Prominent phenotypic variability associated with mutations in Progranulin

https://doi.org/10.1016/j.neurobiolaging.2007.08.022Get rights and content

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 significantly both within and among kindreds. Some kindreds with PGRN mutations exhibited lateralized topography of degeneration across all affected individuals.

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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