We previously reported a kindred with three cases of dementia, in which the proband exhibited features typical of frontotemporal dementia and parkinsonism (FTDP). An arginine insertion at codon 352 (insR352) in the presenilin-1 (PSEN1) gene was identified in the proband, but analyses in plasma and CSF suggested a mechanism of neurodegeneration not directly related to amyloid pathophysiology. The proband was followed with yearly evaluations of functional, clinical, neuropsychologic, neuropsychiatric and radiologic status, which showed relatively linear change over the initial 4 years of assessment. Upon the proband's death at age 63, neuropathologic examination revealed frontotemporal lobar degeneration (FTLD) with ubiquitin-positive inclusions (FTLD-U). We recently identified several kindreds with familial FTDP associated with mutations in the progranulin (PGRN) gene, particularly in those cases with neuronal intranuclear inclusions. Our proband was indeed found to have such inclusions, and PGRN analysis in this proband revealed the G to A mutation in the exon 1 splice donor site (IVS1+1G→A) which is predicted to destroy the 5′-splice site of exon 1 and remove the start methionine codon and hence completely block any PGRN protein from being generated. These findings suggest that the insR352 PSEN1 is not pathogenic, and the IVS1+1G→A mutation in PGRN causes FTDP associated with FTLD-U pathology and represents a new class of neurodegenerative disease—the ‘hypoprogranulinopathies’.