Three VCP Mutations in Patients with Frontotemporal Dementia

Article type: Research Article

Authors: Wong, Tsz Hang^a | Pottier, Cyril^b | Hondius, David C.^c | Meeter, Lieke H.H.^a | van Rooij, Jeroen G.J.^{a; d} | Melhem, Shami^a | The Netherlands Brain bank^e | van Minkelen, Rick^f | van Duijn, Cornelia M.^g | Rozemuller, Annemieke J.M.^c | Seelaar, Harro^a | Rademakers, Rosa^b | van Swieten, John C.^{a; *}

Affiliations: [a] Alzheimer center and Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands | [b] Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL, USA | [c] Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands | [d] Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands | [e] Netherlands Institute for Neuroscience, Amsterdam, The Netherlands | [f] Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands | [g] Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands

Correspondence: [*] Correspondence to: Prof. John C. van Swieten, MD, PhD, Department of Neurology, Erasmus Medical Centre Rotterdam, ’s-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands. Tel.: +3110 7033274; E-mail: j.c.vanswieten@erasmusmc.nl.

Abstract: Valosin-containing protein (VCP) is involved in multiple cellular activities. Mutations in VCP lead to heterogeneous clinical presentations including inclusion body myopathy with Paget’s disease of the bone, frontotemporal dementia and amyotrophic lateral sclerosis, even in patients carrying the same mutation. We screened a cohort of 48 patients with familial frontotemporal dementia (FTD) negative for MAPT, GRN, and C9orf72 mutations for other known FTD genes by using whole exome sequencing. In addition, we carried out targeted sequencing of a cohort of 37 patients with frontotemporal lobar degeneration with Transactive response DNA-binding protein 43 (TDP-43) subtype from the Netherlands Brain bank. Two novel (p.Thr262Ser and p.Arg159Ser) and one reported (p.Met158Val) VCP mutations in three patients with a clinical diagnosis of FTD were identified, and were absence in population-match controls. All three patients presented with behavioral changes, with additional semantic deficits in one. No signs of Paget or muscle disease were observed. Pathological examination of the patient with VCP p.Arg159Ser mutation showed numerous TDP-43 immunoreactive (IR) neuronal intranuclear inclusions (NII) and dystrophic neurites (DN), while a lower number of NII and DN were observed in the patient with the VCP p.Thr262Ser mutation. Pathological findings of both patients were consistent with FTLD-TDP subtype D. Furthermore, only rare VCP-IR NII was observed in both cases. Our study expands the clinical heterogeneity of VCP mutations carriers, and indicates that other additional factors, such as genetic modifiers, may determine the clinical phenotype.

Keywords: Frontotemporal dementia, frontotemporal lobar degeneration, next generation sequencing, TDP-43, VCP gene

DOI: 10.3233/JAD-180301

Journal: Journal of Alzheimer's Disease, vol. 65, no. 4, pp. 1139-1146, 2018