[Clinical, genetic and pathological aspects of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17)]

Abstract

Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) is a group of hereditary, adult-onset, progressive neurodegenerative syndromes, which lead to the accumulation of intracellular deposits of hyperphosphorylated tau protein. Since the original definition of FTDP-17 in the Consensus Conference held in Ann Arbor, Michigan in 1996, it has become apparent that this syndrome has worldwide distribution. More than 80 families have been described in North America, Europe, Australia and Asia. The molecular genetic studies have identified 35 different mutations outside and on exon 10 of tau gene. The symptomatic onset of FTDP-17 is usually insidious. The clinical phenotypes are characterized by behavioral, cognitive and motor disturbances that may occur in various combinations and in varying degrees of severity. Affected individuals develop a constellation of signs, including at least two of the three cardinal manifestations of FTDP-17. It should be noted that there is significant clinical phenotypic heterogeneity in individuals with different mutations. In addition, interfamilial and intrafamilial variability of clinical phenotype is often seen among individuals carrying the same mutation. Macroscopically, the degree of brain atrophy observed varies with a brain weight ranging from approximately 825 to 1,290 grams. In the advanced stages, the degree of atrophy varies and may be present in the frontal and temporal lobes, caudate nucleus, putamen, globus pallidus, amygdala, hippocampus and ventral hypothalamus. Microscopically, the neuropathologic hallmark is the presence of tau protein deposits in neurons or in both neurons and glia. The cellular pathology of the neuron may resemble that of Alzheimer disease (AD) or Pick disease for the presence of neurofibrillary tangles or Pick bodies. The cellular pathology of glial cells may resemble that of progressive supranuclear palsy or corticobasal degeneration for the presence of coiled bodies in oligodendroglial cells, tufted astrocytes or astrocytic plaques. Mutations in exons 1, 10 and intron following exon 10 are associated with neuronal and glial tau deposition. Mutations in exons 9, 11, 12 and 13 lead to deposits of tau filaments predominantly in neurons.