Intra-Familial Clinical Heterogeneity due to FTLD-U with TDP-43 Proteinopathy Caused by a Novel Deletion in Progranulin Gene (PGRN)

Abstract

Frontotemporal dementia (FTD) is one of the commonest forms of early-onset dementia, accounting for up to 20% of all dementia patients. Recently, it has been shown that mutations in progranulin gene (PGRN) cause many familial cases of FTD. Members of a family affected by FTD spectrum disorders were ascertained in Poland and Canada. Clinical, radiological, molecular, genetic, and pathological studies were performed. A sequencing analysis of PGRN exons 1-13 was performed in the proband. Genotyping of the identified PGRN mutation and pathological analysis was carried out in the proband's brother. The onset of symptoms of FTD in the proband included bradykinesia, apathy, and somnolence followed by changes in personality, cognitive deficits, and psychotic features. The proband's clinical diagnosis was FTD and parkinsonism (FTDP). DNA sequence analysis of PGRN revealed a novel, heterozygous mutation in exon 11 (g. 2988_2989delCA, P439_R440fsX6). The mutation introduced a premature stop codon at position 444. The proband's brother with the same mutation had a different course first presenting as progressive non-fluent aphasia, and later evolving symptoms of behavioral variant of FTD. He also developed parkinsonism late in the disease course evolving into corticobasal syndrome. Pathological analysis in the brother revealed Frontotemporal Lobar Degeneration-Ubiquitin (FTLD-U)/TDP-43 positive pathology. The novel PGRN mutation is a disease-causing mutation

Parkinsonism and Frontotemporal Dementia: The Clinical Overlap

“…A number of MAPT mutations have been reported among those with early (N279K, delN296, S305S, +11) (Soliveri et al 2003; Pastor et al 2001; Wszolek et al 2001; Skoglund et al 2008) or late (P301S, N296H, +3, +12, +14, +16; Baba et al 2007; Iseki et al 2001; Rohrer et al 2011) parkinsonism associated with FTLDP-17T/ MAPT , with a picture most often resembling PSP. Similarly, several mutations in PGRN have been reported among those with parkinsonism associated with FTDP-17U/ PGRN , with a phenotype most often suggestive of CBS, with or without language abnormalities (c.26C>A, g.2988_2989delCA, P439_R440fsX6, IVS1+1 G–>A, +1, +11; Wider et al 2008; Gabryelewicz et al 2010; Boeve et al 2006). Psychiatric symptoms and language impairment, particularly in the form of progressive nonfluent aphasia (PNFA), are more common among patients with PGRN mutations (see Fujioka and Wszolek, this issue).…”

Psychosis and Hallucinations in Frontotemporal Dementia with the C9ORF72 Mutation

“…A small series of patients meeting criteria for both FTD and LBD with hallucinations were also noted to have TDP-43 pathology 20 . Others have described psychosis and Parkinsonism in C9 linked families before the specific mutation was discovered 21 and in patients with progranulin mutations 22 . While psychosis is not considered a feature of ALS, small numbers of patients have been described.…”

Management of Frontotemporal Dementia: Targeting Symptom Management in Such a Heterogeneous Disease Requires a Wide Range of Therapeutic Options

“…Over the last 15 years, mutations in tau [30,32–37], progranulin [31,32,38,39], valosin-containing protein [40–42], CHMP2B [43–45] and tar DNA-binding protein (TDP)-43 [46–48] have been linked to FTD. Critical to our understanding of the therapeutics of FTD is an appreciation that all known mutations leading to autosomal dominant FTD can give rise to a myriad of clinical phenotypes even within the same family pedigree [30–32,38,49–52]. Despite the wealth of discovery in the genetics of FTD, no evidence exists to support any contentions that specific neurotransmitter systems and/or neuroanatomic circuits are preferentially involved in any distinct genetic variants identified to date.…”

“…Classic Pick’s disease, FTLD-17 linked to tau mutations, progressive supranuclear palsy and corticobasal degeneration are characterized pathologically by the presence of tau inclusions [33,35,37,54–57]. FTD cases associated with progranulin mutations can be characterized pathologically by the absence of progranulin reactivity in affected regions of the cortex [38,49,50]. Rare cases in familial forms of FTD associated with mutations in the valosin-containing protein gene can be identified with antibodies to valosin [40–42].…”