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Novel Presenilin 1 Mutation (S170F) Causing Alzheimer Disease With Lewy Bodies in the Third Decade of Life
B. Joy Snider, MD, PhD;
Joanne Norton, MSN;
Mary A. Coats, MSN;
Sumi Chakraverty, MS;
Craig E. Hou, MD;
Ramiro Jervis, MD;
Corinne L. Lendon, PhD;
Alison M. Goate, DPhil;
Daniel W. McKeel, Jr, MD;
John C. Morris, MD
Arch Neurol. 2005;62:1821-1830.
Background Cases of early-onset Alzheimer disease (AD) with an autosomal dominant inheritance pattern (familial AD [FAD]) are rare but have greatly advanced our understanding of the molecular pathogenesis of AD. We describe herein a kindred with very early-onset FAD (age, <40 years) with unusual pathological features and a novel mutation in the presenilin 1 (PSEN1) gene (S170F) and review the existing literature on very early-onset FAD.
Objective To analyze the neuropathological and genetic features of a family with onset of AD in the third decade of life.
Design, Setting, and Participants The proband underwent full clinical assessment and postmortem examination at the Washington University Alzheimer’s Disease Research Center, St Louis, Mo. Limited pathological samples and autopsy records of 2 affected family members were available. The proband underwent screening for mutations in genes linked with FAD.
Results Dementia developed in 3 family members in this kindred at a mean age of 27 years; the proband had myoclonus, seizures, and rigidity, similar to findings in previously described kindreds with PSEN1 mutations. All 3 family members were confirmed to have AD by neuropathological examination. The proband also had widespread Lewy body pathology in the brainstem, limbic areas, and neocortex; specific staining for Lewy bodies was not performed in the other 2 family members. The proband had a single mutation (S170F) in exon 6 of the PSEN1 gene, which segregates with disease.
Conclusions A novel PSEN1 mutation causes very-early-onset FAD with associated Lewy bodies. To our knowledge, this kindred has the earliest reported onset of pathologically confirmed FAD and dementia with Lewy bodies.
Author affiliations: Alzheimer’s Disease Research Center (Drs Snider, Goate, McKeel, and Morris and Mss Norton and Coats), Hope Center for Neurological Disorders (Drs Snider, Goate, and Morris), and Departments of Neurology (Drs Snider, Goate, and Morris and Ms Coats), Psychiatry (Mss Norton and Chakraverty and Dr Goate), Genetics (Dr Goate), and Pathology and Immunology (Drs McKeel and Morris), Washington University School of Medicine (Drs Hou, Jervis, and Lendon), St Louis, Mo. Dr Hou is now with the University of California–San Francisco Memory and Aging Center; Dr Jervis, Department of Medicine, Mt Sinai School of Medicine, New York, NY; and Dr Lendon, Division of Neuroscience, University of Birmingham, Birmingham, England.
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