Clinical and neuropathological features of ALS/FTD with TIA1 mutations

Abstract

Mutations in the stress granule protein T-cell restricted intracellular antigen 1 (TIA1) were recently shown to cause amyotrophic lateral sclerosis (ALS) with or without frontotemporal dementia (FTD). Here, we provide detailed clinical and neuropathological descriptions of nine cases with TIA1 mutations, together with comparisons to sporadic ALS (sALS) and ALS due to repeat expansions in C9orf72 (C9orf72+). All nine patients with confirmed mutations in TIA1 were female. The clinical phenotype was heterogeneous with a range in the age at onset from late twenties to the eighth decade (mean = 60 years) and disease duration from one to 6 years (mean = 3 years). Initial presentation was either focal weakness or language impairment. All affected individuals received a final diagnosis of ALS with or without FTD. No psychosis or parkinsonism was described. Neuropathological examination on five patients found typical features of ALS and frontotemporal lobar degeneration (FTLD-TDP, type B) with anatomically widespread TDP-43 proteinopathy. In contrast to C9orf72+ cases, caudate atrophy and hippocampal sclerosis were not prominent. Detailed evaluation of the pyramidal motor system found a similar degree of neurodegeneration and TDP-43 pathology as in sALS and C9orf72+ cases; however, cases with TIA1 mutations had increased numbers of lower motor neurons containing round eosinophilic and Lewy body-like inclusions on HE stain and round compact cytoplasmic inclusions with TDP-43 immunohistochemistry. Immunohistochemistry and immunofluorescence failed to demonstrate any labeling of inclusions with antibodies against TIA1. In summary, our TIA1 mutation carriers developed ALS with or without FTD, with a wide range in age at onset, but without other neurological or psychiatric features. The neuropathology was characterized by widespread TDP-43 pathology, but a more restricted pattern of neurodegeneration than C9orf72+ cases. Increased numbers of round eosinophilic and Lewy-body like inclusions in lower motor neurons may be a distinctive feature of ALS caused by TIA1 mutations.

Keywords: Amyotrophic lateral sclerosis; Frontotemporal dementia; Frontotemporal lobar degeneration; T-cell restricted intracellular antigen-1; TDP-43.

Fig. 1

Pedigree of family UBCU2. Family of European ancestry showing an autosomal dominant pattern of inheritance of ALS ± dementia. Black symbols represent clinically affected individuals and diagonal lines indicate those who are deceased. Genetic analysis was performed on the proband (1), her affected niece (14) and her early affected sister (2); all of whom carried the P362L mutation in TIA1

Fig. 2

Histological changes in TIA1 mutation carriers. Cross section of spinal cord showing severe loss of myelin stain in the corticospinal tracts (CST) (a). Lower motor neurons containing Bunina bodies (arrow) (b) and large, round cored Lewy body-like inclusions (LBLI) (c, d) or round eosinophilic inclusions without distinct cores (e) were present in the medulla and spinal cord. Extra-motor pathology included chronic degeneration with superficial, laminar microvacuolation of the prefrontal cortex (f). a and e, HE/LFB stain; b - d and f, HE stain. Scale bar: a, 1200 μm; b, 7 μm, c, 23 μm; d and e, 15 μm; f, 205 μm

Fig. 3

TDP-43 immunoreactive pathology in TIA1 mutation carriers. Numerous predominantly granular TDP-43 immunoreactive (TDP-ir) neuronal cytoplasmic inclusions (NCI, arrows) were present in the prefrontal cortex (a) and primary motor cortex (b). Hippocampal dentate granule cells (c) and dopaminergic neurons in the substantia nigra (d) were consistently affected in all cases. Lower motor neurons (LMN) of the medulla and spinal cord (e – i) contained NCI that were granular (e), filamentous (f) or round and compact (g and h). Single LMN containing combinations of NCI types were not uncommon (i, arrow points to filamentous inclusions in close proximity to a compact, round NCI). Phosphorylation-independent TDP-43 immunohistochemistry. Scale bar: a and i, 25 μm; b, c and e, 18 μm; d and g, 36 μm; f and h, 9 μm

Fig. 4

Quantitative comparison of spinal cord lower motor neurons (LMN) and different types of neuronal cytoplasmic inclusions (NCI) in LMN in ALS cases with TIA1 mutations, the C9orf72 mutation (C9) and sporadic ALS (sALS). Quantitation in a-c was performed on HE stained sections; whereas d–f was based on TDP-43 immunohistochemistry. There was no difference in the number of spinal cord LMN among groups (a). Round NCI (b) and Lewy body like inclusions (c) were significantly more frequent in TIA1 mutation carriers than in either C9 or sALS cases. In c, the red circle denotes the data point corresponding to the case with only a single section of upper cervical cord available for evaluation. No differences were seen among groups in the number of granular (d) or filamentous (e) TDP-43 NCI; however, round compact NCI were more frequent in TIA1 mutation carriers (f). (** = p < 0.005, * = p < 0.05 compared to C9 and sALS groups, respectively)

Fig. 5

TIA1 immunohistochemistry (IHC) and double-label immunofluorescence (IF) of lower motor neurons from cases with TIA1 mutations. Representative image of TIA1 IHC with the rabbit polyclonal (Santa Cruz #sc-28,237, clone H-120) antibody showing delicate granular cytoplasmic staining (a). Double label IF with pTDP (green) and TIA1 (red) antibodies failed to show co-localization of TIA1 in compact (b), filamentous (c) or granular pTDP-43-ir NCI (d). Scale bar: a and d, 24 μm; b and c, 16 μm