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

Abstract

IntroductionAlthough 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.ResultsWe 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.ConclusionsTARDBP mutation screening should be considered in familial frontotemporal dementia cases, even without signs or symptoms of motor neuron disease, especially when other more frequent causes of genetic frontotemporal dementia (i.e. GRN, C9ORF72, MAPT) have been excluded and when family history is complex and includes parkinsonism, motor neuron disease and frontotemporal dementia. Further investigations in this family may provide insight into the physiological functions of TARDBP.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-015-0190-6) contains supplementary material, which is available to authorized users.

Review: Neuropathology of non‐tau frontotemporal lobar degeneration

“…Descriptions of the neuropathology in cases with FTD are few and the pathogenicity of the reported mutations remains unclear due to current lack of evidence of segregation with the disease. Although TDP‐43 pathology seems to be a consistent feature in these cases, the pattern of FTLD‐TDP is not consistent, often difficult to classify and may be combined with a more complex proteinopathy . Some of the clinical and pathological variation associated with TARDBP mutations may reflect recent findings that different mutations may have different pathomechanisms, including both loss of function and gain of RNA splicing activity .…”

The clinical spectrum of sporadic and familial forms of frontotemporal dementia

“…), associated with a broad phenotype including features of parkinsonism or an overlap syndrome of MND/PSPS (Moreno et al . ). One case of bvFTD with a supranuclear gaze palsy and chorea has been observed (Kovacs et al .…”

“…; Moreno et al . ). FTD cases have had bvFTD or svPPA, with a wide range of age at onset (29–77 years) (Borroni et al .…”

“…Mutations in the TARDBP gene on chromosome 1 were initially identified in familial and sporadic ALS cases (Kabashi et al 2008;Rutherford et al 2008;Sreedharan et al 2008;Van Deerlin et al 2008), and account for 4-6% of familial ALS cases and 1% of sporadic ALS cases. They also account for a small proportion of cases with combined FTD-MND (Benajiba et al 2009;Chio et al 2010), associated with a broad phenotype including features of parkinsonism or an overlap syndrome of MND/PSPS (Moreno et al 2015). One case of bvFTD with a supranuclear gaze palsy and chorea has been observed (Kovacs et al 2009).…”

Charting Frontotemporal Dementia: From Genes to Networks

“…TAR DNA binding protein (TARDBP) gene mutation carriers showed predominant temporal lobe atrophy. [86][87][88] In triggering receptor expressed on myeloid cells (TREM2) gene mutation carriers, frontotemporal atrophy and extensive white matter abnormalities were found. 89…”