Presenilin 1 Glu318Gly polymorphism: interpret with caution.

BACKGROUND The significance of the presenilin 1 (PSEN1) Glu318Gly polymorphism has been described as either a causal mutation with reduced penetrance or a benign polymorphism. When this polymorphism is found in a symptomatic person with a family history of dementia, counseling on recurrence risk becomes very problematic. OBJECTIVE To demonstrate that the PSEN1 Glu318Gly polymorphism should be interpreted cautiously. DESIGN Case histories of 2 patients with presenile dementia and family histories of dementia are described. The PSEN1 gene was sequenced in the patients and in 11 family members of patient 1. RESULTS Two patients with presenile dementia and personality change were found to carry the PSEN1 Glu318Gly polymorphism. The presence of the polymorphism was confirmed in several family members of patient 1 but was absent in 1 symptomatic relative. CONCLUSIONS The Glu318Gly polymorphism may be associated with risk for neurodegenerative disease; however, in the cases described here, it did not appear to be a risk factor. Until there is consensus on whether it is associated with disease, families should be informed that the clinical significance of the polymorphism is uncertain.