Prominent phenotypic variability associated with mutations in Progranulin

Abstract

Mutations in progranulin (PGRN) are associated with frontotemporal dementia with or without parkinsonism. We describe the prominent phenotypic variability within and among eight kindreds evaluated at Mayo Clinic Rochester and/or Mayo Clinic Jacksonville in whom mutations in PGRN were found. All available clinical, genetic, neuroimaging and neuropathologic data was reviewed. Age of onset ranged from 49 to 88 years and disease duration ranged from 1 to 14 years. Clinical diagnoses included frontotemporal dementia (FTD), primary progressive aphasia, FTD with parkinsonism, parkinsonism, corticobasal syndrome, Alzheimer's disease, amnestic mild cognitive impairment, and others. One kindred exhibited maximal right cerebral hemispheric atrophy in all four affected individuals, while another had maximal left hemisphere involvement in all three of the affected. Neuropathologic examination of 13 subjects revealed frontotemporal lobar degeneration with ubiquitin-positive inclusions plus neuronal intranuclear inclusions in all cases. Age of onset, clinical phenotypes and MRI findings associated with most PGRN mutations varied

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

“…This is consistent with correlations described in other imaging studies (Caroppo et al, 2014; Ameur et al, 2016; Kelley et al, 2009; Sudre et al, 2017). Using precise anatomical correlation of cadaveric MRI brain images with tissue slices, we were also able to demonstrate that regions with the most severe WMH displayed the most severe cortical pathology on histological analysis.…”

“…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.…”

“…Increasing evidence implicates GRN in regulation of neuroinflammation (Chitramuthu, Bennett, & Bateman, 2017), particularly in microglial activation and function (Lui et al, 2016). A study of two GRN mutation carriers observed significant microgliosis broadly corresponding to areas of WMH on MRI (Kelley et al, 2009). White matter lesions in GRN mutation carriers could therefore be due to chronic neuroinflammation, and we hypothesized that WMH in our GRN mutation carrier would be associated with regional differences in microglia.…”

“…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.…”

Progranulin plasma levels as potential biomarker for the identification of GRN deletion carriers. A case with atypical onset as clinical amnestic Mild Cognitive Impairment converted to Alzheimer's disease

“…Our patient also showed a significant improvement of extrapyramidal symptoms after Levodopa treatment (300 mg/day), which is not a common feature in FTDP-17. In fact, the majority of patients carrying a GRN mutation usually show no or modest improvement with Levodopa [4,16], although few cases of responders have been reported [17].…”