Retiring the term FTDP-17 as MAPT mutations are genetic forms of sporadic frontotemporal tauopathies

Abstract

See Josephs (doi:10.1093/brain/awx367) for a scientific commentary on this article.In many neurodegenerative disorders, familial forms have provided important insights into the pathogenesis of their corresponding sporadic forms. The first mutations associated with frontotemporal lobar degeneration (FTLD) were found in the microtubule-associated protein tau (MAPT) gene on chromosome 17 in families with frontotemporal degeneration and parkinsonism (FTDP-17). However, it was soon discovered that 50% of these families had a nearby mutation in progranulin. Regardless, the original FTDP-17 nomenclature has been retained for patients with MAPT mutations, with such patients currently classified independently from the different sporadic forms of FTLD with tau-immunoreactive inclusions (FTLD-tau). The separate classification of familial FTLD with MAPT mutations implies that familial forms cannot inform on the pathogenesis of the different sporadic forms of FTLD-tau. To test this assumption, this study pathologically assessed all FTLD-tau cases with a known MAPT mutation held by the Sydney and Cambridge Brain Banks, and compared them to four cases of four subtypes of sporadic FTLD-tau, in addition to published case reports. Ten FTLD-tau cases with a MAPT mutation (K257T, S305S, P301L, IVS10+16, R406W) were screened for the core differentiating neuropathological features used to diagnose the different sporadic FTLD-tau subtypes to determine whether the categorical separation of MAPT mutations from sporadic FTLD-tau is valid. Compared with sporadic cases, FTLD-tau cases with MAPT mutations had similar mean disease duration but were younger at age of symptom onset (55 ± 4 years versus 70 ± 6 years). Interestingly, FTLD-tau cases with MAPT mutations had similar patterns and severity of neuropathological features to sporadic FTLD-tau subtypes and could be classified into: Pick's disease (K257T), corticobasal degeneration (S305S, IVS10‰+‰16, R406W), progressive supranuclear palsy (S305S) or globular glial tauopathy (P301L, IVS10‰+‰16). The finding that the S305S mutation could be classified into two tauopathies suggests additional modifying factors. Assessment of our cases and previous reports suggests that distinct MAPT mutations result in particular FTLD-tau subtypes, supporting the concept that they are likely to inform on the varied cellular mechanisms involved in distinctive forms of sporadic FTLD-tau. As such, FTLD-tau cases with MAPT mutations should be considered familial forms of FTLD-tau subtypes rather than a separate FTDP-17 category, and continued research on the effects of different mutations more focused on modelling their impact to produce the very different sporadic FTLD-tau pathologies in animal and cellular models.

Keywords: MAPT; Pick’s disease; corticobasal degeneration; globular glial tauopathy; progressive supranuclear palsy.

Figure 1

Comparison between the main pathological subtypes of FTLD and known gene associations. For FTLD-TDP subtypes, there is an association between specific gene abnormalities and the morphological type of inclusion pathology, suggesting that specific intracellular processes are involved. For FTLD-tau subtypes, genetic forms are considered as a separate group (FTDP-17). We suggest that different mutations in the MAPT gene could inform more about the specific intracellular processes involved in forming the different morphological types of inclusions observed in FTLD-tau. 3R = 3-repeat tau; 4R = 4-repeat tau; GAI = globular astrocytic inclusion; NCIs = neuronal cytoplasmic inclusions; NNIs = neuronal intranuclear inclusions. *Refer to Table 1.

Figure 2

Diagrammatic representation of the location of different mutations in the MAPT gene associated with the diagnostic pathologies for sporadic FTLD-tau. Those exons not highlighted may contribute to subtype specific neuropathology, but at present require reassessment to confirm. Point mutations in exon 9 and intron 9, and a deletion in exon 10, give rise to more 3R-tau which accumulates in Pick bodies found in Pick’s disease (PiD, colour-coded yellow). Point mutations in exon 13 cause dysfunction of membrane associated 4R-tau, which accumulates in the endfeet of astrocytic plaques in CBD (colour-coded blue). A point mutation in exon 11 gives rise to both short and long 4R-tau filaments that accumulate in globules in GGT (colour-coded green). A point mutation in exon 1 has been associated with longer filaments that accumulate in tufted astrocytes and neurofibrillary tangles in PSP (colour-coded red). Point mutations in exon 10 and intron 10 give rise to increased 4R-tau and CBD, GGT or PSP, suggesting that additional modifying factors can influence the processes producing these pathologies.