TY - JOUR
T1 - Genotype-phenotype correlations in valosin-containing protein disease
T2 - A retrospective muticentre study
AU - Schiava, Marianela
AU - Ikenaga, Chiseko
AU - Villar-Quiles, Rocío Nur
AU - Caballero-Ávila, Marta
AU - Topf, Ana
AU - Nishino, Ichizo
AU - Kimonis, Virginia
AU - Udd, Bjarne
AU - Schoser, Benedikt
AU - Zanoteli, Edmar
AU - Souza, Paulo Victor Sgobbi
AU - Tasca, Giorgio
AU - Lloyd, Thomas
AU - Lopez-de Munain, Adolfo
AU - Paradas, Carmen
AU - Pegoraro, Elena
AU - Nadaj-Pakleza, Aleksandra
AU - de Bleecker, Jan
AU - Badrising, Umesh
AU - Alonso-Jiménez, Alicia
AU - Kostera-Pruszczyk, Anna
AU - Miralles, Francesc
AU - Shin, Jin-Hong
AU - Bevilacqua, Jorge Alfredo
AU - Olivé, Montse
AU - Vorgerd, Matthias
AU - Kley, Rudi
AU - Brady, Stefen
AU - Williams, Timothy
AU - Domínguez-González, Cristina
AU - Papadimas, George K.
AU - Warman, Jodi
AU - Claeys, Kristl G.
AU - de Visser, Marianne
AU - Muelas, Nuria
AU - Laforet, Pascal
AU - Malfatti, Edoardo
AU - Alfano, Lindsay N.
AU - Nair, Sruthi S.
AU - Manousakis, Georgios
AU - Kushlaf, Hani A.
AU - Harms, Matthew B.
AU - Nance, Christopher
AU - Ramos-Fransi, Alba
AU - Rodolico, Carmelo
AU - Hewamadduma, Channa
AU - Cetin, Hakan
AU - García-García, Jorge
AU - Pál, Endre
AU - Farrugia, Maria Elena
AU - Lamont, Phillipa J.
AU - Quinn, Colin
AU - Nedkova-Hristova, Velina
AU - Peric, Stojan
AU - Luo, Sushan
AU - Oldfors, Anders
AU - Taylor, Kate
AU - Ralston, Stuart
AU - Stojkovic, Tanya
AU - Weihl, Conrad
AU - Diaz-Manera, Jordi
AU - VCP International Study Group
AU - Warman-Chardon, Jodi
N1 - Publisher Copyright: © Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.
PY - 2022/10/1
Y1 - 2022/10/1
N2 - 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.
AB - 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.
KW - Frontotemporal dementia
KW - Genetics
KW - Incl body myositis
KW - Muscle disease
KW - Myopathy
UR - http://www.scopus.com/inward/record.url?scp=85135725421&partnerID=8YFLogxK
U2 - https://doi.org/10.1136/jnnp-2022-328921
DO - https://doi.org/10.1136/jnnp-2022-328921
M3 - Article
C2 - 35896379
SN - 0022-3050
VL - 93
SP - 1099
EP - 1111
JO - Journal of Neurology, Neurosurgery and Psychiatry
JF - Journal of Neurology, Neurosurgery and Psychiatry
IS - 10
M1 - 328921
ER -