Frequency and clinical characteristics of progranulin mutation carriers in the Manchester frontotemporal lobar degeneration cohort: comparison with patients with MAPT and no known mutations

Abstract

Two hundred and twenty-three consecutive patients fulfilling clinical diagnostic criteria for frontotemporal lobar degeneration (FTLD), and 259 patients with motor neuron disease (MND), for whom genomic DNA was available, were investigated for the presence of mutations in tau (MAPT) and progranulin (PGRN) genes. All FTLD patients had undergone longitudinal neuropsychological and clinical assessment, and in 44 cases, the diagnosis had been pathologically confirmed at post-mortem. Six different PGRN mutations were found in 13 (6%) patients with FTLD. Four apparently unrelated patients shared exon Q415X 10 stop codon mutation. However, genotyping data revealed all four patients shared common alleles of 15 SNPs from rs708386 to rs5848, defining a 45.8-kb haplotype containing the whole PGRN gene, suggesting they are related. Three patients shared exon 11 R493X stop codon mutation. Four patients shared exon 10 V452WfsX38 frameshift mutation. Two of these patients were siblings, though not apparently related to the other patients who in turn appeared unrelated. One patient had exon 1 C31LfsX34 frameshift mutation, one had exon 4 Q130SfsX130 frameshift mutation and one had exon 10 Q468X stop codon mutation. In addition, two non-synonymous changes were detected: G168S change in exon 5 was found in a single patient, with no family history, who showed a mixed FTLD/MND picture and A324T change in exon 9 was found in two cases; one case of frontotemporal dementia (FTD) with a sister with FTD+MND and the other in a case of progressive non-fluent aphasia (PNFA) without any apparent family history. MAPT mutations were found in 17 (8%) patients. One patient bore exon 10 + 13 splice mutation, and 16 patients bore exon 10 + 16 splice mutation. When PGRN and MAPT mutation carriers were excluded, there were no significant differences in either the allele or genotype frequencies, or haplotype frequencies, between the FTLD cohort as a whole, or for any clinical diagnostic FTLD subgroup, and 286 controls or between MND cases and controls. However, possession of the A allele of SNP rs9897526, in intron 4 of PGRN, delayed mean age at onset by approximately 4 years. Patients with PGRN and MAPT mutations did not differ significantly from other FTLD cases in terms of gender distribution or total duration of illness. However, a family history of dementia in a first-degree relative was invariably present in MAPT cases, but not always so in PGRN cases. Onset of illness was earlier in MAPT cases compared to PGRN and other FTLD cases. PNFA, combined with limb apraxia was significantly more common in PGRN mutation cases than other FTLD cases. By contrast, the behavioural disorder of FTD combined with semantic impairment was a strong predictor of MAPT mutations. These findings complement recent clinico-pathological findings in suggesting identifiable associations between clinical phenotype and genotype in FTLD.

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

“…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).…”

“…Furthermore, other neurodegenerative brain diseases including corticobasal syndrome (CBS) [Masellis et al, 2006;Benussi et al, 2008;Rademakers et al, 2007;Le Ber et al, 2007;Lopez de Munain et al, 2008;Spina et al, 2007b;Le Ber et al, 2008], AD [van Duijn et al, 1994;Rademakers et al, 2002;Brouwers et al, 2007;Rademakers et al, 2007] and PD [Brouwers et al, 2007] were also linked with GRN mutations. However, compared to variants with unclear pathogenic significance, GRN null mutations were not frequently found in patients with a disease other than FTLD Schymick et al, 2007;Brouwers et al, 2007;Sleegers et al, in press;Pickering-Brown et al, 2008].…”

“…The role of GRN as a risk factor in FTLD and other neurodegenerative diseases has not yet been extensively explored. To date, two association studies were reported, one in an ALS series [Sleegers et al, in press] and one in an FTLD and ALS series [Pickering-Brown et al, 2008]. Sleegers et al [in press] showed that genetic variability in GRN reduces age at onset and disease duration in ALS patients; although, overall, a disease association was absent in both studies [Sleegers et al, in press; PickeringBrown et al, in press].…”

Syndromes of nonfluent primary progressive aphasia

“…Various other phenotypes have also been described. 4,[12][13][14][15] Furthermore, nonfluent PPA is pathologically heterogeneous with tau, TDP-43 and Alzheimer pathology all described. [16][17][18][19][20][21] Despite recent progress, a number of key issues remain unresolved: these include the relationship of agrammatism to AOS, and the place of these features in defining nonfluent PPA; relations between PNFA and LPA; and the nosology of nonfluent PPA more broadly.…”

Frontotemporal Lobar Degeneration

“…In a large series from the USA, mutations were found in 10 % of all patients with FTLD and 23 % in cases of familial FTLD (Gass, Cannon et al 2006). Several other studies from France, Italy, the Netherlands, the UK, Belgium, Finland, and the USA have reported lower frequencies of on average 5 % in unselected FTLD groups and 4-10 % in groups of cases of familial FTLD (Le Ber, Camuzat et al 2008;Le Ber, van der Zee et al 2007;Bruni, Momeni et al 2007;Borroni, Archetti et al 2008;Bronner, Rizzu et al 2007; Pickering-Brown, Rollinson et al 2008;Cruts, Gijselinck et al 2006;Gijselinck, van der Zee et al 2008;Gass, Cannon et al 2006;Huey, Grafman et al 2006). The differences in the reported frequencies may be due to differences in the mode of ascertainment of patients, in ethnic variations as well as to founder effects.…”