Date Published: January 9, 2018
Publisher: BioMed Central
Author(s): Emil Ygland, Danielle van Westen, Elisabet Englund, Rosa Rademakers, Zbigniew K. Wszolek, Karin Nilsson, Christer Nilsson, Maria Landqvist Waldö, Irina Alafuzoff, Oskar Hansson, Lars Gustafson, Andreas Puschmann.
The MAPT c.1216C > T (p.Arg406Trp; R406W) mutation is a known cause of frontotemporal dementia with Parkinsonism linked to chromosome 17 tau with Alzheimer’s disease-like clinical features.
We compiled clinical data from a new Swedish kindred with R406W mutation. Seven family members were followed longitudinally for up to 22 years. Radiological examinations were performed in six family members and neuropathological examinations in three. We systematically reviewed the literature and compiled clinical, radiological, and neuropathological data on 63 previously described R406W heterozygotes and 3 homozygotes.
For all cases combined, the median age of onset was 56 years and the median disease duration was 13 years. Memory impairment was the most frequent symptom, behavioral disturbance and language impairment were less common, and Parkinsonism was rare. Disease progression was most often slow. The most frequent clinical diagnosis was Alzheimer’s disease. R406W homozygotes had an earlier age at onset and a higher frequency of behavioral symptoms and Parkinsonism than heterozygotes. In the new Swedish kindred, a consistent imaging finding was ventromedial temporal lobe atrophy, which was evident also in early disease stages as a widening of the collateral sulcus with ensuing atrophy of the parahippocampal gyrus. Unlike previously published R406W carriers, all three autopsied patients from the novel family showed neuropathological similarities with progressive supranuclear palsy, with predominant four-repeat (exon 10+) tau isoform (4R) tauopathy and neurofibrillary tangles accentuated in the basal-medial temporal lobe. Amyloid-β pathology was absent.
Dominance of 4R over three-repeat (exon 10−) tau isoforms contrasts with earlier reports of R406W patients and was not sufficiently explained by the presence of H1/H2 haplotypes in two of the autopsied patients. R406W patients often show a long course of disease with marked memory deficits. Both our neuropathological results and our imaging findings revealed that the ventromedial temporal lobes were extensively affected in the disease. We suggest that this area may represent the point of origin of tau deposition in this disease with relatively isolated tauopathy.
The online version of this article (doi:10.1186/s13195-017-0330-2) contains supplementary material, which is available to authorized users.
Tauopathies constitute a group of neurodegenerative disorders that include Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), Pick’s disease, and others. These diseases are characterized by cerebral accumulation of the microtubule-associated protein tau . Tau is composed of three- or four-microtubule binding domains, depending on alternative splicing of exon 10, leading to the three-repeat (exon 10−) tau isoform (3R) and the four-repeat (exon 10+) tau isoform (4R). Alternative inserts near the N-terminus result in a total of six tau isoforms expressed under physiological circumstances . Mutations in the gene encoding tau, MAPT, can lead to different clinical disorders and neuropathologies, which have been found to depend on the mutation’s location within the gene . Mutations in MAPT exons 9 and 11 and most mutations in exons 12 and 13 were associated with combined 3R and 4R tau pathology. Several mutations in exon 10 and all of the 5′ following intronic mutations inhibit alternative exon 10 splicing, leading to predominant 4R tau deposition in neurons as well as glial cells. Other MAPT mutations, including MAPT c.1216C > T (p.Arg406Trp; R406W) in exon 13, however, did not affect the ratio of 3R to 4R tau isoforms in laboratory models, but they caused aggregations of all six forms of tau, more closely resembling the situation in AD . Clinical symptoms in patients with MAPT mutations are generally heterogeneous and designated as frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17MAPT). Patients with R406W develop clinical features of both AD and FTDP-17  and have brain deposition of tau as neurofibrillary tangles (NFTs), whereas amyloid-β (Aβ) pathology is only rarely present [4–6]. This makes FTDP-17R406W an ideal candidate for studying human tau-only pathology.
We present a novel Swedish R406W kindred with markedly slowly progressive dementia, as well as a systematic review of previous reports on FTDP-17R406W patients. The clinical phenotype of patients with this mutation consists predominantly of memory loss and varying or gradual development of frontotemporal dementia (FTD)-like cognitive dysfunction. Radiological examinations of FTDP-17R406W patients reveal progressing atrophy that starts in the VMTL and spreads to adjacent regions over time. Neuropathology shows a pattern of regional degeneration and accumulation of NFTs. Although previously reported individuals with this mutation had both 3R and 4R tau pathology, all three autopsied members of the present family had a PSP-like pathology, with a regional spread of degeneration and with marked predominance of 4R over 3R, but without some of the other PSP-characteristic traits.
FTDP-17R406W is a distinct disease entity that clinically shares features with AD, but in a novel Swedish family we found it to be associated with PSP-like, predominant 4R tau pathology, most pronounced in the VMTL, and we found a persistent and characteristic imaging pattern of VMTL atrophy. This disease provides an interesting model for the pathomechanisms of tau pathogenesis in humans.