Neuropathology in the brain donors found to harbor an OPTN (A,B) and HNRNPA1 mutation (C). (A,B) Severe degeneration with spongiosis of the primary motor cortex (haematoxylin and eosin, and atypical, predominantly subcortical white matter TDP-43 proteinopathy, A) in the patient with the OPTN mutation. In contrast, in C, the HNRNPA1 mutation was associated with a lower motor neuron phenotype with classical skein-like cytoplasmic mislocalization of TDP-43 (C, hypoglossal nucleus). (A, 200×; B,C, 400×.) (Cx) Cortex, (SCxWm) subcortical white matter.