Novel presenilin 1 mutation with profound neurofibrillary pathology in an indigenous Southern African family with early-onset Alzheimer's disease.
Genetically determined Alzheimer's disease (AD) is virtually unknown in Africa. We report clinicopathological findings and a presenilin 1 (PS1) mutation associated with early-onset AD in a large Xhosa family from Southern Africa. Twelve individuals spanning four generations were affected, four of whom underwent clinical and psychometric evaluation. Their phenotype was characterized by memory impairment beginning in the early part of the fifth decade, with progressive dementing illness lasting 6-7 years that did not appear to be modified by the presence of an apolipoprotein E (APOE)-epsilon 4 allele. Initial linkage-based analysis using known DNA markers suggested allele cosegregation with a locus on chromosome 14. Direct sequencing of the PS1 gene disclosed a novel I143M (ATT to ATG at nucleotide 677) mutation that lies in a cluster in the second transmembrane domain of the protein. Examination of the proband's brain at autopsy revealed severe AD pathology characterized by neuronal loss, abundant beta amyloid (A beta) neuritic plaques (A beta 42) and neurofibrillary degeneration extending into the brainstem. The phenotype of the I143M mutation was clearly associated with a high degree of neurofibrillary change compared with early-onset sporadic AD cases. Although sporadic cases of AD do exist in African populations, our study confirms the existence of early-onset familial AD among indigenous Southern Africans.
Heckmann
Jeannine M
JM
Division of Neurology, Groote Schur Hospital and University of Cape Town, South Africa.
Low
Wee-Chuang
WC
de Villiers
Cora
C
Rutherfoord
Stuart
S
Vorster
Alvera
A
Rao
Harpal
H
Morris
Christopher M
CM
Ramesar
Raj S
RS
Kalaria
Raj N
RN
D017668:Age of Onset; D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics; D004252:DNA Mutational Analysis / Q000379:methods; D018450:Disease Progression; D005260:Female; D008040:Genetic Linkage; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D016874:Neurofibrillary Tangles / Q000473:pathology*; D009483:Neuropsychological Tests; D010375:Pedigree; D053764:Presenilin-1; D011594:Psychometrics; D013019:South Africa
D001057:Apolipoproteins E; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1