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

M. Schiava, C. Ikenaga, R. N. Villar-Quiles, M. Caballero-Avila, A. Topf, I. Nishino, V. Kimonis, B. Udd, B. Schoser, E. Zanoteli, P. V. Sgobbi Souza, Giorgio Tasca, T. Lloyd, A. Lopez-De Munain, C. Paradas, E. Pegoraro, A. Nadaj-Pakleza, J. De Bleecker, U. Badrising, A. Alonso-JimenezA. Kostera-Pruszczyk, F. Miralles, J. -H. Shin, J. A. Bevilacqua, M. Olive, M. Vorgerd, R. Kley, S. Brady, T. Williams, C. Dominguez-Gonzalez, G. K. Papadimas, J. Warman-Chardon, K. G. Claeys, M. de Visser, N. Muelas, P. Laforet, E. Malfatti, L. N. Alfano, S. S. Nair, G. Manousakis, H. A. Kushlaf, M. B. Harms, C. Nance, A. Ramos-Fransi, C. Rodolico, C. Hewamadduma, H. Cetin, J. Garcia-Garcia, E. Pal, M. E. Farrugia, P. J. Lamont, C. Quinn, V. Nedkova-Hristova, S. Peric, S. Luo, A. Oldfors, K. Taylor, S. Ralston, T. Stojkovic, C. Weihl, J. Diaz-Manera, A. Martinez-Pineiro, A. Topf, A. Kaminska, A. Mayhew, A. Rydelius, A. Behin, A. Toscano, A. H. Lain, B. Lannes, B. Velez, B. Kierdaszuk, B. De Paepe, B. Eymard, C. M. Cazcarra, C. Paradasa, C. Hedberg-Oldfors, C. Longman, C. M. Bettollo, C. Papadopoulos, C. Metay, D. Hilton-Jones, E. Zanotelli, E. A. Harrington, E. Eline, E. Gelpi, E. Rivas, F. Miralles, G. Soraru, G. Bisogni, G. Lucente, G. Bassez, J. Francois, J. -B. Chanson, J. Lin, J. Skeoch, J. Palmio, J. Baets, J. A. Perez, J. Diaz, J. J. Vilchez, J. Hudson, K. Hadzsiev, L. Bello, M. Campero, Mario Sabatelli, M. Masingue, Mauro Monforte, M. James, M. Guglieri, M. Inoue, M. Povedano, M. Hofer, M. Olive, N. Garcia-Angarita, N. Earle, N. V. Sarro, P. Laforet, P. Rihard, P. de Jonghe, P. Riguzzi, P. Camano, R. D. Rubio, R. Carlier, R. Muni-Lofra, R. Fernandez-Torron, R. Alvarez, S. Krause, S. Leonard-Louis, S. Souvannanorath, S. Klotz, S. Thiele, S. Xirou, T. Evangelista, T. Grider, V. Rakocevic-Stojanovic, V. Straub, W. Zhu, W. de Ridder, W. Kelly, Y. Saito, Y. -E. Park, Y. Nishimori, Z. Sahenk

Risultato della ricerca: Contributo in rivistaArticolo in rivista

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.
Lingua originaleEnglish
pagine (da-a)1099-1111
Numero di pagine13
RivistaJournal of Neurology, Neurosurgery and Psychiatry
Volume93
DOI
Stato di pubblicazionePubblicato - 2022

Keywords

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

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