Clinical phenotypes and radiological findings in frontotemporal dementia related to TARDBP mutations

Abstract

It has been shown that different genes could be associated with distinctive clinical and radiological phenotypes of FTD. TARDBP gene has been described worldwide in few cases of FTD so its phenotype is still unclear. The objective is to study the clinical and radiological characteristics of TARDBP-related FTD. In the present study, we report clinical, neuropsychological and radiological features of five new Sardinian non-related cases of FTD carriers of the p.A382T TARDBP mutation. Furthermore, we reviewed non-related FTD cases with TARDBP mutations previously described in literature. The p.A382T missense mutation of TARDBP was present in the 21.7 % of familial cases of our FTD cohort (5/23) and in no one of the sporadic patients. 3 of 5 patients showed a temporal variant FTD and 4/5 a predominant temporal involvement at MRI. The review of the literature of FTD cases with TARDBP mutations showed that in 5 of 16 cases, the clinical phenotype was consistent with temporal variant of FTD or semantic dementia (31 %) and in 7 of 16 cases neuroimaging showed predominant temporal lobe involvement (43.7 %). Our study further supports the pathogenetic role of TARDBP mutations in pure FTD and in the full spectrum of FTD/ALS. The presence of a predominant temporal lobe involvement in a high percentage of FTD mutated patients with a peculiar clinical pattern could be useful in the differential diagnosis with other forms of dementia/FTD both sporadic and familial.

Molecular neuropathology of frontotemporal dementia: insights into disease mechanisms from postmortem studies

“…; Floris et al . ). One sporadic case with FTD, PSP, and chorea but no ALS was found to harbor a p.K263E TARDBP mutation (Kovacs et al .…”

RNA-binding proteins with prion-like domains in health and disease

“…Mutations in the gene encoding TDP-43 ( TARDBP ) have been identified in cases of both familial and sporadic ALS, with mutations segregating with disease in the former, further implicating TDP-43 in the pathogenesis of neurodegeneration [29,64–68]. TARDBP mutations are also found in rare instances of FTD [56,69,70]. …”

A genetic association study of two genes linked to neurodegeneration in a Sardinian multiple sclerosis population: The TARDBP Ala382Thr mutation and C9orf72 expansion

“…In our study, all subjects carrying the Ala382Thr mutation did not show any signs or symptoms of other degenerative disease at the time of sampling or later during the follow-up. The TARDBP Ala382Thr mutation has been described in around 30% of Sardinian ALS patients [12,13], in some Sardinian patients with FTLD [15], and also in eight Sardinian individuals with Parkinson's disease [14]. In the latter study three control subjects with the mutation were found, of whom only one did not develop any cognitive/neurological symptom during the follow-up period, while the others developed ALS and dementia, respectively [14].…”

“…In addition, the mutation was found in some individuals affected by frontotemporal dementia, Parkinson's disease, and atypical parkinsonism, leading to the question of whether TARDBP has a role in a widespread range of neurodegenerative diseases [14][15][16]. It is noteworthy that TDP-43 inclusions have been observed in neurons of two MS patients that presented with comorbidity with ALS and semantic dementia [17,18].…”