Clinicopathologic Characterization of 2 Individuals With Variants-1 Novel Splice Variant, 2 Proteinopathies: A Case Series.

Objectives: Here, we report detailed clinicopathologic evaluation of 2 individuals with pathogenic variants in , including one novel likely pathogenic splice variant. We describe the striking diversity of clinical phenotypes among family members and also the brain and spinal cord neuropathology associated with these 2 distinct variants.

Methods: Two individuals with pathogenic variants in and their families were clinically characterized, and the probands subsequently underwent extensive postmortem neuropathologic examination of their brains and spinal cords.

Results: Multiple affected individuals within a single family were found to carry a previously unreported c.358+3A>G variant, predicted to alter splicing. Detailed histopathologic evaluation of our 2 variant carriers demonstrated distinct TDP-43 pathologic subtypes, but shared argyrophilic grain disease (AGD) tau pathology.

Discussion: Although all pathogenic variants are associated with TDP-43 pathology, the clinical and histologic features can be highly variable. Within one family, we describe distinct neurologic presentations which we propose are all caused by a novel c.358+3A>G variant. AGD is typically associated with older age, but it has been described as a copathologic finding in other variant carriers and may be a common feature in FTLD-TDP due to .