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

Schiava, M.; Ikenaga, C.; Villar-Quiles, R.N.; Caballero-Avila, M.; Topf, A.; Nishino, I.; ... ; VCP Int Study Grp (2022)

Article / Letter to editor

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 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.

• MUSCLE DISEASE
• GENETICS
• MYOPATHY
• INCL BODY MYOSITIS
• FRONTOTEMPORAL DEMENTIA

• All authors: Schiava, M.; Ikenaga, C.; Villar-Quiles, R.N.; Caballero-Avila, M.; Topf, A.; Nishino, I.; Kimonis, V.; Udd, B.; Schoser, B.; Zanoteli, E.; Souza, P.V.S.; Tasca, G.; Lloyd, T.; Lopez-de Munain, A.; Paradas, C.; Pegoraro, E.; Nadaj-Pakleza, A.; Bleecker, J. de; Badrising, U.; Alonso-Jimenez, A.; Kostera-Pruszczyk, A.; Miralles, F.; Shin, J.H.; Bevilacqua, J.A.; Olive, M.; Vorgerd, M.; Kley, R.; Brady, S.; Williams, T.; Dominguez-Gonzalez, C.; Papadimas, G.K.; Warman, J.; Claeys, K.G.; Visser, M. de; Muelas, N.; LaForet, P.; Malfatti, E.; Alfano, L.N.; Nair, S.S.; Manousakis, G.; Kushlaf, H.A.; Harms, M.B.; Nance, C.; Ramos-Fransi, A.; Rodolico, C.; Hewamadduma, C.; Cetin, H.; Garcia-Garcia, J.; Pal, E.; Farrugia, M.E.; Lamont, P.J.; Quinn, C.; Nedkova-Hristova, V.; Peric, S.; Luo, S.S.; Oldfors, A.; Taylor, K.; Ralston, S.; Stojkovic, T.; Weihl, C.; Diaz-Manera, J.; VCP Int Study Grp
• Date: 2022-07-27
• Journal: Journal of Neurology, Neurosurgery and Psychiatry
• Volume: 93
• Issue: 10
• Pages: 1099 - 1111
• DOI: doi:10.1136/jnnp-2022-328921