We describe the clinical, neuropsychological and radiological phenotype of a GRN
mutation cohort representing 12% of a large UK FTLD cohort and 20% of those FTLD subjects with a family history. 80% of these patients in four separate families had the DRC255 mutation (c.90_91 insCTGC insertion) but further analysis suggests these families have a common ancestor shared with the UBC17 family previously described (Baker et al., 2006
; Mackenzie et al., 2006
). Similar to the experience of other neurodegenerative diseases (Mead, 2006
), it seems likely that GRN
mutation frequency will vary with geography and ethnicity due to a balance of genetic drift, loss and new mutation. We found four novel pathogenic null-mutations: three frameshift indel mutations and one premature stop codon mutation. Two further missense changes were detected in patients and not in controls although families were too small to demonstrate segregation. The alanine to valine change at codon 199 is located between conserved granulin motifs. The leucine to phenylalanine change at codon 469 is located in granulin D but this residue is not conserved between motifs, indeed, the phenylalanine is found at the homologous residue in granulin motifs A and G. The location and nature of these missense changes do not support pathogenicity, but no effect on protein structure is predictable with certainty. Nonetheless, it is interesting that the phenotype of these possible mutations was similar to that seen in the definite pathogenic mutations. We did not identify splice mutations commonly found in other screening studies, or large-scale deletion of GRN
involving exon 1.
patients presented with bvFTLD, PNFA or CBS. No patient with a classic SD syndrome or PSP was found to have mutations. Considering the clinical presentation in more detail, GRN
patients who present with behavioural symptoms commonly have apathy as the initial presenting feature although most of the common behavioural symptoms of bvFTLD are also seen during the disease. Previous case series have described language output impairment as a feature of GRN
mutations (Cruts et al., 2006
; Gass et al., 2006
; Mesulam et al., 2007
). In our study, different language phenotypes were seen within the cohort: many patients presenting with bvFTLD had decreased spontaneous speech in the absence of speech errors, consistent with dynamic aphasia, often becoming mute as the disease progressed (Snowden et al., 2006
). Other patients presented with PNFA, a primary language syndrome known to be heterogeneous in its clinical presentation (Rohrer et al.
, 2007): some patients had hesitant, effortful speech consistent with apraxia of speech whilst others had agrammatism and phonemic errors without articulatory impairment. Some of these cases also had evidence of semantic errors and early single-word comprehension impairment, consistent with a progressive mixed aphasia (Grossman and Ash, 2004
Seventy per cent of those undergoing neuropsychometry showed deficits on tests of episodic memory. Although patients can fail psychometric tests of memory for a number of reasons, many of these patients also complained of amnestic symptoms () suggesting true episodic memory impairment. This feature has been found in other series of GRN
patients with some patients even receiving an initial diagnosis of Alzheimer's disease (Kelley et al., 2007
, Rademakers et al., 2007
). This is an important aspect that should be borne in mind in the differential diagnosis of patients presenting with dementia.
A number of studies have now reported GRN
mutations in association with CBS (Benussi et al., 2006
; Masellis et al., 2006
; Spina et al., 2007
). We describe two patients with pathogenic mutations who had a CBS although both also had features of PNFA. This is a well-described syndrome overlap (Graham et al., 2003
) although the underlying pathology in many previously reported cases has been tau-positive corticobasal degeneration (CBD) pathology (Knopman et al., 2005
). CBS is classically described as involving the frontal and parietal lobes both clinically and radiologically, differing from other FTLD syndromes with its more posterior cerebral involvement. In fact, despite heterogeneity by established clinical criteria, all of the patients in our series had evidence of early parietal lobe dysfunction. This has been noted by us and other groups previously (Le Ber et al., 2007
; Rademakers et al., 2007
; Spina et al., 2007
; Rohrer et al., in press
) and study of this large FTLD cohort confirms the involvement of the parietal lobes early in GRN
-associated FTLD with much lesser involvement in other genetic and clinical subgroups (except in cases of CBS).
Consistent with previous reports, all of the patients who have come to post-mortem have shown TDP-43/ubiquitin-positive type 3 pathology with the presence of neuronal intranuclear inclusions. Four other patients in the FTLD series (from two families DRC306 and DRC321) were known to have the same pathological findings but were found to be GRN
negative. One recent study suggested that only about 60% of type 3 pathology cases were GRN
-positive with the other 40% being mainly autosomal dominant familial cases without a known genetic mutation (Josephs et al., 2007
). One member from each of our families had volumetric MR brain imaging and it is interesting to note that both scans showed asymmetrical left-sided predominant atrophy with parietal lobe involvement. This intriguing finding suggests that the GRN
phenotype we have described may be a feature of type 3 TDP-43/ubiquitin-positive pathology rather than GRN
mutations per se
The radiological findings support our clinical and neuropsychological findings of parietal lobe involvement with all of the patients showing fronto-temporo-parietal atrophy. Other studies have also shown early parietal lobe atrophy in some patients (Kelley et al., 2007
, Spina et al., 2007
) and a more detailed imaging study using voxel-based morphometry showed greater parietal lobe atrophy in a GRN
mutation group compared to a ubiquitin-positive, GRN
-negative group (Whitwell et al., 2007
). The further feature of GRN
cases that distinguishes them from other FTLD cases is the striking asymmetrical atrophy (and something that will not necessarily be picked up with voxel-based morphometry if there is variable laterality within the group) (Kelley et al., 2007
). Volumetric analysis showed that the GRN
cases as a group were even more asymmetrical than the canonically asymmetrical subtype of FTLD, SD (Chan et al., 2001
). The mechanism for this asymmetry is unclear but suggests focal rather than diffuse onset: involvement of fronto-parietal pathways that are preferentially affected on one side first before affecting the opposite side.
The duration of disease appears to be shorter for patients with GRN
mutations (average 5 years) compared to other FTLD patients studied here, although a weakness of this study is the lack of FTD-MND cases, the particular subgroup of FTLD known to have short duration [a mean of ~3 years (Hodges et al., 2003
)]. One study found that GRN
patients have more generalized atrophy and smaller brains at post-mortem compared to a group of GRN
-negative patients and therefore suggested that GRN
results in a more rapid, ‘malignant’ form of FTLD (Josephs et al., 2007
). This finding of smaller brains at post-mortem could also result from the fact that with early involvement of the parietal lobe more of the brain is involved in GRN
disease compared with other FTLD groups where atrophy is confined to a large extent to the frontal and temporal lobes. Longitudinal studies of the rate of atrophy in GRN
cases are needed to help to answer the question of whether the short duration of disease is associated with a higher rate of atrophy compared to other FTLD subgroups.
Although there was a suggestion of MND in an unexamined GRN
mutation relative, this was not a feature of the well-studied cases and no GRN
mutations were found by screening a UK cohort of non-SOD1
familial MND. This is consistent with other studies suggesting that GRN
is not a common cause of a MND phenotype (Gass et al., 2006
; Schymick et al., 2007
In concordance with other reports (et al.
, 2006) we found evidence that APOE-E4
genotype delays age of clinical onset by around 6 years. Our sample was small so this result is not statistically robust, and a large study of the Arg493X mutation did not find such an association (Rademakers et al., 2007
is thought to have widespread effects on brain metabolism (Scarmeas et al., 2005
) and neuroanatomy (Shaw et al., 2006
), and as our understanding of the pathogenesis of GRN
mutation is at an early stage, it would be premature to speculate on a mechanism.
The distinct GRN phenotype of our series does not necessarily imply an effective management strategy for genetic testing. The most statistically sensitive but costly approach would be to sequence GRN in all patients with FTLD. Indeed, technical improvements in high-throughput sequencing may soon translate into diagnostic genetic testing at a much reduced cost. Although a positive family history, parietal lobe signs and asymmetrical MRI brain scan were found in the majority of GRN cases, these features were not necessarily found at presentation when a decision about genetic testing is usually made. Our series was not large or detailed enough to define the benefits of using these characteristics to filter cases.
In conclusion, patients with GRN mutations: have a shorter disease duration compared to other FTLD groups (with the exception of FTD-MND); present with bvFTLD (commonly apathy initially), language output impairment (either a PNFA or decreased speech output consistent with a dynamic aphasia) or with CBS; have parietal lobe dysfunction seen particularly on neuropsychological testing; and commonly have evidence of asymmetrical atrophy on MR imaging with the frontal, temporal and parietal lobes all affected.