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Brain Advance Access published online on October 21, 2003
Brain, doi:10.1093/brain/awh009
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© 2003 The Guarantors of Brain

Article

Novel presenilin 1 mutation with profound neurofibrillary pathology in an indigenous Southern African family with early-onset Alzheimer’s disease

Jeannine M. Heckmann 1, Wee-Chuang Low 2, Cora de Villiers 1, Stuart Rutherfoord 3, Alvera Vorster 4, Harpal Rao 2, Christopher M. Morris 2, Raj S. Ramesar 4, and Raj N. Kalaria 2*

1 Division of Neurology, Groote Schuur Hospital and University of Cape Town, Cape Town, South Africa
2 Institute for Ageing and Health, Newcastle General Hospital, Westgate Road, Newcastle upon Tyne NE4 6BE, UK
3 Neuropathology Unit, Department of Anatomical Pathology, University of Stellenbosch, Tygerberg, South Africa
4 MRC Human Genetics Research Unit, Division of Human Genetics, Groote Schuur Hospital and University of Cape Town, Cape Town, South Africa

* Corresponding author. E-mail: r.n.kalaria{at}ncl.ac.uk.

Received 27 February 2003 ; revised 22 July 2003 ; accepted 30 July 2003

Abstract

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.

Keywords: Africa; Alzheimer’s disease; apolipoprotein E; neurofibrillary tangles; presenilin
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