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Genotype–phenotype links in frontotemporal lobar degeneration

Abstract

Frontotemporal lobar degeneration (FTLD) represents a group of neurodegenerative brain diseases with highly heterogeneous clinical, neuropathological and genetic characteristics. This high degree of heterogeneity results from the presence of several different underlying molecular disease processes; consequently, it is unlikely that all patients with FTLD will benefit from a single therapy. Therapeutic strategies for FTLD are currently being explored, and tools are urgently needed that enable the selection of patients who are the most likely to benefit from a particular therapy. Definition of the phenotypic characteristics in patients with different FTLD subtypes that share the same underlying disease processes would assist in the stratification of patients into homogeneous groups. The most common subtype of FTLD is characterized by TAR DNA-binding protein 43 (TDP43) pathology (FTLD-TDP). In this group, pathogenic mutations have been identified in four genes: C9orf72, GRN, TBK1 and VCP. Here, we provide a comprehensive overview of the phenotypic characteristics of patients with FTLD-TDP, highlighting shared features and differences among groups of patients who have a pathogenic mutation in one of these four genes.

Key points

  • Comprehension of genotype–phenotype correlations will aid patient selection and stratification for targeted therapeutic strategies.

  • Most individuals with a C9orf72 repeat expansion present with the behavioural variant of frontotemporal dementia (FTD) and frequently have psychotic symptoms, motor neuron disease (MND) and a symmetric pattern of brain impairment that is most predominant in frontotemporal regions.

  • Patients with FTD who carry a GRN mutation are characterized by apathetic behaviour, frequently with language output impairment, parietal lobe dysfunction and parkinsonism, in association with widespread, asymmetric impairment of frontotemporoparietal brain regions.

  • TBK1 mutation in patients with FTD is frequently associated with MND symptomatology and problems with behaviour and language, but the predominant phenotypic features have yet to be distinguished; brain impairment is mostly asymmetric in these individuals.

  • Individuals with FTD who have a VCP mutation can present with or without myopathy or Paget disease of the bone and have characteristic features of apathy, anomia, psychotic signs and a nonspecific pattern of brain impairment.

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Fig. 1: Affected brain regions.
Fig. 2: Phenotype–genotype correlations.

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Acknowledgements

Research by the authors is funded in part by the Belgian Science Policy Office Interuniversity Attraction Poles programme, the Flemish-government-initiated Flanders Impulse Program on Networks for Dementia Research (VIND) and the Methusalem Excellence Program, the Research Foundation Flanders (FWO) and the University of Antwerp Research Fund, Belgium.

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Van Mossevelde, S., Engelborghs, S., van der Zee, J. et al. Genotype–phenotype links in frontotemporal lobar degeneration. Nat Rev Neurol 14, 363–378 (2018). https://doi.org/10.1038/s41582-018-0009-8

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