A novel mutation P112H in the TARDBP gene associated with frontotemporal lobar degeneration without motor neuron disease and abundant neuritic amyloid plaques

Although TDP-43 is the main constituent of the ubiquitinated cytoplasmic inclusions in the most common forms of frontotemporal lobar degeneration, TARDBP mutations are not a common cause of familial frontotemporal dementia, especially in the absence of motor neuron disease.

We describe a pedigree presenting with a complex autosomal dominant disease, with a heterogeneous clinical phenotype, comprising unspecified dementia, parkinsonism, frontotemporal dementia and motor neuron disease. Genetic analyses identified a novel P112H TARDBP double variation located in exon 3 coding for the first RNA recognition motif of the protein (RRM1). This double mutation is probably pathogenic based on neuropathological findings, in silico prediction analysis and exome sequencing. The two autopsied siblings described here presented with frontotemporal dementia involving multiple cognitive domains and behavior but lacking symptoms of motor neuron disease throughout the disease course. The siblings presented with strikingly similar, although atypical, neuropathological features, including an unclassifiable TDP-43 inclusion pattern, a high burden of tau-negative β-amyloid neuritic plaques with an AD-like biochemical profile, and an unclassifiable 4-repeat tauopathy. The co-occurrence of multiple protein inclusions points to a pathogenic mechanism that facilitates misfolded protein interaction and aggregation or a loss of TDP-43 function that somehow impairs protein clearance.