Posterior Cortical Atrophy as an Extreme Phenotype ofGRNMutations

Abstract

Figure 2), which is rather different from PCA with AD pathologic features. In the latter process, the damage remains relatively centered on the posterior lobes, even in the late stage. 1,15 Conclusions This study enlarges the mutational spectrum of PCA to GRN mutations and provides evidence that GRN analyses could be indicated in PCA, particularly when the damage progresses to the anterior cerebral regions and a family history of dementia is present. The link between PCA and genetic forms of FTLD is supported by the recent identification of a MAPT mutation in 1 case of PCA. 16 Analyses of genes in FTLD in patient cohorts will be necessary to better evaluate their genetic contribution to PCA. Finally, this study underlines a possible continuum in degenerative dementias and highlights the limits of actual nosologic boundaries. Clarifying these boundaries by identifying factors driving phenotypic heterogeneity will have important implications for the definition of new diagnosis criteria of degenerative dementias and recruitment for clinical trials in the future. ARTICLE INFORMATION

Clinical, FDG and amyloid PET imaging in posterior cortical atrophy

“…These clinical features differ from those of typical dementia of the Alzheimer’s type (DAT) as they show preservation of memory, insight, and judgment until late in the clinical course, when the clinical features of PCA and DAT overlap [3]. The most frequent pathological findings in PCA are tau neurofibrillary tangles and beta-amyloid neuritic plaques which are characteristic of Alzheimer’s disease [4], although other pathologies have been described in PCA including corticobasal degeneration, diffuse Lewy body disease, and Creutzfeldt-Jakob disease [5–7]; frontotemporal dementia with progranulin mutation has also been reported [8]. …”

Evaluating pathogenic dementia variants in posterior cortical atrophy

“…Until recently, mutation screens in PCA have been limited to case reports which identified PSEN1 I211M (Sitek et al, 2013), PSEN1 G223R (Saint-Aubert et al, 2013), PSEN2 M239I (Tremolizzo et al, 2014), MAPT V363I (Rossi et al, 2014), GRN R110X (Caroppo et al, 2015), in addition to a family with PCA phenotype in which a 120 base pair octapeptide repeat insertion mutation was identified within PRNP (Depaz et al, 2012). A mutation screen of known dementia genes in a cohort of 227 early-onset probable AD subjects revealed PSEN1 P218L and PSEN1 I238M mutations in two subjects with memory and vision loss, although this was not a specific screen for PCA (Wojtas et al, 2012).…”

“…To date, there are six case reports of PCA patients with mutations in known dementia genes (Caroppo et al, 2015; Depaz et al, 2012; Rossi et al, 2014; Saint-Aubert et al, 2013; Sitek et al, 2013; Tremolizzo et al, 2014). Of these six variants, four ( PSEN1 G223R, PSEN2 M239I, MAPT V363I, and GRN R110X) are listed in the AD&FTDMUTDB, as “pathogenic”, but only PSEN2 M239I is included on the NeuroX array.…”

“…Further, given that the onset age for PCA is generally younger, thus often prompting clinical genetic screens, discovery of the full pathogenic mutation spectrum that can lead to PCA can aid the clinician in the choice of genetic tests. To date, there are only case reports of PCA subjects with missense variants in genes previously implicated in early-onset AD (EOAD) (Saint-Aubert et al, 2013; Sitek et al, 2013; Tremolizzo et al, 2014), frontotemporal dementia (FTD) (Caroppo et al, 2015; Rossi et al, 2014), and Creutzfeldt-Jakob disease (CJD) (Depaz et al, 2012). …”

A Case of Posterior Cortical Atrophy with Complex Set of Symptoms and Rapid Course

“…PCA is reported as sporadic disorder but the genetic research could be useful in the atypical cases, to confirm the clinical hypothesis [14,15]. A recent classification distinguishes two variants of PCA: a pure-PCA, which meets the clinic-radiological criteria for PCA; a PCA-plus, with additional features that direct diagnosis to CBD, LBD or CJD [16].…”