Frequency and clinical characteristics of progranulin
mutation carriers in the Manchester frontotemporal
lobar degeneration cohort: comparison with patients
with MAPTand no known mutations
Stuart M. Pickering-Brown,1Sara Rollinson,1Daniel Du Plessis,2Karen E. Morrison,3AnoopVarma,1,2
Anna M.T . Richardson,1,2David Neary,1,2Julie S. Snowden1,2and David M. A. Mann1,2
1Clinical Neuroscience Research Group, Faculty of Medical and Human Sciences,University of Manchester,Oxford Rd,
Manchester M13 9PT,2Greater Manchester Neurosciences Centre, Hope Hospital, Salford Royal Hospitals NHS Foundation
Trust, Salford M6 8HD and3Department of Clinical Neurosciences,Division of Neuroscience,The Medical School,University
of Birmingham, Edgbaston, Birmingham B15 2TTand Queen Elizabeth Hospital,University Hospitals Birmingham NHS
FoundationTrust, Birmingham B15 2TH,UK
Correspondence to: Dr Stuart Pickering-Brown,Clinical Neuroscience Research Group, Faculty of Medical and Human
Sciences,University of Manchester,Oxford Rd, Manchester M13 9PT,UK
T wo hundred and twenty-three consecutive patients fulfilling clinicaldiagnostic criteria for frontotemporallobar
degeneration (FTLD), and 259 patients with motor neuron disease (MND), for whom genomic DNAwas avail-
able, 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
hadbeen pathologicallyconfirmed at post-mortem. Sixdifferent PGRN mutations were foundin13 (6%) patients
with FTLD.Four apparently unrelated patients shared exon Q415X10 stop codon mutation.However, genotyp-
ing data revealed all four patients shared common alleles of15 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. T wo of these patients
were siblings, though not apparently related to the other patients who in turn appeared unrelated.One patient
had exon1C31LfsX34 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,
and16 patients bore exon10+16 splice mutation.When PGRNand 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 »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 dis-
order 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 pheno-
type and genotype in FTLD.
Keywords: progranulin; tau; MAPT; progressive non-fluent aphasia; apraxia; frontotemporal dementia; genetics
doi:10.1093/brain/awm331Brain (2008),131, 721^731
? The Author (2008).Publishedby Oxford University Pressonbehalfofthe Guarantorsof Brain. Allrightsreserved.For Permissions, please email: email@example.com
by guest on May 31, 2013
Abbreviations: ALS=amyotrophic lateral sclerosis; CBD=corticobasal degeneration; FTD=frontotemporal dementia;
FTLD=frontotemporal lobar degeneration; MND=motoneuron; NCI=neuronal cytoplasmic inclusions; NII=neuronal
intranuclear inclusions; NMD=nonsense-mediated decay; PAX=apraxia; PNFA=progressive non-fluent aphasia;
Received October 3, 2007 . Revised December 5, 2007 . Accepted December14, 2007 . Advance Access publication January1 1 , 2008
Frontotemporal lobar degeneration (FTLD) is a descriptive
term that refers to a heterogeneous group of non-Alzheimer
forms of dementia with onset of illness usually before 65
years of age arising from the degeneration of the frontal
and temporal lobes. Frontotemporal dementia (FTD) is the
main syndrome falling under the clinical umbrella of FTLD,
and is associated with bilateral atrophy of the frontal and
temporal lobes. The related disorders of semantic dementia
(SD) and progressive non-fluent aphasia (PNFA) stem from
bilateral atrophy of the temporal lobes and the left cerebral
hemisphere, respectively (Neary et al., 2005). FTD with
motoneuron disease (MND) arises when the behavioural
and personality changes of FTD are accompanied by clinical
changes of MND (Neary et al., 2005).
At post-mortem, about 45% cases FTLD display a
tauopathy in the form of intraneuronal neurofibrillary
tangles or Pick bodies. However, a tau-negative, ubiquitin
positive histology, exemplified by the presence of neuronal
cytoplasmic inclusions (NCI) and/or neuritic changes in
cerebral cortex and known as FTLD-U, is probably the
most common histological
(Bergmann et al., 1996; Hodges et al., 2004; Josephs
et al., 2004; Lipton et al., 2004; Mott et al., 2005; Taniguchi
et al., 2004; Shi et al., 2005; Forman et al., 2006). In some
familial FTLD-U cases, neuronal intranuclear inclusions
(NII) of a ‘cat’s eye’ or ‘lentiform’ appearance (Woulfe
et al., 2001; Mackenzie and Feldman, 2003) have been
described (Rosso et al., 2001; Mackenzie et al., 2006c). Very
recently, the major protein component of these ubiquiti-
nated lesions in FTLD has been identified as the TAR
DNA-binding protein, TDP-43 (Arai et al., 2006; Neumann
et al., 2006; Davidson et al., 2007).
Up to 40% of the individuals with FTLD have similarly
affected first-degree relatives consistent with autosomal
dominant inheritance (Chow et al., 1999; Rizzu et al.,
1999). In some patients, there are mutations in the tau
(MAPT) gene (Hutton et al., 1998; see Pickering-Brown,
2007b for review) whereas others bear mutations in the
progranulin gene (PGRN) (Baker et al., 2006). Since the
initial report (Baker et al., 2006), this latter finding has
been widely confirmed (Benussi et al., 2006; Boeve et al.,
2006; Cruts et al., 2006; Gass et al., 2006; Huey et al., 2006;
Masellis et al., 2006; Mukherjee et al., 2006; Pickering-
Brown et al., 2006; Snowden et al., 2006; Behrens et al.,
2007; Bronner et al., 2007; Le Ber et al., 2007; Leverenz
et al., 2007; Mesulam et al., 2007; Seelaar et al., 2007; Spina
et al., 2007). Reported PGRN mutations include missense
change underlying FTLD
mutations generating premature stop codons, insertion or
deletion mutations resulting in frameshifts or changes
within initiation codons precluding transcription. PGRN
mutations induce PGRN haploinsufficiency through the
creationofa null allele,
transcribed being removed by nonsense-mediated decay
(NMD) (Baker et al., 2006). Other mutations, in exon 0
leading to nuclear degradation, and mutations that affect
the Kosak sequence, preventing translation, are also
believed to result in haploinsufficiency (Cruts et al., 2006).
Nevertheless, most reports on PGRN mutations have
been based upon single cases or families selected from
larger series of patients, or on cases collected from many
different sources specifically for genetic linkage studies.
Consequently, it is not clear what type of PGRN mutations
might be encountered within a given FTLD population
drawn from the same geographical area, or how frequent
PGRN mutations might be within such an unselected
population of cases with FTLD compared with that of
patients with MAPT mutation. Furthermore, all FTLD cases
with PGRN mutations reported so far have shown FTD,
PNFA or CBD clinical phenotype (Benussi et al., 2006;
Boeve et al., 2006; Cruts et al., 2006; Gass et al., 2006; Huey
et al., 2006; Masellis et al., 2006; Mukherjee et al., 2006;
Pickering-Brown et al., 2006; Snowden et al., 2006; Behrens
et al., 2007; Bronner et al., 2007; Le Ber et al., 2007;
Leverenz et al., 2007; Mesulam et al., 2007; Seelaar et al.,
2007; Spina et al., 2007). Hence, it is not known whether
FTD+MND clinical phenotypes. Moreover, despite showing
differing underlying histologies, it is unclear whether cases
differentiated on the basis of their clinical presentations
In the present study, we have sequenced PGRN in 223
consecutively accessioned patients with FTLD, noted what
type of PGRN mutations are present, and looked to see how
frequent these occur in relationship to MAPT mutations.
We have also investigated whether there are distinctive
clinical and pathological phenotypes that might distinguish
bearers of PGRN mutation from those with MAPT
mutation, or indeed either of these from patients with
FTLD without known mutation. This latter goal is
important as the ability to distinguish genetic risk in
patients with FTLD will have clinical, patient management
and potential therapeutic value in centres where genetic
analysis is not always practical or possible. Finally, FTD can
be associated with clinical MND, and TDP-43 pathology is
with anymutant mRNA
722Brain (2008),131, 721^731S. M. Pickering-Brown et al.
by guest on May 31, 2013
a feature of around 65% of FTLD and cases of MND where
SOD-1 mutation is absent (Arai et al., 2006; Neumann
et al., 2006; Davidson et al., 2007; Tan et al., 2007)
suggesting a possible aetiological link between these two
disequilibrium study of the PGRN locus in FTLD patients
without either PGRN or MAPT mutations, and in patients
with MND, in order to assess whether any common
variants of this locus increase the risk of developing either
or both of these conditions.
Material and Methods
The study group comprised 223 consecutive patients, 119 men
and 104 women, referred to the Cerebral Function Unit (CFU),
University of Manchester, who fulfilled clinical diagnostic criteria
for FTLD (Groups, 1994; Neary et al., 1998), and for whom
genomic DNA was available. All patients had undergone long-
itudinal neuropsychological and clinical assessments within the
Cerebral Function Unit, and in 44 cases, the diagnosis had been
pathologically confirmed at post-mortem. Patients’ mean age at
onset of symptoms was 58(9) years. A positive family history of
dementia in a first-degree relative was recorded in 40% of cases.
Forty-three per cent of patients had presented with a prominent
behavioural disorder and dysexecutive syndrome in keeping with
FTD (Neary et al., 1998), 13% of patients showed a circumscribed
semantic disorder, consistent with SD and 8% a circumscribed
expressive language disorder consistent with PNFA. Some patients
exhibited at presentation a mixed picture, in 16% the prominent
behavioural changes of FTD being combined with semantic
impairment, and in 4% with expressive non-fluent aphasia. In
14% of cases, FTLD syndromes (10% FTD, 3% FTD+SD and 1%
PNFA) were associated with physical signs of MND. Two per cent
of cases presented initially with apraxia (PAX).
Blood samples were also available from an unselected sample of
259 patients with MND (mean age at onset 57.8 years, range 28–
79 years), diagnosed in a specialist neurological motoneuron
disease clinic. The majority of patients met El Escorial criteria for
clinically definite or probable amyotrophic lateral sclerosis (ALS)
(Brooks et al., 2000). Sixty-seven of the MND cases have been
used in a similar much smaller study of PGRN (Xiao et al., 2007).
Controls comprised 286 mentally normal people [mean age 54.2
years at time of sampling (SD 12.2 years), range 26–81 years]
collected from the Manchester and Birmingham regions of the
All samples were recruited
approval, and provided informed consent. All samples were of
For all 223 patients with FTLD, exons 1 to 13 of the PGRN were
amplified as previously described (Baker et al., 2006). Sequence
analysis was performed using an ABI3730.
Thirty-eight SNPs covering 174.6kb (position 39683019 to
39857655, Supplementary Table 1) encompassing the whole
PGRN and flanking area were chosen from phase II data from
the International HapMap Project. SNPs were genotyped using the
Sequenom MassArray genotyping technology according to man-
ufacturer’s instructions. SpectroTYPER software was used to
automatically assign the genotype calls.
Haplotype block structure was examined using haploview (http://
www.broad.mit.edu/mpg/haploview). For comparison with this
study, PGRN data (chromosome 17 positions 39683019 to
39857655) from the HapMap project (http://www.hapmap.org/)
was used. Haploview was used to define haplotype blocks using the
confidence intervals option, where 95% confidence bounds on D’
(prime) are generated. To reconstruct haplotypes from genotype
data, Phase version 2.1 was used (Stephens and Donnelly, 2003),
using 10 000 iterations and a burn in of 10000. Stata (v9)was used to
estimate OR and 95% CI for haplotypes using unconditional logistic
regression, the most common haplotype being used as the baseline
for analysis. CLUMP (Sham and Curtis, 1995) was used to assess the
?2significance of the haplotypes between groups. For the univariate
analyses, the study had 93.4% power (P=0.05) to detect an
odds ratio of 0.5 when the exposure level was 40% in the
control population and a power or 57% (P=0.05) to detect an
odds ratio of 1.5.
Brains from the 44 deceased patients had been fixed in 10%
buffered formalin for a period between 1 and 3 months. Blocks of
tissue were cut from frontal (Brodmann areas 8/9), and temporal
(Brodmann areas 21/22) cortex and hippocampus (at the level of
the geniculate bodies) from all patients, and from brainstem (at
levels of trigeminal and facial motor nerve nuclei) and medulla
oblongata (at level of hypoglossus motor nerve nucleus and
including the inferior and superior olivary nuclei) and spinal cord
(at cervical, thoracic and lumbar levels) where these were
available. Tissue blocks were processed routinely into paraffin
wax and sections were cut at a thickness of 5mm.
Sections of frontal and temporal cortex were immunostained
for ubiquitin using an automated staining procedure using a
polyclonal anti-ubiquitin antibody (Dako, Glostrup, Denmark,
1:500) (see Mackenzie et al., 2006d, for details) and manually for
TDP-43 using a commercially available polyclonal antibody
(10782-1-AP, Protein Tech Inc, Chicago, IL, USA) at a dilution
of 1: 1000 (see Davidson et al., 2007). Sections of brainstem and
spinal cord (where available) were similarly immunostained for
TDP-43, and manually for ubiquitin using the same (Dako)
polyclonal anti-ubiquitin antibody (1:500) using a standard ABC
protocol. Tau immunostaining had previously been performed
using AT8 antibody (Shi et al., 2005; Shiarli et al., 2006).
PGRN mutations were found in 13 out of 223 (6%)
patients with FTLD (Table 1). Eight PGRN mutations were
identified from blood samples (see Patients #1–8), and five
from brain tissue (see Patients #9–13). Six different PGRN
mutations were present. Two patients (Patients #5 and 6)
shared exon 11 R493X stop codon mutation. In the case of
Frequency and clinical characteristics of progranulin mutation carriersBrain (2008),131, 721^731 723
by guest on May 31, 2013
Patient #14, no DNA was available for analysis but this
individual was the sibling of Patient #6, and shared a
similar illness. Moreover, DNA analysis of another sibling,
who was not investigated at CFU, but said to have
developed behavioural changes, showed the same mutation
as Patient #6. Patient #14 is therefore presumed to bear the
same mutation as her two siblings. These three patients
(Patients #6, 7 and 14) were not apparently related to
Patient #5. Four also apparently unrelated patients (Patients
#1–4) shared exon Q415X 10 stop codon mutation.
However, inspection of genotyping data revealed all four
patients shared common alleles of 15 SNPs from rs708386
to rs5848, defining a 45.8kb haplotype that contains the
whole PGRN gene, and suggesting these four patients are
indeed related. In none of these four patients was there a
known history of dementia. Four patients (Patients #7–10)
shared exon 10 V452WfsX38 frameshift mutation. Two of
these patients (Patients #7 and 8) were siblings, though not
apparently related to Patients #9 and 10 who in turn
appeared unrelated. Inspection of genotyping data revealed
these patients share alleles of 37 SNPs (rs1476512–
rs11079133)including PGRNand surroundinglocus
defining a common haplotype of 172kb. Patient #11 had
exon 1 C31LfsX34 frameshift mutation, Patient #12 had
exon 4 Q130SfsX130 frameshift mutation and Patient #13
had exon 10 Q468X stop codon mutation. Patients #12 and
13 have been previously reported (Baker et al., 2006;
Snowden et al., 2006).
PGRN association analysis
PGRN association analysis was performed on the 192 FTLD
patients without either PGRN or MAPT mutation, and on
all 259 MND patients and all 286 control subjects. All
PGRN allele and genotype frequencies matched data on
dbSNP or the HapMap data for Caucasian populations, and
were in Hardy–Weinberg equilibrium (data not shown).
Analysis using logistic regression demonstrated no signifi-
cant differences in either the allele or genotype frequencies
between the FTLD cohort as a whole (when the PGRN or
MAPT mutation carriers were excluded), or for any clinical
diagnostic FTLD subgroup and controls (Supplementary
Table 1), or when the 192 FTLD cases were stratified into
those with or without previous family history (data not
T able1 Clinical phenotypes, demographic and genetic details on14 patients with FTLD with PGRN mutations and17 with
Patient Clin phenotypeGenderOnset Death DurationFH Mutation PGRNAPOEMAPT ht
exon 4 Q130SfsX124
724Brain (2008),131, 721^731S. M. Pickering-Brown et al.
by guest on May 31, 2013
shown). However, linear regression analysis identified that
the A allele of SNP rs9897526 significantly delayed mean
age at onset by ?4 years [GG genotype, n=142, mean age
at onset 58.71 (range 23–79); GA genotype, n=35, mean
age at onset 62.42 (range 42–83); AA genotype, n=3, mean
age at onset 54.25; Prob 4F=0.0493]. Using CEPH
HapMap data the haplotype block structure for PGRN
locus was defined using the confidence intervals method of
Gabriel et al. (2002). Comparison of the haplotype data
generated identified four haplotype blocks, with blocks 3
and 4 containing all of PGRN. Eight haplotypes was
observed in block 3 describing 91.75% of the genetic
information, whereas five haplotypes were observed in
block 4 representing 97.6% of the information. No
statistically significant difference was observed in the
frequency of any haplotype, either for all 192 FTLD
patients as a whole (Supplementary Table 2), or when
stratified according to previous family history or clinical
diagnostic FTLD subgroup, when compared with control
data (Supplementary Table 2). The data was likewise
negative when the analysis was restricted to those FTLD
cases withautopsy confirmation:
however lacked statistical power given the small number
of cases. No effect was noted for age and sex for any of the
variants or haplotypes analysed.
Non-synonymous changesin PGRN
In addition to the PGRN mutations described above,
A G168S change in exon 5 was found in a single patient,
with no family history, who showed a mixed FTLD/MND
picture. Also, A324T change in exon 9 was found in two
cases; one case of FTD with a sister with FTD+MND
and the other in a case of PNFA without any apparent
MAPT mutations were found in 17 out of 223 (8%)
(Patients #15–25, Table 1), and six from brain tissue
(Patients #26–31, Table 1). One patient (Patient #15) bore
exon 10+13 splice mutation, and 16 patients (Patients
#16–31) bore exon 10+16 splice mutation. Fourteen of
these patients (Patients #15–23, 26–30) have been reported
previously (Pickering-Brown et al., 2002).
MAPT haplotypes in the PGRN mutation cases (where
performed) were 4 H1H1, 5H1H2 and 2 H2H2 (H1
frequency=59%), whereas all 17 patients with MAPT
mutations had H1H1 haplotype. The APOE e4 allele
frequency in the PGRN mutation cases was 18.2% (8 e3/
e3, 2 e3/e4, 1 e4 e4) and was 20.6% (1 e2/e3, 9 e3/e3, 7 e3
e4) in the MAPT mutation cases. Neither H1 haplotype
frequency nor APOE e4 allele frequency differed between
PGRN and MAPT mutationbearers.
Controland MND cases
Analysis of the 259 MND cases also failed to demonstrate
any significant association with PGRN locus either at the
genotype or haplotype level (Supplementary Table 3) and
there was no apparent effect of age or sex. Unlike that
observed for FTLD rs9897526 had no affect on age at onset
[GG genotype, n=106, mean age at onset 58.51 (range 28–
79); GA genotype, n=35, mean age at onset 57.71 (range
36–70); AA genotype n=0; P=0.563].
Patients with PGRN and MAPT mutations did not differ
significantly from other FTLD cases in terms of gender
distribution. The male: female frequencies for PGRN cases
were 5: 9, for MAPT cases 10:7 and for other FTLD cases
104: 88. A family history of dementia in a first-degree
relative was present in 71% of PGRN cases, 100% of MAPT
cases and 39% of other FTLD cases. Paired-comparisons
showed that the lower familial incidence in PGRN
compared to MAPT cases was statistically significant
(Fisher’s exact test, P=0.04), as was the higher incidence
in PGRN and MAPT cases compared to other FTLD cases
(Fisher’s exact test P=0.006 and P50.001, respectively).
Onset of illness was earlier in MAPT cases [mean 53(6)
years] compared to PGRN [mean 59(5) years] (t=3.1,
P=0.004) and other FTLD cases [mean 59(9), t=2.5,
P=0.01]. Onset age in PGRN cases did not differ
significantly from that in other FTLD cases. Total duration
of illness was comparable across all groups [mean 9(4), 8(4)
and 7(4) years for PGRN, MAPT and non-mutation
In PGRN cases, the clinical presentation took two main
forms (Fig. 1). Approximately half of the patients, i.e. 8/14
(57%) exhibited a severe, yet circumscribed frontal lobe
syndrome, consistent with typical FTD. In these patients,
behavioural changes of apathy and loss of volition
predominated and became increasingly marked over the
course of the disease. Speech output became progressively
attenuated, and there were frontal features of echolalia,
verbal stereotypies and perseverations, prior to the onset of
mutism. Performance on cognitive assessment was char-
acterized by economy of effort, frequent ‘don’t know’
responses, concreteness and
impairments on executive tasks. Despite the reduction
in speech, at no time during the course of the illness was
there evidence of frank aphasia, as defined by the presence
Neuroimaging showed bilateral atrophy affecting predomi-
nantly the frontal and to a lesser extent anterior temporal
lobes. The clinical profile is exemplified by Case #13,
described previously (Snowden et al., 2006) as the proband
of Family F53. The frequency of this typical FTD profile
perseveration and severe
Frequency and clinical characteristics of progranulin mutation carriers Brain (2008),131, 721^731 725
by guest on May 31, 2013
found in PGRN cases was not significantly different from
that in other cases of FTLD.
In 5/14 cases (36%), the presentation was of an
expressive language disorder, consistent with PNFA. The
prominent feature was anomia, the word retrieval difficul-
ties becoming sufficiently pronounced to give rise to a non-
fluent quality to patients’ utterances. Nevertheless, there
were no problems in articulation, and phonological errors
were rare or absent, suggesting problems arising at the level
of accessing word forms rather than in motor production.
One patient (Patient #11), despite being unable to name
objects, could spell out those same object names (Snowden
and Neary, 2003), a finding interpreted as evidence of a
selective impairment in access to the phonological form of
the word. In four anomic patients, a gestural PAX was
documented during the disease course. Neuroimaging
showed severe asymmetric atrophy involving perisylvian
regions of the left hemisphere.
One of the 14 (7%) PGRN cases differed from these two
main profiles. This patient, who was the brother of Patient
#7, presented with an asymmetric, left-sided limb PAX and
parkinsonism, suggestive of a diagnosis of corticobasal
degeneration (CBD). He too developed problems in
language expression, with impaired word retrieval, although
these were subsidiary to his profound PAX. Imaging
indicated asymmetric atrophy affecting the right hemi-
sphere more than the left. This patient alone displayed
akinaesia and rigidity of the limbs at presentation. In all
other PGRN patients neurological examination was normal
at referral. Limb rigidity, generally of mild degree, emerged
over the disease course. No patient showed clinical signs of
MND. PGRN cases presenting with progressive aphasia/
PAX had a later onset than those presenting with a frontal
behavioural syndrome (t=3.1, P=0.01).
Of the17MAPT cases,
alterations in personality and social conduct, consistent
with FTD (Fig. 1). In Patient #15, who, uniquely in the
series, after an exon 10+13 mutation the behavioural
change took the form of loss of volition, apathy, and
inertia. In patients with exon 10+16 mutations, by
contrast, the prevailing characteristic was of a fatuous
affect, purposeless overactivity, inattentiveness and distract-
ibility, disinhibition and inappropriate behaviours that
violated social mores. Apathy emerged only in the later
stages of disease. Similarly, parkinsonian signs typically
emerged as a late feature. Only two patients showed
akinaesia and rigidity of the limbs at initial presentation.
No patient showed clinical signs of MND. All patients
showed on neuropsychological assessment evidence of a
dysexecutive syndrome, with frank ‘frontal’ features of
concreteness and response perseveration. Frontal features
were also present in patients’ language: echolalia, persevera-
tion and stereotypies. In addition, the majority exhibited
evidence of semantic disorder, evidenced by the presence of
semantic errors in naming, impaired word comprehension
and impaired recognition of famous faces and names. In no
MAPT case were phonological errors recorded in their
conversational speech or on formal neuropsychological
assessment. Thus, the prevailing profile in patients with
MAPT mutations was of a dominant behavioural disorder
indicative of frontal lobe dysfunction, combined with
semantic impairment. Individual cases histories have been
described elsewhere (Pickering-Brown et al., 2002).
Figure 1 shows the distribution of clinical presentations
in PGRN, MAPT and other FTLD cases. A clinical
presentation of PNFA was significantly more common in
PGRN cases than in both MAPT cases (Fisher’s Exact test,
P=0.01) and other FTLD cases (P=0.005). A logistic
regression analysis showed that the presence of PNFA
significantly increased the odds of having a PGRN mutation
[Exp(B) 8.0 CI 2.3–27.3]. In contrast, a mixed picture of
FTD combined with semantic impairment increased the
odds of MAPT mutation [Exp(B)26.6 CI 8–89]. In cases
without PGRN or MAPT mutations, the frequency of
clinical phenotypes was largely similar in familial and
sporadic cases (Fig. 1). The only statistically significant
difference was a higher frequency of pure SD in the
sporadic group (Fisher’s exact test, P=0.03).
As we (Baker et al., 2006; Pickering-Brown et al., 2006;
Snowden et al., 2006) and others (for example, Cruts et al.,
2006; Mackenzie et al., 2006b) have described elsewhere, all
six autopsied patients with PGRN mutations displayed a
similar histological phenotype, irrespective of the precise
mutation present. This was characterized by a moderate
number to numerous ubiquitin-immunoreactive neurites,
Fig.1 Percentage of patients presenting with FTD, FTD/SD, pure
SD, PNFA, PAX and FTLD/MND in PGRN and MAPT cases and
familial and sporadic cases with no mutation.
726 Brain (2008),131, 721^731S. M. Pickering-Brown et al.
by guest on May 31, 2013
and NCI within small neurons, in layer II of the frontal and
temporal cortex: NII were present in all six patients, though
these were never numerous (512 per section). Such a
pattern of ubiquitin pathology has been termed by us,
FTLD-U type 1 (Mackenzie et al., 2006d), or by others
(Sampathu et al., 2006) as FTLD-U type 3. Granular
ubiquitin-immunoreactive inclusions were variably present
within granule cells of the dentate gyrus of the hippocam-
pus. Again, as we have previously described (Davidson
et al., 2007), TDP-43 immunohistochemistry revealed
similar pathological structures within the cerebral cortex
and hippocampus as ubiquitin immunohistochemistry.
No tau-immunoreactive neurons or glial cells were present
in any cerebral cortical region. Within the brainstem,
skein-like, spicular or rounded, ubiquitinated, TDP-43
immunoreactive NCI were present in neurons of the
inferior olives in all PGRN mutation cases, though no
such inclusions were seen in motoneurons of trigeminal or
hypoglossal cranial nerve nuclei, or in anterior horn cells of
the spinal cord, where these regions were available for
As we (Pickering-Brown et al., 2002) and others (Janssen
et al., 2002) have reported previously, all seven patients
with MAPT exon 10+16 mutation, and the single patient
with MAPT exon 10+13 mutation, showed identical
pathology with tau-immunoreactive neurons within the
grey matter, and tau-immunoreactive glial cells (probably
oligodendroglia) within the white matter, of the cerebral
cortex (data not shown). Although some of the more NFT-
like tau deposits within neurons of the cerebral cortex were
ubiquitinated, none of these were TDP-43 immunoreactive,
nor were glial cell tangles reactive to TDP-43 antibody (data
Twenty-six patients in the series, without PGRN or
MAPT mutations, showed FTLD-U or tau pathology at
autopsy. Their clinical phenotype is compared with that of
the PGRN and MAPT cases in Table 2. PNFA was more
common in PGRN mutation cases than in FTLD-U cases
with no PGRN mutation (Fisher’s exact test, P=0.05). FTD
combined with semantic impairment predominated in
MAPT mutation cases but was absent in cases with
tauopathy but no MAPT mutation.
In the present study, sequencing of PGRN in 223
consecutive patients with FTLD revealed the presence of
13 mutations, or 14 mutations if a single affected sibling of
two other affected siblings with proven PGRN mutation is
included. The prevalence rate in our series was 5.8% of all
FTLD cases and 17% of familial FTLD. These figures are
largely consistent with other reports. An overall prevalence
rate of ?5% was reported by Gass et al., (2006) and Le Ber
et al. (2007), accounting for 23% of familial cases in the
cohort of Gass et al. and 12.8% in that of Le Ber et al.
In our series, six separate PGRN mutations were
identified, two of these mutations (exon 4 Q130SfsX124
mutation in Patient #12 and exon 10 Q468X mutation in
Patient #13) having been reported previously by us (Baker
et al., 2006). The exon 1 C31LfsX34 and exon 11 R493X
mutations have been reported previously in other popula-
tions by both ourselves (Baker et al., 2006) and others
(Huey et al., 2006; Spina et al., 2007). Haplotype analysis of
microsatellite markers covering the PGRN locus demon-
strates that the Manchester cases with the C31LfsX34 and
Q130SfsX124 mutations shared the same haplotype as the
UBC-17 and UBC-15 families, respectively (data not
shown) suggesting common founders. This is not unex-
pected as UBC-17 is known to be of English origin. Neither
the exon 10 Q415X nor V452WfsX38 mutations have been
reported previously, though the clinical and pathological
(where known) phenotypes of these patients fit with
previously reported patients with PGRN mutation.We also
identified two non-synonymous changes in PGRN in three
patients. The A342T mutation has been reported by others
(Gass et al., 2006). While this particular variant has not
been found in controls, its exact relationship to disease is
unclear. Many of the non-synonymous changes identified in
PGRN, that do not lead to null alleles, have been found in
controls or have been shown not to segregate with disease
in family-based analysis (Gass et al., 2006). Nevertheless,
it is possible that this variant and the G168S variants are
pathogenic via a novel mechanism (van der Zee et al.,
2007). It is noteworthy in this regard that one of the
three patients showed clinical signs of MND, whereas
another had a family history of FTD/MND. MND was
notably absent in all patients with established PGRN and
Association analysis using SNPs covering the PGRN locus
failed to demonstrate any effect on disease risk either at the
genotype or haplotype level. This argues that, while null
mutations of PGRN are pathogenic, common variants
(polymorphisms) in this gene do not contribute greatly to
an individual’s chance of developing FTLD, or indeed
MND alone. While it clear that common variants (poly-
morphisms) in some genes can increase disease risk,
T able 2 Clinical phenotype frequency in PGRN and MAPT
mutation cases compared to cases with FTLD-U and tau
pathology without known mutations
Clinical phenotype PGRN
FTD + semantic
Frequency and clinical characteristics of progranulin mutation carriersBrain (2008),131, 721^731 727
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e.g. MAPT H1 and PSP (Baker et al., 1999), this is not
always so. A mutation in CHMP2B causes FTLD in a single
family from Denmark (Skibinski et al., 2005), yet common
variants of this gene do not increase risk of FTLD (Rizzu
et al., 2006; Schumacher et al., 2007). Furthermore, we have
recently shown that variants in the TDP-43 gene, the major
pathological protein product of FTLD, also do not increase
disease risk (Rollinson et al., 2007). Nevertheless, we did
observe an effect on age at onset with SNP rs9897526. This
polymorphism has also been reported to have the same
effect in FTLD patients with the R493X PGRN mutation
(Rademakers et al., 2007). Presumably, this variant has a
role to play in controlling alternative splicing or expression
levels but functional investigations are required to fully
elucidate its actions. However, no effect on age at onset was
seen for MND, which further supports the concept that
PGRN has little contribution to the aetiology of this
Within the same cohort of patients we have identified
MAPT mutations in 17 individuals, yielding a prevalence of
8% of all FTLD cases and 21% of familial cases. The overall
prevalence is somewhat higher than the figure of 5.9% in all
cases, but 10.5% in just familial cases, reported by (Poorkaj
et al., 2001) and 1.2% by (Huey et al., 2006). The frequency
of mutations in our cohort may be inflated by the
likelihood of a common founder for MAPT exon 10+16
mutation being located within nearby North Wales region
of UK (Pickering-Brown et al., 2004), with residents of
that region falling into the catchment area of our Centre.
A similar inflated frequency of PGRN mutations has been
described in a Belgian FTLD cohort where ?7% of cases
result from a founder family (Cruts et al., 2006; van der Zee
et al., 2006). Present data suggest therefore that PGRN
mutations are no greater a cause of FTLD than MAPT
mutations, with both collectively explaining well under half
of all cases with apparent autosomal dominant inheritance
of FTLD. Such data suggest other genetic loci for inherited
FTLD. It is possible that many of the remaining familial
cases could be accounted for by the unidentified gene on
chromosome 9p (Morita et al., 2006; Vance et al., 2006).
In all instances, FTLD patients with PGRN mutations
displayed a similar tau-negative histological picture (termed
type 1 histology by Mackenzie et al., 2006d) in both
from the presence of numerous ubiquitin- and TDP-43-
immunoreactive neurites and NCI within the cerebral
cortex, all cases displayed lentiform or ‘cat’s eye’ NII.
Indeed, to date, all reported cases with PGRN mutations
where brain examination has been possible have shown this
particular pathological feature, leading some to argue that
the presence of such NII might be pathognomic. However,
within the present series, we observed eight cases with
identical (to known PGRN mutation cases) ubiquitin/TDP-
43 type 1 histology (including the presence of NII) where
no PGRN mutation was present, and in six of these a family
history consistent with autosomal dominance was present.
Such data suggest either that there may be other changes
within PGRN that have not been detected so far, or that
there are other routes to producing this particular histology
that do not involve PGRN mutations, but could likewise
induce a PGRN protein insufficiency state. Leverenz and
colleagues (2007) reported tau and alpha-synuclein pathol-
ogy in a family with a PGRN mutation (c.709 -2A4G)
thought to affect splicing of exon 7, leading to reduced
levels of PGRN message. This is similar to a FTLD family
reported by Wilhelmsen that also had tau and alpha-
synuclein pathology. However, the linkage region in this
latter family was distal to the PGRN locus excluding this
gene as a cause of disease (Wilhelmsen et al., 2004). Despite
these observations, tau and/or alpha-synuclein positive
neuropathological structures were not found in any of
our present patients, and are not common, if present at all,
in other cohorts (Mackenzie et al., 2006b; Josephs et al.,
2007; Pickering-Brown, 2007a).
The R493X mutation appears to be the most common
PGRN mutation associated with FTLD, with numerous
bearers of this particular mutation having been reported in
British, Australian, American and Canadian families (Huey
et al., 2006; Pickering-Brown et al., 2006; Spina et al.,
2007). Recent work has demonstrated these represent a
(Rademakers et al., 2007) and spread through British
emigration akin to the MAPT exon 10+16 mutation as we
have described (Pickering-Brown et al., 2004). In the
V452WfsX38 and 3 with Q415X mutations. Both of these
are novel mutations, and like the previously reported
(Baker et al., 2006) C130SfsX124 (Patient #12) and Q468X
(Patient #11) mutations appear confined to British patients.
The Q415X mutation is notable in that none of the four
mutation bearers had demonstrable family history of FTLD
(or dementia). This is in stark contrast to the other PGRN
mutations where all carriers had clear autosomal dominant
inheritance of disease. Such observations might suggest
Q415X is a relatively rare, though benign, polymorphism
chancing to occur in these four patients with otherwise
sporadic FTLD. There are arguments against this. Firstly,
like many of the other PGRN mutations, the Q415X
mutation introduces a premature stop codon, and there is
no reason why this change should not lead into PGRN
haploinsufficiency, similar to other (nearby) mutations e.g.
R418X. Secondly, we were unable here to show the presence
of this genetic variation within 286 control subjects, or 259
subjects with MND, and this particular change has not been
found in any control subject within any other studies.
Finally, haplotype analysis suggests these four patients are
related and are part of a larger family. Assuming R415X
mutation to be pathogenic, the lack of previous family
history in all four patients raises issues of incomplete
penetrance. The presence of PGRN mutations in apparently
sporadic cases has also been reported by others (Le Ber
et al., 2007). The reason for this apparent incomplete
728 Brain (2008),131, 721^731S. M. Pickering-Brown et al.
by guest on May 31, 2013
penetrance in certain cases remains to be explained, but
compensatorily upregulate the expression of the normal
PGRN allele and negate the effects of the mutation in some
carriers) or environmental factors.
The clinical phenotype associated with present PGRN
mutations was either of the prototypical behavioural
disorder of FTD, or of a non-fluent anomic aphasia,
consistent with PNFA (see also Snowden et al., 2006). No
patient was noted to display neuropsychological changes
reminiscent of SD. Indeed, the ubiquitin histological
changes of SD differ markedly from those seen here, with
SD patients demonstrating a neurite predominant pattern
(Mackenzie et al., 2006a) have termed FTLD-U type 2
(type 1 in Sampathu et al., 2006). Moreover, no PGRN
mutation carriers displayed either clinical or histopatholog-
ical features of MND, and patients with FTD+MND again
demonstrate a separate and distinctive histological pheno-
type on ubiquitin/TDP-43 immunohistochemistry (FTLD-U
type 3;Mackenzie et al., 2006a) and type 2 in (Sampathu
et al., 2006). Such observations suggest patients with SD or
FTD+MND clinical syndromes are unlikely to bear PGRN
mutations, and despite sharing a basic ubiquitin/TDP-43
histopathology with bearers of PGRN mutations, these are
sufficiently different in morphological characteristics as to
suggest separate underlying pathogenetic mechanisms. Such
a conclusion is supported by the lack of PGRN mutations,
or association with common polymorphisms in PGRN, in
patients with clinical MND
Although bearers of PGRN and MAPT mutations all
broadly fell under the clinical umbrella of FLTD there were
notable differences in neuropsychological expression. In
PGRN cases presenting with behavioural change, the
‘frontal lobe’ syndrome was relatively pure, whereas in
MAPT cases it was commonly accompanied by semantic
deficits. In PGRN cases, the dominant behavioural symp-
tom was apathy, whereas in MAPT cases it was social
disinhibition. Most strikingly, the language disorder in
PGRN cases took the form of a non-fluent anomic aphasia
(PNFA), accompanied by gestural PAX and associated with
asymmetric atrophy involving perisylvian regions of the left
hemisphere. This profile was never seen in association with
MAPT mutations. By contrast, in MAPT cases the language
disorder was characterized by semantic loss, and was
associated with bilateral atrophy of the temporal (as well
as frontal) lobes.
Differences were not confined to those between PGRN
and MAPT cases. The PNFA profile was more common in
PGRN mutation cases than in cases with no known PGRN
mutation, including those with established FTLD-U pathol-
ogy. The mixed FTD/SD picture occurred with significantly
higher frequency in MAPT mutation cases than in cases
with no known mutation, including those with established
tau pathology. In cases without PGRN or MAPT mutations,
the frequency of clinical phenotypes was largely similar in
genetic(e.g. variants that
familial and sporadic cases, suggesting that a positive family
history per se does not explain the high frequency
respectively of PNFA in PGRN cases and mixed FTD/SD
in MAPT cases.
There is inevitably a need for caution in drawing strong
conclusions about clinical phenotypic differences. The
cohort ofpatients with
Moreover, the MAPT cases in this series are dominated
by patients with exon 10+16 mutations, which may not be
representative of MAPT mutation cases as a whole. Indeed,
whereas the dominant behavioural change in our exon
10+16 cases was disinhibition, that of the single case with
an exon 10+13 mutation was apathy, despite both
mutations having similar molecular effects. In the literature,
the status of semantic functioning in patients with MAPT
mutations has not been systematically reported, so that it is
not clear whether other cohorts of MAPT cases share a
common clinical phenotype, as represented here.
Nevertheless, a notable feature of studies of PGRN
mutations is the relatively high frequency with which
expressive language impairment is reported (Gass et al.,
2006; Snowden et al., 2006; Davion et al., 2007; Josephs
et al., 2007; Rademakers et al., 2007). Moreover, consistent
with our own findings, an association has also previously
been observed between PAX and PGRN mutations (Le Ber
etal.,2007; Spina etal.,
findings, together with the highly significant phenotypic
differences demonstrated between our PGRN, MAPT and
non-mutation cases, suggest that clinical phenotypic varia-
tion within FTLD is not arbitrary. There is growing
evidence of a predictable relationship between clinical
phenotype and underlying histopathology (Snowden et al.,
2007). The present results suggest that there may also be
identifiable relationships between genetic mutations and
thesemutations is small.
Supplementary material is available at Brain online.
This work is supported by a Medical Research Council
(MRC) New Investigator Award to S.M.P.-B and D.M.A.M.
and S.M.P.-B received grants from MRC, Alzheimers
ResearchTrust and the
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