Genotype–phenotype links in frontotemporal lobar degeneration

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. Frontotemporal lobar degeneration (FTLD) is a highly heterogeneous group of neurodegenerative diseases. This Review considers the phenotypic and genotypic differences among those with the most common form of FTLD—characterized by TDP43 pathology—with a view to improve patient care and facilitate current efforts to identify effective therapies for these individuals. 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 im