Phenotype variability in progranulin mutation carriers: a clinical, neuropsychological, imaging and genetic study

Abstract

Frontotemporal dementia (FTD), characterized by behavioural and language disorders, is a clinically, genetically and pathologically heterogeneous group of diseases. The most recently identified of the four known genes is GRN, associated with 17q-linked FTD with ubiquitin-immunoreactive inclusions. GRN was analysed in 502 probands with frontal variant FTD (fvFTD), FTD with motoneuron disease (FTD-MND), primary progressive aphasia (PPA) and corticobasal degeneration syndrome (CBDS). We studied the clinical, neuropsychological and brain perfusion characteristics of mutation carriers. Eighteen mutations, seven novel were found in 24 families including 32 symptomatic mutation carriers. No copy number variation was found. The phenotypes associated with GRN mutations vary greatly: 20/32 (63%) carriers had fvFTD, the other (12/32, 37%) had clinical diagnoses of PPA, CBDS, Lewy body dementia or Alzheimer's disease. Parkinsonism developed in 13/32 (41%), visual hallucinations in 8/32 (25%) and motor apraxia in 5/21 (24%). Constructional disorders were present in 10/21 (48%). Episodic memory disorders were frequent (16/18, 89%), consistent with hippocampal amnestic syndrome in 5/18 (28%). Hypoperfusion was observed in the hippocampus, parietal lobe and posterior cingulate gyrus, as well as the frontotemporal cortices. The frequency of mutations according to phenotype was 5.7% (20/352) in fvFTD, 17.9% (19/106) in familial forms, 4.4% in PPA (3/68), 3.3% in CBDS (1/30). Hallucinations, apraxia and amnestic syndrome may help differentiate GRN mutation carriers from others FTD patients. Variable phenotypes and neuropsychological profiles, as well as brain perfusion profiles associated with GRN mutations may reflect different patterns of neurodegeneration. Since all the mutations cause a progranulin haploinsufficiency, additional factors probably explain the variable clinical presentation of the disease.

Pathological correlates of white matter hyperintensities in a case of progranulin mutation associated frontotemporal dementia

“…White matter changes such as gliosis and demyelination have long been observed in histological studies of FTD (Englund & Brun, 1987) and several groups have observed significant WMH on MRI brain scans of GRN mutation carriers with FTD who lack vascular risk factors (Caroppo et al, 2014; Ameur et al, 2016; Kelley et al, 2009; Le Ber et al, 2008; Paternicò et al, 2016; Pietroboni et al, 2011; Sudre et al, 2017). However, studies that have characterized in detail the pathological correlates of WMH in GRN mutation associated FTD have until now been lacking.…”

“…However, WMH are less commonly seen in frontotemporal dementia (FTD). Several studies have now reported prominent WMH in patients with familial FTD due to progranulin ( GRN ) mutations (Caroppo et al, 2014; Ameur et al, 2016; Kelley et al, 2009; Le Ber et al, 2008; Paternicò et al, 2016; Pietroboni et al, 2011; Sudre et al, 2017) but the pathological changes underlying these have not previously been studied in detail.…”

Neuroimaging and Biochemical Markers in the Three Variants of Primary Progressive Aphasia

“…The other 2 familial nfvPPA cases presented the expanded hexanucleotide C9ORF72 mutation. Language dysfunction, nfvPPA or mixed PPA is a common presentation of GRN mutations [44]. The frequency of language disturbances at onset in C9ORF72 mutation carriers is variable across series, with 9–27% of patients presenting with nfvPPA [14,15].…”

Granulin mutation drives brain damage and reorganization from preclinical to symptomatic FTLD

“…The underlying mechanism from which PGRN haploinsufficiency determines TDP-43 inclusions and, subsequently, brain damage and the clinical onset of disease is unknown. The behavioral (bvFTD) and the progressive nonfluent aphasia (PNFA) variants of FTLD are the most typical presentations in GRN mutation carriers, with a clinical onset in the 5th and 6th decades of life (LeBer et al, 2008;Masellis et al, 2006;Rademakers et al, 2007;Snowden et al, 2006;Van Deerlin et al, 2007).…”