Friday 18 January 2008
Definition: Frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17) is an autosomal dominant neurodegenerative disorder characterized by behavioural and personality changes, cognitive impairment and motor defects that are caused by mutations in the gene encoding tau. NFTs are abundant in the brain of affected individuals. FTDP-17 is inherited as an autosomal dominant condition, characterized initially by behavioural and motor disturbances that are later associated with cognitive impairment.
As the name implies, FTDP-17 is a genetically determined disorder in which the clinical syndrome of a frontotemporal dementia is often accompanied by parkinsonian symptoms.
In these families, the disease has been mapped to chromosome 17; in particular, it has been linked to a variety of mutations in the tau gene.
Tau is a microtubule binding protein that has numerous sites of potential phosphorylation and exists in six splice forms as the result of alternative splicing of exons 2, 3 and 10. The protein contains either three or four copies of the microtubule binding domain depending on whether exon 10 is included (4 repeat tau) or not (3 repeat tau).
At autopsy, FTDP-17 patients usually display predominant frontotemporal atrophy with neuronal loss, gliosis and cortical spongiform changes in layer 2.
There is evidence of atrophy of frontal and temporal lobes in various combinations and to various degrees. The pattern of atrophy can often be predicted in part by the clinical symptomatology.
The atrophic regions of cortex are marked by neuronal loss and gliosis as well as the presence of tau-containing neurofibrillary tangles. These tangles may contain either 4 repeat tau or a mixture of 3 and 4 repeat tau, depending on the underlying genetic basis for the disease.
Nigral degeneration may also occur. Inclusions can also be found in glial cells in some forms of the disease.
Neuropathological analysis reveals the presence of abundant intraneuronal tau inclusions, and glial inclusions have also been observed in some families.
Tau is a microtubule-associated protein involved in microtubule assembly and stabilization. Abnormal filamentous tau deposits constitute a major defining characteristic of several neurodegenerative diseases, including Alzheimer’s disease.
In 1998, the identification of exonic and intronic tau gene mutations associated with FTDP-17 established that tau dysfunction can cause neurodegeneration.
The study of families with frontotemporal dementia led to the recognition that in some, but not all, pedigrees, there is linkage to mutations in the tau gene. The mutations fall into several broad categories: coding region mutations and intronic mutations that affect the splicing of exon 10.
The intronic mutations result in increased production of 4 repeat forms of tau. Coding region mutations appear to have several different consequences, including alterations in the interaction of tau with microtubules (mutations in exon 10 will change this interaction only for 4 repeat tau) and altering the intrinsic tendency to aggregate.
These findings and subsequent reports have so far identified more than 25 tau mutations, which can be classified according to their positions in the tau gene, their effects on tau mRNA and protein, and the type of tau pathology they lead to.