Table 1 Phenotype-pathology correlations summary of FUS-linked human ALS/FTD

- Degeneration of both upper and lower motor neurons

- Significant neuronal loss within anterior horn of spinal cord

- Moderate neuronal loss of Betz cells within layer V of motor cortex and motor nuclei of brainstem

- Dystrophic neurites, astrogliosis, microglial activation

- TDP43-negative, FUS-positive neuronal cytoplasmic inclusions

FUS – over 50 mutations described, particularly missense variations within C-terminal Nuclear Localization Signal

FUS mutations account for ~4 % fALS and ~1 % sALS

- Progressive muscular atrophy

- Dysphagia

- Dysarthria

- Respiratory

- Rigid spasticity

- Death normally within 2–3 years from symptom onset

FTLD-FUS

Atypical FTLD with Ub (aFTLD-U)

- Widespread degeneration of frontal cortex and ventral temporal lobe

- Tau/TDP43-negative, FUS-positive neuronal or glial inclusions predominantly within hippocampus, amygdala, frontotemporal cortex and striatum

Rare cases of FUS variants in clinical FTLD (not confirmed pathologically)

~10 % FTLD cases display FUS pathology

- Normally behavioural variant FTD

- Changes in personality and emotion

- Irrationality, compulsiveness, confusion, repetition, inappropriate behaviour

- Psychiatric symptoms, depression and anxiety common

- Memory, motor function and perception are relatively preserved until late disease stages

NIFID

- Neuronal cytoplasmic inclusions containing abnormal intermediate filament accumulation

BIBD

- Significant FUS-pathology plus subcortical basophilic inclusions on H&E staining