Objectives: To describe clinical and genealogical data of a Swedish family with a His163Tyr mutation in the presenilin-1 gene (PS1) and to study the Alzheimer disease (AD) penetrance in this family.
Design: Interviews with relatives, studies of medical records, analysis of pedigree, physician examination of the affected individuals, and comparison with other families affected by AD with PS1 mutations.
Setting: Large university-affiliated hospital.
Patients and other participants: Individuals with a His163Tyr mutation in PS1 and their relatives.
Results: A study of this family with a history of very early AD onset (mean age, 47 years) has been previously published, but an investigation of the extended family revealed a new pattern of onset, with a mean age at onset of 54 years (range, 44-65 years). In general, families with AD show a tight cluster of age at onset with high penetrance of the disease. However, in this family, an individual whose child carries the PS1 mutation died at age 67 years free from cognitive symptoms, indicating a very late age at onset or nonpenetration of the disease. No association between age at onset and disease duration was found. Furthermore, the disease duration did not differ between those having an early onset compared with those having a late onset. The earliest clinical manifestations were deficits in memory function and disorientation in time and place. Myoclonic jerks and epileptic seizures were common symptoms later in the disease.
Conclusion: The large range in age at onset in this family with a uniform genetic basis for the disease, a His163Tyr mutation in PS1, supports the existence of other unknown genetic or environmental factors of importance for the expression of the AD phenotype.