Genotype-phenotype correlations in valosin-containing protein disease: a retrospective muticentre study

Marianela Schiava, Chiseko Ikenaga, Rocío Nur Villar-Quiles, Marta Caballero-Ávila, Ana Topf, Ichizo Nishino, Virginia Kimonis, Bjarne Udd, Benedikt Schoser, Edmar Zanoteli, Paulo Victor Sgobbi Souza, Giorgio Tasca, Thomas Lloyd, Adolfo Lopez-De Munain, Carmen Paradas, Elena Pegoraro, Aleksandra Nadaj-Pakleza, Jan De Bleecker, Umesh Badrising, Alicia Alonso-JiménezAnna Kostera-Pruszczyk, Francesc Miralles, Jin Hong Shin, Jorge Alfredo Bevilacqua, Montse Olivé, Matthias Vorgerd, Rudi Kley, Stefen Brady, Timothy Williams, Cristina Domínguez-González, George K. Papadimas, Jodi Warman, Kristl G. Claeys, Marianne De Visser, Nuria Muelas, Pascal Laforet, Edoardo Malfatti, Lindsay N. Alfano, Sruthi S. Nair, Georgios Manousakis, Hani A. Kushlaf, Matthew B. Harms, Christopher Nance, Alba Ramos-Fransi, Carmelo Rodolico, Channa Hewamadduma, Hakan Cetin, Jorge García-García, Endre Pál, Maria Elena Farrugia, Phillipa J. Lamont, Colin Quinn, Velina Nedkova-Hristova, Stojan Peric, Sushan Luo, Anders Oldfors, Kate Taylor, Stuart Ralston, Tanya Stojkovic, Conrad Weihl, Jordi Diaz-Manera

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

Background Valosin-containing protein (VCP) disease, caused by mutations in the VCP gene, results in myopathy, Paget's 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 <70% and being a full-time wheelchair user were associated with death. Conclusion This study expands the knowledge on the phenotypic presentation, natural history, genotype-phenotype correlations and risk factors for disease progression of VCP disease and is useful to improve the care provided to patient with this complex disease.

Original languageEnglish (US)
Pages (from-to)1099-1111
Number of pages13
JournalJournal of Neurology, Neurosurgery and Psychiatry
Volume93
Issue number10
DOIs
StatePublished - Oct 1 2022

Bibliographical note

Publisher Copyright:
© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.

Keywords

  • Frontotemporal dementia
  • Genetics
  • Incl body myositis
  • Muscle disease
  • Myopathy

PubMed: MeSH publication types

  • Journal Article

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