Clinical Heterogeneity Associated with Tau Gene Mutations
Clinical Heterogeneity Associated with Tau Gene Mutations
It is now 10 years since the first descriptions of pathogenic mutations within the gene encoding the microtubule-associated protein tau (MAPT).1–3 Over 60 different sequence variants have now been described, including splice-site and missense mutations and deletions, in both coding regions and introns, over 40 of which are thought to be pathogenic.4 Prior to the identification of MAPT mutations, the umbrella term ‘frontotemporal dementia with parkinsonism linked to chromosome 17’ (FTDP-17) had been coined to describe autosomal-dominant kindreds linked to chromosome 17q21-22 with a highly penetrant disorder characterised clinically by a phenotype of frontotemporal dementia and parkinsonism.5 The FTDP-17 nomenclature superseded the various clinical and clinicopathological labels previously applied to some of these kindreds, which included disinhibition–dementia–parkinsonism– amyotrophy complex, hereditary dysphasic disinhibition dementia, pallido-ponto-nigral degeneration, progressive subcortical gliosis and multiple system tauopathy with pre-senile dementia.
With the description of more MAPT mutations, the clinical and neuropathological heterogeneity of FTDP-17 cases has become increasingly apparent. An awareness of this clinical heterogeneity may be of importance to neurologists managing patients with neurodegenerative disease, informing differential diagnostic considerations and the need for tau gene mutation testing. A brief review of clinical variants associated with MAPT mutations may therefore be of pragmatic use; neuropathological features are not considered in this article, since these are generally available only post mortem and are hence of limited use in clinical practice.
Clinical Phenotypes of MAPT Mutations
The ‘classic’ or ‘prototypical’ phenotype associated with MAPT mutations is a frontotemporal dementia syndrome with altered behaviour and personality, with additional parkinsonian features, hence ‘FTDP’. Either the cognitive syndrome or the movement disorder may be more clinically evident. Prominent early epileptic seizures have been reported on occasion.6
The frequency with which tau mutations are identified in FTD patients varies depending on the source of the cohort examined, ranging from none in a community-based dementia series, to around 10% in cases of familial FTD, to 33% in familial FTD with confirmed tau pathology.7,8 Phenotypes other than FTDP have also been described in association with MAPT mutations.
Progressive Supranuclear Palsy
There have been a number of reports of patients with a phenotype of progressive supranuclear palsy (PSP) who are shown to harbour MAPT mutations, including R5L, N279K, ΔN296, G303V, S305S and IVS 10+16.9–15 The PSP phenotype may be typical (i.e. conforming to widely accepted clinical research criteria for PSP) or atypical (e.g. absence of falls in the first year after symptom onset),14 and cases may be familial or sporadic. In some cases, dementia has been late or questionable.15 In one family, atypical PSP was associated with a homozygous mutation (ΔN296), and typical levodopa-responsive Parkinson’s disease was observed in other family members with the heterozygous mutation.11
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