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A novel PSEN2 mutation associated with a peculiar phenotype

From the Istituto Superiore di Sanità (P.P., A. Crestini, L.M.C., N.V., M.P., A. Confaloni), Rome, Italy; Istituto Neurologico Nazionale Carlo Besta (G.M., F. Tagliavini, G.G.), Milan, Italy; Università di Sassari (M.R.P., E.D., R.C., F. Tanda, A.D.), Italy; and DPSMC (G.M.), Università di Udine, Italy.

Address correspondence and reprint requests to Dr. Annamaria Confaloni, Istituto Superiore di Sanità, 00161 Rome, Italy annamaria.confaloni{at}iss.it

Background: Mutations of presenilin 2 gene are a rare cause of familial Alzheimer disease (AD). We describe an Italian family with hereditary dementia associated with a novel mutation in the presenilin 2 gene.

Methods: Clinical investigations of the diseased subjects; interviews with relatives; studies of medical records; pedigree analysis; and neuroradiologic, neuropathologic, and molecular genetic studies were carried out in the pedigree.

Results: Genetic analysis showed a novel PSEN2 A85V mutation present in the proband and in all analyzed affected members, in a subject presenting with an amnesic mild cognitive impairment, and in a young, still asymptomatic subject. The proband showed a clinical phenotype indicative of Lewy body dementia and the neuropathologic examination demonstrated the presence of unusually abundant and widespread cortical Lewy bodies in addition to the hallmark lesions of AD. Other affected members exhibited a clinical phenotype typical of AD.

Conclusions: Our findings add complexity to the spectrum of atypical phenotypes associated with presenilin mutations and should then be taken into account when considering the nosography of neurodegenerative diseases. They also support previous data that specific mutations of genes associated with familial Alzheimer disease may influence the presence and extent of Lewy bodies.

Abbreviations: AD = Alzheimer disease; CERAD = Consortium to Establish a Registry for Alzheimer's Disease; DLB = dementia with Lewy bodies; FAD = familial Alzheimer disease; FITC = fluorescein isothiocyanate; IgG = immunoglobulin G; LB = Lewy body; MCI = mild cognitive impairment; NIA = National Institute on Aging; SAD = sporadic Alzheimer disease; TM1 = transmembrane domain 1.

*These authors contributed equally to the study.

The study was partially supported by Project 4AN/F6, the Italian Ministry of Health (Project 4AN/F6 and Project P19 to A. Confaloni and 533F/Q/1 and 71.6/2006 to F. Tagliavini).

Disclosure: The authors report no conflicts of interest.

Received August 29, 2007. Accepted in final form January 2, 2008.