Novel presenilin 1 mutation (S170F) causing Alzheimer disease with Lewy bodies in the third decade of life.
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.


METHODS
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.
Snider
B Joy
BJ
Alzheimer's Disease Research Center, Washington University School of Medicine, St Louis, MO, USA. sniderj@neuro.wustl.edu
Norton
Joanne
J
Coats
Mary A
MA
Chakraverty
Sumi
S
Hou
Craig E
CE
Jervis
Ramiro
R
Lendon
Corinne L
CL
Goate
Alison M
AM
McKeel
Daniel W
DW
Morris
John C
JC
D000328:Adult; D017668:Age of Onset; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D019943:Amino Acid Substitution / Q000235:genetics; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D025063:Chromosome Disorders / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D018450:Disease Progression; D005091:Exons / Q000235:genetics; D005192:Family Health; D017809:Fatal Outcome; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D016631:Lewy Bodies / Q000235:genetics* / Q000378:metabolism; D020961:Lewy Body Disease / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D016874:Neurofibrillary Tangles / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010375:Pedigree; D058225:Plaque, Amyloid / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D053764:Presenilin-1; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism
D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D051844:alpha-Synuclein