OBJECTIVES: To describe the clinical and molecular characteristics of a family with young-onset dementia and frontotemporal features associated with a presenilin 1 (PSEN1) mutation. BACKGROUND: Although most families with PSEN1 mutations present with an amnestic phenotype of early-onset Alzheimer's disease, there are some rare reports of PSEN1 mutations associated with frontotemporal features or phenotypes, including at least three cases with Pick bodies at autopsy. METHODS: Family history was collected for 6 symptomatic and 9 asymptomatic members of the same family at the Institutes on Aging and Genetics, Pontificia Universidad Javeriana in Colombia. DNA was collected from 3 symptomatic siblings; two were able to complete a multidisciplinary clinical assessment. DNA samples were processed at the University of Pennsylvania using a targeted next-generation sequencing panel designed to detect genetic variations in 45 genes associated with several neurodegenerative diseases, including AD. RESULTS: PSEN1 c.428T>C, p.Ile143Thr was detected in three affected siblings (proband reported by Arango, et.al., 2001). The proband presented at age 30 with memory problems and subsequent apathy and aphasia; he died at age 35. One sister presented at age 35 with disinhibition, lack of empathy, repetitive behaviors and hyperorality; she died at age 43. A third sibling presented at age 35 with significant executive dysfunction, apathy, lack of social engagement and indifference to the feelings of others. He subsequently developed impairments in memory, language and spatial abilities, as well as myoclonus and seizures. MRI 3-years post-onset showed predominant fronto-insular atrophy. Per report, the remaining 3 symptomatic siblings (not tested) had heterogeneous dementia presentations and died before the age of 45. CONCLUSIONS: PSEN1 mutations may produce FTD-like features or phenotypes. Screening for PSEN1 mutations should be considered in kindreds with early onset frontotemporal dementia. Study supported by: AG046499, AG017586, AG032953, AG043503, Colciencias 371-2011 and 370-201, and Wyncote Foundation