Clinical, Genetic, and Pathologic Characteristics of Patients With Frontotemporal Dementia and Progranulin Mutations

Abstract

Background: Patients with frontotemporal dementia due to mutation of progranulin may have a distinct phenotype. Objective: To identify distinct clinical and pathologic features of patients with frontotemporal dementia who have mutations of progranulin (GRN).

Voxel-based morphometry patterns of atrophy in FTLD with mutations in MAPT or PGRN

“…Patterns of severe temporal lobe atrophy have previously been demonstrated in studies that have investigated subjects with tau exon mutations IVS10 ϩ 16CϾT, 19,33 IVS10 ϩ 3GϾA, 34 and p.Asn279Lys, 35,36 suggesting that MAPT mutations may predispose to temporal lobe atrophy. These findings fit with previous studies that have shown that while the majority of MAPT cases have a diagnosis of behavioral variant FTD, 8,13,15,37 a high proportion show language deficits. 8,15,17 Greater gray matter loss in MAPT subjects was also identified in the putamen.…”

Voxel-based morphometry patterns of atrophy in FTLD with mutations in MAPT or PGRN

“…Patterns of severe temporal lobe atrophy have previously been demonstrated in studies that have investigated subjects with tau exon mutations IVS10 ϩ 16CϾT, 19,33 IVS10 ϩ 3GϾA, 34 and p.Asn279Lys, 35,36 suggesting that MAPT mutations may predispose to temporal lobe atrophy. These findings fit with previous studies that have shown that while the majority of MAPT cases have a diagnosis of behavioral variant FTD, 8,13,15,37 a high proportion show language deficits. 8,15,17 Greater gray matter loss in MAPT subjects was also identified in the putamen.…”

Impairment of episodic memory in genetic frontotemporal dementia: A GENFI study

“…All symptomatic mutation carriers had impaired memory as measured by the FCSRT compared to controls and presymptomatic mutation carriers, whereas only MAPT‐ and C9orf72 ‐associated FTD were impaired presymptomatically. This is in line with previous studies investigating cognitive functioning in people with genetic FTD, demonstrating memory impairment in C9orf72 ‐, 18,22,33,34 GRN ‐, 19,22,35 and MAPT ‐ 22 related FTD, earlier (and presymptomatically) in C9orf7 2 36 and MAPT 21,37,38 mutations, and only in the later symptomatic stages in GRN‐ related FTD 17,22 . Some of these studies interpreted memory impairment as a distinctive characteristic of the specific gene mutation involved, but our results suggest that, although all (symptomatic) genetic groups were impaired, the underlying cause of memory impairment might differ between the genetic groups.…”

“…41 GRN mutation carriers performed better than the other mutation carrier groups on the FCSRT in the presymptomatic stage, whereas they performed significantly worse than C9orf72 mutation carriers in the symptomatic stage. This is in line with previous studies showing that there is minimal cognitive decline in presymptomatic GRN mutation carriers, with often rapidly progressive cognitive decline after symptom onset, 21,22,35,41 whereas in C9orf72-related FTD cognitive decline already starts at an early stage, and then may progress relatively slowly for several years after symptom onset. 18,22,33,34,36 Although the mean and standard deviation of FCSRT scores in the presymptomatic MAPT mutation carriers are similar to the entire control group (Table 1), this group is significantly younger than the overall control group, and the adjusted mean differences seen in Table 2 approximate to the difference between the mean of the presymptomatic MAPT mutation carriers and that of a younger control group ( The VBM analysis revealed that for MAPT mutation carriers both free and total recall were correlated almost exclusively with temporal lobe areas, including parts of the medial temporal lobe memory system (e.g., entorhinal and parahippocampal cortices).…”

“…GRN mutation carriers performed better than the other mutation carrier groups on the FCSRT in the presymptomatic stage, whereas they performed significantly worse than C9orf72 mutation carriers in the symptomatic stage. This is in line with previous studies showing that there is minimal cognitive decline in presymptomatic GRN mutation carriers, with often rapidly progressive cognitive decline after symptom onset, 21,22,35,41 whereas in C9orf72 ‐related FTD cognitive decline already starts at an early stage, and then may progress relatively slowly for several years after symptom onset 18,22,33,34,36 …”

Genetic and Clinical Features of Progranulin-Associated Frontotemporal Lobar Degeneration

“…Of these, the most common was c.1477C>T (p.R493X), found in 18.6% of our GRN cases. Our result accords with previous studies showing c.1477C>T (p.R493X) to be the most common GRN mutation in one large US series 16 and several smaller US series, 38,39 as well as one of the most common GRN mutations in a large UK series. 40 We did not find any meaningful phenotypic differences between the c.1477C>T (p.R493X) mutation carriers and patients with other GRN mutations, although our clinical data were limited to demographic details and diagnosis.…”

Voxel-based morphometry patterns of atrophy in FTLD with mutations in MAPT or PGRN

“…Patterns of severe temporal lobe atrophy have previously been demonstrated in studies that have investigated subjects with tau exon mutations IVS10 ϩ 16CϾT, 19,33 IVS10 ϩ 3GϾA, 34 and p.Asn279Lys, 35,36 suggesting that MAPT mutations may predispose to temporal lobe atrophy. These findings fit with previous studies that have shown that while the majority of MAPT cases have a diagnosis of behavioral variant FTD, 8,13,15,37 a high proportion show language deficits. 8,15,17 Greater gray matter loss in MAPT subjects was also identified in the putamen.…”

Impairment of episodic memory in genetic frontotemporal dementia: A GENFI study

“…All symptomatic mutation carriers had impaired memory as measured by the FCSRT compared to controls and presymptomatic mutation carriers, whereas only MAPT‐ and C9orf72 ‐associated FTD were impaired presymptomatically. This is in line with previous studies investigating cognitive functioning in people with genetic FTD, demonstrating memory impairment in C9orf72 ‐, 18,22,33,34 GRN ‐, 19,22,35 and MAPT ‐ 22 related FTD, earlier (and presymptomatically) in C9orf7 2 36 and MAPT 21,37,38 mutations, and only in the later symptomatic stages in GRN‐ related FTD 17,22 . Some of these studies interpreted memory impairment as a distinctive characteristic of the specific gene mutation involved, but our results suggest that, although all (symptomatic) genetic groups were impaired, the underlying cause of memory impairment might differ between the genetic groups.…”

“…41 GRN mutation carriers performed better than the other mutation carrier groups on the FCSRT in the presymptomatic stage, whereas they performed significantly worse than C9orf72 mutation carriers in the symptomatic stage. This is in line with previous studies showing that there is minimal cognitive decline in presymptomatic GRN mutation carriers, with often rapidly progressive cognitive decline after symptom onset, 21,22,35,41 whereas in C9orf72-related FTD cognitive decline already starts at an early stage, and then may progress relatively slowly for several years after symptom onset. 18,22,33,34,36 Although the mean and standard deviation of FCSRT scores in the presymptomatic MAPT mutation carriers are similar to the entire control group (Table 1), this group is significantly younger than the overall control group, and the adjusted mean differences seen in Table 2 approximate to the difference between the mean of the presymptomatic MAPT mutation carriers and that of a younger control group ( The VBM analysis revealed that for MAPT mutation carriers both free and total recall were correlated almost exclusively with temporal lobe areas, including parts of the medial temporal lobe memory system (e.g., entorhinal and parahippocampal cortices).…”

“…GRN mutation carriers performed better than the other mutation carrier groups on the FCSRT in the presymptomatic stage, whereas they performed significantly worse than C9orf72 mutation carriers in the symptomatic stage. This is in line with previous studies showing that there is minimal cognitive decline in presymptomatic GRN mutation carriers, with often rapidly progressive cognitive decline after symptom onset, 21,22,35,41 whereas in C9orf72 ‐related FTD cognitive decline already starts at an early stage, and then may progress relatively slowly for several years after symptom onset 18,22,33,34,36 …”

Genetic and Clinical Features of Progranulin-Associated Frontotemporal Lobar Degeneration

“…Of these, the most common was c.1477C>T (p.R493X), found in 18.6% of our GRN cases. Our result accords with previous studies showing c.1477C>T (p.R493X) to be the most common GRN mutation in one large US series 16 and several smaller US series, 38,39 as well as one of the most common GRN mutations in a large UK series. 40 We did not find any meaningful phenotypic differences between the c.1477C>T (p.R493X) mutation carriers and patients with other GRN mutations, although our clinical data were limited to demographic details and diagnosis.…”

Voxel-based morphometry patterns of atrophy in FTLD with mutations in MAPT or PGRN

“…Patterns of severe temporal lobe atrophy have previously been demonstrated in studies that have investigated subjects with tau exon mutations IVS10 ϩ 16CϾT, 19,33 IVS10 ϩ 3GϾA, 34 and p.Asn279Lys, 35,36 suggesting that MAPT mutations may predispose to temporal lobe atrophy. These findings fit with previous studies that have shown that while the majority of MAPT cases have a diagnosis of behavioral variant FTD, 8,13,15,37 a high proportion show language deficits. 8,15,17 Greater gray matter loss in MAPT subjects was also identified in the putamen.…”

Impairment of episodic memory in genetic frontotemporal dementia: A GENFI study

“…All symptomatic mutation carriers had impaired memory as measured by the FCSRT compared to controls and presymptomatic mutation carriers, whereas only MAPT‐ and C9orf72 ‐associated FTD were impaired presymptomatically. This is in line with previous studies investigating cognitive functioning in people with genetic FTD, demonstrating memory impairment in C9orf72 ‐, 18,22,33,34 GRN ‐, 19,22,35 and MAPT ‐ 22 related FTD, earlier (and presymptomatically) in C9orf7 2 36 and MAPT 21,37,38 mutations, and only in the later symptomatic stages in GRN‐ related FTD 17,22 . Some of these studies interpreted memory impairment as a distinctive characteristic of the specific gene mutation involved, but our results suggest that, although all (symptomatic) genetic groups were impaired, the underlying cause of memory impairment might differ between the genetic groups.…”

“…41 GRN mutation carriers performed better than the other mutation carrier groups on the FCSRT in the presymptomatic stage, whereas they performed significantly worse than C9orf72 mutation carriers in the symptomatic stage. This is in line with previous studies showing that there is minimal cognitive decline in presymptomatic GRN mutation carriers, with often rapidly progressive cognitive decline after symptom onset, 21,22,35,41 whereas in C9orf72-related FTD cognitive decline already starts at an early stage, and then may progress relatively slowly for several years after symptom onset. 18,22,33,34,36 Although the mean and standard deviation of FCSRT scores in the presymptomatic MAPT mutation carriers are similar to the entire control group (Table 1), this group is significantly younger than the overall control group, and the adjusted mean differences seen in Table 2 approximate to the difference between the mean of the presymptomatic MAPT mutation carriers and that of a younger control group ( The VBM analysis revealed that for MAPT mutation carriers both free and total recall were correlated almost exclusively with temporal lobe areas, including parts of the medial temporal lobe memory system (e.g., entorhinal and parahippocampal cortices).…”

“…GRN mutation carriers performed better than the other mutation carrier groups on the FCSRT in the presymptomatic stage, whereas they performed significantly worse than C9orf72 mutation carriers in the symptomatic stage. This is in line with previous studies showing that there is minimal cognitive decline in presymptomatic GRN mutation carriers, with often rapidly progressive cognitive decline after symptom onset, 21,22,35,41 whereas in C9orf72 ‐related FTD cognitive decline already starts at an early stage, and then may progress relatively slowly for several years after symptom onset 18,22,33,34,36 …”

Genetic and Clinical Features of Progranulin-Associated Frontotemporal Lobar Degeneration

“…Of these, the most common was c.1477C>T (p.R493X), found in 18.6% of our GRN cases. Our result accords with previous studies showing c.1477C>T (p.R493X) to be the most common GRN mutation in one large US series 16 and several smaller US series, 38,39 as well as one of the most common GRN mutations in a large UK series. 40 We did not find any meaningful phenotypic differences between the c.1477C>T (p.R493X) mutation carriers and patients with other GRN mutations, although our clinical data were limited to demographic details and diagnosis.…”