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17q-Linked Frontotemporal Dementia–Amyotrophic Lateral Sclerosis Without Tau Mutations With Tau and  -Synuclein Inclusions
Kirk C. Wilhelmsen, MD, PhD;
Mark S. Forman, MD, PhD;
Howard J. Rosen, MD;
Loren I. Alving, MD;
Jill Goldman, MS;
Jennie Feiger, MS;
James V. Lee, BA;
Samantha K. Segall, BA;
Joel H. Kramer, PsyD;
Catherine Lomen-Hoerth, MD, PhD;
Katherine P. Rankin, PhD;
Julene Johnson, PhD;
Heidi S. Feiler, PhD;
Michael W. Weiner, MD;
Virginia M.-Y. Lee, PhD;
John Q. Trojanowski, MD, PhD;
Bruce L. Miller, MD
Arch Neurol. 2004;61:398-406.
Background Frontotemporal dementia (FTD) is a clinically heterogeneous condition that can be associated with clinical manifestations of an extrapyramidal disorder or motor neuron disease. A range of histologic patterns has been described in patients with FTD. The most common familial form of this condition is caused by mutations in the microtubule-associated protein tau gene (MAP ) and is associated with neuronal or glial tau inclusions.
Objectives To determine the clinical, anatomic, and pathological features of San Francisco family A and to map the mutation responsible for disease in this family.
Design A systematic clinical, neuropsychologic, neuroimaging, and chromosome segregation analysis of San Francisco family A was performed. A pathological and biochemical assessment of a family member was made.
Setting Family study.
Patients San Francisco family A, with FTD, variable extrapyramidal symptoms, and prominent motor neuron disease. Afflicted family members donot have a MAP coding or splice regulatory sequence mutation, and the MAP is genetically excluded.
Main Outcome Measures Comparison of clinical, neuropsychologic, neuroimaging, and linkage findings of San Francisco family A with other familial forms of FTD and amyotrophic lateral sclerosis (ALS).
Results The most probable location for the mutation responsible for this condition is on chromosome arm 17q, distal to the MAP. All previously identified susceptibility loci for FTD and ALS are excluded. Autopsy findings from an afflicted family member show distinctive tau and  -synuclein inclusions. Another unique feature is that the insoluble tau protein consists predominantly of the 4R/0N isoform.
Conclusion The condition affecting members of San Francisco family A is clinically, pathologically, and genetically distinct from previous familial forms of FTD and ALS.
From the Ernest Gallo Clinic and Research Center, Emeryville, Calif (Drs Wilhelmsen and Feiler, Mr Lee, and Ms Segall); the Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine (Drs Forman, Lee, and Trojanowski), and the Institute on Aging (Dr Trojanowski), University of Pennsylvania, Philadelphia; the Department of Neurology, University of California, San Francisco (Drs Wilhelmsen, Rosen, Kramer, Lomen-Hoerth, Rankin, Johnson, Weiner, and Miller and Mss Goldman and Feiger); and the Department of Neurology, University of California, San Francisco at Fresno (Dr Alving). Dr Wilhelmsen is now with the Department of Neurology, University of North Carolina at Chapel Hill.
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