arg155His) was the most frequent variant, identified in the 28%. Full time wheelchair users accounted for 19.1% with a median time from disease onset to been wheelchair user of 8.5 years. Variant c.463C>T (p.Arg155Cys) showed an earlier onset (37.8±7.6 year) and a higher frequency of axial and upper limb weakness, scapular winging and cognitive impairment. Forced vital capacity (FVC) below 50% was as risk factor for being full-time wheelchair user, while FVC