TARDBP variation associated with frontotemporal dementia, supranuclear gaze palsy, and chorea

Abstract

TDP-43 has been identified as the pathological protein in the majority of cases of frontotemporal lobar degeneration and amyotrophic lateral sclerosis (ALS). TARDBP mutations have so far been uniquely associated with familial and sporadic ALS. We describe clinicopathological and genetic findings in a carrier of the novel K263E TARDBP variation, who developed frontotemporal dementia, supranuclear palsy, and chorea, but no signs of motor neuron disease. Neuropathologic examination revealed neuronal and glial TDP-43-immunoreactive deposits, predominantly in subcortical nuclei and brainstem. This is the first report of a TARDBP variation associated with a neurodegenerative syndrome other than ALS.

FIG. 1.

T1 MRI sequences, 1 year prior to death, revealed mild atrophy of the caudate nucleus (A) and prominent tectal and tegmental atrophy in the mesencephalon (B, C). Mild spongiosis in the superficial layers of the frontal cortex (D, Hematoxylin-eosin). Severe loss of neurons in the substantia nigra (E; Hematoxylin-eosin). Severe reactive gliosis in the caudate nucleus demonstrated by anti-GFAP immunostaining (F). Immunohistochemistry for phospho-TDP-43 revealed: thin and long (G) as well as globular neurites (H); spherical (I; caudate nucleus) and skein-like (J; inferior olives) neuronal cytoplasmic inclusions; neuronal intranuclear inclusions (K; inferior olive and L; caudate nucleus). Moderate neuritic phospho-TDP-43-immunoreactivity in the primary visual cortex (M). Mild phospho-TDP-43-pathology in the precentral gyrus (N). Absence of phospho-TDP-43 pathology in the dentate gyrus (O). Phospho-TDP-43-immunoreactive neurites and neuronal inclusions in the caudate nucleus (P) and inferior olive (Q). Thread-like pathology and sparse glial cytoplasmic inclusions in the internal capsule (R). Scale bars = Bar graphs: 150 μm (D, E), 20 μm (G–L), 100 μm (F, M–R).