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Clinical Features and Disease Haplotypes of Individuals With the N279K tau Gene Mutation
A Comparison of the Pallidopontonigral Degeneration Kindred and a French Family
Yoshio Tsuboi, MD;
Ryan J. Uitti, MD;
Marie-Bernadette Delisle, MD;
Joaquim J. Ferreira, MD;
Christine Brefel-Courbon, MD;
Olivier Rascol, MD, PhD;
Bernardino Ghetti, MD;
Jill R. Murrell, MD;
Michael Hutton, PhD;
Matthew Baker, BSc;
Zbigniew K. Wszolek, MD
Arch Neurol. 2002;59:943-950.
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.
From the Departments of Neurology (Drs Tsuboi, Uitti, and Wszolek)
and Research (Dr Hutton and Mr Baker), Mayo Clinic, Jacksonville, Fla; Service
d'Anatomie et de Cytologie Pathologiques and Institut National de la Santé
et de la Récherche Médicale U466, Centre Hospitalier Universitaire
Rangueil (Dr Delisle), and the Clinical Investigation Centre and Neuropharmacology
Unit, Centre Hospitalier Universitaire Purpan (Drs Ferreira, Brefel-Courbon,
and Rascol), Toulouse, France; and the Department of Pathology, Indiana University
School of Medicine, Indianapolis (Drs Ghetti and Murrell).
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