Background The majority of cases of amyotrophic lateral sclerosis (ALS) start in late adult life and are characterised by TDP-43 positive ubiquitinated inclusions. Juvenile ALS is a rare but important exception with regard to age of onset and underlying neuropathology, which is TDP-43 negative, but characterised by basophilic inclusions on H+E stain.

Methods We identified four patients with juvenile ALS with basophilic inclusions, characterised the neuropathology and performed genetic analyses.

Results Motor symptoms began between age 17 and 22, with rapid disease progression without dementia. No family history was identified. Basophilic inclusions were present in all cases and were immunoreactive for various RNA binding proteins, most prominently FUS (fused in sarcoma), but negative for TDP-43. A wide range of FUS deposits was identified in glia and neuronal cytoplasm and nuclei. This was accompanied by disintegration of Nissl substance, ultrastructurally in keeping with aggregation of fragmented rough endoplasmic reticulum. Although no patient had a family history, FUS mutations were found in all three cases with available DNA, one of which was novel.

Conclusion Juvenile ALS with basophilic inclusions is a FUS proteinopathy caused by mutations in FUS, suggesting that altered RNA metabolism is pivotal in disease pathogenesis.