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Lobar neurodegenerative disorders such as Pick’s disease and Dementia of the Frontal Type (DFT) account for less than 10% of late-onset dementias but can pose disproportionate management problems owing to the behavioral disinhibition, loss of judgment, and communication disturbances that often occur early in their course. Presenile onset and a positive family history are common, and it has consequently been suspected that genetic factors play a role in their causation. A series of reports have linked familial forms of frontotemporal dementia to a locus on chromosome 17 (17q21-22). These genetic discoveries may indicate that there is a shared set of mutations accounting for a phenotypically diverse set of disorders, some of which lead to frontotemporal neurodegenerative changes.
Dutch researchers recently studied three large families in which multiple members were affected by frontotemporal dementia in order to evaluate the possibility of linkage to chromosome 17. The average ages of onset in these families were 46.5, 50.4, and 63.4 respectively, with a mean duration of illness of 8.2-8.7 years. Within each family, clinical symptoms and progression were remarkably uniform. Disinhibition, stealing, inappropriate jocularity, and obsessional behaviors were the most common presenting symptoms in two families, while loss of initiative heralded the disease in the third. Language was progressively impaired to the point of eventual mutism, but memory problems were relatively mild until late in the course. General neurologic examinations were usually normal in the initial stages of the disease except for frontal release signs. Pyramidal and extrapyramidal symptoms developed as late disease manifestations. Neuropathologically, the brains showed accentuated atrophy in frontal or frontotemporal regions, as well as in the caudate nucleus in some cases. Neuronal loss, gliosis, and spongiosis were common, but neither senile plaques, neurofibrillary tangles, nor Pick bodies were discovered in the majority of cases.
Multipoint linkage analysis performed on the combined data from the three families implicated a locus on chromosome 17, located between two markers separated by approximately 5 centimorgans. This region of chromosome 17 contains the gene for the microtubule associated protein, tau, the source of the paired helical filaments found in neurofibrillary tangles in Alzheimer’s disease (AD). No common ancestor was identified genealogically among these three families, and this, as well as other evidence, suggests that separate mutations arose independently in these families.
The American neurologic community has lagged behind our European counterparts in recognizing the existence of disorders such as DFT, perhaps owing to the overlap of clinical symptoms and underlying pathology with other forms of dementia. The Dutch study described above is the latest of four investigations to find an association between frontotemporal dementia and mutations on chromosome 17. This adds considerable weight to the argument that frontotemporal dementia constitutes a distinct neurodegenerative syndrome and opens exciting new avenues from which to explore its pathophysiological basis.
Although the tau gene is located in the chromosomal region implicated by this study, immunohistochemical studies of the brain tissue from these families failed to reveal significant tau reactivity, and, likewise, no tangle pathology was reported. Other genes, such as that encoding glial fibrillary acidic protein and nerve growth factor receptor are also present in this region and can be considered candidate disease genes based upon their known functions. Further mapping studies will be necessary to determine the actual gene(s) associated with these disorders and to determine whether these mutations also account for other hereditary disorders linked to this area, such as autosomal dominant Parkinsonism and dementia with pallido-ponto-nigral degeneration. Extrapolating from the recent experience with genetic discoveries about Alzheimer’s disease, these findings could well prove to be the beginning of a new era in understanding, diagnosing, and treating lobar neurodegenerative dementias affecting the frontal and temporal lobes. nrr