Clinical features and disease haplotypes of individuals with the N279K tau gene mutation: A comparison of the pallidopontonigral degeneration kindred and a French family

Background: An N279K missense mutation in exon 10 of the tau gene reported in an American family with pallidopontonigral degeneration (PPND family) was recently found in members of a French kindred with dementia and supranuclear palsy. Objectives: To compare clinical phenotypes of both families and to perform genealogical and molecular genetic studies to determine whether they are derived from a common founder. Design and Methods: We performed clinical examinations of affected members of both families and compared clinical phenotypes, existing genealogical family records, and chromosome 17 microsatellite repeat markers in the vicinity of the tau gene. Results: The inheritance pattern is autosomal dominant in the PPND family and appears so in the French family. Average age at onset of clinical symptoms was 43 years in the PPND family and 41 years in the French family. Mean disease duration was 8 years in the PPND family and 6 years in the French family. Parkinsonism, personality changes, and dementia of the frontotemporal type were seen in both kindreds. All affected patients exhibited rapidly progressive parkinsonism characterized by bradykinesia, tremor, postural instability, and rigidity. Some had a transient response to levodopa therapy during the initial stages. Pyramidal signs and eye movement abnormalities, including supranuclear gaze palsy, were common. Results of linkage studies of the tau region in chromosome 17 did not reveal a haplotype common to both kindreds. Conclusions: Affected members from both families had more clinical similarities than differences. Results of genealogical and molecular genetic studies determined that the families were not related. The N279K mutations found in both families have independent origins.