The tau S305S mutation causes frontotemporal dementia with parkinsonism
Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden. European Journal of Neurology
(Impact Factor: 4.06).
03/2008; 15(2):156-61. DOI: 10.1111/j.1468-1331.2007.02017.x
Members of families with mutations in the tau gene are known to be heterogeneous in their clinical presentation, ranging from frontotemporal dementia to a clinical picture more resembling corticobasal degeneration or progressive supranuclear palsy. In this report, we describe a new phenotype for the tau S305S mutation, previously described as progressive supranuclear palsy. Clinically, the three affected family members showed alterations in personality and behaviour as well as cognitive decline and late levodopa-resistant parkinsonian symptoms, consistent with the diagnosis of frontotemporal dementia with parkinsonism linked to chromosome 17. One autopsied case displayed degeneration of the frontal and temporal lobes together with extensive tau pathology in both neurones and glial cells. Sarkosyl-soluble and -insoluble tau extracted from frontal cortex revealed a ratio shift with decreased levels of tau with three microtubule-binding repeats and increased levels of tau with four microtubule-binding repeats (4R tau). These findings provide further evidence for the clinical and pathological variation both within and between families with mutations in the tau gene. In addition, they support previous studies which demonstrate that the S305S mutation influences the splicing of tau exon 10 and results in an overproduction of 4R tau.
Available from: Alberto Javier Espay
- "It also tends to develop at a younger age, about a decade earlier, than in FTDP linked to chromosome 17 but with ubiquitin and TDP-43-positive pathology (FTDP-17U/PGRN) (Boeve and Hutton 2008). A number of MAPT mutations have been reported among those with early (N279K, delN296, S305S, +11) (Soliveri et al. 2003; Pastor et al. 2001; Wszolek et al. 2001; Skoglund et al. 2008) or late (P301S, N296H, +3, +12, +14, +16; Baba et al. 2007; Iseki et al. 2001; Rohrer et al. 2011) parkinsonism associated with FTLDP-17T/MAPT, with a picture most often resembling PSP. Similarly, several mutations in PGRN have been reported among those with parkinsonism associated with FTDP-17U/PGRN, with a phenotype most often suggestive of CBS, with or without language abnormalities (c.26C>A, g.2988_2989delCA, P439_R440fsX6, IVS1+1 G–>A, +1, +11; Wider et al. 2008; Gabryelewicz et al. 2010; Boeve et al. 2006). "
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ABSTRACT: Frontotemporal dementia is commonly associated with parkinsonism in several sporadic (i.e., progressive supranuclear palsy, corticobasal degeneration) and familial neurodegenerative disorders (i.e., frontotemporal dementia associated with parkinsonism and MAPT or progranulin mutations in chromosome 17). The clinical diagnosis of these disorders may be challenging in view of overlapping clinical features, particularly in speech, language, and behavior. The motor and cognitive phenotypes can be viewed within a spectrum of clinical, pathologic, and genetic disorders with no discrete clinicopathologic correlations but rather lying within a dementia-parkinsonism continuum. Neuroimaging and cerebrospinal fluid analysis can be helpful, but the poor specificity of clinical and imaging features has enormously challenged the development of biological markers that could differentiate these disorders premortem. This gap is critical to bridge in order to allow testing of novel biological therapies that may slow the progression of these proteinopathies.
Available from: Nancy J Woolf
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