FTD-PSP is an Unusual Clinical Phenotype in A Frontotemporal Dementia Patient with A Novel Progranulin Mutation

Abstract

Progranulin (GRN) mutations are a major cause of frontotemporal dementia (FTD); the spectrum of clinical phenotypes of FTD is much more extensive than previously reported. The frequency and locations of GRN mutations in Chinese patients with FTD remain uncertain. We performed cDNA sequencing in one sporadic male patient who initially presented FTD symptoms. Brain magnetic resonance imaging (MRI) and positron emission computed tomography/computed tomography (PET/CT) were applied to further confirm the diagnosis of FTD from this patient. Cellular apoptosis and survival test were performed to identify the function of GRN. We identified one novel missense GRN mutation (c.1498G>A, p.V500I) in this patient, who initially presented typical behavioral-variant frontotemporal dementia (bvFTD) features but then presented progressive supranuclear palsy (PSP) clinical characteristics 5 years after onset. Besides, WT GRN protein showed an adequate trophic stimulus to preserve the survival of SH-SY5Y cells in the medium free of serum, while GRN mutation (c.1498G>A, p.V500I) may impair the ability of supporting cell survival. This study owns significant implications for genetic counseling and clinical heterogeneity. We illustrate the fact that FTD presenting features of bvFTD and PSP in one patient could be considered as a specific phenotype in patients with GRN mutations. GRN p.V500I led to the neuronal degeneration in vitro; this finding provides a significant evidence that this mutation may be a new causative mutation in patients with FTD.

Keywords: Parkinson Syndrome; Progranulin; frontotemporal dementia; mutation; progressive supranuclear palsy.

Figure 1.

Different clinical subtypes of FTD.

Figure 2.

Neuroimaging characteristic of the patient with GRN mutations. (A and B) Axial T2-weighted images showing bilateral lateral fissure deepened and widened (arrow) and dilatation of temporal horn of lateral ventricle (arrow). (C) Sagittal T2-weighted images showing mild generalized cortical atrophy. (D-F) ¹⁸F-DOPA PET/CT scans showing profoundly reduced DOPA metabolism in bilateral corpus striatum (arrow). (G-I)¹⁸F-FDG PET/CT scans showing a symmetrically reduced glucose metabolism in bilateral frontal lobe (arrow). (J-L) ¹⁸F-FDG PET/CT scans showing a symmetrically reduced glucose metabolism in bilateral temporal lobe (arrow). (M) This photograph showing the impossibility of the patient to look downward with the guidance of a neurologist. (N) This photograph showing the difficulty of the patient to look upward with the guidance of a neurologist.

Figure 3.

Genetic sequencing analyses.

Figure 4.

GRN mutation over-expression increases apoptosis of SH-SY5Y cells. Mutant GRN loss the ability to support SH-SY5Y cell survival after the removal of serum. (A) Western Blot analysis confirmed presence of GRN after transfection. (B, E) SH-SY5Y cells transfected with control vector only. (C, F) Transfected with WT hGRN. (D, G) Transfected with mutant V500I. (B-D) Micrographs showing the distribution of DAPI and TxRed. (E-G) Micrographs showing the survival of cells. (H) CCK-8 test showing the cell viability. (I) The quantitative result of fluorescence showing the cell apoptosis. (J) The quantitative result of cell number showing the cell viability.