Characteristics of frontotemporal dementia patients with a Progranulin mutation

Abstract

Objective-Mutations in the Progranulin gene (PGRN) recently have been discovered to be associated with frontotemporal dementia (FTD) linked to 17q21 without identified MAPT mutations. The range of mutations of PGRN that can result in the FTD phenotype and the clinical presentation of patients with PGRN mutations have yet to be determined.Methods-In this study, we examined 84 FTD patients from families not known previously to have illness linked to chromosome 17 for identified PGRN and MAPT mutations and sequenced the coding exons and the flanking intronic regions of PGRN. We compared the prevalence, clinical characteristics, magnetic resonance imaging and 18-fluoro-deoxyglucose positron emission tomography results, and neuropsychological testing of patients with the PGRN R493X mutation with those patients without identified PGRN mutations.Results-We discovered a new PGRN mutation (R493X) resulting in a stop codon in two patients. This was the only PGRN mutation identified in our sample. The patients with the PGRN R493X mutation had a rapid illness course and had predominant right-sided atrophy and hypometabolism on magnetic resonance imaging and 18-fluoro-deoxyglucose positron emission tomography. The affected father of one of the patients with the PGRN R493X mutation showed frontal and temporal atrophy without neurofibrillary tangles on neuropathological examination.Interpretation-Known PGRN and MAPT mutations were rare and of similar prevalence in our sample (2 compared with 1/84). The patients with the PGRN R493X mutation had a clinical presentation comparable with other behavior-predominant FTD patients. The neuropathology of an affected family member of a patient with the PGRN R493X mutation appears not to be Alzheimer's disease. Frontotemporal dementia (FTD) is an umbrella term for a set of progressive disorders affecting predominantly the frontal and/or the anterior temporal lobes of the brain. FTD usually presents clinically with behavior or language changes, or both, and is associated with atrophy and decreased metabolism of the frontal and anterior temporal lobes on imaging. 1,2 The mean age of onset for FTD is in the mid-50s. 3,4 It is the second most common cause of dementia in people younger than 65 (after Alzheimer's disease), comprising approximately one third of these cases. 4,5 Between 35 and 50% of cases are reported to have a family history of FTD. [4][5][6][7][8][9][10] In the majority of these cases, the illness is inherited in a manner consistent with an autosomal dominant mechanism. 5,6,9 Fourteen percent of FTD patients have clinical motor neuron disease (MND), 11 and up to about 40% of patients with behavioral variant FTD show MND-type inclusions. 12 Several mutations have been associated with rare cases of FTD. 13 Mutations in the MAPT gene at 17q21 coding for the tau protein are the most commonly associated with FTD. 14-18 More than 30 MAPT mutations associated with the development of FTD have been discovered (a list of these mutations is available online at: http://www.molgen...

Prominent phenotypic variability associated with mutations in Progranulin

“…Some had progressive asymmetric rigidity and apraxia characteristic of the corticobasal syndrome (Boeve et al 2003). These findings extend the range of phenotypes beyond those of previously published kindreds having PGRN mutations Huey et al 2006;Masellis et al 2006;Mukherjee et al 2006;Snowden et al 2006;Mesulam et al 2007;Spina et al 2007). …”

Granulin mutations associated with frontotemporal lobar degeneration and related disorders: An update

“…These higher frequencies can be explained by the presence of a strong founder effect of the Family DR8 founder mutation IVS115G4C in 8 out of 12 Belgian mutation carriers and the p.R493X mutation in 8 out of 39 U.S. mutation carriers, respectively . In addition, the number of studied patients was relatively low in some other studies [Huey et al, 2006;Bronner et al, 2007;Bruni et al, 2007]. Also, differences in patient recruitment methods, selection criteria, and geographical origin may account for the differences in mutation frequencies.…”

“…The loss of functional protein is mainly the result of loss of GRN transcript caused by NMD of transcripts containing PTCs (n 5 52) or by nuclear degradation of transcripts retaining the first intron due to splice-site mutations in intron 1 (n 5 2) Le Ber et al, 2007]. PTCs can be the result from nonsense mutations (n 5 12), splice-site mutations (n 5 10), and small insertions/deletions (n 5 30) Baker et al, 2006;Huey et al, 2006;Pickering-Brown et al, 2006Boeve et al, 2006;Masellis et al, 2006;Gass et al, 2006;Benussi et al, 2008;Bronner et al, 2007;Mesulam et al, 2007;Behrens et al, 2007;Leverenz et al, 2007;Bruni et al, 2007;Van Deerlin et al, 2007;Brouwers et al, 2007;Rademakers et al, 2007;Llado et al, 2007;Le Ber et al, 2007;Davion et al, 2007;Kelley et al, in press;Spina et al, 2007a;Mukherjee et al, 2008;Beck et al, 2008;Le Ber et al, 2008]. Second, loss of translation as a result of mutations affecting the Kozak sequence (n 5 4) Baker et al, 2006;Pickering-Brown et al, 2006;Boeve et al, 2006;Gass et al, 2006;Le Ber et al, 2008] and reduction of secreted protein due to missense mutations affecting the signal sequence (n 5 2) [Mukherjee et al, 2006;Gass et al, 2006;Kelley et al, in press;Mukherjee et al, 2008;Le Ber et al, 2008], results in reduced GRN.…”

“…Eight studies estimated the GRN mutation frequency in different FTLD series (Table 3) Baker et al, 2006;Huey et al, 2006;Gass et al, 2006;Bronner et al, 2007;Bruni et al, 2007;Le Ber et al, 2007Gijselinck et al, 2008;Pickering-Brown et al, 2008]. The mutation frequencies differed greatly between the different studies ranging from 1.3 to 11.7% in the total group of patients and from 3.4 to 25.6% when only familial patients were considered (Table 3).…”

Mutations other than null mutations producing a pathogenic loss of progranulin in frontotemporal dementia

“…These include 18 frameshift mutations, 7 splice site mutations, 9 nonsense mutations, 1 missense mutation in the signal peptide and 2 mutations destroying the Met1 translation initiation codon Cruts et al, 2006a;Gass et al, 2006;Mukherjee et al, 2006;Huey et al, 2006;Bronner et al, 2006;Le Ber et al, 2007]. Also a splice site mutation that leads to exon 1 skipping, removed the Met1 codon and associated Kozac sequence .…”