Presenilin 1 mutation in an african american family presenting with atypical Alzheimer dementia.
BACKGROUND
Alzheimer disease (AD) is characterized by memory and visuospatial deficits with relative sparing of personality. Mutations in 3 genes (presenilin 1 and 2 and amyloid precursor protein) are associated with presenile AD. Presenilin 1 gene mutations have not been described in African Americans.


METHODS
We studied an African American family with autosomal dominant rapidly progressive dementia and psychosis occurring early in the fifth decade of life. We performed neurologic evaluations, psychometrics, and neuroimaging. We sequenced the amyloid precursor protein gene, presenilin 1 and 2, and tau in affected and unaffected family members. One patient underwent a brain biopsy and subsequent autopsy.


RESULTS
Personality change, auditory and visual hallucinations, delusions, memory impairment, word-finding difficulties, and subsequent rigidity, dystonia, myoclonus, and mutism developed in 2 brothers. Neuropsychometric testing in one was consistent with frontotemporal dementia or atypical AD. Neuroimaging studies showed diffuse cortical involvement. A clinical diagnosis of familial non-Alzheimer dementia was made. However, results of temporal lobe biopsy in one revealed amyloid neuritic plaques, and autopsy results confirmed the diagnosis of AD. Gene sequencing revealed a presenilin 1 point mutation (M139V) cosegregating with the disease. A tau polymorphism in exon 7 (A178T) was found in an affected brother and unaffected relatives.


CONCLUSIONS
We report the first documented presenilin mutation in African American patients presenting with early personality change, psychosis, and memory loss with preserved praxis. The M139V mutation can present differently between kindreds, with some features suggestive of a frontal lobe syndrome. The M139V mutation can lead to atypical AD, and genetic background may have a role in determining the phenotype of genetically defined AD.
Rippon
Gregory A
GA
Department of Neurology, Mayo Clinic, Rochester, MN, USA.
Crook
Richard
R
Baker
Matthew
M
Halvorsen
Elizabeth
E
Chin
Steven
S
Hutton
Michael
M
Houlden
Henry
H
Hardy
John
J
Lynch
Timothy
T
D000328:Adult; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology / Q000523:psychology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D044383:Black People; D001921:Brain / Q000473:pathology; D005260:Female; D005799:Genes, Dominant / Q000235:genetics; D006212:Hallucinations / Q000209:etiology; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008569:Memory Disorders / Q000209:etiology; D008875:Middle Aged; D009460:Neurologic Examination; D009483:Neuropsychological Tests; D010554:Personality Disorders / Q000209:etiology; D010641:Phenotype; D058225:Plaque, Amyloid / Q000473:pathology; D017354:Point Mutation / Q000235:genetics*; D053764:Presenilin-1; D053766:Presenilin-2; D016875:tau Proteins / Q000737:chemistry / Q000235:genetics; D001741:Black or African American
D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D053764:Presenilin-1; D053766:Presenilin-2; D016875:tau Proteins