Genetic and clinical features of progranulin-associated frontotemporal lobar degeneration

Abstract

Objective: To assess the relative frequency of unique mutations and their associated characteristics in 97 individuals with mutations in progranulin (GRN), an important cause of frontotemporal lobar degeneration (FTLD).

Participants and design: A 46-site International Frontotemporal Lobar Degeneration Collaboration was formed to collect cases of FTLD with TAR DNA-binding protein of 43-kDa (TDP-43)-positive inclusions (FTLD-TDP). We identified 97 individuals with FTLD-TDP with pathogenic GRN mutations (GRN+ FTLD-TDP), assessed their genetic and clinical characteristics, and compared them with 453 patients with FTLD-TDP in which GRN mutations were excluded (GRN- FTLD-TDP). No patients were known to be related. Neuropathologic characteristics were confirmed as FTLD-TDP in 79 of the 97 GRN+ FTLD-TDP cases and all of the GRN- FTLD-TDP cases.

Results: Age at onset of FTLD was younger in patients with GRN+ FTLD-TDP vs GRN- FTLD-TDP (median, 58.0 vs 61.0 years; P < .001), as was age at death (median, 65.5 vs 69.0 years; P < .001). Concomitant motor neuron disease was much less common in GRN+ FTLD-TDP vs GRN- FTLD-TDP (5.4% vs 26.3%; P < .001). Fifty different GRN mutations were observed, including 2 novel mutations: c.139delG (p.D47TfsX7) and c.378C>A (p.C126X). The 2 most common GRN mutations were c.1477C>T (p.R493X, found in 18 patients, representing 18.6% of GRN cases) and c.26C>A (p.A9D, found in 6 patients, representing 6.2% of cases). Patients with the c.1477C>T mutation shared a haplotype on chromosome 17; clinically, they resembled patients with other GRN mutations. Patients with the c.26C>A mutation appeared to have a younger age at onset of FTLD and at death and more parkinsonian features than those with other GRN mutations.

Conclusion: GRN+ FTLD-TDP differs in key features from GRN- FTLD-TDP.

Figure 1

Frequency of pathogenic GRN mutations. Of 50 unique pathogenic GRN mutations, 16 were found in more than 1 individual, and none of the people were related. Of these 16 mutations, 7 occurred in more than 2 individuals and constituted nearly 50% of our 97-case cohort.

Figure 2

Comparison of frontotemporal lobar degeneration characterized by TAR DNA-binding protein of 43-kDa–positive inclusions (FTLD-TDP) with and without GRN mutations. A, Comparing 97 patients with GRN mutations vs 453 patients with FTLD-TDP in which GRN mutations had been excluded, we found age at onset and age at death to be significantly younger in patients with GRN mutations. In addition, patients with GRN mutations were more likely to have a family history of FTLD-TDP and less likely to have motor neuron disease (MND). P value was determined by log-rank testing for continuous variables, and Fisher exact testing was used for categorical variables. B, Age at death was significantly younger in patients with FTLD-TDP and GRN mutations (GRN+) vs patients with FTLD-TDP without GRN mutations (GRN−). P value was determined by log-rank testing. C, Disease duration did not differ significantly between FTLD-TDP with (GRN+) and without (GRN−) GRN mutations. P value was determined by log-rank testing. D, Clinical diagnoses for study cohorts of FTLD-TDP with (GRN+) and without (GRN−) GRN mutations. The proportion of patients with diagnoses of Parkinson disease, corticobasal syndrome, or progressive supranuclear palsy (PD/CBS/PSP) was significantly higher in those with GRN mutations (5% vs 1% for GRN− FTLD-TDP; P=.03). ADindicatesAlzheimer disease; FTD, frontotemporal dementia; IQR, interquartile range; and NOS, not otherwise specified.