The Tau R406W Mutation Causes Progressive Presenile Dementia with Bitemporal Atrophy

Abstract

Frontotemporal dementia (FTD) and Alzheimer’s disease (AD) are two frequent causes of dementia that share both clinical and neuropathological features. Common to both disorders are the neurofibrillary tangles consisting of aggregations of hyperphosphorylated tau protein. Recently, a number of different pathogenic mutations in the tau gene have been identified in families with FTD and parkinsonism linked to chromosome 17 (FTDP-17). In the present study, a Swedish family with presenile degenerative dementia with bitemporal atrophy was screened for mutations in the tau gene. As a result, the R406W mutation in exon 13 was identified in all affected cases. This mutation has previously been reported in two different FTDP-17 families of Dutch and Midwestern American origin. Common features to these two kindreds and our family are the late age at onset and long duration of the disease. Our pedigree as well as the American one show early memory impairment and pronounced temporal lobar atrophy similar to AD, while the Dutch cases show more FTD features. This further illustrates the large clinical variability among cases with tau mutations and stresses the importance of genetic classification in addition to the traditional clinical classification of neurodegenerative disorders.

Familial Presenile Dementia with Bitemporal Atrophy

“…However, there is a great pathological and clinical heterogeneity. Four affected cases in this family are carrying the tau R406W mutation [12]. This mutation has previously been described in a few families [19][20][21] and our patients have many similarities with these families.…”

“…The previously described R406W mutation in exon 13 of the tau gene was identified in these cases [12].…”

The Genetics of Alzheimer Disease

“…A missense mutation (R406W) in the tau gene (MAPT) on chromosome 17q was reported to be tightly linked to AD in a Belgian family (Rademakers et al 2003;Ostojic et al 2004). However, before, this mutation can be validated to cause AD, autopsy confirmation will be necessary to rule out a diagnosis of frontotemporal lobe dementia (FTDP-17).…”

On the ‘classification’ of neurodegenerative disorders: discrete entities, overlap or continuum?

“…Cases continue to be described that are difficult to reconcile with any proposed classification of the tauopathies. For example, cases of a familial presenile dementia with bitemporal atrophy linked to exon 13 mutations of the tau gene have been described [111]. Patients exhibit early memory impairment and pronounced lobar atrophy but the disease ultimately deve -lops into a typical AD-type dementia.…”