Prominent phenotypic variability associated with mutations in Progranulin
Introduction
In 1892, Arnold Pick first described behavioral and language abnormalities in association with frontotemporal lobar degeneration. Subsequently, many familial cases of frontotemporal dementia with parkinsonism were linked to chromosome 17 (FTDP-17) (Foster et al., 1997). Some were associated with mutations in the microtubule associated protein tau (MAPT) (Hutton et al., 1998, Ingram and Spillantini, 2002) while others were not (Kertesz et al., 2000, Rademakers et al., 2002, Mackenzie et al., 2006b). Many cases of FTDP-17 did not exhibit immunostaining for tau on pathologic examination (Kertesz et al., 2000, Rosso et al., 2001, Savioz et al., 2003, Mackenzie et al., 2006b, van der Zee et al., 2006), and mutations in MAPT were absent in all of these. We recently reported several FTDP-17 kindreds having frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) neuropathology in association with mutations in the gene encoding Progranulin (PGRN) (Baker et al., 2006, Boeve et al., 2006, Gass et al., 2006, Mackenzie et al., 2006b). The eight families described here extend the phenotypic and MRI findings associated with mutations in PGRN and highlight the variability in presentation, clinical course and neuroimaging findings within and among kindreds.
Section snippets
Subjects
Mutations in PGRN were identified in eight families whose probands were evaluated at Mayo Clinic Rochester (n = 6) or Mayo Clinic Jacksonville (n = 2). At least one affected individual from each family was enrolled in the Mayo Clinic Alzheimer Disease Research Center, a Mayo Foundation Institutional Review Board-approved program. All available clinical records and neuroimaging studies on affected members of these kindreds were reviewed. Genetic analyses, MRI scans, and autopsies were performed
Family descriptions
Pedigrees are shown in Fig. 1. Clinical, radiologic, and neuropathologic findings are summarized in Table 1, with additional clinical details presented in Table 2. Representative MRI scans are shown in Fig. 2, Fig. 3 is a schematic drawing localizing the mutations in PGRN. Descriptions of Kindred 7 (Mesulam et al., 2007), two members of Kindred 1 (Boeve et al., 2002) and the proband of Kindred 5 (Boeve et al., 2006) have previously been reported.
Demographics
Symptom onset among 38 individuals ranged from 49
Clinical considerations
Our data suggest a wide spectrum of cognitive, behavioral, and motor features in FTDP-17 associated with mutations in PGRN. Clinical findings characteristic of FTDP-17 – cognitive impairment (executive dysfunction and/or aphasia), behavioral changes and parkinsonism – comprise the core phenotypic features, but specific clinical and radiologic features varied widely. Prominent early memory impairment – typical of amnestic MCI and Alzheimer's disease (and an exclusionary criterion for the
Conflict of interest
None.
Acknowledgments
This research is supported by National Institute on Aging grants AG06786, AG16574, AG11378 and AG07216, and the Robert H. and Clarice Smith and Abigail Van Buren Alzheimer's Disease Research Program of the Mayo Foundation. RR is a postdoctoral fellow from the Fund for Scientific Research Flanders (FWO-F). We thank the Mayo Clinic Alzheimer's Disease Research Center staff for their assistance in evaluating the subjects. We particularly thank the members of these eight families for participating
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