Abstract
Frontotemporal dementia (FTD) refers to a complex spectrum of clinically and genetically heterogeneous disorders. Although fully penetrant mutations in several genes have been identified and can explain the pathogenic mechanisms underlying a great portion of the Mendelian forms of the disease, still a significant number of families and sporadic cases remains genetically unsolved. We performed whole exome sequencing in 100 patients with a late-onset and heterogeneous FTD-like clinical phenotype from Apulia and screened mendelian dementia and neuronal ceroid lipofuscinosis genes. We identified a nonsense mutation in SORL1 VPS domain (p.R744X), in 2 siblings displaying AD with severe language problems and primary progressive aphasia and a near splice-site mutation in CLCN6 (p.S116P) segregating with an heterogeneous phenotype, ranging from behavioural FTD to FTD with memory onset and to the logopenic variant of primary progressive aphasia in one family. Moreover 2 sporadic cases with behavioural FTD carried heterozygous mutations in the CSF1R Tyrosin kinase flanking regions (p.E573K and p.R549H). By contrast, only a minority of patients carried pathogenic C9orf72 repeat expansions (1%) and likely moderately pathogenic variants in GRN (p.C105Y, p.C389fs and p.C139R) (3%). In concert with recent studies, our findings support a common pathogenic mechanisms between FTD and neuronal ceroid lipofuscinosis and suggests that neuronal ceroid lipofuscinosis genes should be investigated also in dementia patients with predominant frontal symptoms and language impairments.
Highlights
Frontotemporal dementia (FTD) refers to a clinical spectrum of disorders that are genetically, clinically, and neuropathologically heterogeneous
We report one SORL1 mutation in the valosin-containing protein (VCP) domain (p.R744X) that was associated to Alzheimer’s disease (AD) with severe language impairment and progressive aphasia (PPA) and was not detected in a member of the same family that had been initially diagnosed with AD and successively with FTD with memory onset (Table 3, Fig. 2A, B)
We report a novel and likely pathogenic variant identified in CLCN6 (p.S116P) leading to a T to C transition in the last nucleotide of exon 5 (c.346 in coding DNA reference sequence NM_001286.2), at position − 1 of the exon 5 splice donor site (Fig. 3B)
Summary
Frontotemporal dementia (FTD) refers to a clinical spectrum of disorders that are genetically, clinically, and neuropathologically heterogeneous. We report one SORL1 mutation in the valosin-containing protein (VCP) domain (p.R744X) that was associated to AD with severe language impairment and PPA and was not detected in a member of the same family that had been initially diagnosed with AD and successively with FTD with memory onset (Table 3, Fig. 2A, B).
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