SQSTM1 mutations in French patients with frontotemporal dementia or frontotemporal dementia with amyotrophic lateral sclerosis

Abstract

Importance: Mutations in the SQSTM1 gene, coding for p62, are a cause of Paget disease of bone and amyotrophic lateral sclerosis (ALS). Recently, SQSTM1 mutations were confirmed in ALS, and mutations were also identified in 3 patients with frontotemporal dementia (FTD), suggesting a role for SQSTM1 in FTD.

Objective: To evaluate the exact contribution of SQSTM1 to FTD and FTD with ALS (FTD-ALS) in an independent cohort of patients.

Design: A SQSTM1 mutation was first identified in a multiplex family with FTD by use of whole-exome sequencing. To evaluate the frequency of SQSTM1 mutations, we sequenced this gene in a cohort of patients with FTD or FTD-ALS, with no mutations in known FTD and ALS genes.

Setting: Primary care or referral center.

Participants: An overall cohort of 188 French patients, including 132 probands with FTD and 56 probands with FTD-ALS.

Main outcomes and measures: Frequency of SQSTM1 mutations in patients with FTD or FTD-ALS; description of associated phenotypes.

Results: We identified 4 heterozygous missense mutations in 4 unrelated families with FTD; only 1 family had clinical symptoms of Paget disease of bone, and only 1 family had clinical symptoms of FTD-ALS, possibly owing to the low penetrance of some of the clinical manifestations.

Conclusions and relevance: Although the frequency of the mutations is low in our series (4 of 188 patients [2%]), our results, similar to those already reported, support a direct pathogenic role of p62 in different types of FTD.

Figure 1. Pedigrees of Family F297 Carrying c.1160C>T, p.P387L Mutation, Family F523 Carrying c.1142C>T, p.A381V Mutation, Family FR1324 Carrying c.1175C>T, p.P392L Mutation, and Family F480 Carrying c.98C>T, p.A33V Mutation

The individuals are represented by diamonds for confidentiality. The probands are indicated by arrows. The black diamonds indicate individuals with a behavioral variant of frontotemporal dementia; the gray diamonds indicate individuals with dementia with no clinical information; and the white diamonds indicate nonsymptomatic individuals. The ages of individuals (in years) are indicated at onset of frontotemporal dementia (FTD), at onset of Paget disease of bone (PDB), at onset of amyotrophic lateral sclerosis (ALS), at onset of unspecified dementia (D), at onset of parkinsonism (P), and at death (AD), along with the current ages of alive individuals (A) and genotypes. In family F297, individuals 009 and 013, who did not carry the mutation, had no neurological symptoms at 80 and 85 years of age, respectively. ^aDNA samples are available.

Figure 2. Brain Imaging of Patients Carrying SQSTM1 Mutations

Axial T1-weighted magnetic resonance imaging (MRI) scans of the brain of proband 003 of family F297 reveal left-sided predominant frontal and temporal atrophy (A and B), a septum pellucidum cyst (A), and moderate periventricular hyposignals (B [arrow]). Technetium (Tc) 99m ethyl cysteinate dimer (ECD) single-photon emission computed tomographic (SPECT) scans on the axial (C and D) and sagittal (E) sections of proband 003 of family F297 reveal hypoperfusion of predominantly left frontal and bilateral temporal lobes. Computed tomographic scans of the brain of patient 005 of family F523 reveal moderate left-sided perisylvian (F) and bilateral frontal atrophy (G) associated with moderate white matter hypodensities (G [arrow]) and a septum pellucidum cyst (F and G). Tc 99m ECT-SPECT scans of the brain of patient 005 of family F523 reveal diffuse cerebral hypoperfusion on the axial (H) and sagittal (I) sections; the dopamine transporter (DaT) scan is normal (J). Axial fluid-attenuated inversion recovery (FLAIR) MRI scans of patient 010 of family F480 reveal predominantly right-sided perisylvian atrophy associated with moderate periventricular and callosal hypersignals (K and L [arrows]). Axial FLAIR MRI scans of patient 010 from family F1324 reveal predominantly left-sided frontal and perisylvian atrophy associated with moderate periventricular and callosal hypersignals (M [arrow] and N). Tc 99m ECT-SPECT scan of the brain of patient 010 from family F1324 reveals severe, predominantly left-sided frontal and temporal hypoperfusion (O). Axial FLAIR MRI scan of patient 005 from family FR1324 reveals bilateral frontal and temporal atrophy, with periventricular hypersignals (P [arrow]).