Objective: To characterize a chromosome-3 related autosomal dominant fronto-temporal dementia FTD-3 with 23 identified cases and a pedigree that spans 6 generations with over 1000 known individuals.
Design: A prospective follow-up over 18 years of a large Danish FTD-3 family.
Materials and Methods: Cases, spouses, and first degree relatives in a FTD-3 family have been studied with clinical follow-up, neuropsychological testing, genetic testing, brain imaging (CT, MRI and PET), and in 6 cases autopsy.
Results: Average onset is 57 years and all identified cases have had onset before 65 years. Initial symptoms include changes in personality, disinhibition, dyscalculia and hyperorality, progressing to a non-fluent aphasia, speech disturbances, and dystonic posturing. There is no insight and empathy is lost early on, but behavioral disinhibition is not prominent. Retrospective interviews of relatives indicate early preservation of episodic memory and topographical orientation and early affection of personality and drive. Haplotype analyses have restricted the locus to a 4cM region within chromosome 3. Candidate genes are being sequenced to identify any mutation that segregates with the disease. Structural imaging data seem to indicate a frontal preponderance of a global central and cortical atrophy that can be recognized early in the cause of the disease. Quantitative regional cerebral blood flow (rCBF) show normal flow in the primary visual cortex, thalami, basal ganglia, and cerebellum, whereas all other cortical regions are severely impaired indicating an early and widespread involvement of all secondary cortices with no clear fronto-temporal pattern. 6 post mortem examinations have been performed, three of them prior to 1987. All have revealed a similar pattern of macroscopic and microscopic neuropathology. Macroscopically there is global cortical and central atrophy. Microscopically there is neuronal loss and gliosis without any inclusion bodies seen in other dementia diseases. Routine staining does not show tau deposition suggestive of a tauopathy.
Conclusion: There are similarities between individuals in this family and many patients with FTD, and it is possible that mutations or polymorphisms in the chromosome 3 gene may account for a significant proportion of all FTD cases.
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