Clinicopathologic correlations in a family with a TBK1 mutation presenting as primary progressive aphasia and primary lateral sclerosis

Abstract

Mutations in the TANK binding kinase 1 gene (TBK1) are associated with amyotrophic lateral sclerosis and/or frontotemporal dementia; however, the range of clinical phenotypes and neuropathological changes associated with these mutations have not yet been completely elucidated. We present the detailed clinical, neuroimaging, and neuropathological features of two brothers carrying the TBK1 p.Gly272_Thr331del mutation. Both presented with very similar and unusual clinical features including primary progressive aphasia and asymmetric-onset primary lateral sclerosis (PLS). Repeated electrophysiological studies failed to reveal any lower motor neuron involvement. Neuropathological evaluation of both cases revealed frontotemporal lobar degeneration with TDP-43 proteinopathy type B and selective involvement of upper motor neurons with TDP-43 inclusions. The stereotypical clinical presentation and neuropathological findings in these cases widen the phenotypic spectrum of TBK1 mutations and provide insights into the pathogenesis of PLS.

Keywords: TBK1; TDP-43; neuropathology; primary lateral sclerosis; primary progressive aphasia.

Figure 1.

Family pedigree. Proband (case 1) is marked with an arrow. Autopsy of the proband’s aunt confirmed only Alzheimer-type pathology.

Figure 2.

Confirmation of the TBK1 c.992+1G>A mutation and effect on TBK1 splicing. Presence of the c.992+1G>A mutation was confirmed by Sanger sequencing in Case 1 and Case 2 (red rectangle). c.992+1G>A is absent from the genomic DNA of an unaffected sibling (A). RT-PCR using primers specific for TBK1 exons 7 and 9 in Case 1 shows the presence of a product representing the wild-type cDNA (blue rectangle) and a shorter product (red rectangle). Sanger sequencing revealed that the shorter product lacks TBK1 exon 8. MW = molecular-weight size DNA marker.

Figure 3.

MRI scan (A, B) and FDG-PET (C, D) on case 1 and MRI scan on case 2 (E, F) showed asymmetric (left greater than right) temporal lobe atrophy (white arrows) and hypometabolism, with relative preservation of frontal lobes. R= right side.

Figure 4.

Pathological findings. Both cases showed similar gross and microscopic findings, including cerebral atrophy that was more severe on the left and preferentially affected the temporal lobes and primary motor cortex (arrows, Case 2) (A, B). There was moderate-to-severe chronic degeneration of the motor cortex (C) and corticospinal tracts (*, D) with a normal number of healthy-appearing lower motor neurons (E). TDP immunohistochemistry demonstrated neuronal cytoplasmic inclusions (NCI) in all cortical laminae of the primary motor (F), prefrontal (G) and temporal neocortex with relatively few dystrophic neurites and no intranuclear inclusions, consistent with FTLD-TDP type B. Many of the NCI had an unusual crescentic, annular or tangle-like morphology. NCI were also abundant in the basal ganglia (H). Magnifications: C:100x; D:20x; E:200x; F,G and H:600x.