Brain Advance Access originally published online on October 21, 2003
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Brain, Vol. 127, No. 1, 133-142, 2004
© 2004 Guarantors of Brain
doi: 10.1093/brain/awh009
Novel presenilin 1 mutation with profound neurofibrillary pathology in an indigenous Southern African family with early-onset Alzheimer’s disease
,3
1 Division of Neurology and
2 MRC Human Genetics Research Unit, Division of Human Genetics, Groote Schuur Hospital and University of Cape Town, Cape Town,
3 Neuropathology Unit, Department of Anatomical Pathology, University of Stellenbosch, Tygerberg, South Africa and
4 Institute for Ageing and Health, Newcastle General Hospital, Newcastle upon Tyne, UK
Deceased
Correspondence to: Professor R. N. Kalaria, Institute for Ageing and Health, Wolfson Unit, Newcastle General Hospital, Westgate Road, Newcastle upon Tyne NE4 6BE, UK E-mail: r.n.kalaria{at}ncl.ac.uk
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)-
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 ß amyloid (Aß) neuritic plaques (Aß42) 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.
Key Words: Africa; Alzheimer’s disease; apolipoprotein E; neurofibrillary tangles; presenilin
Abbreviations: Aß = ß amyloid peptide; AD = Alzheimer’s disease; APOE = apolipoprotein E; APP = ß amyloid precursor protein; DECO = détérioration cognitive observée; MMSE = Mini-Mental State Examination; PS1 = presenilin1 gene
Received February 27, 2003. Revised July 22, 2003. Accepted July 30, 2003.
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