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

Lookup NU author(s): Professor Giorgio TascaORCiD, Professor Jordi Diaz ManeraORCiD


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

Publication metadata

Author(s): Schiava M, Ikenaga C, Villar-Quiles RN, Caballero-Avila M, Topf A, Nishino I, Kimonis V, Udd B, Schoser B, Zanoteli E, Souza PVS, Tasca G, Lloyd T, Lopez-De Munain A, Paradas C, Pegoraro E, Nadaj-Pakleza A, De Bleecker J, Badrising U, Alonso-Jimenez A, Kostera-Pruszczyk A, Miralles F, Shin J-H, Bevilacqua JA, Olive M, Vorgerd M, Kley R, Brady S, Williams T, Dominguez-Gonzalez C, Papadimas GK, Warman J, Claeys KG, De Visser M, Muelas N, Laforet P, Malfatti E, Alfano LN, Nair SS, Manousakis G, Kushlaf HA, Harms MB, Nance C, Ramos-Fransi A, Rodolico C, Hewamadduma C, Cetin H, Garcia-Garcia J, Pal E, Farrugia ME, Lamont PJ, Quinn C, Nedkova-Hristova V, Peric S, Luo S, Oldfors A, Taylor K, Ralston S, Stojkovic T, Weihl C, Diaz-Manera J

Publication type: Article

Publication status: Published

Journal: Journal of Neurology, Neurosurgery and Psychiatry

Year: 2022

Volume: 93

Issue: 10

Pages: 1099-1111

Print publication date: 01/10/2022

Online publication date: 27/07/2022

Acceptance date: 28/06/2022

ISSN (print): 0022-3050

ISSN (electronic): 1468-330X

Publisher: BMJ Publishing Group


DOI: 10.1136/jnnp-2022-328921

PubMed id: 35896379


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